ANALGESIC AGENTS

Maya Ganda Ratna

Department of Pharmacology and Pharmacy
Faculty of Medicine – Lampung University
 Learning Outcome
 Explain the pathophysiology and mechanism of
pain
 Explain the sites of action of analgesics
 Explain the pharmacokinetics and
pharmacodynamics of analgesics
 Explain about non-opioid and opioid analgesics
 Define the drugs used to treat mild, moderate, or
severe pain
 

Neural pain pathways (A Textbook of Clinical Pharmacology and Therapeutics 5 th

ed, 2008)
Influence of inflammatory mediators on activity of a C-fibre nociceptor (A Textbook of Clinical
Pharmacology and Therapeutics 5th ed, 2008)
Pain mechanisms and pathways (Luellmann
Color Atlas of Pharmacology 3rd ed, 2005)
 Sites of
action of
analgesics

Altering
Altering the
the central
central
appreciation
appreciation ofof
pain
pain (another
(another effect
effect
of
of opioids)
opioids)

Closing
Closing the
the ‘gates’
‘gates’ in
the
the dorsal horn and
dorsal horn
in
and
At the site of
thalamus
thalamus (one
(one action
action of
of injury
opioids and of tricyclic
opioids and of tricyclic
antidepressants)
antidepressants) (NSAIDs)

Blocking
peripheral
nerves (local
anaesthetics)
 NSAIDs-Overview

●
Protective response to tissue injury
Body’s effort to inactivate or destroy
Inflammation
●

invading organisms, remove irritants, and set

the stage for tissue repair

●
PGs as local mediators
Prostaglandins ●
Synthesis of PGs >> COX pathway
Synthesis of prostaglandins and
leukotrienes (Lippincot Illustrated
Reviews 6th ed, 2015).
Scheme for mediators derived from arachidonic acid and sites of drug action (dashed arrows) (Katzung
Basic & Clinical Pharmacology 9th ed)
 NSAIDs

A group of chemically dissimilar agents that differ in their antipyretic, analgesic,

and anti-inflammatory activities

Salicylic acid (aspirin), diflunisal, salsalate, propionic acid (ibuprofen), fenoprofen,

flurbiprofen, ketoprofen, naproxen, oxaprozin, acetic acid (diclofenac), etodolac,
indomethacin, ketorolac, nabumetone, sulindac, tolmetin, enolic acid (meloxicam,
piroxicam), fenamates, and and the selective COX-2 inhibitor (celecoxib)
NSAIDs

MoA ●
Inhibit COX enzymes

Prevention of cardiovascular events and most

↓ COX-1
●

adverse events

↓ COX-2 ●
The anti-inflammatory and analgesic actions
 NSAIDs
 Aspirin, indomethacin, piroxicam, and sulindac were
somewhat more effective in inhibiting COX-1.
 Ibuprofen and meclofenamate inhibited the two
isozymes about equally.
 The efficacy of COX-2-selective drugs equals that of
the older NSAIDs, while gastrointestinal safety may
be improved.
 On the other hand, highly selective COX-2 inhibitors
may increase the incidence of edema and
hypertension.
 Aspirin and other NSAIDs

MoA >> Aspirin is a weak organic acid that irreversibly

acetylates (and, thus, inactivates) COX

The other NSAIDs are all reversible inhibitors of COX

Have three major therapeutic actions: reduce inflammation (anti-

inflammatory), pain (analgesic effect), and fever (antipyretic
effect)
 Aspirin and other NSAIDs-Uses

Anti-inflammatory and analgesic uses

●
Th/ of OA, gout, and RA
●
Headache, arthralgia, myalgia, and dysmenorrhea
●
+ opioid >> pain caused by malignancy

Antipyretic uses

Cardiovascular applications

External applications
 Aspirin-PK

Deacetylated by
Oral adm esterases >>
salicylate

Absorbed from
the upper small
intestine

Converted by the
Cross both BBB
liver to water-
and placenta soluble conjugates
 Other NSAIDs-PK

Highly bound to
Oral adm plasma proteins

Met by the liver

mostly to inactivate
metabolites

Cleared by
the kidney
Aspirin and other NSAIDs-AEs

GI
●
Dyspepsia to bleeding
●
Should be taken with food or fluids
●
PPI or misoprostol >> prevent NSAID-induced ulcers

Blood Increased risk of bleeding (antiplatelet

●

effect)

Cardiac
COX-1 selectivity >> cardiovascular protective
●

COX-2 selectivity have been associated with an increased risk

●

for cardiovascular events, including MI and stroke

Aspirin and other NSAIDs-AEs
●
Retention of sodium and water and may
cause edema
Kidney ●
HF or CKD >> high risk
●
Effect >< anti HT therapy

●
Aspirin-sensitive asthma
Others ●
Hypersensitivity (15%)
●
Fatal anaphylactic shock (rare)
Renal effect of NSAIDs inhibition of prostaglandin synthesis(Lippincot Illustrated
Reviews 6th ed, 2015).
 Aspirin

Interactions Toxicity Pregnancy

80-90% bind to albumin Mild >> nausea, vomiting,

>> warfarin, phenytoin, marked hyperventilation, Most NSAIDs >>
or valproic acid headache, mental category C in the first
confusion, dizziness, and two trimesters
tinnitus
CI >> neonates with
hyperbilirubinaemia
>> kern icterus Severe >> restlessness, In the third trimester
delirium, hallucinations,
>> risk of premature
convulsions, coma,
Gout or in patients respiratory and
closure of the ductus
taking probenecid metabolic acidosis arteriosus
Approximate relationships of plasma salicylate levels to pharmacodynamics and complications (Modified and
reproduced, with permission, from Hollander J, McCarty D Jr: Arthritis and Allied Conditions. Lea & Febiger,
1972.)) (Katzung Basic & Clinical Pharmacology 9 th ed)
 Celecoxib

Th/ >> RA, OA, and

Selective COX-2 Similar efficacy to
acute mild to moderate
inhibitor NSAIDs
pain
Celecoxib

PK >> oral adm, metabolized in liver by cytochrome P450 (CYP2C9),

excreted in feces and urine

T½ is about 11 hrs

CI >> pts with severe hepatic or renal disease

AEs >> headache, dyspepsia, diarrhea, and abdominal pain

 Celecoxib-Caution

Pts who are at high risk of Pts who are

ulcers and require aspirin
for cardiovascular allergic to
prevention sulfonamides

Pts who have had Inhibitors of CYP2C9

anaphylactoid reactions to
aspirin or nonselective
NSAIDs may be at risk for
similar effects with celecoxib
(fluconazole, fluvastatin)
may increase serum levels
of celecoxib
 Acetaminophen
 An antipyretic and mild analgesic with few, if any,
anti-inflammatory properties and no effect on
platelet aggregation
 MoA is not completely understood >> inhibits PG
synthesis in the CNS
 The difference from other NSAIDs is still under
investigation >> has less effect on COX in
peripheral tissues (due to peripheral inactivation),
which accounts for its weak anti-inflammatory
activity
 Acetaminophen-Uses
 Analgesic and antipyretic for those patients with
gastric risks, in those whom a prolongation of
bleeding time is not desirable, those who do not
require the anti-inflammatory action of NSAIDs.
 Choice for children with viral infections or
chickenpox (due to the risk of Reye syndrome
with aspirin)
Acetaminophen-PK
Acetaminophen-AEs

Large doses >> hepatic necrosis

NAPQI binds to sulfhydryl of hepatic protein

Pts with hepatic disease, viral hepatitis, or a history of alcoholism

are at higher risk of acetaminophen induced hepatotoxicity

Antidote >> N-acetylcysteine

 Opioids
 Opioids are natural, semisynthetic, or synthetic
compounds that produce morphine-like effects
 Act by binding to specific opioid receptors in the
CNS to produce effects that mimic the action of
endogenous peptide neurotransmitters (eg.
endorphins, enkephalins, and dynorphins)
 Have a broad range of effects >> primary use is
to relieve intense pain (surgery, injury, or chronic
disease)
Opioid Receptors
μ Μodulate responses to thermal, mechanical, and
●

chemical nociception

κ Contribute to analgesia by modulating the response

●

to chemical and thermal nociception

δ The enkephalins interact more selectively with

●

receptors in the periphery.

●
G protein–coupled receptor family and inhibit adenylyl cyclase.
●
Associated with ion channels, ↑ postsynaptic K+ efflux (hyperpolarization) or ↓
presynaptic Ca2+ influx >> impeding neuronal firing and transmitter release
Mechanism of action of μ opioid receptor
agonists in the spinal cord (Lippincot
Illustrated Reviews 6th ed, 2015).
 Morphine
 Strong μ receptor agonist
 MoA >> interacting stereospecifically with
opioid receptors on the membranes of certain
cells in the CNS and other anatomic structures,
such as the GI tract and the urinary bladder
 Morphine-MoA
 Acts at κ receptors in lamina I and II of the dorsal
horn of the spinal cord >> ↓ release of substance
P, which modulates pain perception in the spinal
cord
 Inhibit the release of many excitatory transmitters
from nerve terminals carrying nociceptive
(painful) stimuli.
 Morphine-Action

Analgesia Euphoria

Respiration >> CI:

head trauma or
Depression of
severe brain injury cough reflex
Characteristic pinpoint pupil associated with morphine use(Lippincot
Illustrated Reviews 6th ed, 2015).
 Morphine-Action

Cardiovas
GI tract
cular

Histamine Hormonal
release actions
Morphine-PK

A Significant first-pass metabolism of morphine occurs in the liver

●

Oral absorption is slow and erratic

●

D All body tissues, including the fetuses of pregnant women

●

●
Only a small percentage crosses the BBB

M
Conjugated with glucuronic acid in the liver
●

Morphine-6-glucuronide (very potent analgesic) morphine-3-

●

glucuronide (no analgesic activity)

E Urine
●

●
Bile (small)
 Morphine
Asthma, liver

AEs
●
●
Hypotension, dysphoria,

Caution
sedation, constipation,
disease, or renal
urinary retention, nausea,
dysfunction
respiratory depression
 Morphine
Interaction
Tolerance and
Rare
Repeated use
●
●
●
Depressant actions are
Withdrawal produces a
physical
●

enhanced by phenothiazines,
series ofand
autonomic,
tricyclic motor,
MAOIs,
s
dependence
and psychological responses
antidepressants
 Other Opioid Agonists

Oxycodon Oxymorph
Codeine e one

Hydromor Hydrocod
phone one Fentanyl

Methadon Meperidin
e e
A comparison of opioid agonistefficacy (Lippincot Illustrated Reviews 6 th
ed, 2015).
Summary of clinically relevant properties for each of the μ receptor
agonists(Lippincot Illustrated Reviews 6th ed, 2015).
Summary of clinically relevant properties for each of the μ receptor
agonists(Lippincot Illustrated Reviews 6th ed, 2015).
 Others: Tapentadol, Tramadol

Centrally acting analgesic, agonist at the μ opioid receptor.

For moderate to severe pain

Tapentadol Tramadol

Meta to inactive metabolites via Extensive met via CYP450 2D6 to an

glucuronidation active metabolite
 Reference
 Lippincott Illustrated Reviews: Pharmacology. 6th
ed. 2015.
 Betram G. Katzung Basic & Clinical
Pharmacology. 9th ed.
 A Textbook of Clinical Pharmacology and
Therapeutics. 5th ed. 2008.
 Luellmann Color Atlas of Pharmacology. 3 rd
ed. 2005.