Pharmacology

ANALGESICS
Pathogenesis of pain
Intense stimulus (e.g. tissue injury)
releases substances that sensitize pain
receptors to mechanical, thermal, and
chemical stimulation.

This triggers pain receptors to send pain

impulses over afferent nerve fibers to the
central nervous system (CNS) .
Pain…
1. Awareness of pain occurs in the thalamus.
2. Pain recognition and localization occur in the cortex.
Examples of pain blocking meds you
know??
ANALGESICS
 These are drugs which are used to decrease pain.
 3 main classes of analgesics:
Non-steroidal anti-inflammatory drugs (NSAIDs)
Paracetamol
Opiods
NSAIDs
• These drugs inhibit COX enzymes and thromboxane
synthetase.

 Inhibitboth COX-1 (produces prostaglandins-

cytoprotective of the stomach lining) and COX-2
(produces prostaglandins responsible for pain and
inflammation).
NSAIDs

• Classified as COX-1 and COX-2 selective agents.

• COX-2 selective agents include

• celecoxib,
• rofecoxib,
• valdecoxib etc,
• Are used mainly for inflammation and pain associated with
osteoarthritis and rheumatoid arthritis.

• Non-selective COX-1 and COX-2 agents include

• Ibuprofen,
• naproxen,
• indomethacin,
• ketoprofen,
• diclofenac etc.
These are used mainly for general pain
NSAIDs

• NSAIDs have
• analgesic,
• antipyretic
• anti-inflammatory effects.

They are effective for mild to moderate pain

associated with inflammation (reduce the cause
of pain as well as the sensation of pain).

The analgesic action results from 2 mechanisms.

NSAIDs MOA
a) Peripheral mechanisms:
◦ Inhibition of prostaglandins (esp. PGE2 in the
pain receptors)

b) Central mechanisms
◦ Prostaglandins act in the spinal cord and higher
centres to promote the transmission of pain
signals to the brain.
◦ They thus block the peripheral generation of
pain impulses mediated by prostaglandins and
other chemicals
NSAIDs
Indications??
NSAIDs
 NSAIDs act on the hypothalamic thermo-regulating
center to produce peripheral vasodilation, via
prostaglandin synthesis inhibition.

 Theyare also effective for headaches (headaches may be

caused by prostaglandins esp PGE2).

 They
can also be used for surgical and cancer pain (if
combined with opiods).
NSAIDs
A/E: GI effects, bleeding, hypersensitivity,
headache, dizziness, nephrotoxicity, fluid
retention.
Drug interactions:
◦ oral anticoagulants (↑bleeding).
◦ Other NSAIDs and aspirin (ulcers).
◦ Lithium (↑ lithium levels).
◦ Methotrexate (↑ methotrexate levels).
◦ Probenecid (inhibit renal excretion of drugs)
Salicylates
Used to relieve mild to moderate pain and reduce
inflammation and fever.

Act on the hypothalamic thermo-regulating center to

produce peripheral vasodilation, which results from
the inhibition of prostaglandin synthesis

Aspirin (acetylsalicylic acid)- also used to reduce

the incidence of some forms of cardiovascular
disease (MI, stable and unstable angina, or coronary
artery bypass surgery).
Salicylates
Aspirin irreversibly inhibits COX in platelets,
which prevents the formation of the aggregating
agent thromboxane A2 .

This results in the antiplatelet and

antithrombotic effects.

A/E: allergic reactions, GI effects, tinnitus,

dizziness, salicylism.
 Salicylates
Interactions:
◦ Potentiate anticoagulants and thrombolytic agents.

◦ Potentiate (at anti-inflammatory doses) the effect of hypoglycemics.

◦ Potentiate the adverse GI reaction resulting from chronic alcohol or

NSAID use (irritation).

◦ Aspirin may competitively inhibit the metabolism of zidovudine,

resulting in potentiation of zidovudine or aspirin toxicity.

◦ Caffeine taken in conjunction with salicylates appears to enhance

the analgesic effect .
ANALGESICS
Paracetamol
Analgesic and antipyretic
Paracetamol is used for:
Analgesia- does not act on the peripheral
nociceptors like the NSAIDs
It inhibits spinal and supraspinal pain pathways.
It can be used to treat mild to moderate pain, but
not pain due to inflammation.
Antipyretic-it inhibits PGE2 synthesis in the
hypothalamus.

It is recommended for use in children with fever.

Aspirin should not be used in fever because that

results in Reyes syndrome which manifests as
liver damage and encephalopathy (a brain
disorder).
ANALGESICS
Beneficial and adverse effects of paracetamol.
 No GI irritation(GI irritation is due to inhibition of
prostaglandins in the mucosal lining, but paracetamol
doesn’t cause inhibition of prostaglandins in the
periphery hence the effect).

 A/E: Minor allergic reactions (rare), overdose can

cause liver damage.
 OPIOD ANALGESICS
 These
agents have a different mechanism of action to paracetamol and
NSAIDs (don’t inhibit COX).

 Use is highly controlled.

 Receptors are located in the brain and spinal cord (μ, κ, δ , σ, and ε).

 Stimulation of μ receptors produces the characteristic narcotic (morphine

- like) effects.
◦ Analgesia
◦ Miosis
◦ Euphoria
◦ Respiratory depression
◦ Sedation
◦ Bradycardia
◦ Physical dependence
MOA:
a) inhibit the transmission of pain signals
by preventing the primary afferent fibre
from releasing neurotransmitter .

 b) prevent the interneuron from firing,

thus allowing descending inhibitory fibres
to work again.
OPIOD ANALGESICS
OPIOD
ANALGESICS
Effects of opiods??
OPIOD ANALGESICS
 Opiods have actions on the CNS and at the periphery.
CNS effects
Analgesia.
Reduce nociception.
Also reduce the affective component of pain (i.e. the
response to pain).
Euphoria (elevated mood, relief of anxiety associated
with pain-reason for abuse).
Dysphoria can occur in some instances.
At therapeutic levels, respiratory depression occurs
(fatal if overdose occurs).
Antitussive (anticough) effect.
Nausea and vomiting.
Constriction of the pupil.
OPIOD ANALGESICS
Peripheral effects
Decrease in propulsive motility of the GIT, increase in
sphincter tone (causes slow transit time allowing
increased absorption of water, thus resulting in
constipation).

Urinary retention (this is due to increased tone of the

bladder sphincter muscle).

Histamine release

A/E: constipation, anticholinergic effects, N/V, sedation,

hypersensitivity, respiratory depression, CNS excitement.
OPIOD ANALGESICS
Opiod receptors: 4 types μ, σ, δ, κ.
 μ and δ are functionally identical (they cause
hyperpolarization of a nerve terminal by opening K
channels).

μ receptors are highly concentrated in the areas of the

brain involved in nociception and it is the receptor with
which morphine predominantly interacts with.

 The κ receptor inhibits membrane Ca channels.

OPIOD ANALGESICS

Pharmacokinetics
 Well absorbed in the GIT.
 Undergoes significant first pass hepatic metabolism (low
bioavailability of 20-30% ).
 As a result there is a greater level of activity if morphine
is given IV.
Disadvantage of IV morphine:
 Increased risk of tolerance (tolerance to one opiod can
lead to tolerance of other opiods).
 Tolerance occurs through:
◦ Uncoupling of the receptors and 2nd messengers.
◦ Small rise in the # of 2nd messengers which are
activated by the receptor hence there is a lower
response.
◦ A decrease in the # of receptors.
OPIOD ANALGESICS
 Dependence (usually accompanies the tolerance i.e. the
more tolerant you are, the more dependent you become).

 Physical dependence is characterized by an

abstinence/withdrawal syndrome.

 Inorder to maintain normal physiological function, the

body now requires the presence of a drug.

 The intensity of the withdrawal syndrome for morphine

is proportional to the degree of tolerance.
OPIOD DEPENDENCY
OPIOD ANALGESICS

Extent of tolerance developed to some of the effects of opiods

High degree of Moderate degree of Minimal or no
tolerance tolerance tolerance

Analgesia Bradycardia Miosis (pupil

constriction)
Euphoria Constipation
Mental clouding Convulsions
Respiratory depression Antagonist actions
Sedation
Antidiuresis
Nausea and vomiting
Cough
Interactions
Alcohol, sedatives, anaesthetics
(potentiate depressant effects of opiods)
Antidiarrhoeals (↑ constipation)
Anticholinergics (↑ constipation and
urinary retention)
Antihypertensives (↑ hypotensive effect)
Cimetidine (↑toxic effects)
OPIOD ANALGESICS
Naloxone
 Pure opiod receptor antagonist.
 Has an affinity for opiod receptors.
 Not orally active due to hepatic metabolism(use
IV/IM/SC).
 It will induce severe withdrawal reaction symptoms
because of the rapid decline in activity of opiods.
 It will inhibit the pain relieving effects of opiods.
 It rapidly reverses respiratory depression and
cardiovascular depression.
 It has a short half life, therefore, actions of the opiods
can start working again when the effects of naloxone
wear off.
OPIOD ANALGESICS