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Pharmacology B S.Y.

2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz

ANTISEIZURE/ ANTIEPILEPTIC DRUGS Impaired memory of ictal


phase
SEIZURES Classically preceded by aura
• Abnormal neuronal synchronous discharge Partial seizures with Initially as simple or
• Dysfunction or breakdown of protective brain Secondary Generalization complex partial with
mechanisms: evolution into tonic-clonic
1. Cellular Level Protection-refractory periods Loss of consciousness
to delay production of new action potential Preceded by aura
(increase time to generate new action PRIMARY GENERALIZED KEY FEATURES
potential) SEIZURES
• Refractory period – Na+ channel Petit mal (Absence) Sudden, short interruptions
inactivation, K+ channel activation of consciousness
(hyperpolarization) Blank stares
• 3 conformational changes of Na+ Lip smacking, rapid blinks
channels: No aura
• Closed state before activation Myoclonic Very brief muscle
• Open state during contraction occurring in
depolarization individual muscles or
• Inactivated state immediately generalized muscle groups
after peak depolarization Associated with systemic
2. Network Level protection- surround diseases such are uremia or
inhibition; restrict the effect of an action hepatic failure
potential within a distinct area Grand Mal (generalized Abrupt onset of
• Causes of loss of protective mechanisms tonic-clonic) contractions involving
1. Primary - genetic defects like in channel muscle groups
abnormalities Loss of consciousness
2. Secondary - changes in neuronal Incontinence
environment due to toxins, drug overdoses, Patient may fall to the
lesions in strokes or neoplasms. ground
Postictal disorientation
CLASSIFICATION OF SEIZURES (see page 8-9 for drugs) Atonic seizures Often in pediatrics
PARTIAL OR FOCAL KEY FEATURES Abrupt loss of
Simple Partial Symptoms depend on consciousness with fall to
location: the ground
Motor complex: No actual convulsions
 Repetitive Infantile spasms Rare, affects individuals in
movements the first year of life (usually
Sensory cortex: 3-7 months age)
 Paresthesias Clusters of brief fast
Visual cortex: movements of a few
 Flashes of light seconds to be repeated
Consciousness is preserved. multiple times (head falling
Spreads to ipsilateral forward, arm or body
cortical regions flexion)
Complex Partial (temporal Abnormal activity in the
lobe seizures) temporal lobe (amygdala, Adequate control of seizures is seen only in about 2/3 of
hippocampus) or frontal cases. Resistance to AED may develop even from start of tx.
lobe Options in these cases include surgery, vagus nerve
Consciousness is altered stimulation (VNS), and the relatively new responsive
Associated with involuntary neurostimulator system (RNS).
automatisms

1|P age
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz

Newer AEDs are being developed based on the following • no appreciable plasma protein binding
mechanisms: • Exceptions- phenytoin, tiagabine, valproate
1. GABA transmission enhancement • Clearance via hepatic metabolism
2. Reduction of excitatory or glutaminergic • active metabolites
transmission • medium to long-acting
3. Changes in ionic conduction processes • slow plasma clearance
• t1/2=12 h or more
CURRENTLY AEDS ARE MAINLY FOR PALLIATION. • older AEDs (ex. phenytoin, etc.) induce CYP450
• potential for drug interactions
BASIC PHARMACOLOGY • have extended release formulations

GOAL: INHIBIT ACTION POTENTIAL GENERATION OR


CONTROL

MECHANISM OF ACTION OF AEDS:


Current agents control or prevent seizures by one or several
ways.

Although AEDs are grouped according to their MAIN


mechanism of action, some actually have several MOAs.

Classifications of older drugs (1990):


1. Barbiturates
2. Hydantoins
3. Oxazolidinediones
4. Succinimides
5. Acetylureas

They have a common heterocyclic ring and vary in terms


of the substituents. The substituent type will determine
which type of seizure the drug can inhibit. If the
substituent is anti-pentylenetetrazol, the agent is good for
absence type of seizure. Examples are ethosuximide (a
succinimide) and valproate. If the substituent is anti-
maximal electroshock (anti MES), the drug is more active 1. Reduction of neuronal excitability by use-
against generalized tonic-clonic and complex partial dependent blockade of sodium channels
seizures. Examples are phenytoin, carbamazepine, and
lamotrigine. Minor changes in the chemical structure
produces marked changes in their mechanism of action
and properties. The other agents-Carbamazepine, Valproic
acid, benzodiazepines and the newer AEDs are not alike in
structure.

AEDS: GENERAL KINETIC FEATURES


• good oral absorption
• all enter the brain
• Good bioavailability (80-100%)

2|P age
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz

AEDS THAT BLOCK SODIUM CHANNELS OR ENHANCE permitted to reach steady state before
SODIUM CHANNEL INHIBITION incrementing the dose.
a. PHENYTOIN • Dose adjustment in hypoalbuminemia and in renal
b. CARBAMAZEPINE disease (because of ↑ protein binding)
c. LAMOTRIGINE (NEWER AGENT) • reduced protein binding raises the free
d. PRIMIDONE concentrations of phenytoin
For partial, secondarily generalized seizures, and • May affect thyroid function tests
generalized tonic-clonic seizures • Drug Interactions:
• Hepatic microsomal enzyme inducer-
PHENYTOIN – enzyme inducer increases inactivation of:
• OLDEST NON SEDATING AED (in therapeutic doses) • OCPs
• Use-dependence sodium channel blockade (same • Cyclosporine
with carbamazepine, lamotrigine, and valproate) • Quinidine
• Agent is able to preferentially inhibit the • Methadone
excitation of cells that are repetitively • Doxycycline
firing. Increase threshold for AP • Levodopa
• ↑ freq. of firing, ↑ block produced; can • Adverse Effects: (think of ocular effects)
block abnormal high freq. seizures but do • Shares many with other AEDS in this group:
not interfere with lower freq. activities of • nystagmus, extraocular muscle
normal cells dysfunction, diplopia, ataxia,
• SPECIFIC TARGET: Na Channels in the inactivated sedation
state • Long term use: gingival hyperplasia,
• Partial seizure and prevention of secondary seizure hirsutism, peripheral neuropathy, reduced
generalization DTRs, Vit D metab abnormalities,
• INEFFECTIVE IN ABSENCE TYPE osteomalacia,
• Use-dependency prolongs the inactivated • Teratogenicity
conformation and increases the number of • Rare toxicities: hypersensitivity and skin
abnormal cells in the inactivated state to rash, lymphadenopathy, fever and
control against partial and tonic-clonic agranulocytosis.
seizures
• Absorption kinetics depends on formulation CARBAMAZEPINE – enzyme inducer
• High plasma protein binding • related to the TCAs
• hepatic metab, active metabolites • non- sedating in usual doses
• Renal excretion, dose dependent elimination • Active metabolite: 10,11 epoxycarbamazepine
• 2 phases of metab: First order-low dose; zero order- • DOC for simple and complex partial seizures (slowly
high dose being replaced by newer agents)
• T1/2= 24h (average) • Also used for trigeminal neuralgia, bipolar disorders
• Oral preparations (Phenytoin sodium) is almost (manic phases)
100% but peak serum levels vary from 3 to 12 hours • Variable absorption rates but is completely
• The IM formulation is not used because it is more absorbed (peak levels by 6-8 h)
unpredictable because drug molecules may • Slow distribution
precipitate in muscle • 70% protein binding
• inactive prodrug fosphenytoin is preferred • First order metab; doesn’t undergo zero order (safer
as it is more soluble and is better absorbed than Phenytoin)
with IM administration • T1/2= 36 h but this decreases in time
• Steady state 5-7 d • 8-12 hours as the drug induces activity of
• Therapeutic levels is usually 10-20 mcg/ml. CYP450
• The usual adult starting dose is 300 mg/d • dosage adjustments in the first days of
with usual increments of 25-30 mg if treatment
needed. However, enough time should be • Oral formulation only
• Drug interaction:

3|P age
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz

• Also a CYP450 inducer • Valproic acid increases T1/2 (interference


• Increases metabolism rates of other AEDS with clearance); reduce dose of
(primidone, phenytoin, ethosuximide, Lamotrigine when given w/ valproic acid
valproic acid, and clonazepam) • Adverse effects:
• Valproic acid increases Carbamazepine • Dizziness
serum levels • Nausea
• Phenytoin or phenobarbital reduces • Diplopia
Carbamazepine serum levels • Headache
• Adverse Effects: • Sleepiness
• Most common (dose-related): diplopia • Rashes - Hypersensitivity rash may be
(manifests first), ataxia, GIT upset, avoided by gradual drug introduction
unsteadiness • Steven-Johnson syndrome (long term use)
• High doses: drowsiness, hypernatremia,
water intoxication PRIMADONE
• Elderly: Blood dyscracias • Gives rise to two active metabolites
• Most common idiosyncratic reaction: Phenylethylmalonamide (PEMA) and Phenobarbital
erythematous rash – effective for same seizure types
• Initiated slowly at low doses to avoid sedation and
LAMOTRIGINE GIT upset
• Additional MOA: Glutamate antagonist (AMPA • Steady state: 30-40 hours
receptors) • Active metabolites reach theirs more slowly
• Possible broader spectrum of use
• Partial Seizure, absence, myoclonic S in children,
Lennox-Gastaut syndrome, bipolar disorders
2. Inhibition of T-type calcium channels (e.g. in
Lennox-Gastaut syndrome (LGS) - epilepsy with absence seizures)
multiple different types of seizures: particularly
tonic (stiffening) and atonic (drop) seizures

• Intellectual development is usually, but not


always, impaired.
• The EEG shows a classic pattern of
background slowing and spike-wave bursts
at frequencies less than 2.5 per second.
• The cause of the disorder is unknown in 1
out of 4 children.

• Complete absorption
DRUGS THAT ACT AT THE T-TYPE CALCIUM
• Low protein binding 55%
• Phase 2 hepatic metab (via glucuronide conjugation CHANNELS
followed by renal excretion) a. VALPROIC ACID/VALPROATE
• Renal excretion b. ETHOSUXIMIDE
• T1/2= 24 hours
AEDs under this category are utilized for absence
• Concomitant intake of enzyme inducing
meds such as other AEDs shortens this to or petit mal seizures. Recall that in the awake
about 13-15 hours. state, the T type calcium channel is depolarized
• Valproic acid increases lamotrigine half-life and inactive. In petit mal, such channels are
by two fold so the starting dose should by activated during the awake state which is the
adjusted accordingly main feature in this type of seizure.
• Drug interaction:
• Half-life is reduced to 13-15h if taken with
enzyme inducing AEDs

4|P age
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz

VALPROIC ACID/VALPROATE – CYP450 inhibitor • T1/2 long=40h


• Additional MOAs- sodium channel blockade and • Dose and steady state- linear relationship
increases GABA levels (enhance glutamic acid • Usual dose is BID.
decarboxylase); higher doses inhibit T-type calcium • Drug interaction:
channels • Valproic acid inhibits metabolism and
• Versatile agent lowers clearance of Ethosuximide
• DOC: absence or petit-mal (2nd line – if resistant to • Adverse effects:
ethosuximide) • Common, Dose-related: Abdominal pain,
• Also for generalized tonic-clonic, mixed type, partial nausea, vomiting, fatigue, lethargy
type, and sometimes status epilepticus; generalized • Less: Headache, hiccups,dizziness,
idiopathic seizures, mania of bipolar states and euphoria
migraine • Idiosyncracies to the drug is very rare.
• Good oral absorption
• 80% bioavailability
• Serum peak-2 h
• Food retards absorption (take drug on empty 3. Boosting GABA-mediated synaptic inhibition
stomach)
• 90% protein binding
• Dose dependent clearance
• T1/2 is 9-18 h
• 20% excreted as conjugated compounds
• Therapeutic levels are around 50-100 mcg/ml.
• Drug interaction:
• Displaces phenytoin from plasma protein
binding
• Inhibits biotransformation of other AEDS
(Phenobarbital, phenytoin, and
carbamazepine)-enzyme inhibitor
• Reduces Lamotrigine clearance
• Adverse effects: DRUGS THAT ENHANCE GABA-MEDIATED INHIBITION
a. GABAPENTIN, PREGABALIN
• Common(GIT): nausea, vomiting,
b. BENZODIAZEPINES
abdominal pain, heartburn
c. PHENOBARBITAL
• High Doses: Fine tremors, sedation (if
taken with phenobarbital), weight gain, Unlike the first two groups of AEDS whose
increased appetite, alopecia mechanisms of action correlate well with clinical
• Idiosyncratic: Hepatotoxicity(maybe fatal activity, the following agents produce more variable
in children for less than 2 years or those on effects.
combined therapy), thrombocytopenia
• Teratogenic - spina bifida, cardiovascular, GABAPENTIN, PREGABALIN
orofacial and digit abnormalities • Amino acid analogs of GABA
• Increases brain levels of GABA
ETHOSUXIMIDE • Decreases synaptic release of glutamate
• DOC –absence or petit mal (1st line) • do not act directly on GABA receptors but instead
• Superior to lamotrigine for above indication affect the release of the neurotransmitter
• Complete absorption after oral administration • Great affinity for the 2 subunit of voltage-gated N-
• Serum peak: 3-7 h after type Ca+2 channels (MAIN ANTI-SEIZURE EFFECT).
Binding reduces levels of Ca+2 influx especially on
• NO protein binding nor active metabolites
presynaptic channels

5|P age
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz

• For Partial Seizures, adjunct for grand mal and • Strong sedative property
some pain conditions; also marketed as analgesics • May worsen ABSENCE seizure
• may also be effective for this seizures when • The drug acts on all GABA receptors and can
given alone, although this may require very potentiate GABA in the reticular nucleus
high doses. and thalamic relay cells
• Additional indications for both drugs • Enhance T-type calcium currents – underlie
include postherpetic neuralgia, the occurrence of absence seizures
neuropathic pain, and fibromyalgia. • pKa is near plasma pH 7.4
• Given at night time • pKA close to that of plasma pH 7.4 and
• SE: somnolence, dizziness, ataxia, tremors, hence slight changes in normal acid-base
headache balance can affect the ratio of ionized to
• Excreted unchanged, not metabolized in the liver non-ionized forms of the drug
• No effects on CYP450 • Distribution rates can vary
• No plasma protein binding
• T1/2=5 hours
• Multiple daily doses required

BENZODIAZEPINES 4. Glutamic acid antagonism (glutamate is elevated in


 increase Cl- current flow through the channels and seizure activity)
increase receptor affinity of GABA
 surround inhibition is enhanced
 threshold of action potential is raised
 6 prototypes:

Limiting factors for the use of benzodiazepines:  Inhibition of NMDA and AMPA subtypes of
1. Profound sedative effects glutamate receptors
2. Paradoxical hypersensitivity in children o Inhibit generation of seizure
3. Development of tolerance within a few months of o Protect neurons from seizure-
use induced injury

PHENOBARBITAL
NEWER AGENTS:
• Oldest available AED
a. LEVETIRACETAM
• Enhances GABA by keeping Cl- channels open
b. TIAGABINE
• Not selective for GABA A receptors
• Potentiate GABA A receptors in RETICULAR c. TOPIRAMATE
NUCLEUS and THALAMIC RELAY CELLS d. VIGABATRIN
(enhances T-type calcium currents =
responsible for absence seizures) LEVETIRACETAM
• Other MOAs in higher doses: • Possible MOA:
• Na+ ion conductance inhibition 1. Modification of glutamate and GABA release by
• N- and T-type calcium channel blockade selective binding to SV2A
• Reduction of glutamate release 2. Blockade of N-type calcium channels and
• Alternative drug for tonic-clonic and partial calcium release from storage
seizures; seizures in infants, febrile seizures • Current use: MONOTHERAPY
• Being replaced by other agents
• tonic-clonic seizures

6|P age
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz

• complex partial seizures • Acts similarly to phenytoin and


• Current use: ADJUNCT carbamazepine- inhibition of voltage-
• partial seizures in adults gated Na+ channels
• primary generalized tonic-clonic seizures in • Blocks high-voltage activated L-type Ca+2
children channels and enhances GABA inhibition
• juvenile myoclonic seizures but site of action for the latter differs from
• Fast oral absorption rates (unaffected by food) that of benzodiazepines or barbiturates.
• Serum levels by 1.3 h • Also blocks effect of excitatory ligands like
• Linear kinetics kainate on glutamate receptors.
• Low protein binding • Monotherapy in partial and generalized tonic-clonic,
• No important DI Lennox gestaut, Infantile spasms, Absence seizures
• Not a CYP450 substrate, no acticve metabolite (Petit mal), and Migraines
• 60% excreted unchanged in urine • Side effects: dose-related, appear during the first
• Oral, extended release, IV month of use
• Side Effects: • Somnolence, Dizziness, Fatigue,
• Somnolence, Dizziness, Ataxia, Asthenia, Paresthesias, Cognitive slowness,
Behavioral and mood changes Nervousness, Confusion
TIAGABINE • Acute myopia and Glaucoma – grounds for
• Blocks GABA uptake in brain cells by inhibiting GAT- discontinuation
1 - extracellular GABA levels are increased in the • Hypospadia in male fetus
region of the forebrain and hippocampus where this • Urolithiasis
transporter abounds • Fast Absorption
• Adjunct in partial seizures as an oral agent • 80% bioavailability
• Multiple daily doses • Not affected by food
• Adverse effects • Low protein binding (15%)
• Dose-related - nervousness, dizziness, • Mainly excreted in urine unchanged
difficulty in concentration, tremors, and • 20% is metabolized
depression • No active metabolites
• In some cases: extreme confusion, • Linear kinetics
somnolence and ataxia, the drug is • Decreases levels of estrogen and oral contraceptives
discontinued
• Psychotic reactions and idiosyncratic VIGABATRIN
rashes are rare. • Irreversible inhibits GABA-T
• May also cause seizures in those taking it • Blocks vesicular GABA transporter
for other reasons. • Sustained extracellular GABA elevation which
• Good bioavailability (90% and more) reduces glutamate synthetase activity
• High protein binding • Partial seizures and Infantile spasms nonresponsive
• T1/2 5-8 h to other AEDs
• Excreted in the feces but 25% via urine • Racemic mixture formulations
• Substrate of CYP 450 so half-life is shorter with • T1/2= 6 h but effects are more prolonged
concomitant intake of an enzyme inducer • Adverse effects:
• Hepatic dysfunction warrants dose adjustment • Common SE: Drowsines, Dizziness, Vertigo
• Less common: Agitation, Confusion,
TOPIRAMATE Psychotic reaction (avoided in px w/
• Chemically distinct from the other AEDs mental disorders)
(monosacharride) • Peripheral visual defects in 30—50%
• Has all four MOAs patients in long term use (check eyes)

7|P age
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz

• development of irreversible No aura sedation and


retinal lesions which progress with tolerance)
increasing drug exposure Myoclonal Very brief Valproic acid,
• Can be inhibited by valproic acid at very high conc. Syndromes muscle Clonazepam
contraction (clonazepam and
occurring in other BZDs often
individual mandate higher
muscles or doses),
CLINICAL PHARMACOLOGY
generalized Levetiracetam,
Monotherapy is preferred but some intractable muscle Zonisamide
seizure cases may need combination therapy. groups
Associated
with systemic
diseases such
Type of Symptoms: Drugs are uremia or
seizures hepatic
Partial (see table on Traditional: failure
Seizures page 1)  phenytoin, Juvenile Valproic Acid,
and Grand carbamazepine, myoclonic Lamotrigine,
Mal phenobarbital epilepsy Topiramate
Newer agents: (Phenytoin and
better tolerated, carbamazepine can
broader spectrum of aggravate this
activity condition)
 lamotrigine, Refractory Often in Valproic,
levetiracetam, atonic pediatrics Lamotrigine, (BZDs –
topiramate, seizures Abrupt loss of conflicting results)
zonisamide consciousness
Generalized with fall to
seizures the ground
Grand mal Abrupt onset same as partial, No actual
(“big bad” of Valproic acid convulsions
seizure – contractions Infantile Rare, affects Vigabatrin (DOC),
Tonic- involving spasms individuals in traditional
Clonic) muscle the first year mainstream
groups of life (usually treatment is
Loss of 3-7 months corticotropin or
consciousness age) corticosteroids.
Incontinence Clusters of Some give
Patient may brief fast benzodiazepines
fall to the movements (clonazepam,
ground of a few nitrazepam)
Postictal seconds to be
disorientation repeated
Absence Sudden, short Valproic acid and multiple
(Petit mal – interruptions Ethosuximide (non- times (head
“small bad” of sedating and are falling
seizure; consciousness more commonly forward, arm
very Blank stares used), Clonazepam or body
sudden) Lip smacking, (has more side flexion)
rapid blinks effects including

8|P age
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz

STATUS Drugs Description • Orofacial Abnormalities


EPILEPTICUS • Digital Abnormalities
Acute seizure Diazepam (short  IV Diazepam is the most • Cardiovascular Defects
attack (IV) - 30-40 minutes); effective in controlling • Topiramate – hypospadia
Lorazepam the acute seizure attack However, pregnant patient with epilepsy or seizure disorder
(longer)  Maximum total dose: 20- should receive medication.
30 mg
 can cause respiratory
and cardiovascular
depression
Continuing IV Phenytoin, or  Traditional mainstay
treatment Fosphenytoin continuing treatment
(more potent, was phenytoin (doses of
less cardiotoxic) 13-18 mg/kg (adults) by
direct IV push with
High dose careful surveillance of
phenobarbital heart rhythm and blood
(nonresponders) pressure); may cause
ataxia, a dose-related
toxicity
 fosphenytoin is less
cardiotoxic and more
potent
 Nonresponsive cases
may benefit from high
dose phenobarbital (may
cause respiratory
depression especially
with prior administration
of diazepam or
lorazepam)
 Provisions for possible
intubation and
ventilation must be
available. Generalized
anesthesia is reserved
for severe, WITHDRAWAL FROM AEDS
nonresponding cases • Discontinuation may cause increase in frequency
Absence Status Benzodiazepines, BZDs are the drugs of and severity
Epilepticus IV Valproic acid choice for absence status. • Two factors to consider
(nonresponders) IV valproate is given for 1. effects of D/c on patient
unresponsive cases 2. need for continued therapy
TERATOGENICITY
• Easier for absence type than drugs for partial or
• Two fold increased risk for congenital anomalies in
generalized tonic-clonic seizures. (Most difficult will
babies born to mothers on AEDs
be stopping barbiturates and benzodiazepines)
• Fetal hydantoin syndrome, Fetal carbamazepine
• gradual (several weeks to months)
syndrome, Fetal phenobarbital syndrome(similar
• trial of gradual AED suspension For those seizure
effects)
free for 3-4 years at least
• Valproic acid
• Spina Bifida

9|P age
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz

Drugs and their Mechanisms of Action


Drug Na+ channel T-type Ca++ High-voltage GABA system Glutamate antagonism
channel activated Ca++
channel

Main effects on Ion Channels


Phenytoin
Carbamazepine
Lamotrigine
Zonizamide
Ethoxusimide
Main effects on GABA Mechanisms
Benzodiazepines
Tiagabine
Mixed Actions
Valproic acid
Gabapentin
Levitiracetam
Topiramate
Felbamate
Phenobarbital

List of CYP Inducers and Inhibitors


CYP INDUCERS CYP INHIBITORS
EFFECTS ↑ metab/excretion = ↓ efficacy ↓ metab/excretion; delays
clearance of other agents = ↑
risk for toxicity
DRUGS CARBAMAZEPINE AMIODARONE
PHENYTOIN CIMETIDINE (COMMON)
PHENOBARBITAL CIPROFLACIN, ERYTHROMYCIN
DEXAMETHASONE AZOLES (ANTIFUNGALS)
GRISEOFULVIN FLUVOXAMINE, FLUOXETINE
ISONIAZID GRAPEFRUIT
RIFAMPACIN ISONIAZID
PRIMADONE ORAL CONTRACEPTIVES
TABACCO SMOKE VALPROIC ACID
CHARBROILED FOOD VERAPAMIL
CHRONIC ALCOHOLISM ACUTE ALCOHOLISM

10 | P a g e
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz

SEDATIVE HYPNOTICS 6. Other Agents


a. Chloral hydrate
Terms to remember:
Hypnosis – encourage sleep b. Meprobamate
Sedation – anxiolytic effect
BENZODIAZEPINES are the most widely used anxiolytics,
Utilized clinically not only for their ability to produce or having replaced the barbiturates over the years, because of
encourage sleep but also for their anxiolytic effect. more effectiveness and better safety profile.

 Some are also used in seizures


 Minimum therapeutic effect of sedative hypnotics is
the relief of anxiety or calming effect.
(Figure 1. Basic and Clinical Pharmacology 13th Edition, Katzung et

al.)
FLUMAZENIL
 Lone marketed benzodiazepine antagonist
↑ Dose = hypnosis is achieved, greater degree of CNS  Used for cases of BZD overdose and the newer
depression (graded dose-dependent effect) agents but have no action against barbiturates,
o Linear relationship between dose and degree of CNS meprobamate, alcohol, and anesthetics
effect exists for the older agents such as alcohols and
 Competitive inhibitor for the BZD binding site in the
barbiturates (Drug A).
o Further ↑ dose = general anesthesia, respiratory GABA A receptor.
depression, coma, and death o More consistent in reversing SEDATIVE
o Benzodiazepines and newer drugs (Drug B) appears EFFECTS but less predictable in respiratory
to have a deviation from this linear relationship depression.
o Proportionately more drug increments are needed to  Rapid action, short half-life (0.7-1.3h), rapid hepatic
achieve CNS effects beyond hypnosis (hence safer) as clearance
depicted in the dose response curves. o Repeated administration may be required
 ADVERSE EFFECTS:
SEDATIVE HYPNOTICS INCLUDE THE FOLLOWING: o Agitation, confusion, nausea, dizziness
1. Benzodiazepines (most common) o Chronic users – may trigger severe
2. Barbiturates (most replaced by BZDs) abstinence syndrome
3. Melatonin receptor antagonists o BZD + tricyclic antidepressant (TCA) +
a. Ramelteon Flumazenil = arrhythmias or convulsions
b. Tasimelteon
4. 5-HT Receptor agonist BASIC PHARMACOLOGY
a. Buspirone I. KINETICS
5. New Hypnotics (EZZ)  Lipophilicity – major factor in determining the rate of
a. Eszopicline absorption; also determines how fast the sedative-
b. Zalepton hypnotic can enter the CNS
c. Zolpidem

11 | P a g e
Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz

o Triazolam and Diazepam – exhibit very rapid KINETICS OF BARBITURATES


rates in contrast to other BZDs  Most are exclusively metabolized in the liver rather
o Barbiturates and newer agents – rapidly than excreted in the urine unchanged
absorbed  Undergo PHASE 1 and PHASE 2
o Chlorazepate – prodrug; first converted to its  Metabolic rates vary but are generally slow;
active form desmethyldiazepam cumulative effects can result from multiple dosing
(nordiazepam) in the stomach  Only PHENOBARBITAL has considerable portion
o Triazolam, thiopental, newer agents – have (25%) that is not metabolized.
rapid action on CNS
 Can cross the placenta and breast milk = can KINETICS OF NEWER AGENTS (HYPNOTICS)
cause depression in the neonate and  ZOLPIDEM – available in oral (including extended
breastfeeding infant release tablets), oral spray, sublingual
 Metabolized in the liver o Peak plasma levels: 1-3 hours after oral
o PHASE 1 REACTIONS – hepatic administration
microsomal enzymes are prominent o Half-life: 1.5-3.5 hours (takes longer in
and rates of elimination depend on how women and elderly)
fast they are biotransformed o Metabolism: rapid (phase 1), no active
o PHASE 2 REACTIONS – conjugation metabolites
reactions; some BZDs proceed to phase  ZALEPLON and ESZOPICLONE – metabolized via
2 before excretion CYP3A4
o doses should be reduced on px with liver
KINETICS OF BENZODIAZEPINES diseases and elderly
 Pass through microsomal oxidation via CYP3A4 then
undergo glucoronidation conjugation prior to renal ENZYME INHIBITORS – elevate their serum levels; ex.
excretion Cimetidine
 Many of their initial (PHASE 1) metabolites retain
ENZYME INDUCERS – reduce their serum levels; ex.
activity and may even have longer half-lives,
Rifampicin
 DESMETHYLDIAZEAM – active metabolite of several
parent drugs: diazepam, chlordiazepoxide, Excretion of sedative-hypnotics – through kidneys after
prazepam, chlorazepate they are biotransformed into conjugates in the liver.
o Has half-life of at least 40 hours  Usually elimination of parent drugs are not
 TRIAZOLAM AND ALPRAZOLAM – undergo alpha- significantly affected by changes in renal function
hydroxylation to produce metabolites of very short o EXCEPT PHENOBARBITAL – bec. 25% is
activity and are rapidly inactivated. excreted unchanged; elimination rates
o TRIAZOLAM – half-life is only 2-3 hours; can be affected by changes in urine pH
used more as a hypnotic than anxiolytic  Phenobarbital – weak acid
 Active metabolites prolong drug action; BZDs with hence alkalinization of urine
long half-lives or have active metabolites tend to ionizes a significant proportion
produce CUMULATIVE and GREATER RESIDUAL of the drug in the filtrate;
EFFECTS when given for multiple doses (e.g. more increases its excretion
drowsiness)
 Rate of metabolism for some BZDs are altered when Factors that affect biotransformation of Sedative Hypnotics:
they are taken concomitantly with CYP inducers of 1. Hepatic function
inhibitors. 2. CYP enzyme activity

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Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz

BARBITURATES when used on a long-term basis can induce


enzyme activity, hence hasten their own metabolism and that
of other drugs. These effects are not seen in BZDs and newer
sedative hypnotics.

II. DYNAMICS

Benzodiazepines facilitates or enhances chloride ion flow when


GABA binds to the receptor by increasing frequency of channel
opening. Hence, while BZDs do not directly activate GABAA
receptors or directly open the chloride ion channel, they heighten
the response to the neurotransmitter and increase efficiency of
GABA inhibition. They attach to an allosteric rather than the
active binding site of GABA in the receptor.

Above is the schematic diagram of the GABAA receptor


which is actually a chloride channel whose ligand is gamma
amino butyric acid or GABA, the main inhibitory
neurotransmitter of the brain. Sedative hypnotics and
other agents bind to this receptor which is located the
neuronal cell membrane. It is a pentameric structure
composed of five or more subunits (𝛂, 𝜷,𝜸 etc.) each
subunit themselves are made of several subtypes (𝛂 has 6, BZs attach to an allosteric rather than the active binding site of
𝜷has 4, 𝜸has 3). Hence GABAA receptor has multiple so GABA in the receptor. Barbiturates, on the other hand, prolong
called isoforms depending on the combinations of the time that the chloride channels remain open and at higher
subtypes. In many brain regions, the major GABAA doses, can actually directly activate the receptors. Their binding
receptor isoform is one that has two 𝛂1, two 𝜷2, and one site in the receptor is different from that of GABA and of the
𝜸 2 subunits. Benzodiazepines bind to these but also to benzodiazepines. Barbiturates also have more effects such as
other isoforms. The same is true for the barbiturates but inhibition of excitatory glutaminergic activity and nonsynaptic
inhibitory membrane effects. They are less selective, have
the binding site is different from that of the
greater CNS depressant potential and can induce full anesthetic
benzodiazepines. The newer agents such as zolpidem, effects hence a lower safety profile.
zaleplon, and eszopiclone are specific only for isoforms
that bear𝛂 1 subunits. This may partly explain the
differences in drug effects. The sedative hypnotics do not
have much affinity for GABAB receptors.

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Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz

BZ PROTOYPES AND
ZOLPIDEM WITH DURATION
OF ACTION:
SHORT ACTING= 3-8 H
INTERMEDIATE= 10-20 H
LONG= 1-3 DAYS
BZDs ARE USED FOR ACUTE
ANXIETY STATES AND FOR
RAPID CONTROL OF PANIC
ATTACKS.
ALPRAZOLAM AND
CLONAZEPAM – greater
efficacy than other BZDs in
longer term treatment of
panic and phobic disorders

Higher doses of the agents can induce sleep.


EFFECTS OF SEDATIVE HYPNOTICS:
1. Sedation
Generally, BZDs and older drugs have the following
 low doses anxiolytic effects
effects:
 decreased in cognitive and psychomotor
• Reduction of sleep onset latency
functions
• Increase in stage 2 NREM sleep
 behavioral disinhibition
• Decreases duration of REM sleep and stage 4
 anterograde amnesia
NREM slow-wave sleep
 behavioral disinhibition:
o euphoria, judgement impairment, loss Newer drugs reduce persistent sleep latency:
of self-restraint Zolpidem
2. Hypnosis • Decreases REM
• Minimal effect on slow wave sleep
Zaleplon
• Decreases sleep onset latency
• Min effect on total sleep time, NREM, REM
Eszopiclone
• Increases total sleep time esp. stage 2 NREM
• Decreases REM (high doses)

Abrupt cessation of intake of older sedative-hypnotics


can cause REM rebound.
 REM sleep stage increases in duration and
frequency. A similar effect is seen with sleep
deprivation.
 Newer drugs have not been associated with
this phenomenon after discontinuation at the
usual dose. At high dose however, they are
associated with rebound insomnia.

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Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz

3. Anesthesia o Anxiety, insomnia, photophobia,


 Used as anesthetic adjuncts phonophobia, cramps, depression,
 Sustainability depends on physicochemical convulsions
features, onset and duration of action o The higher the dose used and the longer it
 Useful for induction- agents with rapid onset, is used, the more serious the withdrawal
brief duration of action and rapid redistribution  Psychological dependence – addiction;
(thiopental, methohexital – very lipid soluble) development of strong compulsion to take the drug
 IV BZDs – used as adjuncts in general anesthesia; regardless of the negative consequences
assoc. with respiratory depression
o Reversed by FLUMAZENIL CLINICAL PHARMACOLOGY:
4. Anti-seizures Anxiolytics
 Commonly used Benzodiazepines: clonazepam,  Anxiety secondary to organic illness
nitrazepam, diazepam, and lorazepam.  Situational anxiety
 Phenobarbital and its derivatives are also used  Generalized disorders
for grand-mal. The newer agents however lack  Acute anxiety states, panics, phobias
anticonvulsant action.  BZs are not for long term management due to
5. Muscle relaxation development of tolerance, addiction, and
 Some of the benzodiazepines and carbamate dependence (SSRIs are better and safer; considered
have been used for muscle spasm. first line)
 Newer agents do not have this effect.  Factors in choosing BZs for anxiolysis
6. Respiratory and Cardiovascular function o Rapid onset of action
 Dose-related respiratory depression o High therapeutic index
especially those with pulmonary o Availability of flumazenil for overdose
conditions. o Low risk for DI due to enzyme induction
 In those with no cardiovascular o Minimal effects on cardiovascular and
compromise, these agents do not usually autonomic functions
cause significant effects on cardiac function  Disadvantages
or blood pressure. Cardiovascular function o Potential for dependence
including contractility and vascular tone are o CNS depression
however affected (depression) at toxic o Amnestic effects
doses or those with cardiac failure, o Additive CNS depressant effects – when
hypovolemia or impaired cardiovascular taken with other drugs with sedative effects
function. like alcohol
 Precautions for use
CONSEQUENCES OF REPEATED OR PROLONGED EXPOSURE: o Dose should not impair cognitive or motor
 Tolerance – reduced drug response that occurs with function during awake hours (lower dose in
repeated exposure to sedative hypnotics AM, higher at bedtime)
o Cross tolerance to alcohol – significant o Prescription-Brief use only
phenomenon o Physician assessment of patient response
o Mechanism of tolerance may be due to ↑ o Drug combinations avoided (avoid alcohol,
metabolic rate or adaptive changes in brain antihistaminics, and anticholinergics, SH
o Down regulation of receptors combinations)
o Also observed in newer agents
SLEEP DISORDERS
 Physical dependence – abrupt cessation causes
• Used only for short term (not more than 7-10 days)
withdrawal/abstinence symptoms
• Discontinuation may cause rebound insomnia

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Pharmacology B S.Y. 2017-2018
SEDATIVE/HYPNOTICS AND ANTISEIZURES
Dr. J. O. Cruz

• Newer agents-minimal effects on sleep patterns


unlike older agents and BZs can reduce REM and
slow-wave sleep esp. in high doses

CLINICAL CRITERIA FOR DRUG EFFICACY:


• Decrease sleep latency, rapid onset of sleep
• Less hangover effects

HYPNOSIS
• Current/commonly used: BZs and newer agents
• BZs with longer T1/2 and active metabolites- more
daytime somnolence (ex. Lorazepam, flurazepam)
• BZs at hypnotic doses possible anterograde
amnesia
• Newer agents: rapid onset, less morning-after SE

Sources: Recordings, PPT, Manual, and


Wini Ong Trans (reference for tables and
other notes)

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