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 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
Pain

A consequence of complex neurochemical processes in the


peripheral and central nervous systems (CNS)

Alleviation of pain depends on the specific type of pain

Nociceptive Neuropathic

Neural pain pathways (A Textbook of Clinical Pharmacology and


Therapeutics 5th 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)
Closing the ‘gates’
in the dorsal horn
Blocking peripheral
and thalamus (one
nerves (local
action of opioids
anaesthetics)
and of tricyclic
antidepressants)

Altering the central


At the site of injury appreciation of
(NSAIDs) pain (another
effect of opioids)
Sites of
action of
analgesics
• Protective response to tissue
injury
• Body’s effort to inactivate or
Inflammation destroy invading organisms,
remove irritants, and set the
stage for tissue repair

• PGs as local mediators


• Synthesis of PGs >> COX
pathway
Prostaglandins
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)
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)
MoA • Inhibit COX enzymes

• Prevention of cardiovascular events


↓ COX-1 and most adverse events

• The anti-inflammatory and analgesic


↓ COX-2 actions
 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.
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)
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
Deacetylated Absorbed from
Oral adm by esterases >> the upper small
salicylate intestine

Converted by
Cleared by the
the liver to Cross both BBB
kidney (organic
water-soluble and placenta
acid)
conjugates
Highly bound to
Oral adm
plasma proteins

Met by the liver


Cleared by the mostly to
kidney inactivate
metabolites
• Dyspepsia to bleeding
• Should be taken with food or fluids
GI • PPI or misoprostol >> prevent NSAID-induced ulcers

• Increased risk of bleeding (antiplatelet effect)


Blood

• COX-1 selectivity >> cardiovascular protective


• COX-2 selectivity have been associated with an increased
Cardiac risk for cardiovascular events, including MI and stroke
• Retention of sodium and water and may
cause edema
• HF or CKD >> high risk
Kidney • Effect >< anti HT therapy

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

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


>> warfarin, phenytoin, vomiting, marked
Most NSAIDs >>
or valproic acid hyperventilation,
category C in the first
headache, mental
two trimesters
confusion, dizziness,
and tinnitus
CI >> neonates with
hyperbilirubinaemia >>
kern icterus
Severe >> restlessness,
In the third trimester >>
delirium, hallucinations,
risk of premature
convulsions, coma,
Gout or in patients closure of the ductus
respiratory and
taking probenecid arteriosus
metabolic acidosis
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 9th ed)
• Selective • Th/ >> RA, • Similar
COX-2 OA, and efficacy to
inhibitor acute mild NSAIDs
to moderate
pain
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
Pts who are at high risk
of ulcers and require
Pts who are allergic to
aspirin for
sulfonamides
cardiovascular
prevention

Pts who have had


anaphylactoid reactions Inhibitors of CYP2C9
to aspirin or (fluconazole, fluvastatin)
nonselective NSAIDs may increase serum
may be at risk for similar levels of celecoxib
effects with celecoxib
 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
 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)
Rapidly absorbed from the GI tract (available in IV and rectal formulations
too)

Conjugated in the liver to form inactive glucuronidated or sulfated


metabolites

A portion is hydroxylated to form N-acetyl-p-benzoquinoneimine (NAPQI) >>


react with sulfhydryl group of glutathione >> forming a nontoxic substance

Exc >> urine


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 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)
• Μodulate responses to thermal, mechanical, and chemical nociception
μ

• Contribute to analgesia by modulating the response to chemical and thermal


nociception
κ

• The enkephalins interact more selectively with receptors in the periphery.


δ

• 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).
 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
 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.
Respiration >>
CI: head trauma
Analgesia Euphoria
or severe brain
injury

Depression of
Miosis Emesis
cough reflex
Characteristic pinpoint pupil associated with morphine
use(Lippincot Illustrated Reviews 6th ed, 2015).
Histamine
GI tract Cardiovascular
release

Hormonal
Labor
actions
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)
• Hypotension,
dysphoria, sedation,
constipation, urinary
AEs
retention, nausea,
respiratory
depression

• Asthma, liver
Caution disease, or renal
dysfunction
• Repeated use
• Withdrawal
Tolerance and produces a series of
physical dependence autonomic, motor,
and psychological
responses

• Rare
• Depressant actions
Interactions are enhanced by
phenothiazines,
MAOIs, and tricyclic
antidepressants
Codeine Oxycodone Oxymorphone

Hydromorphone Hydrocodone Fentanyl

Methadone Meperidine
A comparison of opioid agonistefficacy (Lippincot Illustrated
Reviews 6th 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).
Centrally acting analgesic, agonist at the μ opioid receptor.
For moderate to severe pain

Tapentadol Tramadol

Meta to inactive Extensive met via CYP450


metabolites via 2D6 to an active
glucuronidation metabolite
 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. 3rd ed. 2005.