CENTRAL NERVOUS SYSTEM STIMULANTS

Psychopharmacologic advances continue to dramatically expand the parameters of psychiatric treatments.

Greater understanding of how the brain functions has led to more effective, less toxic, better-tolerated,
and more specifically targeted therapeutic agents. With the ever-increasing sophistication and array of
treatment options, clinicians, however, must remain aware of potential adverse effects, drug-drug (and
drug-food or drug supplement) interactions, and how to manage the emergence of unwanted or
unintended consequences. Newer drugs could ultimately lead to side effects that are not recognized
initially. Keeping up with the latest research findings is increasingly important as these findings
proliferate. A thorough understanding of the management of medication-induced side effects (either
through treating the effect with another agent or substituting another primary agent) is necessary.

Stimulants (also often referred to as psycho stimulants or colloquially as uppers) is an overarching term
that covers many drugs including those that increase activity of the central nervous system and the body,
drugs that are pleasurable and invigorating, or drugs that have sympathomimetic effects. Stimulants are
widely used throughout the world as prescription medicines as well as without a prescription (either
legally or illicitly) as performance-enhancing or recreational drugs. The most frequently prescribed
stimulants as of 2013 were lisdexamfetamine, methylphenidate, and amphetamine. It is estimated that the
percentage of the population that has abused amphetamine-type stimulants (e.g., amphetamine,
methamphetamine, MDMA, etc.) and cocaine combined is between 0.8% and 2.1%.

Effects of central nervous system stimulants

Acute effect:

Stimulants in therapeutic doses, such as those given to patients with ADHD, increases ability to focus,
vigor, sociability, libido and may elevate mood. However, in higher doses stimulants may actually
decrease the ability to focus, a principle of the Yerkes-Dodson Law. In higher doses stimulants may also
produce euphoria, vigor, and decrease need for sleep. Many, but not all, stimulants have ergogenic
effects. Drugs such as ephedrine, pseudoephedrine, amphetamine and methylphenidate have well
documented ergogenic effects, while cocaine has the opposite effect. Neurocognitive enhancing effects of
stimulants, specifically modafinil, amphetamine and methylphenidate have been documented in healthy
adolescents, and is a commonly cited reason among illicit drug users for use, particularly among college
students in the context of studying

In some cases psychiatric phenomenon may emerge such as stimulant psychosis, paranoia, and suicidal
ideation. Acute toxicity has been reportedly associated with a homicide, paranoia, aggressive behavior,
motor dysfunction, and punding. The violent and aggressive behavior associated with acute stimulant
toxicity may partially be driven by paranoia. Most drugs classified as stimulants are sympathomimetic,
that is they stimulate the sympathetic branch of the autonomic nervous system. This leads to effects such
as mydriasis, increased heart rate, blood pressure, respiratory rate and body temperature. When these
changes become pathological, they are called arrhythmia, hypertension, and hyperthermia, and may lead
to rhabdomyolysis, stroke, cardiac arrest, or seizures. However, given the complexity of the mechanisms
that underly these potentially fatal outcomes of acute stimulant toxicity, it is impossible to determine what
dose may be lethal.

Chronic effect:

1
Assessment of the effects of stimulants is relevant given the large population currently taking stimulants.
A systematic review of cardiovascular effects of prescription stimulants found no association in children,
but found a correlation between prescription stimulant use and ischemic heart attacks. A review over a
four-year period found that there were few negative effects of stimulant treatment, but stressed the need
for longer term studies.] A review of a year long period of prescription stimulant use in those with ADHD
found that cardiovascular side effects were limited to transient increases in blood pressure only. Initiation
of stimulant treatment in those with ADHD in early childhood appears to carry benefits into adulthood
with regard to social and cognitive functioning, and appears to be relatively safe.

Abuse of prescription stimulants (not following physician instruction) or of illicit stimulants carries many
negative health risks. Abuse of cocaine, depending upon route of administration, increases risk of
cardiorespiratory disease, stroke, and sepsis. Some effects are dependent upon the route of administration,
with intravenous use associated with the transmission of many disease such as Hepatitis C, HIV/AIDS
and potential medical emergencies such as infection, thrombosis or pseudoaneurysm. while inhalation
may be associated with increased lower respiratory tract infection, lung cancer, and pathological
restricting of lung tissue. Cocaine may also increase risk for autoimmune disease and damage nasal
cartilage. Abuse of methamphetamine produces similar effects as well as marked degeneration of
dopaminergic neurons, resulting in an increased risk for Parkinson's Disease.[

HISTORY OF CNS STIMULANTS

The effects of central stimulants were identified early in the history of mankind; plants containing these
substances are among the most ancient of known drugs. The use of ma huang (Ephedra vulgaris) in
China, khat (Catha edulis) in Africa, and coca (Erythroxylon coca) in South America are examples of this
early recognition. Thus, the Chinese herb ma huang, of acknowledged central stimulating activity, had
been in use as a circulatory stimulant, diaphoretic, antipyretic, and antitussive agent (Chen and Schmidt,
1925) for some 5100 years before its main active ingredient, the sympathomimetic ephedrine, was
introduced into clinical practice in the West for the treatment of asthma and similar conditions.

History of amphetamine development : It was first synthesized in 1887 (in Germany) seeking a
synthetic form of ephedrine marketed first in 1932 as a Benzedrine inhaler, for tx. of asthma, congestion
(Benzedrine = d,l – amphetamine). In 1935 dextroamphetamine (Dexedrine) was marketed for treatment
of narcolepsy (Dexedrine = d-amphetamine). By 1940s amphetamines were widely used as “diet pills”
do decrease food/drink intake for short term (& increase duration of times between meals), but eat more
rapidly and same amounts overall when do eat overall, not helpful for long-term weight loss/control .

It used in WWII by military to decrease fatigue (Germans, USA, Japanese, etc.). The Rebuilding of Japan
after WWII: after WWII Japanese government sold large stock piles of amphetamines to its citizens .By
1954 it is estimated that 2/100 persons in Japan were abusing amphetam. and the abuse potential
of the drug was finally acknowledged . By 1960 Japanese government had decreased public access to
drug and of abusers had begun to decrease.

By l960s in USA also began to recognize abuse potential for amphetamine. It made a Schedule II drug in
late 1960 and abusers switched to cocaine! In 1970 10 billion amphetamine pills were produced in USA
per year. At least 10% of USA population > 14 years old had used some form of this drug (dieters,
students, truck drivers, laborers, etc.) . In 1954 methylphenidate (Ritalin) was synthesized, followed by
pemoline (Cylert) both have abuse potential,

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 Ritalin > Cylert

It is now used for several specific medical conditions: ADHD/ADD, narcolepsy (although this is
changing), and IHS but not used for weight loss.

History of Cocaine Use : It is obtained from leaves of Erythroxylon coca plant (So.America) fresh,
green leaves chewed by native peoples --- less fatigue, greater endurance, more resistance to cold about a
200mg/day “dose” at most

 1855 – the active ingredient (cocaine) isolated

 l850-1860 – invention/perfection of syringe & hypodermic needle
 1880 – cocaine used as a local anesthetic
 1885 – cocaine & caffeine both used in USA as “helpful nerve tonics” e.g. Coca-Cola (60 mg
cocaine/8 oz.) to give S energy, sense of well-being!
 Late 1880s – Freud used cocaine himself & recommended it for his pts.
 Addition potential unrecognized at first by early 1900s Freud was discouraging its use
 1910 – President Taft speakes out against use of cocaine specifically
 1914 – passage of the Harrison Narcotic Act (includes prohibition against cocaine) . Cocaine
banned for use in medicines or beverages
 1918 – 1st synthetic local anesthetic developed (Novocaine/procaine) and has no dependency-
producing effects
 1930s – use of cocaine had decreased
 1940s – to be replaced by use of newly synthesized “ephedrine-like” drugs

Mechanisms of action

Stimulants can have a wide variety of mechanisms. Many stimulants exert their effects through
manipulations of monoamine neurotransmission. Monoamines are a class of neurotransmitter relevant in
reward, motivation, temperature regulation and pain sensation that include dopamine, norepinephrine, and
serotonin. Stimulants usually block the reuptake or stimulate the efflux of dopamine and norepinephrine
resulting in increased activity of their circuits. Some stimulants, notably those with empathogenic and
hallucinogenic effects alter serotonergic neurotransmission. Interference with vesicular storage, activating
TAAR1, and reversing the flow of monoamine transporters may play a mechanism in the activity of these
drugs. Adrenergic stimulants, such as ephedrine, may act by directly binding and activating the receptors
that norepinephrine and epinephrine normally bind to (adrenergic receptors), producing sympathomimetic
effects. Some drugs, such as MDMA and derivatives may decrease regulatory capability by antagonizing
regulatory pre-synaptic auto receptors. Caffeine is a notable exception, as it exerts its effects by
antagonizing adenosine receptors instead of acting directly on monoamines.

3
General signs and symptoms of CNS stimulation:

   ↑ Heart rate.
   ↑ Respiratory rate.
   Instability & restlessness.
   Muscle twitching (tremors).   Hair erection.
   Convulsion but at high dose may lead to death.

Therapeutic Indications of CNS Stimulants:

Attention deficit hyperactivity disorder

* Narcolepsy
* Neonatal apnea
* Chronic lethargy
* Postural orthostatic tachycardia syndrome
* Prolonged depression that is not responding to antidepressants
* Morbid obesity (it is not recommended that people use CNS stimulants for normal weight loss due to
unwanted side effects)

Contraindications for CNS Stimulants: anorexia, insomnia, asthenia, psychopathic personality, a

history of homicidal or suicidal tendencies.

Classification of CNS Stimulants

I. Analeptic Stimulants
Respiratory Stimulants

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 Convulsants
II. Psychomotor Stimulant
Sympathomimetics or Adrenergic CNS Stimulants
III. Methylxanthines

I . ANALEPTIC STIMULANTS : These are diverse chemical class of agents . The majority can be
absorbed orally . They have a short duration of action - primary have a short duration of action - primary
expression of pharmacological effect uncoordinated convulsions (tonic-clonic). The pharmacological
effect is terminated through hepatic metabolism hepatic metabolism . The possible common mechanism
of action is its ability to alter movement of chloride ions across neuronal membranes . The therapeutic
Uses Group as a whole has limited .

Doxapram and Nikithamide : It is used to counteract postanesthetic respiratory depression and for acute
hypercapnia in chronic pulmonary disease.

Pentylenetetrazole: It is used clinically as a tool for screening latent epileptics and experimentally to
screen compounds for anti-epileptic activity.

Picrotoxin : It is used to study CNS mechanisms . It interferes with pathways that are strychnine
resistant.

Strychnine :is a source of accidental poisoning. It is also used to study CNS mechanism because of its
relatively specific action as a glycine antagonist.

Adverse Reactions: Convulsion is characterized by opisthotonos, i.e., tonic extension of body and all
limbs. Back is arched and only the back of the head and the heels are touching surface. All sensory
stimuli produce exaggerated response and slight sensory stimulation may trigger and slight sensory
stimulation may trigger convulsion.

Treatment of Strychnine Poisoning : (1) Remove/reduce external sensory stimuli (2) Diazepam or
Clonazepam I.V. or nitrous oxide by inhalation to depress CNS and stop convulsions which can be fatal.

II. PSYCHOMOTOR STIMULANTS : The drugs of Primary Importance are Amphetamine –

prototype, Methamphetamine and Methylphenidate . These all compounds are absorbed well orally . The
large portion of untransformed amphetamine is excreted and unchanged in the urine. Consequently,
acidifying the urine with ammonium chloride hastens its clearance, and thus reduces its reabsorption in
the renal tubules. Its overdose leads to hyper reflexia, tremors and convulsions. The fatalities are
hyperthermia rather than cardiovascular effects .

The primary effects of an oral dose are wakefulness, alertness, decrease fatigue; mood elevation,
increased ability to concentrate; an increase in motor and speech activity. Amphetamines also diminish
the awareness of fatigue; person may push exertion to the point of severe damage or even death.

It stimulate the respiratory center, especially when respiration is depressed by centrally acting drugs,
(barbiturates and alcohol). Amphetamine can reverse the marked sedation and behavioral retardation
resulting from reserpine-like drug. It depresses appetite by their action on the lateral hypothalamus rather
than an effect on metabolic rate .

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III. METHYLXANTINES: Caffeine, the most widely used drug in the world, is a stimulant. Commonly
found in coffee, tea, soft drinks, chocolate and a wide variety of over the-counter medications, it is legal
to buy and easily accessible. Caffeine is a physically addictive drug

Caffeine:

Coffee (100-150 mg/cup)

Tea (30-40 mg/cups)

Cocoa (15-18mg/cup)

Theophylline: Tea and cocoa

Theo bromine: Cocoa

Mechanisms of Action:

 It increase cyclic nucleotide concentration

 It blocks adenosine receptors
 It alters intracellular calcium distribution

Pharmacological Activity/ Adverse Effects :

Low Doses : 50-250mg/Caffeine (Oral Doses) Increase mental alertness, decrease drowsiness , Lessen
fatigue

Larger Doses: 250-600mg/Caffeine causes Irritability, restlessness, tremor, insomnia, headache, and
hyperesthesia, GIT upset , palpitations .

Large Doses: > 1000 mg leads to Overt excitement , delirium and clonic seizures

A. Cardiovascular System: Increase rate and force of the heart by directly stimulating myocardium
(low doses) Tachycardia and arrhythmias at higher doses. Peripheral vasodilation causes decease
in blood pressure (acute administration) . Hypotension and cardiac arrest (rapid IV theophylline)
B. Smooth Muscles: It relaxes vascular smooth muscle (Theophylline »Caffeine)
C. Kidney: All xanthines are capable of producing some degree of diuresis in humans
(Theophylline > Caffeine)
D. Miscellaneous: Xanthines shorten clotting time by increasing tissue prothrombin and factor V.

Adverse effects :

 Stimulate gastric secretions in patients with ulcer

 Dehydration in children due to vomiting and transient diuretic action (theophyline)
 Allergic reaction (aminophylline)
 Psychic Dependence (Caffeine)

DOXAPRAM

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  Generic Name: doxapram
 Brand Name: Dopram
 Class : Analeptic stimulants

Doxapram hydrochloride (marketed as Dopram, Stimulex or Respiram) is a respiratory stimulant.

Administered intravenously, doxapram stimulates an increase in tidal volume, and respiratory rate.
Doxapram is a drug that was synthesized initially in the 1960s and then investigated clinically and used
therapeutically over the next 20 years. Doxapram hydrochloride is a white to off-white, crystalline
powder, sparingly soluble in water, alcohol and chloroform. Chemically, doxapram hydrochloride is 1-
ethyl-4-[2-(4-morpholinyl)ethyl]- 3,3-diphenyl-2-pyrrolidinone monohydrochloride, monohydrate.

The chemical structure is:

DOPRAM Injection (doxapram hydrochloride injection, USP) is a clear, colorless, sterile, nonpyrogenic,
aqueous solution with pH 3.5 to 5, for intravenous administration.

Each 1 mL contains:

Doxapram Hydrochloride, USP 20 mg

Benzyl Alcohol, NF (as preservative) 0.9%
Water for Injection, USP q.s.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Doxapram hydrochloride produces respiratory stimulation mediated through the peripheral carotid
chemoreceptors. As the dosage level is increased, the central respiratory centers in the medulla are
stimulated with progressive stimulation of other parts of the brain and spinal cord.

The onset of respiratory stimulation following the recommended single intravenous injection of doxapram
hydrochloride usually occurs in 20 to 40 seconds with peak effect at 1 to 2 minutes. The duration of effect
may vary from 5 to 12 minutes.The respiratory stimulant action is manifested by an increase in tidal
volume associated with a slight increase in respiratory rate.

A pressor response may result following doxapram administration. Provided there is no impairment of
cardiac function, the pressor effect is more marked in hypovolemic than in normovolemic states. The
pressor response is due to the improved cardiac output rather than peripheral vasoconstriction. Following

7
doxapram administration, an increased release of catecholamines has been noted.Although opiate-induced
respiratory depression is antagonized by doxapram, the analgesic effect is not affected.

Pharmacokinetics: Doxapram is metabolized via ring hydroxylation to ketodoxapram, an active

metabolite readily detected in the plasma.

Mechanism of action:
Doxapram produces respiratory stimulation mediated through the peripheral carotid chemoreceptors. It is
thought to stimulate the carotid body by inhibiting certain potassium channels. When given intravenously
to normal subjects, it causes a increase in tidal volume and respiratory rate, thereby increasing minute
volume with a concomitant fall in PaCO2 and rise in PaO2. This effect in animals is dependent upon an
intact respiratory centre and is mediated by increased neuromuscular drive in a dose dependent fashion.
The main mode of action is thought to be due to specific stimulation of peripheral chemoreceptors,
especially in the carotid body. Doxapram can antagonise the blunted ventilatory response to carbon
dioxide caused by opiates and can also antagonise respiratory depression caused ethanol. Doxapram also
has effects on the cardiovascular system including an increase in stroke volume and an increase in blood
pressure. In higher dosages, there is non-specific stimulation of the central nervous system which may
lead to convulsions.

DRUG INTERACTION DRUG GROUP

7,8-Dichloro-1,2,3,4- 7,8-Dichloro-1,2,3,4- Experimental
tetrahydroisoqunioline tetrahydroisoquinoline may
increase the hypertensive
activities of Doxapram.
Amphetamine Amphetamine may increase the Approved, Illicit, Investigational
hypertensive activities of
Doxapram.
Benmoxin Benmoxin may increase the
hypertensive activities of Withdrawn
Doxapram.

Brofaromine Brofaromine may increase the

hypertensive activities of Experimental
Doxapram.

Caroxazone Caroxazone may increase the

hypertensive activities of Withdrawn
Doxapram.

Furazolidone Furazolidone may increase the

Approved, Investigational, Vet
hypertensive activities of
Approved
Doxapram.

Harmaline Harmaline may increase the Experimental

hypertensive activities of

8
 Doxapram.

Hydracarbazine Hydracarbazine may increase the

hypertensive activities of Experimental
Doxapram.

Iproclozide Iproclozide may increase the

hypertensive activities of Withdrawn
Doxapram.

Iproniazid Iproniazid may increase the

hypertensive activities of Withdrawn
Doxapram.

INDICATIONS :

 Post anesthesia:

When the possibility of airway obstruction and/or hypoxia have been eliminated, doxapram may
be used to stimulate respiration in patients with drug-induced post anesthesia respiratory
depression or apnea other than that due to muscle relaxant drugs.,/

To pharmacologically stimulate deep breathing in the postoperative patient. (A quantitative

method of assessing oxygenation, such as pulse oximetry, is recommended.)

 Drug-Induced Central Nervous System Depression:

Exercising care to prevent vomiting and aspiration, doxapram may be used to stimulate
respiration, hasten arousal, and to encourage the return of laryngopharyngeal reflexes in patients
with mild to moderate respiratory and CNS depression due to drug overdosage.

 Chronic Pulmonary Disease Associated With Acute Hypercapnia:

Doxapram is indicated as a temporary measure in hospitalized patients with acute respiratory

insufficiency superimposed on chronic obstructive pulmonary disease. Its use should be for a
short period of as an aid in the prevention of elevation of arterial CO2 tension during the
administration of oxygen. It should not be used in conjunction with mechanical ventilation.

Dosage in In Post anesthetic Use

I.V. Administration Recommended Dosage Maximum dose per Maximum total dose*
mg/kg single injection mg/kg
mg/kg

Single Injection 0.5-1 1.5 1.5

Repeat Injections (5 0.5-1 1.5 2

9
min. intervals)

Infusion 0.5-1 - 4

By I.V. Injection

The recommended dose for I.V. administration is 0.5 – 1 mg/kg for a single injection and at 5-minute
intervals. Careful observation of the patient during administration and for some time subsequently are
advisable. The maximum total dosage by I.V. injection is 2 mg/kg.

By Infusion

The solution is prepared by adding 250 mg of doxapram (12.5 mL) to 250 mL of dextrose 5% or 10% in
water or normal saline solution. The infusion is initiated at a rate of approximately 5 mg/minute until a
satisfactory respiratory response is observed, and maintained at a rate of 1 to 3 mg/minute. The rate of
infusion should be adjusted to sustain the desired level of respiratory stimulation with a minimum of side
effects. The maximum total dosage by infusion is 4 mg/kg, or approximately 300 mg for the average
adult.

In The Management Of Drug-Induced CNS Depression:

Level of Depression METHOD ONE METHOD TWO
Priming dose single/repeat I.V. Rate of Intermittent I.V.
Injection Infusion
mg/kg mg/kg/hr

Mild* 1 1-2

Moderate† 2 2-3

*Mild Depression
Class 0: Asleep, but can be aroused and can answer questions.
Class 1: Comatose, will withdraw from painful stimuli, reflexes intact.
†
Moderate Depression
Class 2: Comatose, will not withdraw from painful stimuli, reflexes intact.
Class 3: Comatose, reflexes absent, no depression of circulation or respiration.

METHOD ONE

Using Single and/or Repeat Single I.V. Injections

a. Give priming dose of 2 mg/kg body weight and repeat in 5 minutes. The priming dose for
moderate depression is 2 mg/kg and the priming dose for mild depression is 1 mg/kg.
b. Repeat same dose q 1 to 2h until patient wakens. Watch for relapse into unconsciousness or
development of respiratory depression, since DOPRAM does not affect the metabolism of CNS
depressant drugs.
c. If relapse occurs, resume injections q 1 to 2h until arousal is sustained, or total maximum daily
dose (3 grams) is given. After maximum dose has been given (3 grams), allow patient to sleep

10
 until 24 hours have elapsed from first injection of DOPRAM, using assisted or automatic
respiration if necessary.
d. Repeat procedure the following day until patient breathes spontaneously and sustains desired
level of consciousness, or until maximum dosage (3 grams) is given.
e. Repetitive doses should be administered only to patients who have shown response to the initial
dose.
f. Failure to respond appropriately indicates the need for neurologic evaluation for a possible central
nervous system source of sustained coma.

METHOD TWO

By Intermittent I.V. Infusion

a. Give priming dose as in Method One.

b. If patient wakens, watch for relapse; if no response, continue general supportive treatment for 1 to
2 hours and repeat priming dose of DOPRAM. If some respiratory stimulation occurs, prepare
I.V. infusion by adding 250 mg of DOPRAM (12.5 mL) to 250 mL of saline or dextrose solution.
Deliver at rate of 1 to 3 mg/min (60 to 180 mL/hr) according to size of patient and depth of coma.
Discontinue DOPRAM if patient begins to waken or at end of 2 hours.
c. Continue supportive treatment for ½ to 2 hours and repeat Step b.
d. Do not exceed 3 grams/day.

Chronic Obstructive Pulmonary Disease Associated With Acute Hypercapnia

a. One vial of doxapram (400 mg) should be mixed with 180 mL of dextrose 5% or 10% or normal
saline solution (concentration of 2 mg/mL). The infusion should be started at 1 to 2 mg/minute (½
to 1 mL/minute); if indicated, increase to a maximum of 3 mg/minute. Arterial blood gases
should be determined prior to the onset of doxapram’s administration and at least every half hour
during the two hours of infusion to insure against the insidious development of CO2 -
RETENTION AND ACIDOSIS. Alteration of oxygen concentration or flow rate may necessitate
adjustment in the rate of doxapram infusion.
b. Predictable blood gas patterns are more readily established with a continuous infusion of
doxapram. If the blood gases show evidence of deterioration, the infusion of doxapram should be
discontinued.
c. ADDITIONAL INFUSIONS BEYOND THE SINGLE MAXIMUM TWO HOUR
ADMINISTRATION PERIOD ARE NOT RECOMMENDED.

SIDE EFFECTS

Adverse reactions reported coincident with the administration of DOPRAM (doxapram hydrochloride,
USP) include:

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 Central And Autonomic Nervous Systems :Pyrexia, flushing, sweating; pruritus and
paresthesia, such as a feeling of warmth, burning, or hot sensation, especially in the area of
genitalia and perineum; apprehension, disorientation, pupillary dilatation, hallucinations,
headache, dizziness, hyperactivity, involuntary movements, muscle spasticity, muscle
fasciculations, increased deep tendon reflexes, clonus, bilateral Babinski, and convulsions.

Respiratory :Dyspnea, cough, hyperventilation, tachypnea, laryngospasm, bronchospasm,

hiccough, and rebound hypoventilation.

Cardiovascular: Phlebitis, variations in heart rate, lowered T-waves, arrhythmias (including

ventricular tachycardia and ventricular fibrillation), chest pain, tightness in chest. A mild to
moderate increase in blood pressure is commonly noted and may be of concern in patients with
severe cardiovascular diseases.

Gastrointestinal : Nausea, vomiting, diarrhea, desire to defecate.

Genitourinary : Stimulation of urinary bladder with spontaneous voiding; urinary retention.

Elevation of BUN and albuminuria.

Hemic And Lymphatic: Hemolysis with rapid infusion. A decrease in hemoglobin, hematocrit,
or red blood cell count has been observed in postoperative patients. In the presence of pre-
existing leukopenia, a further decrease in WBC has been observed following anesthesia and
treatment with doxapram hydrochloride.

WARNINGS

Doxapram should not be used in conjunction with mechanical ventilation.

Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension,
metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in
small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with
exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is
usually considered negligible compared to that received in flush solutions containing benzyl alcohol.
Administration of high dosages of medications containing this preservative must take into account the
total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is
not known. If the patient requires more than the recommended dosages or other medications containing
this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these
combined sources .

In Postanesthetic Use

a. Doxapram is neither an antagonist to muscle relaxant drugs nor a specific narcotic antagonist.
More specific tests (eg, peripheral nerve stimulation, airway pressures, head lift, pulse oximetry,
and endtidal carbon dioxide) to assess adequacy of ventilation are recommended before
administering doxapram.
b. Doxapram should be administered with great care and only under careful supervision to patients
with hypermetabolic states such as hyperthyroidism or pheochromocytoma.

12
 c. Since narcosis may recur after stimulation with doxapram, care should be taken to maintain close
observation until the patient has been fully alert for ½ to 1 hour.
d. In patients who have received general anesthesia utilizing a volatile agent known to sensitize the
myocardium to catecholamines, administration of doxapram should be delayed until the volatile
agent has been excreted in order to lessen the potential for arrhythmias, including ventricular
tachycardia and ventricular fibrillation

In Drug-Induced CNS And Respiratory Depression

Doxapram alone may not stimulate adequate spontaneous breathing or provide sufficient arousal in
patients who are severely depressed either due to respiratory failure or to CNS depressant drugs, but may
be used as an adjunct to established supportive measures and resuscitative techniques.

In Chronic Obstructive Pulmonary Disease

Because of the associated increased work of breathing, do not increase the rate of infusion of doxapram in
severely ill patients in an attempt to lower pCO2 .

PRECAUTIONS

General

a. An adequate airway is essential and airway protection should be considered since doxapram may
stimulate vomiting.
b. Recommended dosages of doxapram should be employed and maximum total dosages should not
be exceeded. In order to avoid side effects, it is advisable to use the minimum effective dosage.
c. Monitoring of the blood pressure, pulse rate, and deep tendon reflexes is recommended to prevent
overdosage.
d. Vascular extravasation or use of a single injection site over an extended period should be avoided
since either may lead to thrombophlebitis or local skin irritation.
e. Rapid infusion may result in hemolysis.
f. Lowered pCO2 induced by hyperventilation produces cerebral vasoconstriction and slowing of
the cerebral circulation. This should be taken into consideration on an individual basis. In certain
patients a pressor effect of doxapram on the pulmonary circulation may result in a fall of the
arterial pO2 probably due to a worsening of ventilation perfusion-matching in the lungs despite an
overall improvement in alveolar ventilation and a fall in pCO2 . Patients should be carefully
supervised taking into account available blood gas measurements.
g. There is a risk that doxapram will produce adverse effects (including seizures) due to general
central nervous system stimulation. Muscle involvement may range from fasciculation to
spasticity. Anticonvulsants such as intravenous short-acting barbiturates, along with oxygen and
resuscitative equipment should be readily available to manage overdosage manifested by
excessive central nervous system stimulation. Slow administration of the drug and careful
observation of the patient during administration and for some time subsequently are advisable.
These precautions are to assure that the protective reflexes have been restored and to prevent
possible post-hyperventilation or hypoventilation.
h. Doxapram should be administered cautiously to patients receiving sympathomimetic or
monoamine oxidase inhibiting drugs, since an additive pressor effect may occur.
i. Blood pressure increases are generally modest but significant increases have been noted in some
patients. Because of this, doxapram is not recommended for use in patients with severe
hypertension

13
 j. Cardiovascular effects may include various dysrhythmias. Patients receiving doxapram should be
monitored for disturbance of their cardiac rhythm.
k. If sudden hypotension or dyspnea develops, doxapram should be stopped.
l. Doxapram should be administered with caution to patients with significantly impaired hepatic or
renal function as a reduction in the rate of metabolism or excretion of metabolites may alter the
response.

In Postanesthetic Use

a. The same consideration to pre-existing disease states should be exercised as in non-anesthetized

individuals. See CONTRAINDICATIONS and WARNINGS covering use in hypertension,
asthma, disturbances of respiratory mechanics including airway obstruction, CNS disorders
including increased cerebrospinal fluid pressure, convulsive disorders, acute agitation, and
profound metabolic disorders.
b. See DRUG INTERACTIONS .

In Chronic Obstructive Pulmonary Disease

a. Arrhythmias seen in some patients in acute respiratory failure secondary to chronic obstructive
pulmonary disease are probably the result of hypoxia. Doxapram should be used with caution in
these patients.
b. Arterial blood gases should be drawn prior to the initiation of doxapram infusion and oxygen
administration, then at least every ½ hour during the infusion period to prevent development of
CO2 retention and acidosis in patients with chronic obstructive pulmonary disease with acute
hypercapnia. Doxapram administration does not diminish the need for careful monitoring of the
patient or the need for supplemental oxygen in patients with acute respiratory failure. Doxapram
should be stopped if the arterial blood gases deteriorate, and mechanical ventilation should be
initiated.

Carcinogenesis , Mutagenesis , Impairment Of Fertility

No carcinogenic or mutagenic studies have been performed using doxapram. Doxapram did not adversely
affect the breeding performance of rats.

Pregnancy:

Reproduction studies have been performed in rats at doses up to 1.6 times the human dose and have
revealed no evidence of impaired fertility or harm to the fetus due to doxapram. There are, however, no
adequate and well-controlled studies in pregnant women. Because the animals in the reproduction studies
were dosed by the IM and oral routes and animal reproduction studies, in general, are not always
predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human
milk, caution should be exercised when doxapram hydrochloride is administered to a nursing woman.

14
Pediatric Use

Safety and effectiveness in pediatric patients below the age of 12 years have not been established. This
product contains benzyl alcohol as a preservative. Benzyl alcohol, a component of this product, has been
associated with serious adverse events and death, particularly in pediatric patients. The “gasping
syndrome”, (characterized by central nervous system depression, metabolic acidosis, gasping respirations,
and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated
with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth-weight neonates. Additional
symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic
abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular
collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are
substantially lower than those reported in association with the “gasping syndrome”, the minimum amount
of benzyl alcohol at which toxicity may occur is not known. Premature and low-birthweight infants, as
well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners
administering this and other medications containing benzyl alcohol should consider the combined daily
metabolic load of benzyl alcohol from all sources.

Premature neonates given doxapram have developed hypertension, irritability, jitteriness, hyperglycemia,
glucosuria, abdominal distension, increased gastric residuals, vomiting, bloody stools, necrotizing
enterocolitis, erratic limb movements, excessive crying, disturbed sleep, premature eruption of teeth, and
QT prolongation that has resulted in heart block. In premature neonates with risk factors such as a
previous seizure, perinatal asphyxia, or intracerebral hemorrhage, seizures have occurred. In many
instances, doxapram was administered following administration of xanthine derivatives such as caffeine,
aminophylline or theophylline.

OVERDOSE

Signs And Symptoms

Symptoms of overdosage are extensions of the pharmacologic effects of the drug. Excessive pressor
effect, such as hypertension, tachycardia, skeletal muscle hyperactivity, and enhanced deep tendon
reflexes may be early signs of overdosage. Therefore, the blood pressure, pulse rate, and deep tendon
reflexes should be evaluated periodically and the dosage or infusion rate adjusted accordingly.

Other effects may include agitation, confusion, sweating, cough, and dyspnea.

Convulsive seizures are unlikely at recommended dosages. In unanesthetized animals, the convulsant
dose is 70 times greater than the respiratory stimulant dose. Intravenous LD values in the mouse and rat
were approximately 75 mg/kg and in the cat and dog were 40 to 80 mg/kg.

Except for management of chronic obstructive pulmonary disease associated with acute hypercapnia, the
maximum recommended dosage is 3 GRAMS/24 HOURS.

Management

There is no specific antidote for doxapram. Management should be symptomatic. Anticonvulsants, along
with oxygen and resuscitative equipment should be readily available to manage overdosage manifested by
excessive central nervous system stimulation. Slow administration of the drug and careful observation of
the patient during administration and for some time subsequently are advisable. These precautions are to

15
assure that the protective reflexes have been restored and to prevent possible post- hyperventilation or
hypoventilation.

There is no evidence that doxapram is dialyzable; further, the half-life of doxapram makes it unlikely that
dialysis would be appropriate in managing overdose with this drug.

CONTRAINDICATIONS

Doxapram is contraindicated in patients with known hypersensitivity to the drug or any of the injection
components.

Doxapram should not be used in patients with epilepsy or other convulsive disorders.

Doxapram is contraindicated in patients with proven or suspected pulmonary embolism.

Doxapram is contraindicated in patients with mechanical disorders of ventilation such as mechanical

obstruction, muscle paresis (including neuromuscular blockade), flail chest, pneumothorax, acute
bronchial asthma, pulmonary fibrosis, or other conditions resulting in restriction of the chest wall,
muscles of respiration, or alveolar expansion.

Doxapram is contraindicated in patients with evidence of head injury, cerebral vascular accident, or
cerebral edema, and in those with significant cardiovascular impairment, uncompensated heart failure,
severe coronary artery disease, or severe hypertension, including that associated with hyperthyroidism or
pheochromocytoma.

AMPHETAMINE

Generic Name: amphetamine and dextroamphetamine (am FET a meen and DEX troe am FET a meen)
Brand Name: Adderall, Adderall XR, Mydayis

Amphetamine is a CNS stimulant that causes hypertension and tachycardia with feelings of increased
confidence, sociability and energy. It suppresses appetite and fatigue and leads to insomnia. A synthetic
substance. Normally seen as a white powder, it acts as a stimulant of the central nervous system (CNS). It
is believed that amphetamine was first manufactured in the 1880s by the German chemist Leuckart,
although evidence for this is lacking. It appears that, as in the case of methamphetamine, systematic
studies of its chemistry did not come about until the early twentieth century. Amphetamine has some
limited therapeutic use, but most is manufactured in clandestine laboratories in Europe. It is under
international control and closely related to methamphetamine.

16
Chemistry

Amphetamine (CAS-300-62-9) is a member of the phenethylamine family, which includes a range of

substances that may be stimulants, entactogens or hallucinogens. Thus, amphetamine is N,α-
methylphenethylamine.

According to IUPAC, the fully systematic name is N,α-methylbenzeneethanamine. The asymmetric α-

carbon atom gives rise to two enantiomers. These two forms were previously called the [–]- or l-
stereoisomer and the [+]- or d-stereoisomer, but in modern usage are defined as the R- and S-
stereoisomers.

Molecular structure

Molecular formula: C9H13N

Molecular weight: 135.2

Pharmacodynamics:

Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.[37] Once
inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2.[37][149] When amphetamine enters
synaptic vesicles through VMAT2, it collapses the vesicular pH gradient, which in turn causes dopamine
to be released into the cytosol (light tan-colored area) through VMAT2.[149][150] When amphetamine binds
to TAAR1, it reduces the firing rate of the dopamine neuron via potassium channels and activates protein
kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylate DAT.[37][151][152] PKA-
phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[37]
PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize
and cease transport.[37] Amphetamine is also known to increase intracellular calcium, an effect which is
associated with DAT phosphorylation through a CAMKIIα-dependent pathway, in turn producing
dopamine efflux.

Pharmacokinetics

The oral bioavailability of amphetamine varies with gastrointestinal pH;[144] it is well absorbed from the
gut, and bioavailability is typically over 75% for dextroamphetamine.[9] Amphetamine is a weak base
with a pKa of 9.9;[4] consequently, when the pH is basic, more of the drug is in its lipid soluble free base
form, and more is absorbed through the lipid-rich cell membranes of the gut epithelium.[4][144] Conversely,
an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is
absorbed.[4] Approximately 15–40% of amphetamine circulating in the bloodstream is bound to plasma
proteins.[10] Following absorption, amphetamine readily distributes into most tissues in the body, with
high concentrations occurring in cerebrospinal fluid and brain tissue.[16]

17
The half-life of amphetamine enantiomers differ and vary with urine pH.[4] At normal urine pH, the half-
lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[4]
Highly acidic urine will reduce the enantiomer half-lives to 7 hours;[16] highly alkaline urine will increase
the half-lives up to 34 hours.[16] The immediate-release and extended release variants of salts of both
isomers reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively.[4] Amphetamine
is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[4]
When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[4] When urine pH
is abnormal, the urinary recovery of amphetamine may range from a low of 1% to a high of 75%,
depending mostly upon whether urine is too basic or acidic, respectively.[4] Following oral administration,
amphetamine appears in urine within 3 hours.[16] Roughly 90% of ingested amphetamine is eliminated
3 days after the last oral dose

Metabolic pathways of amphetamine in humans

MECHANISM OF ACTION:

Amphetamine (AMPH) exerts its rewarding and reinforcing effects by elevating extracellular dopamine
(DA) and prolonging DA receptor signaling in the striatum. Traditionally, AMPH has been characterized
as a DA releaser that elevates DA by three major mechanisms. First, it is a substrate for the DA
transporter (DAT) that competitively inhibits DA uptake; second, it facilitates the movement of DA out of
vesicles and into the cytoplasm; and third, it promotes DAT-mediated reverse-transport of DA into the
synaptic cleft independently of action-potential-induced vesicular release (Fleckenstein et al., 2007). In
vitro studies on the mechanisms of AMPH action have demonstrated that AMPH causes DA release,
which can result in saturation of DA receptors (Richfield et al., 1989), and eventually lead to depletion of
intracellular DA stores (Jones et al., 1998; Schmitz et al., 2001). In their recent publication in The Journal
of Neuroscience, Daberkow et al. (2013) propose a new model of AMPH action that not only extends
accepted mechanisms, but also calls some traditional hypotheses of AMPH action into question. Their
main conclusion is that low-dose (1 mg/kg) AMPH administration facilitates both electrical- and cue-
evoked vesicular DA release and does not change DA-dependent behaviors in vivo, contrary to what one
would expect if AMPH were depleting terminals as shown in vitro.

I. These are sympathomimetic agents which are NEpi, Epi, & DA agonists and acts to
increase the release of NE & DA from presynaptic neurons in CNS.
II. These increase the release of NE & E from post-ganglionic neurons in SNS .

18
III. They may have medium effects (<cocaine) on blocking reuptake of DA
IV. They release of DA in mesolimbic pathway --- reinforcing effects .
V. They increase release of DA in basal ganglia (caudate nucl. & putamen) and leads to
stereotypic behavior “punding”

INDICATIONS:

o Attention Deficit Disorder with Hyperactivity

o Narcolepsy
o Obesity
o depression and
o chronic pain.

A) Attention deficit hyperactivity disorder

ADHD is characterized by hyperactivity, irritability, mood instability, attention difficulties, lack

of organization, and impulsive behaviors. It often appears in children, but it can continue into
adulthood. Amphetamines reverse some of these symptoms and have been shown to improve
brain development and nerve growth in children with ADHD. Long-term treatment with
amphetamine-based medication in children appears to prevent unwanted changes in brain
function and structure.Scientists carrying out a review of 20 studies concluded that stimulants are
probably helpful for people with ADHD.They found that the brain structures of people who took
stimulants for ADHD were more likely to resemble the brain structures of people without the
condition than to resemble those with ADHD who did not use the drugs.

A review published in Cochrane in 2011 suggested that adults with ADHD might benefit from
short-term use of amphetamines, but that they were unlikely to persist with the treatment because
of adverse effects. Those who use mixed amphetamine salts, however, were more likely to
continue with the treatment.

B) Narcolepsy

A person with narcolepsy will experience excessive daytime sleepiness and irresistible sleep
episodes, called "sleep attacks."In a person with this condition, strong emotions can trigger a
sudden loss of muscle tone, or cataplexy, which causes a person to collapse and possibly fall
down. It also involves frequent and unexpected bouts of sleep.Amphetamines and amphetamine
derivatives have been used in the past to treat narcolepsy. Due to concerns over their side effects,
however, amphetamines are increasingly being replaced by modafinil, a medication that promotes
wakefulness.

C) Obesity

Under the name Benzedrine, amphetamines were first used to treat obesity in the 1930s, due to
their appetite-suppressing capabilities. Fears of the drug's side effects and its potential for
addiction and abuse caused them to fall out of favor for this purpose. In the 1950s, reports of
malnutrition, psychosis, and depression on withdrawal caused doctors to stop prescribing
amphetamines for weight loss. Currently, medical professionals do not recommend using
amphetamines and their derivatives to help reduce obesity.

19
 However, in 2015, after carrying out a small study, researchers suggested that dexamphetamine
might be a safe and effective way of boosting people's motivation for lifestyle changes that can
lead to weight loss. They proposed a 6-month use of the drug to help people who have not
responded to other treatment to improve their diet and increase exercise levels. This, they say,
could help curb obesity and related complications, such as diabetes and cardiovascular disease.

D) Depression

From the 1930s, amphetamine was used to treat affective disorders, obsessive-compulsive
disorder (OCD), and schizophrenia. However, in the 1950s and 1960s, amid growing concern
about its adverse effects, it was replaced by newly available antidepressants. In rare cases,
amphetamines are used alongside standard antidepressants to treat some types of depression that
do not respond to other treatments, especially in people who also experience fatigue and apathy.
In a study that followed 65 patients taking amphetamines alongside normal medication, 38
"showed significant improvement, in particular with respect to energy, mood, and psychomotor
activity."

CONTRAINDICATIONS:

According to the International Programme on Chemical Safety (IPCS) and United States Food and Drug
Administration (USFDA), amphetamine is contraindicated in people with a history of drug abuse,
cardiovascular disease, severe agitation, or severe anxiety. It is also contraindicated in people currently
experiencing advanced arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure),
hyperthyroidism (excessive production of thyroid hormone), or moderate to severe hypertension. People
who have experienced allergic reactions to other stimulants in the past or who are taking monoamine
oxidase inhibitors (MAOIs) are advised not to take amphetamine, although safe concurrent use of
amphetamine and monoamine oxidase inhibitors has been documented. These agencies also state that
anyone with anorexia nervosa, bipolar disorder, depression, hypertension, liver or kidney problems,
mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette syndrome should
monitor their symptoms while taking amphetamine. Evidence from human studies indicates that
therapeutic amphetamine use does not cause developmental abnormalities in the fetus or newborns (i.e., it
is not a human teratogen), but amphetamine abuse does pose risks to the fetus . Amphetamine has also
been shown to pass into breast milk, so the IPCS and USFDA advise mothers to avoid breastfeeding
when using it. Due to the potential for reversible growth impairments, the USFDA advises monitoring the
height and weight of children and adolescents prescribed an amphetamine pharmaceutical.

Drug Interactions:

Many types of substances are known to interact with amphetamine, resulting in altered drug action or
metabolism of amphetamine, the interacting substance, or both.[4][144] Inhibitors of enzymes that
metabolize amphetamine (e.g., CYP2D6 and FMO3) will prolong its elimination half-life, meaning that
its effects will last longer. Amphetamine also interacts with MAOIs, particularly monoamine oxidase A
inhibitors, since both MAOIs and amphetamine increase plasma catecholamine’s (i.e., norepinephrine and
dopamine); therefore, concurrent use of both is dangerous. Amphetamine modulates the activity of most
psychoactive drugs. In particular, amphetamine may decrease the effects of sedatives and depressants and
increase the effects of stimulants and antidepressants. Amphetamine may also decrease the effects of

20
antihypertensive and antipsychotics due to its effects on blood pressure and dopamine respectively. Zinc
supplementation may reduce the minimum effective dose of amphetamine when it is used for the
treatment of ADHD.

In general, there is no significant interaction when consuming amphetamine with food, but the pH of
gastrointestinal content and urine affects the absorption and excretion of amphetamine, respectively.
Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline
substances do the opposite. Due to the effect pH has on absorption, amphetamine also interacts with
gastric acid reducers such as proton pump inhibitors and H2 antihistamines, which increase
gastrointestinal pH (i.e., make it less acidic).

Tell your doctor about all your current medicines and any you start or stop using, especially:

 lithium or other medicine to treat depression or mental illness;

 blood pressure medicine;
 a blood thinner such as warfarin, Coumadin, Jantoven;
 cold or allergy medicine that contains a decongestant;
 opioid (narcotic) medicine; or
 seizure medicine.

Dosage :

 Children:

In children with ADHD who are 6-12 years of age and are either starting treatment for the first time or
switching from another medication, start with 10 mg once daily in the morning; daily dosage may be
adjusted in increments of 5 mg or 10 mg at weekly intervals. When in the judgment of the clinician a
lower initial dose is appropriate, patients may begin treatment with 5 mg once daily in the morning. The
maximum recommended dose for children is 30 mg/day; doses greater than 30 mg/day of have not been
studied in children. has not been studied in children under 6 years of age.

 Adolescents:

The recommended starting dose for adolescents with ADHD who are 13-17 years of age and are either
starting treatment for the first time or switching from another medication is 10 mg/day. The dose may be
increased to 20 mg/day after one week if ADHD symptoms are not adequately controlled.

 Adults:

In adults with ADHD who are either starting treatment for the first time or switching from another
medication, the recommended dose is 20 mg/day.

Effects of drug vs. dose levels:

LOW DOSES (< 20 MG)

 increased BP, HR
 relaxation of bronchial muscles (opening of airway)
 increased alertness, euphoria, wakefulness, mood, decreased fatigue

21
  increased motor activity & speech production
 increased sense of well-being & power
 may improve performance on simple motor tasks, esp. repetitive “boring” tasks but
impairs fine motor skills;
 usually improves athletic performance
 can detect in urine up to 48 hours after use

MODERATE DOSES (20-50 MG) : All of the above,

 increased respiration rate

 increase in tremors & motor restlessness
 increase in insomnia, agitation
 decreased appetite

HIGH DOSES (> 50 MG) : All of the above,

 sudden aggression & violence

 marked increase in purposeless, repetitive acts (“punding”, stereotypies)
 paranoid delusions
 severe anorexia --- wt. loss, malnutrition, skin sores, infections
 psychosis (esp. with abuse of methamphetamine)
 lack of sleep
 progressive deterioration of social, personal, job skills

side effects of Amphetamine : All drugs may cause side effects. However, many people have no side
effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or
any other side effects bother you or do not go away:

 Dizziness.
 Dry mouth.
 Not hungry.
 Not able to sleep.
 Hard stools (constipation).
 Headache.
 Weight loss.
 Upset stomach or throwing up.
 Loose stools (diarrhea).
 Bad taste in your mouth.
 Feeling nervous and excitable.
 Restlessness.
 Belly pain.
 Feeling tired or weak.

Unwanted effects of Amphetamines

22
When amphetamines are used at higher doses and through routes that are not prescribed by a doctor, they
can have severe adverse effects. Dopamine levels in the brain can rise quickly, and to a great extent.
Overuse and repeated abuse can lead to:

 psychosis and delusions

 feelings of paranoia and hostility
 cardiovascular problems, including stroke
 reduction in cognitive ability
 breakdown of muscle and malnutrition
 Withdrawal symptoms include depression and sleep disturbances.

Overdose

An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.
The severity of overdose symptoms increases with dosage and decreases with drug tolerance to
amphetamine. Tolerant individuals have been known to take as much as 5 grams of amphetamine in a
day, which is roughly 100 times the maximum daily therapeutic dose. Symptoms of a moderate and
extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions
and coma. In 2013, overdose on amphetamine, methamphetamine, and other compounds implicated in an
"amphetamine use disorder" resulted in an estimated 3,788 deaths worldwide (3,425–4,145 deaths,
95% confidence).

System Minor or moderate overdose Severe overdose

 Cardiogenic shock (heart not

pumping enough blood)
 Cerebral hemorrhage (bleeding in
 Abnormal heartbeat
the brain)
Cardiovascular  High or low blood pressure
 Circulatory collapse (partial or
complete failure of the circulatory
system)

 Acute amphetamine psychosis

(e.g., delusions and paranoia)
 Confusion  Compulsive and repetitive
Central  Abnormally fast reflexes movement
nervous  Severe agitation  Serotonin syndrome (excessive
system  Tremor (involuntary muscle serotonergic nerve activity)
twitching)  Sympathomimetic toxidrome
(excessive adrenergic nerve
activity)

 Rhabdomyolysis (rapid muscle

Musculoskeletal  Muscle pain
breakdown)

23
  Pulmonary edema (fluid
accumulation in the lungs)
 Pulmonary hypertension (high
Respiratory  Rapid breathing blood pressure in the arteries of
the lung)
 Respiratory alkalosis (reduced
blood CO2)

 Painful urination
 No urine production
Urinary  Urinary retention (inability to
 Kidney failure
urinate)

 Elevated or low blood potassium

 Hyperpyrexia (extremely elevated
 Elevated body temperature
Other core body temperature)
 Mydriasis (dilated pupils)
 Metabolic acidosis (excessively
acidic bodily fluids)

Precautions :

 Do not use this medicine if you have taken an MAO inhibitor in the past 14 days. A dangerous
drug interaction could occur. MAO inhibitors include isocarboxazid, linezolid, methylene blue
injection, phenelzine, rasagiline, selegiline, tranylcypromine, and others.
 You may not be able to use Adderall XR if you are allergic to any stimulant medicine. You may
not be able to use this medicine if you have:

high blood pressure, heart disease, coronary artery disease (hardened arteries);
overactive thyroid;
glaucoma;
severe anxiety, tension, or agitation (stimulant medicine can make these symptoms
worse); or
a history of drug or alcohol addiction.

 Some medicines can interact with Adderall XR and cause a serious condition called serotonin
syndrome. Be sure your doctor knows if you also take opioid medicine, herbal products, or
medicine for depression, mental illness, Parkinson's disease, migraine headaches, serious
infections, or prevention of nausea and vomiting.
 Ask your doctor before making any changes in how or when you take your medications.
 Amphetamine and dextroamphetamine can pass into breast milk and may harm a nursing baby.
You should not breast-feed while you are using this medicine.
 Taking this medicine during pregnancy can cause premature birth, low birth weight, or
withdrawal symptoms in the newborn baby. Tell your doctor if you are pregnant or plan to
become pregnant.
 To make sure this medicine is safe for you, tell your doctor if you or anyone in your family has
ever had:

o depression, mental illness, bipolar disorder, psychosis, or suicidal thoughts or actions;

24
 o motor tics (muscle twitches) or Tourette's syndrome;
o seizures or epilepsy;
o an abnormal brain wave test (EEG); or
o blood circulation problems in the hands or feet.

 Never share this medicine with another person, especially someone with a history of drug
abuse or addiction. Keep the medication in a place where others cannot get to it. Selling or
giving away this medicine is against the law.
 You may take this medicine with or without food, first thing in the morning.
 Do not crush, chew, break, or open an extended-release capsule. Swallow it whole.
 To make swallowing easier, you may open the capsule and sprinkle the medicine into a spoonful
of applesauce. Swallow right away without chewing. Do not save the mixture for later use.
 While using this medicine, your doctor will need to check your progress at regular visits. Tell any
doctor who treats you that you are using this medicine.

Dependence and withdrawal

According to another Cochrane Collaboration review on withdrawal in individuals who

compulsively use amphetamine and methamphetamine, "when chronic heavy users abruptly
discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs
within 24 hours of their last dose." This review noted that withdrawal symptoms in chronic, high-
dose users are frequent, occurring in roughly 88% of cases, and persist for 3–4 weeks with a
marked "crash" phase occurring during the first week. Amphetamine withdrawal symptoms can
include anxiety, drug craving, depressed mood, fatigue, increased appetite, increased movement
or decreased movement, lack of motivation, sleeplessness or sleepiness, and lucid dreams.[136] The
review indicated that the severity of withdrawal symptoms is positively correlated with the age of
the individual and the extent of their dependence. Mild withdrawal symptoms from the
discontinuation of amphetamine treatment at therapeutic doses can be avoided by tapering the
dose.

Toxicity

In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic

neurotoxicity, or damage to dopamine neurons, which is characterized by dopamine terminal
degeneration and reduced transporter and receptor function. There is no evidence that
amphetamine is directly neurotoxic in humans. However, large doses of amphetamine may
indirectly cause dopaminergic neurotoxicity as a result of hyperpyrexia, the excessive formation
of reactive oxygen species, and increased autoxidation of dopamine. Animal models of
neurotoxicity from high-dose amphetamine exposure indicate that the occurrence of hyperpyrexia
(i.e., core body temperature ≥ 40 °C) is necessary for the development of amphetamine-induced
neurotoxicity.[138] Prolonged elevations of brain temperature above 40 °C likely promote the
development of amphetamine-induced neurotoxicity in laboratory animals by facilitating the
production of reactive oxygen species, disrupting cellular protein function, and transiently
increasing blood–brain barrier permeability.

Psychosis

A severe amphetamine overdose can result in a stimulant psychosis that may involve a variety of
symptoms, such as delusions and paranoia. A Cochrane Collaboration review on treatment for
amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of

25
 users fail to recover completely. According to the same review, there is at least one trial that
shows antipsychotic medications effectively resolve the symptoms of acute amphetamine
psychosis. Psychosis very rarely arises from therapeutic use.

MODAFINIL

Generic Name: Modafinil (moe DAF i nil)

Brand Name: Provigil , Alertec, Modavigil,

Modafinil is a smart drug, also known as a nootropic. It enhances your cognitive function in a variety of
ways (more on that in a second). Modafinil, sold under the brand name Provigil among others, is a
wakefulness-promoting drug used for treatment of disorders such as narcolepsy, shift work sleep disorder,
idiopathic hypersomnia, and excessive daytime sleepiness associated with obstructive sleep apnea. It has
also seen widespread off-label use as a purported cognitive enhancer. In the United States modafinil is
classified as a schedule IV controlled substance and restricted in availability and usage, due to concerns
about possible addiction potential. In most other countries it is a prescription drug but not otherwise
legally restricted.

Modafinil acts as an atypical, selective, and weak dopamine reuptake inhibitor which indirectly activates
the release of orexin neuropeptides and histamine from the lateral hypothalamus and tuberomammillary
nucleus, respectively, by unknown mechanisms, all of which contribute to heightened arousal.

There are plenty of smart drugs, but modafinil stands in a class of its own for a few reasons:

 It’s not a stimulant. Modafinil acts sort of like a stimulant, but it’s actually a eugeroic – a
wakefulness-promoting agent. It doesn’t make you speedy or jittery like most classical stimulants
do. Modafinil also doesn’t have a crash or withdrawal, the way many smart drugs do.
 It’s not addictive. In fact, modafinil can help people kick addictions.
 It has few to no side effects. Modafinil is very safe.
 It works. Really well. This stuff gives you superhuman mental processing, with few to no
downsides.

26
 Modafinil; 68693-11-8; Provigil; Modiodal; 2-(Benzhydrylsulfinyl)acetamide; 2-
Chemical Names:
[(diphenylmethyl)sulfinyl]acetamide

MolecularFormula: C15H15NO2S

Pharmacodynamics

As of 2017, the therapeutic mechanism of action of modafinil for narcolepsy and sleep-wake disorders
remains unknown.

Dopamine transporter blocker

Research found that modafinil elevates histamine levels in the hypothalamus in animals. The locus of the
monoamine action of modafinil was also the target of studies, with effects identified on dopamine in the
striatum and, in particular, nucleus accumbens, norepinephrine in the hypothalamus and ventrolateral
preoptic nucleus, and serotonin in the amygdala and frontal cortex. Modafinil was screened at a large
panel of receptors and transporters in an attempt to elucidate its pharmacology. Of the sites tested, it was
found to significantly affect only the dopamine transporter (DAT), acting as a dopamine reuptake
inhibitor (DRI) with an IC50 value of 4 μM. Subsequently, it was determined that modafinil binds to the
same site on the DAT as cocaine, but in a different manner. In accordance, modafinil increases locomotor
activity and extracellular dopamine concentrations in animals in a manner similar to the selective DRI
vanoxerine (GBR-12909), and also inhibits methamphetamine-induced dopamine release (a common
property of DRIs, since DAT transport facilitates methamphetamine's access to its intracellular targets).

Modafinil has been described as an "atypical" DAT inhibitor, and shows a profile of effects that is very
different from those of other dopaminergic stimulants. For instance, modafinil produces wakefulness
reportedly without the need for compensatory sleep, and shows a relatively low, if any, potential for
abuse. Aside from modafinil, examples of other atypical DAT inhibitors include vanoxerine and
benztropine, which have a relatively low abuse potential similarly to modafinil. These drugs appear to
interact molecularly with the DAT in a distinct way relative to "conventional" DAT blockers such as
cocaine and methylphenidate.

DAT-independent actions

Against the hypothesis that modafinil exerts its effects by acting as a DRI, tyrosine hydroxylase inhibitors
(which deplete dopamine) fail to block the effects of modafinil in animals. In addition, modafinil fails to
reverse reserpine-induced akinesia, whereas dextroamphetamine, a dopamine releasing agent (DRA), is
able to do so. Moreover, one of the first published structure-activity relationship studies of modafinil
found in 2012 that DAT inhibition did not correlate with wakefulness-promoting effects in animals
among modafinil analogues, and a variety of analogues without any significant inhibition of the DAT still
produced wakefulness-promoting effects.[54] Furthermore, "[the] neurochemical effects [of modafinil] and
anatomical pattern of brain area activation differ from typical psychostimulants and are consistent with its
beneficial effects on cognitive performance processes such as attention, learning, and memory" and a
study found that modafinil-induced increased locomotor activity in animals was dependent on histamine
release and could be abolished by depletion of neuronal histamine, whereas those of methylphenidate
were not and could not be. As such, although it is established that modafinil is a clinically significant
DRI, its full pharmacology remains unclear and may be more complex than this single property (i.e., may
also include DAT-independent actions, such as "activation of the orexin system").

27
In any case, there is nonetheless a good deal of evidence to indicate that modafinil is producing at least a
portion of its wakefulness-promoting effects by acting as a DRI, or at least via activation of the
dopaminergic system. In support of modafinil acting as a dopaminergic agent, its wakefulness-promoting
effects are abolished in DAT knockout mice (although it is important to note that DAT knockout mice
show D1 and D2 receptor and norepinephrine compensatory abnormalities, which might confound this
finding), reduced by both D1 and D2 receptor antagonists (although conflicting reports exist), and
completely blocked by simultaneous inactivation of both D1 and D2 receptors. In accordance, modafinil
shows full stimulus generalization to other DAT inhibitors including cocaine, methylphenidate, and
vanoxerine, and discrimination is blocked by administration of both ecopipam (SCH-39166), a D1
receptor antagonist, and haloperidol, a D2 receptor antagonist. Partial substitution was seen with the DRA
dextroamphetamine and the D2 receptor agonist PNU-91356A, as well as with nicotine (which indirectly
elevates dopamine levels through activation of nicotinic acetylcholine receptors).

Modafinil may possess yet an additional mechanism of action. Both modafinil and its metabolite,
modafinil sulfone, possess anticonvulsant properties in animals, and modafinil sulfone is nearly as potent
as modafinil in producing this effect. However, modafinil sulfone lacks any wakefulness-promoting
effects in animals, indicating that a distinct mechanism may be at play in the anticonvulsant effects of
both compounds.

D2 receptor partial agonist

Modafinil has been found to directly inhibit the firing of midbrain dopaminergic neurons in the ventral
tegmental area and substantia nigra of rats via activation of D2 receptors.

Miscellaneous

Modafinil's efficacy in improving vigor and well-being in sleep deprivation subjects is dependent on
catechol-O-methyl transferase (COMT) status. Research suggests that individuals with the Val/Val
genotype experience a great improvement in their cognitive function, while those with the Met/Met allele
experience very little improvement.

Pharmacokinetics

Modafinil induces the cytochrome P450 enzymes CYP1A2, CYP3A4, and CYP2B6, as well as inhibiting
CYP2C9 and CYP2C19 in vitro. It may also induce P-glycoprotein (Pgp), which may affect drugs
transported by Pgp, such as digoxin. The bioavailability of modafinil is greater than 80% of the
administered dose. Food slows absorption, but does not affect the total AUC (AUC – area under the curve
– meaning, food may slow absorption, but the total amount of the chemical will be absorbed with or
without food). Half-life is generally in the 10–12 hour range, subject to differences in CYP genotypes,
liver function and renal function. It is metabolized in the liver, and its inactive metabolite is excreted in
the urine. Urinary excretion of the unchanged drug ranges from 0% to as high as 18.7%, depending on
various factors.

MECHANISM OF ACTION: The exact mechanism of action is unclear, although in vitro studies have
shown it to inhibit the reuptake of dopamine by binding to the dopamine reuptake pump, and lead to an
increase in extracellular dopamine. Modafinil activates glutamatergic circuits while inhibiting GABA.
Modafinil is thought to have less potential for abuse than other stimulants due to the absence of any
significant euphoric or pleasurable effects. It is possible that modafinil acts by a synergistic combination
of mechanisms including direct inhibition of dopamine reuptake, indirect inhibition of noradrenalin

28
reuptake in the VLPO and orexin activation. Modafinil has partial alpha 1B-adrenergic agonist effects by
directly stimulating the receptors.
INDICATIONS : To improve wakefulness in adults with excessive sleepiness associated with
narcolepsy, obstructive sleep apnea (OSA), or shift work disorder (SWD).

Occupational use

Armed forces of several countries are known to have expressed interest in modafinil as an alternative to
amphetamine—the drug traditionally employed in combat situations or lengthy missions where troops
face sleep deprivation. The French government indicated that the Foreign Legion used modafinil during
certain covert operations.[citation needed] The United Kingdom's Ministry of Defense commissioned research
into modafinil from QinetiQ and spent £300,000 on one investigation. In 2011, the Indian Air Force
announced that modafinil was included in contingency plans

In the United States military, modafinil has been approved for use on certain Air Force missions, and it is
being investigated for other uses. As of November 2012, modafinil is the only drug approved by the Air
Force as a "go pill" for fatigue management. The use of dextroamphetamine is no longer approved.

The Canadian Medical Association Journal also reports that modafinil is used by astronauts on long-term
missions aboard the International Space Station. Modafinil is "available to crew to optimize performance
while fatigued" and helps with the disruptions in circadian rhythms and with the reduced quality of sleep
astronauts experience.

Contraindications

Allergy and hypersensitivity are the only contraindications of the drug, but literature distributed by
Cephalon advises that it is important to consult a physician before using it, as problems may arise for
people who are sensitive to constituents of the tablets, people with cirrhosis (which may impair the
metabolism of the drug), and people with various cardiovascular problems.

DRUG INTERACTIONS :
DRUG INTERACTION DRUG GROUP

The metabolism of
Acenocoumarol can be decreased Approved, Investigational
when combined with Modafinil.

The metabolism of Adinazolam

can be decreased when combined Approved
with Modafinil.

The metabolism of Almotriptan

can be decreased when combined Approved, Investigational
with Modafinil.

The metabolism of Ambrisentan

can be decreased when combined Approved, Investigational
with Modafinil.

29
 The metabolism of
Aminophenazone can be
Approved, Withdrawn
decreased when combined with
Modafinil.

The metabolism of Modafinil can

be decreased when combined Approved, Investigational
with Amiodarone.

The metabolism of Amitriptyline

can be decreased when combined Approved
with Modafinil.

The metabolism of Amoxicillin

can be decreased when combined Approved, Vet Approved
with Modafinil.

The metabolism of Antipyrine

can be decreased when combined Approved, InvestigationaL
with Modafinil.

The serum concentration of

Modafinil can be decreased when Approved, Investigational
it is combined with Apalutamide.

Dosage Forms & Strengths

tablet: Schedule IV

 100mg
 200mg

 Obstructive Sleep Apnea/Hypopnea Syndrome (OSAHS): 200 mg PO qAM; no more than

400 mg
 Narcolepsy: 200 mg PO qAM; not to exceed 400 mg
 Shift Work Sleep Disorder: 200 mg PO 1 hr prior to patient's work shift

Dosage Modifications

Hepatic impairment, severe: 100 mg PO qAM

Narcolepsy (Orphan)

Orphan designation of a fixed dose combination of modafinil and flecainide for narcolepsy

Side effects : The serious side effects:

30
  fever, sore throat, headache, and vomiting with a severe blistering, peeling, and red skin rash;
 bruising, severe tingling, numbness, pain, muscle weakness;
 easy bruising or bleeding;
 white patches or sores inside your mouth or on your lips;
 hallucinations, unusual thoughts or behavior;
 depression, anxiety, aggression; or
 chest pain, uneven heart beats.

Less serious side effects may include:

 headache, dizziness;
 feeling nervous or agitated;
 nausea, diarrhea;
 trouble sleeping (insomnia); or
 dry mouth.

WARNINGS

Serious Rash, including Stevens-Johnson Syndrome: Serious rash requiring hospitalization and
discontinuation of treatment has been reported in adults and children in association with the use of
modafinil. Modafinil is not approved for use in pediatric patients for any indication.In clinical trials of
modafinil, the incidence of rash resulting in discontinuation was approximately 0.8% (13 per 1,585) in
pediatric patients (age < 17 years); these rashes included 1 case of possible Stevens-Johnson Syndrome
(SJS) and 1 case of apparent multi-organ hypersensitivity reaction. Several of the cases were associated
with fever and other abnormalities (e.g., vomiting, leukopenia). The median time to rash that resulted in
discontinuation was 13 days. No such cases were observed among 380 pediatric patients who received
placebo. No serious skin rashes have been reported in adult clinical trials (0 per 4,264) of modafinil.

Rare cases of serious or life-threatening rash, including SJS, Toxic Epidermal Necrolysis (TEN), and
Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have been reported in adults and
children in worldwide post-marketing experience. The reporting rate of TEN and SJS associated with
modafinil use, which is generally accepted to be an underestimate due to underreporting, exceeds the
background incidence rate. Estimates of the background incidence rate for these serious skin reactions in
the general population range between 1 to 2 cases per million-person years.

Although benign rashes also occur with modafinil, it is not possible to reliably predict which rashes will
prove to be serious. Accordingly, modafinil should ordinarily be discontinued at the first sign of rash,
unless the rash is clearly not drug-related. Discontinuation of treatment may not prevent a rash from
becoming life-threatening or permanently disabling or disfiguring.

31
Angioedema and Anaphylactoid Reactions: One serious case of angioedema and one case of
hypersensitivity (with rash, dysphagia, and bronchospasm), were observed among 1,595 patients treated
with armodafinil, the R enantiomer of modafinil (which is the racemic mixture). No such cases were
observed in modafinil clinical trials. However, angioedema has been reported in postmarketing
experience with modafinil. Patients should be advised to discontinue therapy and immediately report to
their physician any signs or symptoms suggesting angioedema or anaphylaxis (e.g., swelling of face, eyes,
lips, tongue or larynx; difficulty in swallowing or breathing; hoarseness).

Multi-organ Hypersensitivity Reactions: Multi-organ hypersensitivity reactions, including at least one

fatality in postmarketing experience, have occurred in close temporal association (median time to
detection 13 days: range 4-33) to the initiation of modafinil.

Although there have been a limited number of reports, multi-organ hypersensitivity reactions may result
in hospitalization or be life-threatening. There are no factors that are known to predict the risk of
occurrence or the severity of multi-organ hypersensitivity reactions associated with modafinil. Signs and
symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented
with fever and rash associated with other organ system involvement. Other associated manifestations
included myocarditis, hepatitis, liver function test abnormalities, hematological abnormalities (e.g.,
eosinophilia, leukopenia, thrombocytopenia), pruritus, and asthenia. Because multi-organ hypersensitivity
is variable in its expression, other organ system symptoms and signs, not noted here, may occur.

If a multi-organ hypersensitivity reaction is suspected, PROVIGIL (modafinil) should be discontinued.

Although there are no case reports to indicate cross-sensitivity with other drugs that produce this
syndrome, the experience with drugs associated with multi-organ hypersensitivity would indicate this to
be a possibility.

Persistent Sleepiness: Patients with abnormal levels of sleepiness who take PROVIGIL (modafinil)
should be advised that their level of wakefulness may not return to normal. Patients with excessive
sleepiness, including those taking PROVIGIL (modafinil) , should be frequently reassessed for their
degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous
activity. Prescribers should also be aware that patients may not acknowledge sleepiness or drowsiness
until directly questioned about drowsiness or sleepiness during specific activities.

Psychiatric Symptoms: Psychiatric adverse experiences have been reported in patients treated with
modafinil. Post marketing adverse events associated with the use of modafinil have included mania,
delusions, hallucinations, suicidal ideation and aggression, some resulting in hospitalization. Many, but
not all, patients had a prior psychiatric history. One healthy male volunteer developed ideas of reference,
paranoid delusions, and auditory hallucinations in association with multiple daily 600 mg doses of
modafinil and sleep deprivation. There was no evidence of psychosis 36 hours after drug discontinuation.

In the adult modafinil controlled trials database, psychiatric symptoms resulting in treatment
discontinuation (at a frequency ≥ 0.3%) and reported more often in patients treated with modafinil
compared to those treated with placebo were anxiety (1%), nervousness (1%), insomnia ( < 1%),
confusion ( < 1%), agitation ( < 1%), and depression ( < 1%). Caution should be exercised when
PROVIGIL (modafinil) is given to patients with a history of psychosis, depression, or mania.
Consideration should be given to the possible emergence or exacerbation of psychiatric symptoms in
patients treated with PROVIGIL (modafinil) . If psychiatric symptoms develop in association with
PROVIGIL (modafinil) administration, consider discontinuing PROVIGIL (modafinil) .

32
PRECAUTIONS: Diagnosis of Sleep Disorders

PROVIGIL (modafinil) should be used only in patients who have had a complete evaluation of their
excessive sleepiness, and in whom a diagnosis of either narcolepsy, OSA, and/or SWD has been made in
accordance with ICSD or DSM diagnostic criteria (See Clinical Trials). Such an evaluation usually
consists of a complete history and physical examination, and it may be supplemented with testing in a
laboratory setting. Some patients may have more than one sleep disorder contributing to their excessive
sleepiness (e.g., OSA and SWD coincident in the same patient).

General

Although modafinil has not been shown to produce functional impairment, any drug affecting the CNS
may alter judgment, thinking or motor skills. Patients should be cautioned about operating an automobile
or other hazardous machinery until they are reasonably certain that PROVIGIL (modafinil) therapy will
not adversely affect their ability to engage in such activities.

CPAP Use in Patients with OSA

In OSA, PROVIGIL (modafinil) is indicated as an adjunct to standard treatment(s) for the underlying
obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for a patient, a
maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating
PROVIGIL (modafinil) . If PROVIGIL (modafinil) is used adjunctively with CPAP, the encouragement
of and periodic assessment of CPAP compliance is necessary.

Cardiovascular System

Modafinil has not been evaluated in patients with a recent history of myocardial infarction or unstable
angina, and such patients should be treated with caution.

In clinical studies of PROVIGIL (modafinil) , signs and symptoms including chest pain, palpitations,
dyspnea and transient ischemic T-wave changes on ECG were observed in three subjects in association
with mitral valve prolapse or left ventricular hypertrophy. It is recommended that PROVIGIL (modafinil)
tablets not be used in patients with a history of left ventricular hypertrophy or in patients with mitral valve
prolapse who have experienced the mitral valve prolapse syndrome when previously receiving CNS
stimulants. Such signs may include but are not limited to ischemic ECG changes, chest pain, or
arrhythmia. If new onset of any of these symptoms occurs, consider cardiac evaluation.

Blood pressure monitoring in short-term ( < 3 months) controlled trials showed no clinically significant
changes in mean systolic and diastolic blood pressure in patients receiving PROVIGIL (modafinil) as
compared to placebo. However, a retrospective analysis of the use of antihypertensive medication in these
studies showed that a greater proportion of patients on PROVIGIL (modafinil) required new or increased
use of antihypertensive medications (2.4%) compared to patients on placebo (0.7%). The differential use
was slightly larger when only studies in OSA were included, with 3.4% of patients on PROVIGIL
(modafinil) and 1.1% of patients on placebo requiring such alterations in the use of antihypertensive
medication. Increased monitoring of blood pressure may be appropriate in patients on PROVIGIL
(modafinil) .

33
Patients Using Steroidal Contraceptives

The effectiveness of steroidal contraceptives may be reduced when used with PROVIGIL (modafinil)
tablets and for one month after discontinuation of therapy (See PRECAUTIONS: DRUG
INTERACTIONS). Alternative or concomitant methods of contraception are recommended for patients
treated with PROVIGIL (modafinil) tablets, and for one month after discontinuation of PROVIGIL
(modafinil) .

Patients Using Cyclosporine

The blood levels of cyclosporine may be reduced when used with PROVIGIL . Monitoring of circulating
cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered
when these drugs are used concomitantly.

Patients with Severe Hepatic Impairment

In patients with severe hepatic impairment, with or without cirrhosis (See CLINICAL
PHARMACOLOGY), PROVIGIL (modafinil) should be administered at a reduced dose (See DOSAGE
AND ADMINISTRATION).

Patients with Severe Renal Impairment

There is inadequate information to determine safety and efficacy of dosing in patients with severe renal
impairment.

Elderly Patients

In elderly patients, elimination of modafinil and its metabolites may be reduced as a consequence of
aging. Therefore, consideration should be given to the use of lower doses in this population.

Carcinogenesis

Carcinogenicity studies were conducted in which modafinil was administered in the diet to mice for 78
weeks and to rats for 104 weeks at doses of 6, 30, and 60 mg/kg/day. The highest dose studied is 1.5
(mouse) or 3 (rat) times greater than the recommended adult human daily dose of modafinil (200 mg) on a
mg/m² basis. There was no evidence of tumorigenesis associated with modafinil administration in these
studies. However, since the mouse study used an inadequate high dose that was not representative of a
maximum tolerated dose, a subsequent carcinogenicity study was conducted in the Tg.AC transgenic
mouse. Doses evaluated in the Tg.AC assay were 125, 250, and 500 mg/kg/day, administered dermally.
There was no evidence of tumorigenicity associated with modafinil administration; however, this dermal
model may not adequately assess the carcinogenic potential of an orally administered drug.

Mutagenesis

Modafinil demonstrated no evidence of mutagenic or clastogenic potential in a series of in vitro (i.e.,

bacterial reverse mutation assay, mouse lymphoma tk assay, chromosomal aberration assay in human
lymphocytes, cell transformation assay in BALB/3T3 mouse embryo cells) assays in the absence or

34
presence of metabolic activation, or in vivo (mouse bone marrow micronucleus) assays. Modafinil was
also negative in the unscheduled DNA synthesis assay in rat hepatocytes.

Impairment of Fertility

Oral administration of modafinil (doses of up to 480 mg/kg/day) to male and female rats prior to and
throughout mating, and continuing in females through day 7 of gestation produced an increase in the time
to mate at the highest dose; no effects were observed on other fertility or reproductive parameters. The
no-effect dose of 240 mg/kg/day was associated with a plasma modafinil exposure (AUC) approximately
equal to that in humans at the recommended dose of 200 mg.

Pregnancy

Pregnancy Category C: In studies conducted in rats and rabbits, developmental toxicity was observed at
clinically relevant exposures.

Modafinil (50, 100, or 200 mg/kg/day) administered orally to pregnant rats throughout the period of
organogenesis caused, in the absence of maternal toxicity, an increase in resorptions and an increased
incidence of visceral and skeletal variations in the offspring at the highest dose. The higher no-effect dose
for rat embryo fetal developmental toxicity was associated with a plasma modafinil exposure
approximately 0.5 times the AUC in humans at the recommended daily dose (RHD) of 200 mg. However,
in a subsequent study of up to 480 mg/kg/day (plasma modafinil exposure approximately 2 times the
AUC in humans at the RHD) no adverse effects on embryo fetal development were observed.

Modafinil administered orally to pregnant rabbits throughout the period of organogenesis at doses of 45,
90, and 180 mg/kg/day increased the incidences of fetal structural alterations and embryo fetal death at
the highest dose. The highest no-effect dose for developmental toxicity was associated with a plasma
modafinil AUC approximately equal to the AUC in humans at the RHD.

There are no adequate and well-controlled studies in pregnant women. Two cases of intrauterine growth
retardation and one case of spontaneous abortion have been reported in association with armodafinil and
modafinil. Although the pharmacology of modafinil and armodafinil is not identical to that of the
sympathomimetic amines, they do share some pharmacologic properties with this class. Certain of these
drugs have been associated with intrauterine growth retardation and spontaneous abortions. Whether the
cases reported are drug-related is unknown.

Modafinil should be used during pregnancy only if the potential benefit justifies the potential risk to the
fetus.

Pregnancy Registry

A pregnancy registry has been established to collect information on the pregnancy outcomes of women
exposed to PROVIGIL (modafinil) . Healthcare providers are encouraged to register pregnant patients, or
pregnant women may enroll themselves in the registry by calling 1866-404-4106 (toll free).

Labor and Delivery

The effect of modafinil on labor and delivery in humans has not been systematically investigated.

35
Nursing Mothers

It is not known whether modafinil or its metabolites are excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when PROVIGIL (modafinil) tablets are
administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients, below age 17, have not been established. Serious skin
rashes, including erythema multiforme major (EMM) and Stevens-Johnson Syndrome (SJS) have been
associated with modafinil use in pediatric patients (see WARNINGS, Serious Rash, including Stevens-
Johnson Syndrome).

In a controlled 6-week study, 165 pediatric patients (aged 5-17 years) with narcolepsy were treated with
modafinil (n=123), or placebo (n=42). There were no statistically significant differences favoring
modafinil over placebo in prolonging sleep latency as measured by MSLT, or in perceptions of sleepiness
as determined by the clinical global impression-clinician scale (CGI-C).

In the controlled and open-label clinical studies, treatment emergent adverse events of the psychiatric and
nervous system included Tourette's syndrome, insomnia, hostility, increased cataplexy, increased
hypnagogic hallucinations and suicidal ideation. Transient leukopenia, which resolved without medical
intervention, was also observed. In the controlled clinical study, 3 of 38 girls, ages 12 or older, treated
with modafinil experienced dysmenorrhea compared to 0 of 10 girls who received placebo.

There were three 7 to 9 week, double-blind, placebo-controlled, parallel group studies in children and
adolescents (aged 6-17 years) with Attention-Deficit Hyperactivity Disorder (ADHD, DSMIV). Two of
the studies were flexible-dose studies (up to 425 mg/day), and the third was a fixed-dose study (340
mg/day for patients < 30 kg and 425 mg/day for patients ≥ 30 kg). Although these studies showed
statistically significant differences favoring modafinil over placebo in reducing ADHD symptoms as
measured by the ADHD-RS (school version), there were 3 cases of serious rash including one case of
possible SJS among 933 patients exposed to modafinil in this program.

Modafinil is not approved for use in pediatric patients for any indication, including ADHD (see
WARNINGS, Serious Rash, including Stevens-Johnson Syndrome).

Geriatric Use

Experience in a limited number of patients who were greater than 65 years of age in clinical trials showed
an incidence of adverse experiences similar to other age groups. In elderly patients, elimination of
modafinil and its metabolites may be reduced as a consequence of aging. Therefore, consideration should
be given to the use of lower doses in this population

Addiction and dependence potential

The addiction and dependence liabilities of modafinil are very low. It shares biochemical mechanisms
with addictive stimulant drugs, and some studies have reported it to have similar mood-elevating
properties, although to a lesser degree. Monkeys will self-administer modafinil if they have previously
been trained to self-administer cocaine. Although modafinil does not produce reinforcing effects in mice
at doses that are equivalent to those used therapeutically in humans, it does do so at higher doses. In

36
accordance, although very rare, case reports of modafinil abuse exist. As such, modafinil is classified by
the United States FDA as a schedule IV controlled substance, a category for drugs with valid medical uses
and low but significant addiction potential.

Psychological dependence upon modafinil has only been noted in case reports involving daily overdoses
on modafinil for an extended period of time. Reported withdrawal symptoms include anhedonia ,
lethargy, anxiety, and insomnia.

DEXTROAMPHETAMINE

Generic Name: dextroamphetamine (DEX tro am FET a meen)

Brand Name: Dexedrine Spansule, ProCentra, Zenzedi, Dexedrine, Dextrostat, Liquadd
Chemical Formula: C9H13N
IUPAC Name : (2S)-1-phenylpropan-2-amine
Dextroamphetamine is a central nervous system stimulant. It affects chemicals in the brain and nerves that
contribute to hyperactivity and impulse control. It is prescribed for the treatment of attention deficit
hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance and cognitive
enhancer, and recreationally as an aphrodisiac and euphoriant . Dextroamphetamine was also used by
military air, tank and special forces as a 'go-pill' during fatigue-inducing missions such as night-time
bombing missions or extended combat operations.

Pharmacodynamics : Amphetamines such as dextroamphetamine are non catecholamine,

sympathomimetic amines with CNS stimulant activity. Peripheral actions include elevations of systolic
and diastolic blood pressures and weak bronchodilator and respiratory stimulant action. There is neither
specific evidence that clearly establishes the mechanism whereby amphetamines produce mental and
behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition
of the central nervous system.

Pharmacokinetics : The oral bioavailability of amphetamine varies with gastrointestinal pH; it is well
absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine . Amphetamine is
a weak base with a pKa of 9.9; consequently, when the pH is basic, more of the drug is in its lipid soluble
free base form, and more is absorbed through the lipid-rich cell membranes of the gut epithelium.
Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less
is absorbed. Approximately 15–40% of amphetamine circulating in the bloodstream is bound to plasma
proteins. Following absorption, amphetamine readily distributes into most tissues in the body, with high
concentrations occurring in cerebrospinal fluid and brain tissue.

Mechanism of action : The exact mechanism of action is not known. Dextroamphetamine stimulates the
release of norepinephrine from central adrenergic receptors. At higher dosages, it causes release of
dopamine from the meso corticolimbic system and the nigro striatal dopamine systems by reversal of the
monoamine transporters. Dextroamphetamine may also act as a direct agonist on central 5-HT receptors
and may inhibit monoamine oxidase (MAO). In the periphery, amphetamines are believed to cause the
release of noradrenaline by acting on the adrenergic nerve terminals and alpha- and beta-receptors.
Modulation of serotonergic pathways may contribute to the calming affect.

37
Indication:

 Used to treat attention deficit hyperactivity disorder (ADHD)

 Narcolepsy
 Depression and obesity.

Contraindications

According to the International Programme on Chemical Safety (IPCS) and United States Food and Drug
Administration (USFDA), amphetamine is contraindicated in people with a history of drug abuse,
cardiovascular disease, severe agitation, or severe anxiety. It is also contraindicated in people currently
experiencing advanced arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure),
hyperthyroidism (excessive production of thyroid hormone), or moderate to severe hypertension. People
who have experienced allergic reactions to other stimulants in the past or who are taking monoamine
oxidase inhibitors (MAOIs) are advised not to take amphetamine, although safe concurrent use of
amphetamine and monoamine oxidase inhibitors has been documented. These agencies also state that
anyone with anorexia nervosa, bipolar disorder, depression, hypertension, liver or kidney problems,
mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette syndrome should
monitor their symptoms while taking amphetamine. Evidence from human studies indicates that
therapeutic amphetamine use does not cause developmental abnormalities in the fetus or newborns (i.e., it
is not a human teratogen), but amphetamine abuse does pose risks to the fetus. Amphetamine has also
been shown to pass into breast milk, so the IPCS and USFDA advise mothers to avoid breastfeeding
when using it. Due to the potential for reversible growth impairments, the USFDA advises monitoring the
height and weight of children and adolescents prescribed an amphetamine pharmaceutical.

Drug Interactions:

Drug Interaction Drug group

7,8-Dichloro-1,2,3,4-
tetrahydroisoquinoline may
Experimental
increase the hypertensive
activities of Dextroamphetamine.

The serum concentration of

Dextroamphetamine can be
Approved
increased when it is combined
with Abiraterone.

Acepromazine may decrease the

stimulatory activities of Approved, Vet Approved
Dextroamphetamine.

Aceprometazine may decrease

the stimulatory activities of Approved
Dextroamphetamine.

Acetazolamide may decrease the Approved, Vet Approved

38
 excretion rate of
Dextroamphetamine which could
result in a higher serum level.

Acetophenazine may decrease

the stimulatory activities of Approved
Dextroamphetamine.

Dextroamphetamine may
decrease the sedative activities of Approved
Acrivastine.

Dextroamphetamine may
decrease the sedative activities of Approved
Alcaftadine.

Dextroamphetamine may
increase the analgesic activities Approved, Illicit
of Alfentanil.

Dextroamphetamine may
decrease the sedative activities of Approved, Vet Approved
Alimemazine.

Side effects

Physical

At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and from
person to person.[58] Cardiovascular side effects can include hypertension or hypotension from a
vasovagal response, Raynaud's phenomenon (reduced blood flow to the hands and feet), and tachycardia
(increased heart rate).[58][49][68] Sexual side effects in males may include erectile dysfunction, frequent
erections, or prolonged erections.[58] Abdominal side effects may include abdominal pain, appetite loss,
nausea, and weight loss.[1][58][69] Other potential side effects include blurred vision, dry mouth, excessive
grinding of the teeth, nosebleed, profuse sweating, rhinitis medicamentosa (drug-induced nasal
congestion), reduced seizure threshold, and tics (a type of movement disorder).[sources 1] Dangerous
physical side effects are rare at typical pharmaceutical doses.

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths. In a
normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already
compromised, it may be evident. Amphetamine also induces contraction in the urinary bladder sphincter,
the muscle which controls urination, which can result in difficulty urinating. This effect can be useful in
treating bed wetting and loss of bladder control. The effects of amphetamine on the gastrointestinal tract
are unpredictable. If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate
at which content moves through the digestive system); however, amphetamine may increase motility
when the smooth muscle of the tract is relaxed. Amphetamine also has a slight analgesic effect and can
enhance the pain relieving effects of opioids.

39
USFDA-commissioned studies from 2011 indicate that in children, young adults, and adults there is no
association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the
medical use of amphetamine or other ADHD stimulants. However, amphetamine pharmaceuticals are
contraindicated in individuals with cardiovascular disease.

Psychological

At normal therapeutic doses, the most common psychological side effects of amphetamine include
increased alertness, apprehension, concentration, initiative, self-confidence, and sociability, mood swings
(elated mood followed by mildly depressed mood), insomnia or wakefulness, and decreased sense of
fatigue. Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or
obsessive behaviors, and restlessness; these effects depend on the user's personality and current mental
state. Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users. Although very
rare, this psychosis can also occur at therapeutic doses during long-term therapy. According to the
USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.

Amphetamine has also been shown to produce a conditioned place preference in humans taking
therapeutic doses, meaning that individuals acquire a preference for spending time in places where they
have previously used amphetamine.

Overdose

An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.
The severity of overdose symptoms increases with dosage and decreases with drug tolerance to
amphetamine. Tolerant individuals have been known to take as much as 5 grams of amphetamine in a
day, which is roughly 100 times the maximum daily therapeutic dose. Symptoms of a moderate and
extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions
and coma. In 2013, overdose on amphetamine, methamphetamine, and other compounds implicated in an
"amphetamine use disorder" resulted in an estimated 3,788 deaths worldwide (3,425–4,145 deaths,
95% confidence).

Pathological over activation of the mesolimbic pathway, a dopamine pathway that connects the ventral
tegmental area to the nucleus accumbens, plays a central role in amphetamine addiction. Individuals who
frequently overdose on amphetamine during recreational use have a high risk of developing an
amphetamine addiction, since repeated overdoses gradually increase the level of accumbal ΔFosB, a
"molecular switch" and "master control protein" for addiction. Once nucleus accumbens ΔFosB is
sufficiently overexpressed, it begins to increase the severity of addictive behavior (i.e., compulsive drug-
seeking) with further increases in its expression. While there are currently no effective drugs for treating
amphetamine addiction, regularly engaging in sustained aerobic exercise appears to reduce the risk of
developing such an addiction. Sustained aerobic exercise on a regular basis also appears to be an effective
treatment for amphetamine addiction; exercise therapy improves clinical treatment outcomes and may be
used as a combination therapy with cognitive behavioral therapy, which is currently the best clinical
treatment available.

Side effects:

 Metabolic
 Very common (10% or more): Decreased appetite, reduced weight gain, weight loss
Common (1% to 10%): Anorexia
Frequency not reported: Acidosis[Ref]

40
 Psychiatric
 Very common (10% or more): Insomnia, nervousness
Common (1% to 10%): Abnormal behavior, aggression/hostility, excitation, anxiety, depression,
irritability
Uncommon (0.1% to 1%): Psychotic episodes/psychosis
Very rare (less than 0.01%): Suicidal behavior (including completed suicide), mania,
hallucinations
Frequency not reported: Overstimulation, restlessness, euphoria, dysphoria, confusion,
dependence, emotional lability, impaired cognitive test performance, altered libido, night terrors,
obsessive-compulsive behavior, panic states, paranoia[Ref]
 Cardiovascular
 Common (1% to 10%): Arrhythmia, palpitations, tachycardia
Rare (less than 0.1%): Angina pectoris
Very rare (less than 0.01%): Cardiac arrest
Frequency not reported: Blood pressure and heart rate changes (usually elevated),
cardiomyopathy, myocardial infarction, chest pain, cardiovascular collapse, Raynaud's
phenomenon[Ref]
 Gastrointestinal
 Common (1% to 10%): Abdominal pain and cramps, nausea, vomiting, dry mouth
Frequency not reported: Ischemic colitis, unpleasant taste, diarrhea, constipation, other
gastrointestinal disturbances[Ref]
 Musculoskeletal
 Common (1% to 10%): Arthralgia
Rare (less than 0.1%): Growth retardation
Very rare (less than 0.01%): Muscle cramps
Frequency not reported: Rhabdomyolysis[Ref]
 Nervous system
 Common (1% to 10%): Vertigo, dyskinesia, headache, hyperactivity
Very rare (less than 0.01%): Tourette syndrome, tics, exacerbation of pre-existing motor and
phonic tics, convulsions, choreoathetoid movements, intracranial hemorrhage, cerebral vasculitis
and/or occlusion, neuroleptic malignant syndrome (NMS)
Frequency not reported: Dizziness, tremor, ataxia, dysgeusia, concentration difficulties,
hyperreflexia, stroke[Ref]
 Dermatologic
 Rare (less than 0.1%): Rash, urticaria
Very rare (less than 0.01%): Erythema multiforme, exfoliative dermatitis, fixed drug eruption
Frequency not reported: Sweating, alopecia[Ref]
 Ocular
 Rare (less than 0.1%): Visual accommodation difficulties, blurred vision, mydriasis[Ref]
 Other
 Rare (less than 0.1%): Fatigue
Frequency not reported: Hyperpyrexia, sudden death[Ref]
 Hematologic
 Very rare (less than 0.01%): Anemia, leukopenia, thrombocytopenia, thrombocytopenic
purpura[Ref]
 Hepatic
 Very rare (less than 0.01%): Abnormal liver function ranging from hepatic enzyme elevations to
hepatic coma[Ref]
 Endocrine
 Frequency not reported: Impotence, libido changes, frequent or prolonged erections[Ref]
 Hypersensitivity

41
  Frequency not reported: Hypersensitivity reactions (e.g., angioedema and anaphylaxis)[Ref]
 Renal
 Frequency not reported: Renal damage

hat Are Warnings and Precautions for Dextroamphetamine ( Vasostrict, ADH)?

Warnings

 Dextroamphetamine has a high potential for abuse; particular attention should be paid to the
possibility of patients obtaining dextroamphetamine for nontherapeutic use or distribution to
others, and the drugs should be prescribed or dispensed sparingly.
 Administration of dextroamphetamine for prolonged periods of time may lead to drug
dependence and must be avoided.
 Misuse of dextroamphetamine may cause sudden death and serious cardiovascular adverse
events.
 This medication contains dextroamphetamine. Do not take Dexedrine, ProCentra, or Zenzedi if
you are allergic to dextroamphetamine or any ingredients contained in this drug.
 Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control
Center immediately.

Contraindications

 Hypersensitivity to drug or components

 Hyperthyroidism
 Glaucoma
 High blood pressure (hypertension), advanced arteriosclerosis, symptomatic cardiovascular
disease
 Agitated states, history of drug abuse
 Within 14 days of administering monoamine oxidase inhibitors (MAOIs)

Effects of Drug Abuse

 No information available

Short-Term Effects

 See "What Are Side Effects Associated with Using Dextroamphetamine?"

Long-Term Effects

 See "What Are Side Effects Associated with Using Dextroamphetamine?"

Cautions

Risk of sudden death in children and adolescents with structural cardiac abnormalities; generally avoid.

Risk of adverse psychiatric events; e.g., hallucinations and mania.

42
Caution in mild high blood pressure (hypertension).

Associated with peripheral vasculopathy, including Raynaud's phenomenon.

Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.

Sudden deaths, stroke, and myocardial infarction reported in adults taking stimulants at usual doses.

Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms
suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation.

Particular care should be taken in using stimulants to treat ADHD patients with comorbid bipolar disorder
because of concern for possible induction of mixed/manic episode in such patients.

Aggressive behavior or hostility is often observed in children and adolescents with ADHD; monitor for
the appearance of or worsening of aggressive behavior or hostility.

Monitor growth of children ages 7 to 10 years during treatment with stimulants; may need to interrupt
therapy in patients not growing or gaining weight as expected.

Stimulants may lower convulsive threshold in patients with prior history of seizure, patients with prior
EEG abnormalities in absence of seizures, and very rarely, patients without a history of seizures and no
prior EEG evidence of seizures; discontinue therapy in the presence of seizures.

Use with caution in patients who use other sympathomimetic drugs.

Amphetamines may exacerbate motor and phonic tics and Tourette's syndrome; perform clinical
evaluation for tics and Tourette's syndrome in children and their families prior to treating with stimulant
medications.

Rare instances of prolonged and sometimes painful erections (priapism), sometimes requiring surgical
intervention, reported with methylphenidate products; typically not reported during initiation, but often
subsequent to an increase in dose; seek immediate medical attention for abnormally sustained or frequent
and painful erections.

Drug interaction overview

 Serotonin syndrome, a potentially life-threatening reaction, may occur when amphetamines are
used in combination with other drugs that affect the serotonergic neurotransmitter systems such
as monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs),
serotonin norepinephrine reuptake inhibitors (SNRIs), triptans, tricyclic antidepressants, fentanyl,
lithium, tramadol, tryptophan, buspirone, and St. John's wort
 Amphetamines are known to be metabolized, to some degree, by cytochrome P450 2D6
(CYP2D6) and display minor inhibition of CYP2D6 metabolism; potential for a pharmacokinetic
interaction exists with coadministration of CYP2D6 inhibitors which may increase risk with
increased exposure to amphetamines; in these situations, consider alternative non-serotonergic
drug or alternative drug that does not inhibit CYP2D6

43
  If concomitant use with other serotonergic drugs or CYP2D6 inhibitors is clinically warranted,
initiate therapy with lower doses, monitor patients for emergence of serotonin syndrome during
drug initiation or titration, and inform patients of increased risk for serotonin syndrome

Pregnancy and Lactation

 Use dextroamphetamine with caution during pregnancy if benefits outweigh risks. Animal studies
show risk and human studies are not available or neither animal nor human studies were done.
 Dextroamphetamine enters breast milk; it is not recommended for use while breastfeeding.

COCAINE

 Brand names: Goprelto, C-Topical Solution

 Drug class(es): topical anesthetics
 Generic Name: cocaine

Cocaine is a local anesthetic indicated for the introduction of local (topical) anesthesia of accessible
mucous membranes of the oral, laryngeal and nasal cavities.Cocaine is a naturally occurring chemical
found in the leaves of Erythroxylum coca or coca plant, which is native to South America. Coca leaves
have been used and abused for hundreds of years. Cocaine is a highly addictive stimulant drug that
directly affects the nervous system, including the brain. Effects of cocaine include short-term euphoria,
energy, talkativeness, and it may cause dangerous increases in heart rate and blood pressure.

Cocaine is addictive due to its effect on the reward pathway in the brain. After a short period of use, there
is a high risk that dependence will occur. Its use also increases the risk of stroke, myocardial infarction,
lung problems in those who smoke it, blood infections, and sudden cardiac death. Cocaine sold on the
street is commonly mixed with local anesthetics, cornstarch, quinine, or sugar, which can result in
additional toxicity. Following repeated doses a person may have decreased ability to feel pleasure and be
very physically tired.

CHEMICAL STRUCTURE:

44
MECHANISM OF ACTION:

Cocaine produces anesthesia by inhibiting excitation of nerve endings or by blocking conduction in

peripheral nerves. This is achieved by reversibly binding to and inactivating sodium channels. Sodium
influx through these channels is necessary for the depolarization of nerve cell membranes and subsequent
propagation of impulses along the course of the nerve. Cocaine is the only local anesthetic with vaso
constrictive properties. This is a result of its blockade of norepinephrine reuptake in the autonomic
nervous system. Cocaine binds differentially to the dopamine, serotonin, and norepinephrine transport
proteins and directly prevents the re-uptake of dopamine, serotonin, and norepinephrine into pre-synaptic
neurons. Its effect on dopamine levels is most responsible for the addictive property of cocaine. Cocaine
is absorbed from all sites of application, including mucous membranes and gastrointestinal mucosa. By
oral or intra-nasal route, 60 to 80% of cocaine is absorbed.

Dosages of Cocaine Should Be Given As Follows:

Dosage Forms & Strengths

Topical solution: Schedule II

 4% (pediatric and adult strength)

 10%

Dosage Considerations for Topical Anesthesia

As local anesthetic for accessible mucous membranes (oral, nasal and laryngeal)

1-10% solution: Use lowest dose necessary to produce adequate anesthesia.

Do not exceed 3 mg/kg or 300 mg.

Dosage variables include tissue vascularity, anesthetic technique and patient tolerance.

Reduce dose for elderly or debilitated patients.

Administration

Administer using cotton applicators or packs, instilled into a cavity, or as a spray.

Apply only on mucous membranes of mouth, laryngeal, or nasal cavities.

45
The fatal dose of cocaine has been approximated at 1.2 g., although severe toxic effects have been
reported from doses as low as 20 mg.

Overdose

The symptoms of cocaine poisoning are referable to the CNS, namely the patient becomes excited,
restless, garrulous, anxious and confused. Enhanced reflexes, headache, rapid pulse, irregular respiration,
chills, rise in body temperature, mydriasis, exophthalmos, nausea, vomiting and abdominal pain are
noticed. In severe overdoses, delirium, Cheyne-Stokes respiration, convulsions, unconsciousness, and
death from respiratory arrest result. Acute poisoning by cocaine develops rapidly in time.

USES:

Medical

Cocaine hydrochloride

Topical cocaine can be used as a local numbing agent to help with painful procedures in the mouth or
nose.[21] TAC is one such formulation used for pediatrics.

Cocaine is now predominantly used for nasal and lacrimal duct surgery. The major disadvantages of this
use are cocaine's potential for cardiovascular toxicity, glaucoma, and pupil dilation.[21] Medicinal use of
cocaine has decreased as other synthetic local anesthetics such as benzocaine, proparacaine, lidocaine,
and tetracaine are now used more often.[21] If vasoconstriction is desired for a procedure (as it reduces
bleeding), the anesthetic is combined with a vasoconstrictor such as phenylephrine or epinephrine. Some
ENT specialists occasionally use cocaine within the practice when performing procedures such as nasal
cauterization. In this scenario dissolved cocaine is soaked into a ball of cotton wool, which is placed in
the nostril for the 10–15 minutes immediately before the procedure, thus performing the dual role of both
numbing the area to be cauterized, and vasoconstriction. Even when used this way, some of the used
cocaine may be absorbed through oral or nasal mucosa and give systemic effects.[citation needed] An
alternative method of administration for ENT surgery is mixed with adrenaline and sodium bicarbonate,
as Moffett's solution.

Recreational

Cocaine is a powerful nervous system stimulant.[22] Its effects can last from fifteen or thirty minutes to an
hour. The duration of cocaine's effects depends on the amount taken and the route of administration.[23]
Cocaine can be in the form of fine white powder, bitter to the taste. When inhaled or injected, it causes a
numbing effect. Crack cocaine is a smokeable form of cocaine made into small "rocks" by processing
cocaine with sodium bicarbonate (baking soda) and water.[24][25] Crack cocaine is referred to as "crack"
because of the crackling sounds it makes when heated.[25]

Cocaine use leads to increases in alertness, feelings of well-being and euphoria, increased energy and
motor activity, and increased feelings of competence and sexuality.[26]

Coca leaves

Coca leaves are typically mixed with an alkaline substance (such as lime) and chewed into a wad that is
retained in the mouth between gum and cheek (much the same as chewing tobacco is chewed) and sucked

46
of its juices. The juices are absorbed slowly by the mucous membrane of the inner cheek and by the
gastrointestinal tract when swallowed. Alternatively, coca leaves can be infused in liquid and consumed
like tea. Ingesting coca leaves generally is an inefficient means of administering cocaine.

Pharmacokinetics

Cocaine is well absorbed when administered via mucous membranes (e.g. intranasally), the
gastrointestinal tract and intravenously. Peak concentrations occur within five to ten minutes after
intravenous injection or smoking and within 60 minutes after intranasal administration (Cone, 1995).
Cocaine is shorter acting than amphetamines and effects or blood levels may diminish after as little as one
hour (Inaba, 1989).

Some cocaine is excreted unchanged in the urine, but the majority is metabolised to benzoylecgonine,
ecgonine methyl ester, norcocaine and other metabolites (Jufer, Wstadik, Walsh, Levine & Cone, 2000;
Klingmann, Skopp & Aderjan, 2001). Although cocaine has a short half-life, elimination half-lives of
cocaine metabolites are substantially longer (Jufer et al., 2000). The half-life of cocaine may increase
after chronic dosing (Jufer et al., 2000; Moolchan, Cone, Wstadik, Huestis & Preston, 2000).

Pharmacodynamics

Cocaine also enhances the activity of dopamine. It does this by blocking its reuptake into the nerve
terminal via the transporter and thus increasing the amount of dopamine available to act at receptors in the
synapse (Silvia et al., 1997; Volkow, Wang, Fischman, Foltin et al., 2000). Cocaine may also block
reuptake of noradrenaline and serotonin (Rasmussen, Carroll, Maresch, Jensen et al., 2001; Ritz, Cone &
Kuhar, 1990), with some authors suggesting that it may enhance noradrenaline release (Tuncel, Wang,
Arbique, Fadel et al., 2002).

In addition to these effects cocaine is also a local anaesthetic agent. Like other local anaesthetics, it
produces direct effects on cell membranes — cocaine blocks sodium channel activity and thus prevents
the generation and conduction of nerve impulses in electrically active cells, such as myocardial and nerve
cells

What are the medical complications of cocaine?

Cocaine causes many adverse effects to many organ systems. Some complications are dependent on the
route of exposure.

 Bones
o Cocaine, when inserted in the nose (snorted) can cause breakdown of the cartilage and
bones in and around the nose creating holes in the septum (the septum separates the
nostrils).
 Brain and nerves
o Cocaine use can cause difficulty walking, headache, seizures, spontaneous bleeding,
stroke, temporary or permanent memory and attention problems, and tremors. Intranasal
(in the nose) users can lose their sense of smell and suffer from frequent nosebleeds.
Intravenous (in the veins) users are at risk for infections that can be located in the brain in
addition to other areas of the body.
 Gastrointestinal

47
 o Cocaine can cause severe abdominal pain, bloody diarrhea, nausea and vomiting.
Intravenous users are at increased risk for viral hepatitis if they use contaminated needles.
 Heart
o Cocaine can cause chest pain, high blood pressure, fast or abnormal heart rate, heart
attack, problems with heart muscle contraction and rupture of the aorta (main blood
vessel from the heart). Intravenous users are at increased risk for infections of the heart
and its valves.
 Lung
o People who smoke cocaine can have shortness of breath and fluid or bleeding in the lung.
They can rupture the lung, which results in air leaking into the chest.
 Kidney
o Cocaine can cause kidney damage
 Muscles
o Cocaine can cause severe muscle damage and pain.
 Cocaine use during pregnancy
o Cocaine use is associated with premature delivery, vaginal bleeding, sudden death, and
birth defects.

What Other Drugs Interact with Cocaine?

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of
any possible drug interactions and may be monitoring your health for them. Do not start, stop, or change
the dosage of any medicine before checking with your doctor, health care provider or pharmacist first.
Alcohol should be avoided while using this drug.

Severe Interactions of Cocaine inlcude:

 Eliglustat
 Iobenguane I 123

Serious Interactions of Cocaine inlcude:

 Citalopram
 Desvenlafaxine
 Idelalisib
 Isocarboxazid
 Ivacaftor
 Linezolid
 Lorcaserin
 Methylene blue
 Phenelzine
 Procarbazine
 Tranylcypromine
 Vilazodone
 Vortioxetine

Moderate Interactions of Cocaine: Cocaine has a known moderate interaction with at least 73 different
drugs.Minor Interactions of Cocaine: Cocaine has mild interactions with at least 32 different drugs.

48
What Are Warnings and Precautions for Cocaine?

This medication contains cocaine. Do not take cocaine if you are allergic to cocaine or any ingredients
contained in this drug.

Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center
immediately.

Contraindications

Hypersensitivity to ester-type local anesthetics, para-aminobenzoic acid (PABA), or parabens

Ophthalmologic anesthesia (causing sloughing of the corneal epithelium)

Effects of Drug Abuse

None.

Short-Term Effects

None.

Long-Term Effects

User may develop tolerance if this drug is used as a sedative/hypnotic.

Cautions

Do not administer parenterally or apply to eye.

Do not dilute with epinephrine for topical application as "cocaine mud."

Serious toxic effects (eg, seizures, cardiac death) have been described in people following topical cocaine
application used to anesthetize minor skin lacerations, especially on the face or scalp (eg, TAC [tetracaine
0.5%, epinephrine (Adrenalin) 1:2000, and cocaine 11.8%]); this risk is greater in pediatrics.

Use caution in patients with cardiovascular disease.

Avoid beta-blocker use when patients are being treated for cardiovascular complications caused by
cocaine abuse.

Pregnancy and Lactation

Use cocaine with caution during pregnancy if prescribed and benefits outweigh risks. Animal studies
show risk and human studies not available or neither animal nor human studies done. Do not use cocaine
during pregnancy for non-medicinal use. Cocaine enters breast milk; use while breastfeeding is
contraindicated.

49
Crack cocaine

"Rocks" of crack cocaine

Crack is a lower purity form of free-base cocaine that is usually produced by neutralization of cocaine
hydrochloride with a solution of baking soda (sodium bicarbonate, NaHCO3) and water, producing a very
hard/brittle, off-white-to-brown colored, amorphous material that contains sodium carbonate, entrapped
water, and other by-products as the main impurities.

The "freebase" and "crack" forms of cocaine are usually administered by vaporization of the powdered
substance into smoke, which is then inhaled.

The origin of the name "crack" comes from the "crackling" sound (and hence the onomatopoeic moniker
"crack") that is produced when the cocaine and its impurities (i.e. water, sodium bicarbonate) are heated
past the point of vaporization. Pure cocaine base/crack can be smoked because it vaporizes smoothly,
with little or no decomposition at 98 °C (208 °F), which is below the boiling point of water.

In contrast, cocaine hydrochloride does not vaporize until heated to a much higher temperature (about
197 °C), and considerable decomposition/burning occurs at these high temperatures. This effectively
destroys some of the cocaine and yields a sharp, acrid, and foul-tasting smoke. Smoking or vaporizing
cocaine and inhaling it into the lungs produces an almost immediate "high" that can be very powerful
(and addicting) quite rapidly – this initial crescendo of stimulation is known as a "rush". While the
stimulating effects may last for hours, the euphoric sensation is very brief, prompting the user to smoke
more immediately.

Toxicity

Symptoms of intoxication include bizarre, erratic and violent behaviour. Users experience tremors,
vertigo, muscle twitches, paranoia and other symptoms of psychosis. Physical symptoms include chest
pain, nausea, intense thirst, blurred vision, fever, muscle spasms, convulsions and coma (Brownlow &
Pappachan, 2002).

Chronic cocaine use can lead to a range of cardiac complications. Acute myocardial infarction and
myocardial ischaemia are the most common cardiac complications associated with cocaine use
(Hollander, Hoffman, Burstein, Shih & Thode, 1995; Qureshi, Suri, Guterman & Hopkins, 2001). A
range of cocaine-related effects are thought to contribute to myocardial ischaemia and infarction risk.

50
These include increased oxygen demand, vasoconstriction of coronary arteries, increased platelet
aggregation and thrombus formation (Lange & Hillis, 2001). Potentially fatal arrhythmias and
dysrhythmias may also occur (Benchimol, Bartall & Desser, 1978; Nanji & Filipenko, 1984).

Longer-term complications include accelerated atherosclerosis, cardiomyocyte apoptosis,

sympathoadrenal-induced myocyte damage, chronic arrhythmias, cardiac hypertrophy and dilated
cardiomyopathy (Brownlow & Pappachan, 2002; Knuepfer, 2003).

Regular cocaine use has also been associated with a number of abnormalities in the cerebral vasculature.
The most common complications are haemorrhagic or thromboembolic strokes, but cerebral haemorrhage
may also occur.The pathogenesis of cocaine-related cerebrovascular events is complex. It has been
suggested that contributing factors may include cocaine-related rapid increases in blood pressure, smooth
muscle effects producing vasospasm and ischaemia, vascular malformations and enhanced platelet
aggregation (Auer et al., 2001). Other neurological complications include seizures (Dhuna, Pascual-
Leone, Langendorf & Anderson, 1991; Lason, 2001; Lathers, Tyau, Spino & Agarwal, 1988; Satel &
Gawin, 1989); sensitivity to seizures may be increased by chronic exposure.

Some individuals are vulnerable to cocaine-induced excited delirium. This is characterised by

hyperthermia, extreme behavioural agitation and, in some cases, violent behaviour. This may also result
in cardiac collapse and sudden cardiac death. Rhabdomyolysis may also occur (Merigian & Roberts,
1987). This may be part of the same syndrome as delirium, induced by changes in dopamine processing
associated with chronic use of the drug rather than acute toxic effects (Ruttenber, McAnally & Wetli,
1999).

Regular intranasal use of cocaine may lead to damaging effects on the nasal mucosa. This ranges in
severity from chronic rhinitis, reduced sense of smell, nosebleeds and septal perforation (Schwartz et al.,
1989) to more serious damage such as necrosis of the sinonasal tract and oronasal fistula (Braverman,
Raviv & Frenkiel, 1999; Gertner & Hamlar, 2002; Mari, Arranz, Gimeno, Lluch et al., 2002). This is
thought to be mediated by ischaemia secondary to vasoconstriction, although adulterants may also play a
role (Mari et al., 2002). Smoking of crack cocaine can lead to a variety of acute pulmonary complications,
including severe exacerbations of asthma and an acute lung injury syndrome associated with a broad
spectrum of histopathologic changes ('crack lung') (Tashkin, 2001). Habitual cocaine smoking may also
produce more subtle long-term pulmonary consequences due to chronic alveolar epithelial and
microvascular lung injury (Brownlow & Pappachan, 2002; Tashkin, 2001) including pulmonary oedema
and pulmonary haemorrhage.

It is unclear whether cocaine use produces neurotoxicity. Since cocaine does not induce dopamine release,
it may pose a lower risk for neurotoxic effects than other agents such as methamphetamine (Cappon,
Morford & Vorhees, 1998). Cocaine use has been associated with certain neurological abnormalities
(Fein, Sclafani & Meyerhoff, 2002; Franklin, Acton, Maldjian, Gray et al., 2002; Li et al., 2001).
However, whether this represents neurotoxicity, neuroadaptation or other aetiology has not been
established.

51
 CAFFEINE

Brand Name: NoDoz, Vivarin, Revive, Stay Awake, Enerjets, Lucidex

Generic Name: Caffeine

Chemical Names: Caffeine; 58-08-2; 1,3,7-Trimethylxanthine; Guaranine; Thein; Cafeina

Molecular Formula: C8H10N4O2

A methylxanthine naturally occurring in some beverages and also used as a pharmacological agent.
Caffeine's most notable pharmacological effect is as a central nervous system stimulant, increasing
alertness and producing agitation. It also relaxes smooth muscle, stimulates cardiac muscle, stimulates
diuresis, and appears to be useful in the treatment of some types of headache. Several cellular actions of
caffeine have been observed, but it is not entirely clear how each contributes to its pharmacological
profile. Among the most important are inhibition of cyclic nucleotide phosphodiesterases, antagonism of
adenosine receptors, and modulation of intracellular calcium handling.

Caffeine is a central nervous system stimulant. It works by stimulating the brain. Caffeine is found
naturally in foods and beverages such as coffee, tea, colas, energy and chocolate. Botanical sources of
caffeine include kola nuts, guarana, and yerba mate. Caffeine is also available in prescription and non-
prescription medications.

Caffeine is used to restore mental alertness or wakefulness during fatigue or drowsiness. Caffeine is also
found in some headache and migraine medications, in certain dietary supplements used for weight loss,
and in many popular energy drinks.Caffeine citrate (Cafcit) is available by prescription only. It is used for
short-term treatment of neonatal apnea (breathing problems).Caffeine may also be used for other
conditions as determined by your health care provider.

Pharmacodynamics

Caffeine, a naturally occurring xanthine derivative like theobromine and the bronchodilator theophylline,
is used as a CNS stimulant, mild diuretic, and respiratory stimulant (in neonates with apnea of
prematurity). Often combined with analgesics or with ergot alkaloids, caffeine is used to treat migraine

52
and other headache types. Over the counter, caffeine is available to treat drowsiness or mild water-weight
gain.

Mechanism of action

Caffeine stimulates medullary, vagal, vasomotor, and respiratory centers, promoting bradycardia,
vasoconstriction, and increased respiratory rate. This action was previously believed to be due primarily
to increased intracellular cyclic 3′,5′-adenosine monophosphate (cyclic AMP) following inhibition of
phosphodiesterase, the enzyme that degrades cyclic AMP. It is now thought that xanthines such as
caffeine act as antagonists at adenosine-receptors within the plasma membrane of virtually every cell. As
adenosine acts as an autocoid, inhibiting the release of neurotransmitters from presynaptic sites but
augmenting the actions of norepinephrine or angiotensin, antagonism of adenosine receptors promotes
neurotransmitter release. This explains the stimulatory effects of caffeine. Blockade of the adenosine A1
receptor in the heart leads to the accelerated, pronounced "pounding" of the heart upon caffeine intake.

What Should I Know Before Using Caffeine?

Some medical conditions may interact with caffeine. Tell your health care provider if you have ANY
medical conditions, especially if any of the following apply to you:

 if you have allergies to caffeine, other medicines, foods, or other substances

 if you are taking any prescription or nonprescription medicine, or herbal or dietary supplement
 if you have anxiety, agitation or nervousness, liver or stomach (ulcer) problems, insomnia
(trouble sleeping), seizures (convulsions), or heart disease, especially any abnormal heart rhythms
or high blood pressure
 if you are pregnant, planning to become pregnant, or are breast-feeding

Drug interactions may occur with caffeine. Tell your health care provider if you are taking any other
medicines, especially any of the following:

 Quinolones (i.e., ciprofloxacin)

 Theophyllines
 Duloxetine
 Ephedra or Guarana
 Rasagiline
 Tizanidine

Use

Medical

Caffeine is used in:

 Bronchopulmonary dysplasia in premature infants for both prevention[18] and treatment.[19] It may
improve weight gain during therapy[20] and reduce the incidence of cerebral palsy as well as
reduce language and cognitive delay.[21][22] On the other hand, subtle long-term side effects are
possible.[23]
 Apnea of prematurity as a primary treatment,[24] but not prevention.[25][26]
 Orthostatic hypotension treatment.[26][27]

53
  In moderate doses, caffeine may reduce symptoms of depression and lower suicide risk.[28]

Enhancing performance

Cognitive

Caffeine is a central nervous system stimulant that reduces fatigue and drowsiness. At normal doses,
caffeine has variable effects on learning and memory, but it generally improves reaction time,
wakefulness, concentration, and motor coordination. The amount of caffeine needed to produce these
effects varies from person to person, depending on body size and degree of tolerance. The desired effects
arise approximately one hour after consumption, and the desired effects of a moderate dose usually
subside after about three or four hours.

Caffeine can delay or prevent sleep and improves task performance during sleep deprivation. Shift
workers who use caffeine make fewer mistakes due to drowsiness.

A systematic review and meta-analysis from 2014 found that concurrent caffeine and L-theanine use has
synergistic psychoactive effects that promote alertness, attention, and task switching; these effects are
most pronounced during the first hour post-dose.

Physical

Caffeine is a proven ergogenic aid in humans. Caffeine improves athletic performance in aerobic
(especially endurance sports) and anaerobic conditions. Moderate doses of caffeine (around 5 mg/kg) can
improve sprint performance, cycling and running time trial performance, endurance (i.e., it delays the
onset of muscle fatigue and central fatigue), and cycling power output. Caffeine increases basal metabolic
rate in adults

DOSE :

Age range Maximum recommended daily caffeine intake

4–6 45 mg (slightly more than in 12 oz of a typical caffeinated soft drink)

7–9 62.5 mg

10–12 85 mg (about ½ cup of coffee)

Adverse effects

Physical Coffee and caffeine can affect gastrointestinal motility and gastric acid secretion. Caffeine in
low doses may cause weak bronchi dilation for up to four hours in asthmatics. In postmenopausal women,
high caffeine consumption can accelerate bone loss.

Doses of caffeine equivalent to the amount normally found in standard servings of tea, coffee and
carbonated soft drinks appear to have no diuretic action. However, acute ingestion of caffeine in large
doses (at least 250–300 mg, equivalent to the amount found in 2–3 cups of coffee or 5–8 cups of tea)
results in a short-term stimulation of urine output in individuals who have been deprived of caffeine for a

54
period of days or weeks. This increase is due to both a diuresis (increase in water excretion) and a
natriuresis (increase in saline excretion); it is mediated via proximal tubular adenosine receptor
blockade.[60] The acute increase in urinary output may increase the risk of dehydration. However, chronic
users of caffeine develop a tolerance to this effect and experience no increase in urinary output.[61][62]

Psychological

Minor undesired symptoms from caffeine ingestion not sufficiently severe to warrant a psychiatric
diagnosis are common and include mild anxiety, jitteriness, insomnia, increased sleep latency, and
reduced coordination.[29][63] Caffeine can have negative effects on anxiety disorders.[64] According to a
2011 literature review, caffeine use is positively associated with anxiety and panic disorders.[65] At high
doses, typically greater than 300 mg, caffeine can both cause and worsen anxiety.[66] For some people,
discontinuing caffeine use can significantly reduce anxiety.[67]

Some textbooks state that caffeine is a mild euphoriant,[68][69][70] others state that it is not a
euphoriant,[71][72] and one states that it is and is not a euphoriant.[73]

Reinforcement disorders

Addiction

Whether or not caffeine can result in an addictive disorder depends on how addiction is defined. Some
diagnostic models, such as the ICDM-9 and ICD-10, include a classification of caffeine addiction under a
broader diagnostic model. Some state that certain users can become addicted and therefore unable to
decrease use even though they know there are negative health effects.

Caffeine does not appear to be a reinforcing stimulus, and some degree of aversion may actually occur,
with people preferring placebo over caffeine in a study on drug abuse liability published in an NIDA
research monograph. Some state that research does not provide support for an underlying biochemical
mechanism for caffeine addiction. Other research states it can affect the reward system.

"Caffeine addiction" was added to the ICDM-9 and ICD-10. However, its addition was contested with
claims that this diagnostic model of caffeine addiction is not supported by evidence. The American
Psychiatric Association's DSM-5 does not include the diagnosis of a caffeine addiction but proposes
criteria for the disorder for more study.

Dependence and withdrawal

Withdrawal can cause mild to clinically significant distress or impairment in daily functioning. The
frequency at which this occurs is self reported at 11%, but in lab tests only half of the people who report
withdrawal actually experience it, casting doubt on many claims of dependence. Mild to increasingly
severe physical dependence and withdrawal symptoms may occur upon abstinence, with greater than
100 mg caffeine per day; some symptoms associated with psychological dependence may also occur
during withdrawal. Caffeine dependence can involve withdrawal symptoms such as fatigue, headache,
irritability, depressed mood, reduced contentedness, inability to concentrate, sleepiness or drowsiness,
stomach pain, and joint pain. Withdrawal headaches are experienced by roughly half of those who stop
consuming caffeine for two days following an average daily intake of 235 mg.

55
The ICD-10 includes a diagnostic model for caffeine dependence, but the DSM-5 does not. The APA,
which published the DSM-5, acknowledged that there was sufficient evidence in order to create a
diagnostic model of caffeine dependence for the DSM-5, but they noted that the clinical significance of
this disorder is unclear. The DSM-5 instead lists "caffeine use disorder" in the emerging models section
of the manual.

Tolerance varies for daily, regular caffeine users and high caffeine users. High doses of caffeine (750 to
1200 mg/day spread throughout the day) have been shown to produce complete tolerance to some, but not
all of the effects of caffeine. Doses as low as 100 mg/day, such as a 6 oz cup of coffee or two to three 12
oz servings of caffeinated soft-drink, may continue to cause sleep disruption, among other intolerances.
Non-regular caffeine users have the least caffeine tolerance for sleep disruption. Some coffee drinkers
develop tolerance to its undesired sleep-disrupting effects, but others apparently do not.

Risk of other diseases

A protective effect of caffeine against Alzheimer's disease is possible, but the evidence is inconclusive.
Caffeine increases intraocular pressure in those with glaucoma but does not appear to affect normal
individuals. It may protect people from liver cirrhosis. Caffeine may lessen the severity of acute mountain
sickness if taken a few hours prior to attaining a high altitude.

Overdose

Primary symptoms of caffeine intoxication

Consumption of 1–1.5 grams (0.035–0.053 oz) per day is associated with a condition known as
caffeinism.[96] Caffeinism usually combines caffeine dependency with a wide range of unpleasant
symptoms including nervousness, irritability, restlessness, insomnia, headaches, and palpitations after
caffeine use.

56
Caffeine overdose can result in a state of central nervous system over-stimulation called caffeine
intoxication (DSM-IV 305.90).his syndrome typically occurs only after ingestion of large amounts of
caffeine, well over the amounts found in typical caffeinated beverages and caffeine tablets (e.g., more
than 400–500 mg at a time). The symptoms of caffeine intoxication are comparable to the symptoms of
overdoses of other stimulants: they may include restlessness, fidgeting, anxiety, excitement, insomnia,
flushing of the face, increased urination, gastrointestinal disturbance, muscle twitching, a rambling flow
of thought and speech, irritability, irregular or rapid heart beat, and psychomotor agitation. In cases of
much larger overdoses, mania, depression, lapses in judgment, disorientation, disinhibition, delusions,
hallucinations, or psychosis may occur, and rhabdomyolysis (breakdown of skeletal muscle tissue) can be
provoked.

Massive overdose can result in death. The LD50 of caffeine in humans is dependent on individual
sensitivity, but is estimated to be 150–200 milligrams per kilogram of body mass (75–100 cups of coffee
for a 70 kilogram adult). A number of fatalities have been caused by overdoses of readily available
powdered caffeine supplements, for which the estimated lethal amount is less than a tablespoon. The
lethal dose is lower in individuals whose ability to metabolize caffeine is impaired due to genetics or
chronic liver diseaseA death was reported in a man with liver cirrhosis who overdosed on caffeinated
mints.

Treatment of mild caffeine intoxication is directed toward symptom relief; severe intoxication may
require peritoneal dialysis, hemodialysis, or hemofiltration.

Interactions

Alcohol

According to DSST, alcohol provides a reduction in performance and caffeine has a significant
improvement in performance. When alcohol and caffeine are consumed jointly, the effects produced by
caffeine are affected, but the alcohol effects remain the same. For example, when additional caffeine is
added, the drug effect produced by alcohol is not reduced. However, the jitteriness and alertness given by
caffeine is decreased when additional alcohol is consumed. Alcohol consumption alone reduces both
inhibitory and activational aspects of behavioral control. Caffeine antagonizes the activational aspect of
behavioral control, but has no effect on the inhibitory behavioral control.

Tobacco

Smoking tobacco increases caffeine clearance by 56%.

Birth control

Birth control pills can extend the half-life of caffeine, requiring greater attention to caffeine consumption

Medications

Caffeine sometimes increases the effectiveness of some medications, such as those for headaches.

PRECAUTIONS :Use caffeine as directed by your health care provider. If the medication is OTC, check
the label on the bottle for the exact dosing instructions. If you have any questions about the use of an
OTC medication, ask your pharmacist.

57
  Caffeine may be taken with or without food. If caffeine upsets your stomach, take it with food.
 Do not exceed the recommended dose of caffeine. Caffeine can be habit-forming.
 Most OTC medications used for mental alertness contain 200 milligrams of caffeine per tablet or
capsule. The usual maximum recommended dose of OTC caffeine is no more than 200 mg every
3-4 hours, or 1600 mg per day.
 Do not double-up on your caffeine dose if you should miss the time for next dose.
 The average cup of coffee contains 150-200 milligrams (mg) of caffeine per cup, while a cup of
tea will have about 60 mg of caffeine. Cola products have about 30-40 mg of caffeine, and most
energy drinks have about 60-70 mg. Be sure to account for any dietary caffeine that is consumed.

NURSE RESPONSIBILITIES:

 Caffeine may cause dizziness. Do not drive or operate machinery, or engage in dangerous tasks
until you know how caffeine might affect you.
 Avoid large amounts of caffeine-containing foods and beverages, such as coffee, tea, cocoa, cola
drinks, energy drinks and chocolate if you are taking higher doses of caffeine tablets. This also
includes any herbal, dietary, or prescription medications that contain caffeine.
 Caffeine is not to be used as a substitute for sleep.
 Caffeine use may alter blood sugar levels. Diabetes patients should more closely regulate their
blood sugar while taking caffeine.
 Caffeine is not recommended for use in children less than 12 years of age. Safety and
effectiveness in this age group have not been confirmed.
 If you are pregnant, discuss with your health care provider if caffeine is appropriate for your use.
 Caffeine is excreted into breast milk. Consult with your health care provider about the risks of
using caffeine while you are breast-feeding. Caffeine may cause side effects in your baby.

RITALIN

Brand name : Ritalin, Concerta, Inspiral, Addwize, Aptensio

Generic name : Methylphenidate hydrochloride

A central nervous system stimulant used most commonly in the treatment of attention-deficit disorders in
children and for narcolepsy. Its mechanisms appear to be similar to those of

dextroamphetamine.

Uses

Medical

58
Methylphenidate is a commonly prescribed psycho stimulant and works by increasing the activity of the
central nervous system. It produces such effects as increasing or maintaining alertness, combating
fatigue, and improving attention. The short-term benefits and cost effectiveness of methylphenidate are
well established. Methylphenidate is not approved for children under six years of age. Methylphenidate
may also be prescribed for off-label use in treatment-resistant cases of bipolar disorder and major
depressive disorder.

Meta-analyses and systematic reviews of magnetic resonance imaging (MRI) studies suggest that long-
term treatment with ADHD stimulants (specifically, amphetamine and methylphenidate) decreases
abnormalities in brain structure and function found in subjects with ADHD. Moreover, reviews of clinical
stimulant research have established the safety and effectiveness of the long-term use of ADHD stimulants
for individuals with ADHD.

Attention deficit hyperactivity disorder

Methylphenidate is approved by the US Food and Drug Administration (FDA) for the treatment of
attention deficit hyperactivity disorder. The addition of behavioural modification therapy (e.g. cognitive
behavioral therapy (CBT)) can have additional benefits on treatment outcome. The dosage used can vary
quite significantly among individuals; consequently, dosage must be titrated precisely.

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's
neurotransmitter systems, particularly those involving dopamine and norepinephrine. Psycho stimulants
like methylphenidate and amphetamine may be effective in treating ADHD because they increase
neurotransmitter activity in these systems. Approximately 70% of those who use these stimulants see
improvements in ADHD symptoms. Children with ADHD who use stimulant medications generally have
better relationships with peers and family members, generally perform better in school, are less
distractible and impulsive, and have longer attention spans.[22][31] People with ADHD have an increased
risk of substance use disorders, and stimulant medications reduce this risk.Some studies suggest that since
ADHD diagnosis is increasing significantly around the world, using the drug may cause more harm than
good in some populations with ADHD. This applies to people who potentially may be experiencing a
different issue and are misdiagnosed with ADHD. People in this category can then experience negative
side-effects of the drug which worsen their condition, and make it harder for them to receive adequate
care as providers around them may believe the drugs are sufficient and the problem lies with the user.[35]

Neuroprotective effects

Methylphenidate may provide possible protection from methamphetamine induced dopamine neuron
damage and possible protection from Parkinson disease according to 1 review [36] Methylphenidate has
also shown to increase brain plasticity in the amygdala of mice and enhance the speed of learning
according to one study.[37]

Narcolepsy

Narcolepsy, a chronic sleep disorder characterized by overwhelming daytime drowsiness and sudden need
for sleep, is treated primarily with stimulants. Methylphenidate is considered effective in increasing
wakefulness, vigilance, and performance.[38] Methylphenidate improves measures of somnolence on
standardized tests, such as the Multiple Sleep Latency Test (MSLT), but performance does not improve to
levels comparable to healthy controls.[39]

59
Other

Methylphenidate may be used in addition to an antidepressant for refractory major depressive disorder. It
can also improve depression in several groups including stroke, cancer, and HIV-positive patients.[40]
However, the use of stimulants such as methylphenidate in cases of treatment-resistant depression is
controversial.[41] Stimulants may have fewer side-effects than tricyclic antidepressants in the elderly and
medically ill.[42] In individuals with terminal cancer, methylphenidate can be used to counteract opioid-
induced somnolence, to increase the analgesic effects of opioids, to treat depression, and to improve
cognitive function.[43]

Methylphenidate and other stimulants are also used to improve vasoconstriction in the treatment of
orthostatic intolerance (OI), a dysautonomic/autonomic nervous system (ANS) disorder.

Enhancing performance

In 2015, a systematic review and a meta-analysis of high quality clinical trials found that therapeutic
doses of amphetamine and methylphenidate result in modest yet unambiguous improvements in
cognition, including working memory, episodic memory, and inhibitory control, in normal healthy
adults;[44][45] the cognition-enhancing effects of these drugs are known to occur through the indirect
activation of both dopamine receptor D1 and adrenoceptor α2 in the prefrontal cortex.[44] Methylphenidate
and other ADHD stimulants also improve task saliency and increase arousal.[46][47] Stimulants such as
amphetamine and methylphenidate can improve performance on difficult and boring tasks [48][46][47] and
are used by some students as a study and test-taking aid.[49][35] Based upon studies of self-reported illicit
stimulant use, performance-enhancing use, rather than use as a recreational drug, is the primary reason
that students use stimulants.[50] Excessive doses of methylphenidate, above the therapeutic range, can
interfere with working memory and cognitive control.[46][47] Like amphetamine and bupropion,
methylphenidate increases stamina and endurance in humans primarily through reuptake inhibition of
dopamine in the central nervous system.[51] Similar to the loss of cognitive enhancement when using large
amounts, large doses of methylphenidate can induce side effects that impair athletic performance, such as
rhabdomyolysis and hyperthermia.[52] While literature suggests it might improve cognition, most authors
agree that using the drug recreationally as a study aid when ADHD diagnosis is not present does not
actually improve GPA.[35] Moreover, it has been suggested that students who use the drug for studying
may be self-medicating for potentially deeper underlying issues.

Contraindications

Methylphenidate is contraindicated for individuals using monoamine oxidase inhibitors (e.g., phenelzine
and tranylcypromine), or individuals with agitation, tics, or glaucoma, or a hypersensitivity to any
ingredients contained in methylphenidate pharmaceuticals.[55]

The US FDA gives methylphenidate a pregnancy category of C, and women are advised to only use the
drug if the benefits outweigh the potential risks.[56] Not enough animal and human studies have been
conducted to conclusively demonstrate an effect of methylphenidate on fetal development. In 2007,
empirical literature included 63 cases of prenatal exposure to methylphenidate across three empirical
studies

Pharmacodynamics

60
Methylphenidate is a central nervous system stimulant used most commonly in the treatment of attention-
deficit disorders in children and for narcolepsy. Methylphenidate also blocks the reuptake of
norepinephrine and dopamine. Its mechanisms appear to be similar to those of dextroamphetamine.
Furthermore, it is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer
is more pharmacologically active than the l-threo enantiomer.

Pharmacokinetics:

Methylphenidate taken orally has a bioavailability of 11–52% with a duration of peak action around 2–
4 hours for instant release (i.e. Ritalin), 3–8 hours for sustained release (i.e. Ritalin SR), and 8–12 hours
for extended release (i.e. Concerta). The half-life of methylphenidate is 2–3 hours, depending on the
individual. The peak plasma time is achieved at about 2 hours.

Dextromethylphenidate is much more bioavailable than levomethylphenidate when administered orally,

and is primarily responsible for the psychoactivity of racemic methylphenidate.

Contrary to the expectation, taking methylphenidate with a meal speeds absorption.

Methylphenidate is metabolized into ritalinic acid by CES1A1. Dextromethylphenidate is selectively

metabolized at a slower rate than levomethylphenidate.

Mechanism of action:

Methylphenidate blocks dopamine uptake in central adrenergic neurons by blocking dopamine transport
or carrier proteins. Methylphenidate acts at the brain stem arousal system and the cerebral cortex and
causes increased sympathomimetic activity in the central nervous system. Alteration of serotonergic
pathways via changes in dopamine transport may result.

Target Actions Organism

Sodium-dependent dopamine
Inhibitor Human
transporter

Sodium-dependent noradrenaline
Inhibitor Human
transporter

Sodium-dependent serotonin
Inhibitor Human
transporter

Adverse effects

Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police
and legal services engaged in delphic analysis regarding 20 popular recreational drugs. Methylphenidate
was ranked 13th in dependence, 12th in physical harm, and 18th in social harm.

61
Methylphenidate is generally well tolerated. The most commonly observed adverse effects with a
frequency greater than placebo include appetite loss, dry mouth, anxiety/nervousness, nausea, and
insomnia. Gastrointestinal adverse effects may include abdominal pain and weight loss. Nervous system
adverse effects may include akathisia (agitation/restlessness), irritability, dyskinesia (tics), lethargy
(drowsiness/fatigue), and dizziness. Cardiac adverse effects may include palpitations, changes in blood
pressure and heart rate (typically mild), tachycardia (rapid resting heart rate), and Raynaud's phenomenon
(reduced blood flow to the hands and feet). Ophthalmologic adverse effects may include blurred vision
and dry eyes, with less frequent reports of diplopia and mydriasis. Other adverse effects may include
depression, emotional lability, confusion, and bruxism. Hyperhidrosis (increased sweating) is common.
Chest pain is rarely observed.

There is some evidence of mild reductions in growth rate with prolonged treatment in children, but no
causal relationship has been established and reductions do not appear to persist long-term.
Hypersensitivity (including skin rash, urticaria, and fever) is sometimes reported. The Daytrana patch has
a much higher rate of dermal reactions than oral methylphenidate.

Methylphenidate can worsen psychosis in psychotic patients, and in very rare cases it has been associated
with the emergence of new psychotic symptoms. It should be used with extreme caution in patients with
bipolar disorder due to the potential induction of mania or hypomania There have been very rare reports
of suicidal ideation, but evidence does not support a link. Logorrhea is occasionally reported. Libido
disorders, disorientation, and hallucinations are very rarely reported. Priapism is a very rare adverse event
that can be potentially serious.

USFDA-commissioned studies from 2011 indicate that in children, young adults, and adults there is no
association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the
medical use of methylphenidate or other ADHD stimulants.

Because some adverse effects may only emerge during chronic use of methylphenidate, a constant watch
for adverse effects is recommended.

Overdose

The symptoms of a moderate acute overdose on methylphenidate primarily arise from central nervous
system overstimulation; these symptoms include: vomiting, agitation, tremors, hyperreflexia, muscle
twitching, euphoria, confusion, hallucinations, delirium, hyperthermia, sweating, flushing, headache,
tachycardia, heart palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous
membranes.[52][71] A severe overdose may involve symptoms such as hyperpyrexia, sympathomimetic
toxidrome, convulsions, paranoia, stereotypy (a repetitive movement disorder), rapid muscle breakdown,
coma, and circulatory collapse.[52][71][72] A methylphenidate overdose is rarely fatal with appropriate
care.[72] Severe toxic reactions involving abscess and necrosis have been reported following injection of
methylphenidate tablets into an artery.[73]

Treatment of a methylphenidate overdose typically involves the application of benzodiazepines, with

antipsychotics, α-adrenoceptor agonists, and propofol serving as second-line therapies.[72]

Addiction and dependence : Pharmacological texts describe methylphenidate as a stimulant with effects,
addiction liability, and dependence liability similar to amphetamine, a compound with moderate liability
among addictive drugs; accordingly, addiction and psychological dependence are possible and likely
when methylphenidate is used at high doses as a recreational drug. When used above the medical dose
range, stimulants are associated with the development of stimulant psychosis. As with all addictive drugs,

62
the overexpression of ΔFosB in D1-type medium spiny neurons in the nucleus accumbens is implicated in
methylphenidate addiction.

Pharmacological texts describe methylphenidate as a stimulant with effects, addiction liability, and
dependence liability similar to amphetamine, a compound with moderate liability among addictive drugs;
accordingly, addiction and psychological dependence are possible and likely when methylphenidate is
used at high doses as a recreational drug. When used above the medical dose range, stimulants are
associated with the development of stimulant psychosis. As with all addictive drugs, the overexpression
of ΔFosB in D1-type medium spiny neurons in the nucleus accumbens is implicated in methylphenidate
addiction.

Biomolecular mechanisms: Methylphenidate has the potential to induce euphoria due to its
pharmacodynamic effect (i.e., dopamine reuptake inhibition) in the brain's reward system. At therapeutic
doses, ADHD stimulants do not sufficiently activate the reward system, or the reward pathway in
particular, to the extent necessary to cause persistent increases in ΔFosB gene expression in the D1-type
medium spiny neurons of the nucleus accumbens; consequently, when taken as directed in doses that are
commonly prescribed for the treatment of ADHD, methylphenidate use lacks the capacity to cause an
addiction. However, when methylphenidate is used at sufficiently high recreational doses through a
bioavailable route of administration (e.g., insufflation or intravenous administration), particularly for use
of the drug as a euphoriant, ΔFosB accumulates in the nucleus accumbens. Hence, like any other
addictive drug, regular recreational use of methylphenidate at high doses eventually gives rise to ΔFosB
overexpression in D1-type neurons which subsequently triggers a series of gene transcription-mediated
signaling cascades that induce an addiction .

Interactions

Methylphenidate may inhibit the metabolism of coumarin anticoagulants, certain anticonvulsants, and
some antidepressants (tricyclic antidepressants and selective serotonin reuptake inhibitors). Concomitant
administration may require dose adjustments, possibly assisted by monitoring of plasma drug
concentrations. There are several case reports of methylphenidate inducing serotonin syndrome with
concomitant administration of antidepressants.

When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via
hepatic trans esterification not unlike the hepatic formation of coca ethylene from cocaine and alcohol.
The reduced potency of ethyl phenidate and its minor formation means it does not contribute to the
pharmacological profile at therapeutic doses and even in overdose cases methylphenidate concentrations
remain negligible. Co ingestion of alcohol (ethanol) also increases the blood plasma levels of d-
methylphenidate by up to 40%.

Liver toxicity from methylphenidate is extremely rare, but limited evidence suggests that intake of β-
adrenergic agonists with methylphenidate may increase the risk of liver toxicity.

Legal status

63
Legal warning printed on Ritalin packaging

 Internationally, methylphenidate is a Schedule II drug under the Convention on Psychotropic

Substances.
 In the United States, methylphenidate is classified as a Schedule II controlled substance, the
designation used for substances that have a recognized medical value but present a high potential
for abuse.
 In the United Kingdom, methylphenidate is a controlled 'Class B' substance. Possession without
prescription carries a sentence up to 5 years or an unlimited fine, or both; supplying
methylphenidate is 14 years or an unlimited fine, or both.
 In Canada, methylphenidate is listed in Schedule III of the Controlled Drugs and Substances Act
and is illegal to possess without a prescription, with unlawful possession punishable by up to
three years imprisonment, or by up to one year imprisonment and/or fines of up to two thousand
dollars. Unlawful possession for the purpose of trafficking is punishable by up to ten years
imprisonment, or (via summary conviction) by up to eighteen months imprisonment.
 In New Zealand, methylphenidate is a 'class B2 controlled substance'. Unlawful possession is
punishable by six-month prison sentence and distribution by a 14-year sentence.
 In Australia, methylphenidate is a 'Schedule 8' controlled substance. Such drugs must be kept in a
lockable safe until dispensed and possession without prescription is punishable by fines and
imprisonment.
 In Sweden, methylphenidate is a List II controlled substance with recognized medical value.
Possession without a prescription is punishable by up to three years in prison.
 In France, methylphenidate is covered by the "narcotics" schedule, prescription and distribution
conditions are restricted with hospital-only prescription for the initial treatment and yearly
consultations.
 In India, methylphenidate is a schedule X drug and is controlled by the Drugs and Cosmetics
Rule, 1945. It is dispensed only by physician's prescription. Legally, 2 grams of methylphenidate
are classified as a small quantity, and 50 grams as a large or commercial quantity.

Controversy

Methylphenidate has been the subject of controversy in relation to its use in the treatment of ADHD. The
prescription of psychostimulant medication to children to reduce ADHD symptoms has been a major
point of criticism. The contention that methylphenidate acts as a gateway drug has been discredited by
multiple sources, according to which abuse is statistically very low and "stimulant therapy in childhood
does not increase the risk for subsequent drug and alcohol abuse disorders later in life". A study found
that ADHD medication was not associated with increased risk of cigarette use, and in fact stimulant
treatments such as Ritalin seemed to lower this risk.

]
where research shows that the drug was the most commonly abused substance among intravenous
substance abusers. The study involved 108 IV substance abusers and 88% of them had injected

64
methylphenidate within the last 30 days and for 63% of them, methylphenidate was the most preferred
substance.

Treatment of ADHD by way of methylphenidate has led to legal actions, including malpractice suits
regarding informed consent, inadequate information on side effects, misdiagnosis, and coercive use of
medications by school systems.

In the US and the UK, it is approved for use in children and adolescents. In the US, the Food and Drug
Administration approved the use of methylphenidate in 2008 for use in treating adult ADHD. In the UK,
while not licensed for use in adult ADHD, NICE guidelines suggest it be prescribed off-license for the
condition. Methylphenidate has been approved for adult use in the treatment of narcolepsy.

PRECAUTIONS

Serious Cardiovascular Events

Sudden Death And Preexisting Structural Cardiac Abnormalities Or Other Serious Heart Problems

Children and Adolescents

Sudden death has been reported in association with CNS stimulant treatment at usual doses in children
and adolescents with structural cardiac abnormalities or other serious heart problems. Although some
serious heart problems alone carry an increased risk of sudden death, stimulant products generally should
not be used in children or adolescents with known serious structural cardiac abnormalities,
cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place
them at increased vulnerability to the sympathomimetic effects of a stimulant drug.

Adults

Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at
usual doses for ADHD. Although the role of stimulants in these adult cases is also unknown, adults have
a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy,
serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults
with such abnormalities should also generally not be treated with stimulant drugs.

Hypertension And Other Cardiovascular Conditions

Stimulant medications cause a modest increase in average blood pressure (about 2 to 4 mm Hg) and
average heart rate (about 3 to 6 bpm) [see ADVERSE REACTIONS], and individuals may have larger
increases. While the mean changes alone would not be expected to have short-term consequences, all
patients should be monitored for larger changes in heart rate and blood pressure. Caution is indicated in
treating patients whose underlying medical conditions might be compromised by increases in blood
pressure or heart rate, e.g., those with preexisting hypertension, heart failure, recent myocardial infarction,
or ventricular arrhythmia.

Assessing Cardiovascular Status In Patients Being Treated With Stimulant Medications

Children, adolescents, or adults who are being considered for treatment with stimulant medications should
have a careful history (including assessment for a family history of sudden death or ventricular

65
arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further
cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients
who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms
suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation.

Psychiatric Adverse Events

Preexisting Psychosis

Administration of stimulants may exacerbate symptoms of behavior disturbance and thought disorder in
patients with a preexisting psychotic disorder.

Bipolar Illness

Particular care should be taken in using stimulants to treat ADHD in patients with comorbid bipolar
disorder because of concern for possible induction of a mixed/manic episode in such patients. Prior to
initiating treatment with a stimulant, patients with comorbid depressive symptoms should be adequately
screened to determine if they are at risk for bipolar disorder; such screening should include a detailed
psychiatric history, including a family history of suicide, bipolar disorder, and depression.

Emergence Of New Psychotic Or Manic Symptoms

Treatment-emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in

patients without a prior history of psychotic illness or mania can be caused by stimulants at usual doses. If
such symptoms occur, consideration should be given to a possible causal role of the stimulant, and
discontinuation of treatment may be appropriate. In a pooled analysis of multiple short-term, placebo-
controlled studies, such symptoms occurred in about 0.1% (4 patients with events out of 3482 exposed to
methylphenidate or amphetamine for several weeks at usual doses) of stimulant-treated patients compared
to 0 in placebo-treated patients.

Aggression

Aggressive behavior or hostility is often observed in patients with ADHD, and has been reported in
clinical trials and the postmarketing experience of some medications indicated for the treatment of
ADHD. Although there is no systematic evidence that stimulants cause aggressive behavior or hostility,
patients beginning treatment for ADHD should be monitored for the appearance of or worsening of
aggressive behavior or hostility.

Seizures

There is some clinical evidence that stimulants may lower the convulsive threshold in patients with prior
history of seizures, in patients with prior EEG abnormalities in absence of seizures, and, very rarely, in
patients without a history of seizures and no prior EEG evidence of seizures. In the presence of seizures,
the drug should be discontinued.

Priapism

Prolonged and painful erections, sometimes requiring surgical intervention, have been reported with
methylphenidate products, including CONCERTA®, in both pediatric and adult patients [see ADVERSE

66
REACTIONS]. Priapism was not reported with drug initiation but developed after some time on the
drug, often subsequent to an increase in dose. Priapism has also appeared during a period of drug
withdrawal (drug holidays or during discontinuation). Patients who develop abnormally sustained or
frequent and painful erections should seek immediate medical attention.

Peripheral Vasculopathy, Including Raynaud's Phenomenon

Stimulants, including CONCERTA®, used to treat ADHD are associated with peripheral vasculopathy,
including Raynaud's phenomenon. Signs and symptoms are usually intermittent and mild; however, very
rare sequelae include digital ulceration and/or soft tissue breakdown. Effects of peripheral vasculopathy,
including Raynaud's phenomenon, were observed in post-marketing reports at different times and at
therapeutic doses in all age groups throughout the course of treatment. Signs and symptoms generally
improve after reduction in dose or discontinuation of drug. Careful observation for digital changes is
necessary during treatment with ADHD stimulants. Further clinical evaluation (e.g., rheumatology
referral) may be appropriate for certain patients.

Long-Term Suppression Of Growth

Careful follow-up of weight and height in children ages 7 to 10 years who were randomized to either
methylphenidate or nonmedication treatment groups over 14 months, as well as in naturalistic subgroups
of newly methylphenidate-treated and nonmedicationtreated children over 36 months (to the ages of 10 to
13 years), suggests that consistently medicated children (i.e., treatment for 7 days per week throughout
the year) have a temporary slowing in growth rate (on average, a total of about 2 cm less growth in height
and 2.7 kg less growth in weight over 3 years), without evidence of growth rebound during this period of
development. Published data are inadequate to determine whether chronic use of amphetamines may
cause similar suppression of growth; however, it is anticipated that they likely have this effect as well.
Therefore, growth should be monitored during treatment with stimulants, and patients who are not
growing or gaining height or weight as expected may need to have their treatment interrupted.

Visual Disturbance

Difficulties with accommodation and blurring of vision have been reported with stimulant treatment.

Potential For Gastrointestinal Obstruction

Because the CONCERTA® tablet is nondeformable and does not appreciably change in shape in the GI
tract, CONCERTA® should not ordinarily be administered to patients with preexisting severe
gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small
bowel inflammatory disease, “short gut” syndrome due to adhesions or decreased transit time, past history
of peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, or Meckel's diverticulum). There have
been rare reports of obstructive symptoms in patients with known strictures in association with the
ingestion of drugs in nondeformable controlled-release formulations. Due to the controlled-release design
of the tablet, CONCERTA® should be used only in patients who are able to swallow the tablet whole [see
PATIENT INFORMATION].

Hematologic Monitoring

Periodic CBC, differential, and platelet counts are advised during prolonged therapy.

67
Patient Counseling Information

See Medication Guide

Priapism

Advise patients, caregivers, and family members of the possibility of painful or prolonged penile
erections (priapism). Instruct the patient to seek immediate medical attention in the event of
priapism [see WARNINGS AND PRECAUTIONS].

Circulation Problems In Fingers and Toes [Peripheral Vasculopathy, including Raynaud's Phenomenon]

Instruct patients beginning treatment with CONCERTA® about the risk of peripheral vasculopathy,
including Raynaud's phenomenon, and associated signs and symptoms: fingers or toes may feel numb,
cool, painful, and/or may change color from pale, to blue, to red.

Instruct patients to report to their physician any new numbness, pain, skin color change, or sensitivity to
temperature in fingers or toes.

Further clinical evaluation (e.g., rheumatology referral) may be appropriate for certain patients.

General Considerations

Prescribers or other health professionals should inform patients, their families, and their caregivers about
the benefits and risks associated with treatment with methylphenidate and should counsel them in its
appropriate use. A patient Medication Guide is available for CONCERTA®. The prescriber or health
professional should instruct patients, their families, and their caregivers to read the Medication Guide and
should assist them in understanding its contents. Patients should be given the opportunity to discuss the
contents of the Medication Guide and to obtain answers to any questions they may have. The complete
text of the Medication Guide is reprinted at the end of this document.

Administration Instructions

Patients should be informed drug should be swallowed whole with the aid of liquids. Tablets should not
be chewed, divided, or crushed. The medication is contained within a non absorbable shell designed to
release the drug at a controlled rate. The tablet shell, along with insoluble core components, is eliminated
from the body; patients should not be concerned if they occasionally notice in their stool something that
looks like a tablet.

EPHEDRINE

 Generic Name: ephedrine

 Brand Name: Ephedrine

Ephedrine sulfate is a potent sympathomimetic that stimulates both α and β receptors and has clinical uses
related to both actions. Its peripheral actions, which it owes in part to the release of norepinephrine,

68
simulate responses that are obtained when adrenergic nerves are stimulated. These include an increase in
blood pressure, stimulation of heart muscle, constriction of arterioles, relaxation of the smooth muscle of
the bronchi and gastrointestinal tract, and dilation of the pupils. In the bladder, relaxation of the detrusor
muscle is not prominent, but the tone of the trigon and vesicle sphincter is increased.

Ephedrine sulfate also has a potent effect on the CNS. It stimulates the cerebral cortex and subcortical
centers, which accounts for its use in narcolepsy. The cardiovascular responses reported in man include
moderate tachycardia, unchanged or augmented stroke volume, enhanced cardiac output, variable
alterations in peripheral resistance and usually a rise in blood pressure. The action of ephedrine is more
prominent on the heart than on the blood vessels. Ephedrine sulfate increases the flow of coronary,
cerebral and muscle blood.

An alpha- and beta-adrenergic agonist that may also enhance release of norepinephrine. It has been used
in the treatment of several disorders including asthma, heart failure, rhinitis, and urinary incontinence, and
for its central nervous system stimulatory effects in the treatment of narcolepsy and depression. It has
become less extensively used with the advent of more selective agonists.

Pharmacodynamics

Ephedrine is similar in structure to the derivatives amphetamine and methamphetamine. Chemically, it is

an alkaloid derived from various plants in the genus Ephedra (family Ephedraceae). It works mainly by
increasing the activity of noradrenaline on adrenergic receptors.

Mechanism of action

Ephedrine is a sympathomimetic amine - that is, its principal mechanism of action relies on its direct and
indirect actions on the adrenergic receptor system, which is part of the sympathetic nervous system.
Ephedrine increases post-synaptic noradrenergic receptor activity by (weakly) directly activating post-
synaptic α-receptors and β-receptors, but the bulk of its effect comes from the pre-synaptic neuron being
unable to distinguish between real adrenaline or noradrenaline from ephedrine. The ephedrine, mixed
with noradrenaline, is transported through the noradrenaline reuptake complex and packaged (along with
real noradrenaline) into vesicles that reside at the terminal button of a nerve cell. Ephedrine's action as an
agonist at most major noradrenaline receptors and its ability to increase the release of both dopamine and
to a lesser extent, serotonin by the same mechanism is presumed to have a major role in its mechanism of
action.

Medical use

69
Ephedrine Sulphate (1932), Ephedrine Compound (1932), and Swan-Myers Ephedrine Inhalant No. 66
(circa 1940)

Both ephedrine and pseudoephedrine increase blood pressure and act as bronchodilators, with
pseudoephedrine having considerably less effect.[8]

Weight loss

Ephedrine promotes modest short-term weight loss,[9] specifically fat loss, but its long-term effects are
unknown.[10] In mice, ephedrine is known to stimulate thermogenesis in the brown adipose tissue, but
because adult humans have only small amounts of brown fat, thermogenesis is assumed to take place
mostly in the skeletal muscle. Ephedrine also decreases gastric emptying. Methylxanthines such as
caffeine and theophylline have a synergistic effect with ephedrine with respect to weight loss. This led to
creation and marketing of compound products.[11] One of them, known as the ECA stack, contains
caffeine and aspirin besides ephedrine. It is a popular supplement taken by bodybuilders seeking to cut
body fat before a competition.[12]

Recreational use

Ephedrine tablets

As a phenethylamine, ephedrine has a similar chemical structure to amphetamines and is a

methamphetamine analogue having the methamphetamine structure with a hydroxyl group at the β
position. Because of ephedrine's structural similarity to methamphetamine, it can be used to create

70
methamphetamine using chemical reduction in which ephedrine's hydroxyl group is removed; this has
made ephedrine a highly sought-after chemical precursor in the illicit manufacture of methamphetamine.
The most popular method for reducing ephedrine to methamphetamine is similar to the Birch reduction, in
that it uses anhydrous ammonia and lithium metal in the reaction. The second-most popular method uses
red phosphorus, iodine, and ephedrine in the reaction.

Through oxidation, ephedrine can be easily synthesized into methcathinone. Ephedrine is listed as a table-
I precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and
Psychotropic Substances.[13]

Detection of use

Ephedrine may be quantified in blood, plasma, or urine to monitor possible abuse by athletes, confirm a
diagnosis of poisoning, or assist in a medicolegal death investigation. Many commercial immunoassay
screening tests directed at the amphetamines cross-react appreciably with ephedrine, but chromatographic
techniques can easily distinguish ephedrine from other phenethylamine derivatives. Blood or plasma
ephedrine concentrations are typically in the 20-200 µg/l range in persons taking the drug therapeutically,
300-3000 µg/l in abusers or poisoned patients and 3–20 mg/l in cases of acute fatal overdosage. The
current WADA limit for ephedrine in an athlete's urine is 10 µg/ml.[14][15][16][17]

Contraindications

Ephedrine should not be used in conjunction with certain antidepressants, namely norepinephrine-
dopamine reuptake inhibitors (NDRIs), as this increases the risk of symptoms due to excessive serum
levels of norepinephrine.

Bupropion is an example of an antidepressant with an amphetamine-like structure similar to ephedrine,

and it is an NDRI. Its action bears more resemblance to amphetamine than to fluoxetine in that its primary
mode of therapeutic action involves norepinephrine and to a lesser degree dopamine, but it also releases
some serotonin from presynaptic clefts. It should not be used with ephedrine, as it may increase the
likelihood of side effects.

Ephedrine should be used with caution in patients with inadequate fluid replacement, impaired adrenal
function, hypoxia, hypercapnia, acidosis, hypertension, hyperthyroidism, prostatic hypertrophy, diabetes
mellitus, cardiovascular disease, during delivery if maternal blood pressure is >130/80 mmHg, and
lactation.[18]

Contraindications for the use of ephedrine include: closed-angle glaucoma, phaeochromocytoma,

asymmetric septal hypertrophy (idiopathic hypertrophic subaortic stenosis), concomitant or recent
(previous 14 days) monoamine oxidase inhibitor (MAOI) therapy, general anaesthesia with halogenated
hydrocarbons (particularly halothane), tachyarrhythmias or ventricular fibrillation, or hypersensitivity to
ephedrine or other stimulants.

Ephedrine should not be used at any time during pregnancy unless specifically indicated by a qualified
physician and only when other options are unavailable.[18]

Adverse effects

Ephedrine is a potentially dangerous natural compound; as of 2004 the US Food and Drug Administration
had received over 18,000 reports of adverse effects in people using it.[19]

71
Adverse drug reactions (ADRs) are more common with systemic administration (e.g. injection or oral
administration) compared to topical administration (e.g. nasal instillations). ADRs associated with
ephedrine therapy include:[20]

 Cardiovascular: tachycardia, cardiac arrhythmias, angina pectoris, vasoconstriction with

hypertension
 Dermatological: flushing, sweating, acne vulgaris
 Gastrointestinal: nausea
 Genitourinary: decreased urination due to vasoconstriction of renal arteries, difficulty urinating is
not uncommon, as alpha-agonists such as ephedrine constrict the internal urethral sphincter,
mimicking the effects of sympathetic nervous system stimulation
 Nervous system: restlessness, confusion, insomnia, mild euphoria, mania/hallucinations (rare
except in previously existing psychiatric conditions), delusions, formication (may be possible, but
lacks documented evidence) paranoia, hostility, panic, agitation
 Respiratory: dyspnea, pulmonary edema
 Miscellaneous: dizziness, headache, tremor, hyperglycemic reactions, dry mouth

DOSAGE AND ADMINISTRATION

Adults

The usual parenteral dose is 25 to 50 mg given subcutaneously or intramuscularly. Intravenously, 5 to 25

mg may be administered slowly, repeated in 5 to 10 minutes, if necessary.

Children

The usual subcutaneous or intramuscular dose is 0.5 mg/kg of body weight or 16.7 mg/square meter of
body surface every 4 to 6 hours.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
administration, whenever solution and container permit.

PRECAUTIONS

General

Special care should be used when administering Ephedrine Sulfate Injection, USP to patients with heart
disease, angina pectoris, diabetes, hyperthyroidism, prostatic hypertrophy or hypertension and to patients
receiving digitalis. Prolonged use may produce a syndrome resembling an anxiety state. Tolerance to
ephedrine sulfate may develop, but temporary discontinuance to the drug restores its original
effectiveness.

Pregnancy Category C

Animal reproduction studies have not been conducted with Ephedrine Sulfate Injection, USP. Also, it is
not known whether the drug can cause fetal harm when administered to a pregnant woman or can affect
reproduction capacity. Ephedrine Sulfate Injection, USP should be given to a pregnant woman only if
clearly indicated.

72
It is not known what effect Ephedrine Sulfate Injection, USP may have on the newborn or on the child's
later growth and development when the drug is administered to the mother just before or during labor.

Nursing Mothers

Ephedrine sulfate is excreted in breast milk. Use by nursing mothers is not recommended because of the
higher than usual risk for infants.

OVERDOSE

Symptoms

The principal manifestation of ephedrine sulfate poisoning is convulsions. In acute poisoning the
following signs and symptoms may occur: nausea, vomiting, chills, cyanosis, irritability, nervousness,
fever, suicidal behavior, tachycardia, dilated pupils, blurred vision, opisthotonos, spasms, convulsions,
pulmonary edema, gasping respirations, coma and respiratory failure. Initially, the patient may have
hypertension, followed later by hypotension accompanied by anuria.

Treatment

If respirations are shallow or cyanosis is present, artificial respiration should be administered.

Vasopressors are contraindicated. In cardiovascular collapse blood pressure should be maintained.

Antidote

For hypertension, 5 mg phentolamine mesylate diluted in saline may be administered slowly

intravenously, or 100 mg may be given orally. Convulsions may be controlled by diazepam or
paraldehyde. Cool applications and dexamethasone 1 mg/kg, administered slowly intravenously, may
control pyrexia.

ATOMOXETINE

 Brand name: Strattera

 Generic name :Atomoxetine
 Chemical formula : (R)-N-Methyl-3-phenyl-3-(o-tolyloxy)propan-1-amine

Atomoxetine, sold under the brand name Strattera among others, is a norepinephrine
(noradrenaline) reuptake inhibitor which is approved for the treatment of attention deficit
hyperactivity disorder (ADHD).[6] As of 2017, it is available as a generic medication in the
United States Atomoxetine is the first non-stimulant drug approved for the treatment of
attention-deficit hyperactivity disorder (ADHD). It is sold in the form of the hydrochloride salt

of atomoxetine.

73
Pharmacodynamics :

Atomoxetine is the first non-stimulant drug approved for the treatment of attention-deficit
hyperactivity disorder (ADHD). Atomoxetine is classified as a norepinephrine reuptake inhibitor,
and is approved for use in children, adolescents, and adults. However, its efficacy has not been
studied in children under six years old. Its advantage over stimulants for the treatment of ADHD
is that it has less abuse potential than stimulants, is not scheduled as a controlled substance and
has proven in clinical trials to offer 24 hour coverage of symptoms associated with ADHD in
adults and children.

Mechanism of action :

The precise mechanism by which atomoxetine produces its therapeutic effects in Attention-
Deficit/Hyperactivity Disorder (ADHD) is unknown, but is thought to be related to selective
inhibition of the pre-synaptic norepinephrine transporter, as determined through in-vitro studies.
Atomoxetine appears to have minimal affinity for other noradrenergic receptors or for other
neurotransmitter transporters or receptors.

Medical uses

Attention deficit hyperactivity disorder

Atomoxetine is approved for use in children, adolescents, and adults.[6] However, its efficacy has
not been studied in children under six years old.[2] Its primary advantage over the standard
stimulant treatments for ADHD is that it has little known abuse potential.[2] While it has been
shown to significantly reduce inattentive and hyperactive symptoms, the responses were lower
than the response to stimulants. Additionally, 40% of participants who were treated with
atomoxetine experienced significant residual ADHD symptoms.[8]

The initial therapeutic effects of atomoxetine usually take 2–4 weeks to become apparent.[1] A
further 2–4 weeks may be required for the full therapeutic effects to be seen.[9] Its efficacy may
be less than that of stimulant medications.[10]

Unlike α2 adrenoceptor agonists such as guanfacine and clonidine, atomoxetine's use can be
abruptly stopped without significant discontinuation effects being seen.[2]

Contraindications
Contraindications include:[2]

 Hypersensitivity to atomoxetine or any of the excipients in the product

 Symptomatic cardiovascular disease including:

-moderate to severe hypertension

-atrial fibrillation

74
 -atrial flutter

-ventricular tachycardia

-ventricular fibrillation

-ventricular flutter

-advanced arteriosclerosis

 Severe cardiovascular disorders

 Pheochromocytoma
 Concomitant treatment with monoamine oxidase inhibitors
 Narrow angle glaucoma
 Poor metabolizers (due to the metabolism of atomoxetine by CYP2D6)

Adverse effects
Incidence of adverse effects:[2][3][11][12]

Very common (>10% incidence) adverse effects include:

 Nausea (26%)
 Xerostomia (Dry mouth) (20%)
 Appetite loss (16%)
 Insomnia (15%)
 Fatigue (10%)
 Headache
 Cough

Common (1-10% incidence) adverse effects include:

 Constipation (8%)
 Dizziness (8%)
 Erectile dysfunction (8%)
 Somnolence (sleepiness) (8%)
 Abdominal pain (7%)
 Urinary hesitation (6%)
 Tachycardia (high heart rate) (5-10%)
 Hypertension (high blood pressure) (5-10%)
 Irritability (5%)
 Abnormal dreams (4%)
 Dyspepsia (4%)
 Ejaculation disorder (4%)
 Hyperhidrosis (abnormally increased sweating) (4%)
 Vomiting (4%)
 Hot flashes (3%)

75
  Paraesthesia (sensation of tingling, tickling, etc.) (3%)
 Menstrual disorder (3%)
 Weight loss (2%)
 Depression
 Sinus headache
 Dermatitis
 Mood swings

Uncommon (0.1-1% incidence) adverse effects include:

 Suicide-related events
 Hostility
 Emotional lability
 Aggression
 Psychosis
 Syncope (fainting)
 Tremor
 Migraine
 Hypoaesthesia
 Seizure
 Palpitations
 Sinus tachycardia
 QT interval prolongation
 Increased blood bilirubin
 Allergic reactions

Rare (0.01-0.1% incidence) adverse effects including:

 Raynaud's phenomenon
 Abnormal/increased liver function tests
 Jaundice
 Hepatitis
 Liver injury
 Acute liver failure
 Urinary retention
 Priapism[13]
 Male genital pain

The FDA of the US has issued a black box warning for suicidal behaviour/ideation.[3] Similar
warnings have been issued in Australia.[2][14] Unlike stimulant medications, atomoxetine does not
have abuse liability or the potential to cause withdrawal effects on abrupt discontinuation.[2]

Overdose
Atomoxetine is relatively non-toxic in overdose. Single-drug overdoses involving over 1500 mg
of atomoxetine have not resulted in death.[2] The most common symptoms of overdose include:[2]

76
  Gastrointestinal symptoms
 Somnolence
 Dizziness
 Tremor
 Abnormal behaviour
 Hyperactivity
 Agitation
 Dry mouth
 Tachycardia
 Hypertension
 Mydriasis

Less common symptoms:[2]

 Seizures
 QTc interval prolongation

The recommended treatment for atomoxetine overdose includes use of activated charcoal to
prevent further absorption of the drug.[2]

Interactions
Atomoxetine is a substrate for CYP2D6. Concurrent treatment with a CYP2D6 inhibitor such as
bupropion, fluoxetine, or paroxetine has been shown to increase plasma atomoxetine by 100% or
more, as well as increase N-desmethylatomoxetine levels and decrease plasma 4-
hydroxyatomoxetine levels by a similar degree.[15][16][17]

Atomoxetine has been found to directly inhibit hERG potassium currents with an IC50 of 6.3 μM,
which has the potential to cause arrhythmia.[16][18] QT prolongation has been reported with
atomoxetine at therapeutic doses and in overdose; it is suggested that atomoxetine not be used
with other medications that may prolong the QT interval, concomitantly with CYP2D6
inhibitors, and caution to be used in poor metabolizers.[16]

Other notable drug interactions include:[2]

 Antihypertensive agents, due to atomoxetine acting as an indirect sympathomimetic

 Indirect-acting sympathomimetics, such as pseudoephedrine, norepinephrine reuptake
inhibitors, or MAOIs
 Direct-acting sympathomimetics, such as phenylephrine or other α1 adrenoceptor agonists,
including pressors such as dobutamine or isoprenaline and β2 adrenoceptor agonists
 Highly plasma protein-bound drugs: atomoxetine has the potential to displace these drugs from
plasma proteins which may potentiate their adverse or toxic effects. In vitro, atomoxetine does
not affect the plasma protein binding of aspirin, desipramine, diazepam, paroxetine, phenytoin,
or warfarin

Usual Adult Dose for Attention Deficit Disorder

77
-Initial Dose: 40 mg/day orally.
-Maintenance Dose: Increase dose to 80 mg/day orally after a minimum of 3 days at the initial
dose.
-Maximum Dose: After 2 to 4 additional weeks, the dose may be increased up to 100 mg/day in
patients who have not achieved an optimal response.

Comments: Take dose once a day in the morning OR as evenly divided doses in the morning and
late afternoon/early evening.

Use: Treatment of Attention Deficit Hyperactivity Disorder (ADHD).

Usual Pediatric Dose for Attention Deficit Disorder

70 kg or Less:
-Initial Dose: 0.5 mg/kg/day orally.
-Maintenance dose: Increase dose to 1.2 mg/kg/day after a minimum of 3 days at the initial dose.
-Maximum dose: 1.4 mg/kg/day or 100 mg/day, whichever is less.

Over 70 kg:
-Initial Dose: 40 mg/day orally.
-Maintenance dose: Increase dose to 80 mg/day after a minimum of 3 days at the initial dose.
-Maximum dose: After 2 to 4 additional weeks, the dose may be increased up to 100 mg/day in
patients who have not achieved an optimal response.

Comments: Take dose once a day in the morning OR as evenly divided doses in the morning and
late afternoon/early evening.

Use: Treatment of Attention Deficit Hyperactivity Disorder (ADHD) in pediatric patients age 6
and older.

Renal Dose Adjustments

No adjustment recommended.

Liver Dose Adjustments

-Mild Liver Dysfunction (Child-Pugh A): No adjustment recommended.
-Moderate Liver Dysfunction (Child-Pugh B): Reduce initial and maintenance doses to 50% of
the usual dose.
-Severe Liver Dysfunction (Child-Pugh C): Reduce initial and maintenance doses to 25% of the
usual dose.

Dose Adjustments

78
Concomitant Use with Strong CYP450 2D6 Inhibitor or in CYP450 2D6 Poor Metabolizers
(PMs):
-70 kg or Less: 0.5 mg/kg/day; only increase dose to 1.2 mg/kg/day if symptoms fail to improve
after 4 weeks and the initial dose is well-tolerated.
-Over 70 kg: 40 mg/day; only increase dose to 80 mg/day if symptoms fail to improve after 4
weeks and the initial dose is well-tolerated.

PRECAUTIONS: If you have an allergy to atomoxetine or any other part of atomoxetine.

 If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell
your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of
breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
 If you have any of these health problems: Glaucoma, very bad heart disease, high blood
pressure, or pheochromocytoma.
 If you have taken certain drugs used for low mood (depression) like isocarboxazid, phenelzine,
or tranylcypromine or drugs used for Parkinson's disease like selegiline or rasagiline in the last
14 days. Taking atomoxetine within 14 days of those drugs can cause very bad high blood
pressure.

Administration Advice:
-Take this drug with or without food.
-Swallow drug capsules whole and not opened.
-Do not mix the oral solution formulation in food or water as it can prevent the patient from
receiving a full dose or could negatively affect the taste.
-Take a missed dose as soon as possible; however, do not take more than the prescribed total
daily amount in any 24-hour period.
-This drug can be discontinued without being tapered.

General:
-In pediatric patients 70 kg or less, no additional benefit has been demonstrated for doses higher
than 1.2 mg/kg/day and the safety of single doses over 1.8 mg/kg and total daily doses above 1.8
mg/kg/day have not been systematically evaluated.
-In pediatric patients over 70 kg and adults, no additional benefit has been demonstrated for
doses higher than 80 mg and the safety of single doses over 120 mg and total daily doses above
150 mg have not been systematically evaluated.
-This drug has not been associated with a pattern of response that suggests stimulant or
euphoriant properties, and there is no evidence of symptom rebound or adverse reactions
suggesting drug-discontinuation or withdrawal symptoms.
-Overdosage: Activated charcoal may be useful in limiting absorption; dialysis is not likely to be
useful as this drug is highly protein-bound.

Monitoring:
-Cardiovascular: Blood pressure and heart rate (baseline, at dose adjustments, periodically)
-Other: Height and weight in pediatric patients; long-term usefulness of drug (periodically)
-Psychiatric: Emergence or worsening of aggression/hostility, suicidal thinking and behavior,
clinical worsening, unusual changes in behavior (periodically)

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Patient Advice:
-If the contents of a drug capsule or the oral solution make contact with your eye, flush that eye
immediately with water and wash your hands and any potentially contaminated surfaces as soon
as possible.
-Avoid driving and other potentially dangerous activities such as operating machinery until you
know how this drug affects you.

PHENTERMINE

Generic Name: phentermine (FEN ter meen)

Brand Names: Adipex-P, Oby-Cap, Suprenza, T-Diet, Zantryl

Phentermine (contracted from phenyl-tertiary-butylamine), also known as α,α-

dimethylphenethylamine, is a psychostimulant drug of the substituted amphetamine chemical
class, with pharmacology similar to amphetamine. It is used medically as an appetite suppressant
for short term use, as an adjunct to exercise and reducing calorie intake.

Phentermine may produce cardiovascular, gastrointestinal, and CNS side effects; rare cases of
pulmonary hypertension and cardiac valvular disease have been reported. It should not be used
by people who have a history of drug abuse, have cardiovascular disease, hyperthyroidism,
glaucoma, or are pregnant, planning to become pregnant, or breast-feeding. It should not be
taken by anyone taking a monoamine oxidase inhibitor. Drinking alcohol while using
phentermine may cause adverse effects.

It was first introduced in 1959, and became part of the drug combination fen-phen that was
withdrawn from the market in 1997 due to the fenfluramine component damaging people's heart
valves. In 2012 a different combination drug, phentermine/topiramate was approved in the US.

Medical uses
Phentermine is used for a short period of time to promote weight loss, if exercise and calorie
reduction are not sufficient, and in addition to exercise and calorie reduction.[1][3]

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Phentermine is approved for up to 12 weeks of use and most weight loss occurs in the first
weeks. However, significant loss continues through the sixth month and has been shown to
continue at a slower rate through the ninth month.

Phentermine is used with a doctor-approved exercise, behavior change, and reduced-calorie diet
program to help you lose weight. It is used by certain overweight people, such as those who are
obese or have weight-related medical problems. Losing weight and keeping it off can lessen the
many health risks that come with obesity, including heart disease, diabetes, high blood pressure,
and a shorter life.

Contraindications
Phentermine use is contraindicated in those who:

 have a history of drug abuse.

 are allergic to sympathomimetic amine drugs.
 are taking a monoamine oxidase inhibitor (MAOI) or have taken one within the last 14 days.
 have cardiovascular disease, hyperthyroidism, or glaucoma.
 are pregnant, planning to become pregnant, or breast-feeding.

Drug interactions
Phentermine may decrease the effect of drugs like clonidine, methyldopa, and guanethidine.
Drugs to treat hypothyroidism may increase the effect of phentermine.

Adverse effects
Rare cases of pulmonary hypertension and cardiac valvular disease have been reported.
Tolerance usually occurs however risks of dependence and addiction are considered negligible.
People taking phentermine may be impaired when driving or operating machinery. Consumption
of alcohol with phentermine may produce adverse effects. There is no evidence that phentermine
is safe for women who are pregnant. Other adverse effects include:

 Cardiovascular effects like palpitations, tachycardia, high blood pressure, precordial pain; rare
cases of stroke, angina, myocardial infarction, cardiac failure and cardiac arrest have been
reported.
 Central nervous system effects like overstimulation, restlessness, nervousness, insomnia,
tremor, dizziness and headache; there are rare reports of euphoria followed by fatigue and
depression, and very rarely, psychotic episodes and hallucinations.
 Gastrointestinal effects include nausea, vomiting, dry mouth, cramps, unpleasant taste,
diarrhea, and constipation.
 Other adverse effects include trouble urinating, rash, impotence, changes in libido, and facial
swelling.

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Mechanism of action:
Phentermine has some similarity in its pharmacodynamics with its parent compound,
amphetamine, as they both are TAAR1 agonists, where the activation of TAAR1 in monoamine
neurons facilitates the efflux or, release into the synapse, of these neurochemicals; at clinically
relevant doses, phentermine primarily acts as a releasing agent of norepinephrine in neurons,
although, to a lesser extent, it releases dopamine and serotonin into synapses as well.
Phentermine may also trigger the release of monoamines from VMAT2, which is a common
pharmacodynamic effect among substituted amphetamines. The primary mechanism of
phentermine's action in treating obesity is the reduction of hunger perception, which is a
cognitive process mediated primarily through several nuclei within the hypothalamus (in
particular, the lateral hypothalamic nucleus, arcuate nucleus, and ventromedial nucleus). Outside
the brain, phentermine releases norepinephrine and epinephrine – also known as noradrenaline
and adrenaline respectively – causing fat cells to break down stored fat as well.

NURSES’ RESPONSIBILITIES:

Advice patient to :

Take this medication by mouth as directed by your doctor, usually once a day, 1 hour before
breakfast or 1 to 2 hours after breakfast. If needed, your doctor may adjust your dose to take a
small dose up to 3 times a day. Carefully follow your doctor's instructions. Taking this
medication late in the day may cause trouble sleeping (insomnia).

If you are using sustained-release capsules, the dose is usually taken once a day before breakfast
or at least 10 to 14 hours before bedtime. Swallow the medication whole. Do not crush or chew
sustained-release capsules. Doing so can release all of the drug at once, increasing the risk of
side effects.

If you are using the tablets made to dissolve in the mouth, the dose is usually taken once a day in
the morning, with or without food. First, dry your hands before handling the tablet. Place your
dose on top of the tongue until it dissolves, then swallow it with or without water.

The dosage is based on your medical condition and response to therapy. Your doctor will adjust
the dose to find the best dose for you. Use this medication regularly and exactly as prescribed in
order to get the most benefit from it. To help you remember, take it at the same time(s) each day.

This medication is usually taken for only a few weeks at a time. It should not be taken with other
appetite suppressants (see also Drug Interactions section). The possibility of serious side effects
increases with longer use of this medication and use of this drug along with certain other diet
drugs.

This medication may cause withdrawal reactions, especially if it has been used regularly for a
long time or in high doses. In such cases, withdrawal symptoms (such as depression, severe
tiredness) may occur if you suddenly stop using this medication. To prevent withdrawal

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reactions, your doctor may reduce your dose gradually. Consult your doctor or pharmacist for
more details, and report any withdrawal reactions right away.

Though it helps many people, this medication may sometimes cause addiction. This risk may be
higher if you have a substance use disorder (such as overuse of or addiction to drugs/alcohol).
Do not increase your dose, take it more often, or use it for a longer time than prescribed.
Properly stop the medication when so directed.

This medication may stop working well after you have been taking it for a few weeks. Talk with
your doctor if this medication stops working well. Do not increase the dose unless directed by
your doctor. Your doctor may direct you to stop taking this medication.

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