Pharmacology of pain medication

(Analgesics)
NSAIDs and Opioid analgesics
Pain (algesia)
Unpleasant sensory & emotional experience
Associated with actual or potential tissue damage
Evoked by an external or internal noxious stimuli
Mediated by different NTs & peptides such as
glutamate & substance P
It is a warning, primarily protective in nature
The pain can be
Superficial
Stimulation of skin & mucous membranes
Fast response
Deep
Arises from muscles, joints, tendons, heart, e.t.c.
Slow response
 Analgesics
Drugs that selectively relieve pain with out significant change on
patient consciousness
Act on CNS or periphery pain mechanism

Analgesic classification
Narcotics /opioids/

Morphine & morphine like drugs

Non-narcotics

NSAID, Acetaminophen
Adjuvant analgesic /coanalgesics

TCAs, Antiepileptics, Steroids

Management of pain

1. Mild pain
NSAID + adjuvant
2. Moderate pain
Weak narcotic + NSAID + adjuvant
3. Severe pain
Strong narcotic + NSAID + adjuvant
Opioid Analgesics
 Morphine
Prototypical opioid agonist
The opium poppy is the source of crude
opium
Opium: a mixture of alkaloids from seed
capsule of opium poppy (10% morphine)
After incision, the poppy seed pod exudes a
white substance that turns into a brown gum
that is crude opium
Morphine remains the standard against
which all drugs that have strong analgesic
action are compared
Opioids
Most opioid analgesics are related to morphine
morphine has 5 rings, 3- & 6-OH groups (phenolic & alcoholic), piperidine ring with
N-methyl group & a quaternary carbon at position 13
Codeine is morphine O-methylated at position 3
Heroin is morphine O-acetylated at positions 3 & 6
Replacing the N-methyl with something larger (allyl, cyclopropyl, cyclobutyl) produces
opioid with antagonist properties
Meperidine (pethidine) is a synthetic opioid with only fragments of the morphine
structure
 Opioid drugs include:
Full agonists,
Partial agonists, and
Antagonists
Morphine is a full agonist at the (mu)-opioid receptor,
the major analgesic opioid receptor
In contrast, codeine functions as a partial (or weak) -receptor
agonist.
Other opioid receptor subtypes include (delta) and (kappa)
receptors
Some opioids, eg, nalbuphine, are capable of producing an agonist (or
partial agonist) effect at one opioid receptor subtype and an
antagonist effect at another.
Naloxone is a strong antagonist at -receptor
Endogenous Opioid Peptides
Opioids may be exogenous or endogenous

Three families of endogenous opioid peptides

Endorphins,
Enkephalins (met-enkephalin and leu-enkephalin),
Dynorphins
Endogenous opioid peptides

Enkephalins
Relatively selective ligands for receptors
Endorphins
Bind preferentially to receptors
Dynorphins
Highly selective agonist at receptors
 Opioid receptor subtypes, their functions, and their endogenous
peptide affinities.
The major effects of the
opioids are mediated by
these three receptor families
All belong to the family of
GPCRs and inhibit adenylyl
cyclase
They are also associated with
ion channels, increasing
postsynaptic K+ efflux
(hyperpolarization) or
reducing presynaptic Ca2+
influx, thus impeding neuronal
firing and transmitter release
 Mechanism of action of opiates
Opioids produce analgesia by binding to specific GPCRs
located in brain & spinal cord regions involved in the
transmission & modulation of pain
Inhibit adenylyl cyclase cAMP
Reduce neuronal excitability
sed K+ conductance causes hyperpolarisation of
the membrane
Reduce transmitter release
Due to inhibition of Ca 2+ entry
 Strong Agonists
A. Morphine
Actions:
Analgesia: Morphine causes analgesia (relief of pain without the loss
of consciousness)
Euphoria: Morphine produces a powerful sense of contentment and
well-being
Respiration: Morphine causes respiratory depression. Respiratory
depression is the most common cause of death in acute opioid
overdose.
Depression of cough reflex: Both morphine and codeine have
antitussive properties. The receptors involved in the antitussive action
appear to be different from those involved in analgesia.
Emesis: Morphine directly stimulates the chemoreceptor trigger zone
in the area postrema that causes vomiting.
 Actions cont
Gastrointestinal tract:
Morphine relieves diarrhea and dysentery
by decreasing the motility
increasing the tone of the intestinal circular smooth muscle.
Morphine also increases the tone of the anal sphincter.
Overall, morphine produces constipation
Miosis:
The pinpoint pupil, characteristic of morphine use,
results from stimulation of and receptors.
There is little tolerance to the effect, and all morphine
abusers demonstrate pinpoint pupils.
[Note: This is important diagnostically, because many
other causes of coma and respiratory depression
produce dilation of the pupil.]

Morphine causes enhanced parasympathetic stimulation to the eye, resulting in pinpoint pupils.
 Strong Agonists cont
Therapeutic uses:
Analgesia: when pain is present and sleep is necessary, opiates may be used to
supplement the sleep-inducing properties of benzodiazepines,
Treatment of diarrhea: Morphine decreases the motility and increases the tone of
intestinal circular smooth muscle. [Note: This can cause constipation.]
Relief of cough: Morphine suppresses the cough reflex; however, codeine or
dextromethorphan are more widely used for this purpose. Codeine has greater
antitussive action than morphine.
Treatment of acute pulmonary edema: Intravenous (IV) morphine dramatically
relieves dyspnea caused by pulmonary edema associated with left ventricular failure
(possibly by its vasodilatory effect).
Adverse effects commonly observed in individuals treated with opioids
 Strong Agonists cont
B. Meperidine (pethidine)
Used during obstetric labor
As opioids cross the placental barrier, care must be taken to
minimize neonatal depression
If it occurs, immediate injection of the antagonist naloxone
will reverse the depression
Opioids like meperidine produce less depression
(particularly respiratory depression) in newborn infants than
does morphine
Significantly less effects on uterine smooth muscle than
morphine
Because of its shorter action and different route of metabolism,
meperidine is preferred over morphine for analgesia during labor
Meperidine does not cause pinpoint pupils but, rather, causes the pupils
to dilate because of an atropine-like action.
 Strong Agonists cont
C. Methadone
Approximately equal in potency to morphine but
Induces less euphoria and has a somewhat longer duration of action.
Methadone is used as an analgesic as well as in the controlled
withdrawal of dependent abusers from heroin and morphine
 Strong Agonists cont
D. Fentanyl
It is chemically related to meperidine
Has 100-fold the analgesic potency of morphine and is used in
anesthesia
The drug is highly lipophilic and has a rapid onset and short duration
of action (15 to 30 minutes).
It is usually injected IV, epidurally, or intrathecally
Epidural fentanyl is used for analgesia postoperatively and during labor.
An oral transmucosal preparation and a transdermal patch are also
available.
Unlike meperidine, it causes pupillary constriction
 Strong Agonists cont Time to peak effect and duration of
action of several opioids administered
intravenously.
E. Sufentanil, alfentanil, and remifentanil
Three drugs related to fentanyl
Differ in their potency and metabolic
disposition.
Sufentanil is even more potent than
fentanyl, whereas the other two are less
potent but much shorter-acting
 Strong Agonists cont
F. Heroin
Heroin does not occur naturally.
It is produced by diacetylation of morphine, which
leads to a three-fold increase in its potency.
Its greater lipid solubility allows it to cross the BBB more rapidly than
morphine, causing a more exaggerated euphoria when the drug is
taken by injection.
Heroin is converted to morphine in the body,
It has no accepted medical use
 Strong Agonists cont

G. Oxycodone
It is a semisynthetic derivative of morphine.
Orally active and is sometimes formulated with aspirin or
acetaminophen.
It is used to treat moderate to severe pain
 Moderate Agonists
A. Codeine
Codeine is synthesized commercially from morphine.
The analgesic actions of codeine are due to its conversion to
morphine, whereas the drug's antitussive effects are due to codeine
itself.
Codeine shows good antitussive activity at doses that do not cause
analgesia
Codeine produces less euphoria than morphine
In most cough preparations, codeine has been replaced by drugs such
as dextromethorphan (a synthetic cough depressant that has
relatively no analgesic action)
 Moderate Agonists

B. Propoxyphene
Propoxyphene is a derivative of methadone
Propoxyphene is a weaker analgesic than codeine
requiring approximately twice the dose to achieve an effect equivalent to that
of codeine
often used in combination with acetaminophen for an analgesia
greater than that obtained with either drug alone
Mixed Agonist-Antagonists and Partial Agonists

Drugs that stimulate one receptor but block another are termed
mixed agonist-antagonists

Effects of these drugs depend on previous exposure to opioids

Nave patients,---- mixed agonist-antagonists show agonist activity

Non-Nave patients , -----may show primarily blocking effects

Mixed Agonist-Antagonists and Partial Agonists
A. Pentazocine

Pentazocine acts as an agonist on receptors and is a weak

antagonist at and receptors

B. Buprenorphine

Buprenorphine is classified as a partial agonist, acting at the

receptor

A major use is in opiate detoxification

C. Nalbuphine and butorphanol

 Other Analgesics
A. Tramadol

Tramadol is a centrally acting analgesic that binds to the -opioid

receptor.

In addition, it weakly inhibits reuptake of norepinephrine and

serotonin

Of concern are the seizures that can occur, especially in patients

taking SSRIs, TCAs, or in overdose.

Tramadol should also be avoided in patients taking MAOIs

 Antagonists
Administration of opioid antagonists produces no
profound effects in normal individuals.

However, in patients dependent on opioids, antagonists

rapidly reverse the effect of agonists, such as heroin, and
precipitate the symptoms of opiate withdrawal

naloxone, naltrexone, and nalmefene are morphine

derivatives with bulkier substituents at the N17 position
 Antagonists
A. Naloxone

Naloxone is used to reverse the coma and respiratory depression of opioid overdose

It rapidly displaces all receptor-bound opioid molecules and, therefore, is able to reverse
the effect of a heroin overdose

Within 30 seconds of IV injection of naloxone, the respiratory depression and coma are
reversed, causing the patient to be revived and alert.

Naloxone has a half-life of 60 to 100 minutes.

Naloxone is a competitive antagonist at , , and , receptors, with a 10-fold higher

affinity for than for receptors.
This may explain why naloxone readily reverses respiratory depression with only minimal reversal
of the analgesia that results from agonist stimulation of receptors in the spinal cord
 Antagonists
B. Naltrexone
Naltrexone has actions similar to those of naloxone.
It has a longer duration of action than naloxone
a single oral dose of naltrexone blocks the effect of injected heroin for up to 48 hours.

C. Nalmefene
Nalmefene is a parenteral opioid antagonist with actions similar to that of
naloxone and naltrexone.
It can be administered IV, IM, or SC.
Its half-life of 8 to10 hours is significantly longer than that of naloxone and
several opioid agonists.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
A class of chemically dissimilar agents that act by inhibiting COX
enzyme and, subsequently, prostaglandin synthesis
COX-1 isoform tends to be homeostatic in function,
COX-2 is induced during inflammation and tends to facilitate the
inflammatory response
These drugs exert anti-inflammatory, antipyretic and analgesic effects
The antiinflamatory action is mainly due to inhibition of COX-2 and
their unwanted effects particularly those affecting the GIT are results
of their inhibition of COX-1.
 Structural differences in active sites of cyclooxygenase (COX)-1 and COX-2.
 NSAIDs
Inflammation is the body's effort to inactivate or destroy invading
organisms, remove irritants, and set the stage for tissue repair.
pain is related to the intensity of the inflammatory process.
It is their anti-inflammatory properties that make them most useful in
the management of disorders in which pain is related to the intensity
of the inflammatory process.
Example: rheumatoid arthritis (RA).
Aspirin, Diclofenac, Ibuprofen, Indomethacin, Phenyl butazone,
Pyroxicam, Sulindac
 The treatment of patients with inflammation involves two primary
goals:
First-- the relief of pain, which is often the presenting symptom and the major
complaint of the patient; and
Second-- the slowing of the tissue-damaging process
 NSAIDs
NSAIDs activity is mediated chiefly through inhibition of prostaglandin
biosynthesis
Various NSAIDs have additional possible mechanisms of action:
inhibition of chemotaxis,
down-regulation of interleukin-1 production,
decreased production of free radicals and superoxide, and
interference with calcium-mediated intracellular events.
Aspirin irreversibly inhibit COX.
The non-COX-selective NSAIDs are reversible inhibitors
1. ASPIRIN (Acetyl salicylic acid) (ASA)
Its a weak organic acid.
Aspirin is absorbed as such and is rapidly hydrolyzed to acetic acid
and salicylate by esterases in tissue and blood
ASPIRIN (Acetyl salicylic acid) (ASA)

The salicylates are rapidly absorbed from the stomach and upper
small intestine
Salicylates (except for diflunisal) cross blood-brain barrier
Diflunisal has no antipyretic effect, why??
Alkalinization of the urine increases the rate of excretion of free
salicylate and its water-soluble conjugates.
 Metabolism of aspirin and acetylation of COX by aspirin

Mechanism of action
Aspirin is a nonselective inhibitor of both COX
isoforms
Aspirin irreversibly inhibits COX
Inhibit the synthesis of prostaglandins,
important mediators of inflammation.
Prostaglandin E2 (PGE2) is thought to sensitize nerve endings
to the action of bradykinin, histamine
PGE2 synthesis elevation of hypothalamic
thermoregulatory center
Inhibition of platelet aggregation is attributable to the
inhibition of platelet synthesis of thromboxane A2, a
potent vasoconstrictor and inducer of platelet
aggregation
ASPIRIN (Acetyl salicylic acid) (ASA)
Actions:-
1. Anti-inflammatory, analgesic & antipyretic action.
2. ASA block PG synthesis so:
Normally, prostacyclin (PGI2) inhibits gastric acid secretion, whereas PGE2 and
PGF2 stimulate synthesis of protective mucus
In the presence of aspirin, these prostanoids are not formed, resulting in
increased gastric acid secretion and
diminished mucus protection.
This may cause epigastric distress, ulceration, hemorrhage, and iron-
deficiency anemia
3. Effects on platelets- Low dose ASA block synthesis of TXA2---anti
coagulant effect. lasts for the life of the platelet (8 days).
4. Delays labor if given during the time of labor.
ASPIRIN (Acetyl salicylic acid) (ASA)
Clinical Uses
Analgesia, Antipyresis, And Anti-inflammatory Effects
Aspirin is employed for mild to moderate pain but is not effective for severe
visceral pain.
Aspirin and other NSAIDs have been combined with opioid analgesics for
treatment of cancer pain.
High-dose salicylates are effective for treatment of rheumatic fever,
rheumatoid arthritis, and other inflammatory joint conditions.
Commonly treated conditions requiring analgesia include headache,
arthralgia, and myalgia.
Other Effects
Cardiovascular application: inhibitor of platelet aggregation and thrombus
formation
Aspirin decreases the incidence of transient ischemic attacks, unstable angina, coronary
artery thrombosis with myocardial infarction.
ASPIRIN (Acetyl salicylic acid) (ASA)

Adverse effects
1. GI-ulceration & bleeding
3. Contraindicated in gout patients.
Toxicity:-At fairly high doses it causes salicylism (mental confusion,
tinnitus, vertigo, decrease hearing, nausea and vomiting).
Aspirin may cause Reys syndrome (Liver disorder and
encephalopathy) when given to children with viral infections. So it is
best avoided in children under 12 years of age.
Drug interaction
1. Aspirin increases the effect of warfarin by displacing it from plasma
protein binding and also due to its effect on platelets.
2. Aspirin interferes with the effects of uricosuric drugs such as
probenecid and sulphinpyrazone.
2. Propionic acid derivatives
Ibuprofen was the first in this class
It has been followed by naproxen, fenoprofen, ketoprofen,
flurbiprofen, and oxaprozin.
All these drugs possess anti-inflammatory, analgesic, and antipyretic
activity;
Additionally, they can alter platelet function and prolong bleeding
time.
Their GI effects are generally less intense than those of aspirin.
These drugs are reversible inhibitors of COX
3. Acetic acid derivatives
Includes indomethacin, sulindac, and etodolac.
All have anti-inflammatory, analgesic, and antipyretic activity.
They act by reversibly inhibiting COX

4. Oxicam derivatives
Piroxicam and meloxicam
They have long half-lives, which permit once-daily administration
Meloxicam inhibits both COX-1 and COX-2, with preferential binding
for COX-2,---- less GI irritation than piroxicam at low dose
5. Heteroaryl acetic acids
Diclofenac, tolmetin and Ketorolac
Diclofenac is among the most extensively used NSAIDs
Diclofenac is more potent than indomethacin
Diclofenac accumulates in synovial fluid
Tolmetin is an effective anti-inflammatory, antipyretic, and analgesic
agent
Toxicities of these two agents are similar to those of the other
NSAIDs.
Ketorolac is a potent analgesic but has moderate anti-inflammatory
effects
6. COX-2 Selective Inhibitors
COX-2 selective inhibitors, or coxibs,
inhibit PG synthesis by the COX-2 isoenzyme induced at sites of
inflammation
without affecting the "housekeeping" COX-1 isoenzyme found in the GI
tract, kidneys, and platelets
COX-2 inhibitors have analgesic, antipyretic, and anti-inflammatory
effects similar to those of nonselective NSAIDs
COX-2 inhibitors at usual doses have no impact on platelet aggregation,
which is mediated by the COX-1 isoenzyme
As a result, COX-2 inhibitors do not offer the cardioprotective effects of
traditional nonselective NSAIDs
Celecoxib
Celecoxib is a selective COX-2 inhibitorabout 1020
times more selective for COX-2 than for COX-1
Effective as other NSAIDs in the treatment of
rheumatoid arthritis and osteoarthritis
Reduced gastrointestinal adverse effects
It may cause rashes, Probably because it is a
sulfonamide
Does not affect platelet aggregation at usual doses
Other coxibs:-- Etoricoxib, Valdecoxib
Acetaminophen (paracetamol)
This drug does not belong to the NSAIDs.
Unlike the NSAIDs has little or no anti-
inflammatory activity.
Act by inhibiting PG synthesis in CNS & less
effect on peripheral tissue (antipyretic &
analgesic but weak anti-inflammatory
properties),
Therapeutic use- analgesic and antipyretic.
substitute analgesic and antipyretic effects of aspirin for:
those patients with gastric complaints,
those in whom prolongation of bleeding time would be a disadvantage, or
those who do not require the anti-inflammatory action of aspirin.
Acetaminophen is the analgesic/antipyretic of choice for children with viral
infections or chickenpox (recall that aspirin increases the risk of Reye's
syndrome).
Acetaminophen does not antagonize the uricosuric agents probenecid or
sulfinpyrazone and, therefore, may be used in patients with gout who are
taking these drugs.
Adverse effects
They lack many of the side effects of NSAIDs.
Therapeutic dose: - free of any significant side effects.
Large doses: - Very serious hepatic toxicity.