Pain controllers

a. Non-steroidal Anti-Inflammatory
Drugs
b. Opoids

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 Non-steroidal
Anti-inflammatory Drugs (NSAIDS)
• The NSAIDs are a group of chemically dissimilar
agents that differ in their antipyretic, analgesic, and
anti-inflammatory activities.
• They act primarily by inhibiting the cyclooxygenase
enzymes that catalyze the first step in prostanoid
biosynthesis.
• This leads to decreased prostaglandin synthesis
with both beneficial and unwanted effects

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 COX-1,__expressed constitutively in most cells,
is the dominant source of prostanoids for
housekeeping functions, such as gastric epithelial
cytoprotection and hemostasis.
 Conversely, COX-2, induced by cytokines, shear
stress, and tumor promoters, is the more important
source of prostanoid formation in inflammation
and perhaps in cancer .

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• The final product of the COX pathway is tissue
specific.
– Platelets_ produce thromboxane A2 (TxA2);
– vascular endothelial cells_ produce prostacyclin
(PGI2);
– mast cells_ produce prostaglandin D2 (PGD2)
– The vasculature, gastrointestinal (GI) tract, lung,
and other tissues_ produce prostaglandin
E2(PGE2).
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 NSAIDs
• Have a variety of clinical uses as antipyretics,
analgesics, and anti-inflammatory agents.
1. Non selective COX inhibitors
 Aspirin, ibuprofen, mephenamic acid, declofenac,
indomethacin, phenylbutazole
2. Preferentially COX- 2 inhibitors
 Nemesulide, meloxicam, nabumetone
3. Selective COX -2 inhibitors
 Celecoxib, etoricoxib, parecoxib

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 Aspirin and other salicylic acid
derivatives
 Aspirin is the prototype of traditional NSAIDs
 It is the drug to which all other anti-inflammatory agents
are compared.
Mechanism of action:
 It irreversibly inactivates cyclooxygenase.
 The other NSAIDs are all reversible inhibitors of
cyclooxygenase.

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 Aspirin has anti-inflammatory, antipyretic, and analgesic
effects.
 This salicylate effects are due to:
– Primarily to the blockade of prostaglandin synthesis
at the thermoregulatory centers in the hypothalamus
and at peripheral target sites.
– Decreasing prostaglandin synthesis also prevents the
sensitization of pain receptors to both mechanical
and chemical stimuli.
– Aspirin may also depress pain stimuli at subcortical
sites
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Actions:
 The NSAIDs, including aspirin, have three major
therapeutic actions: they reduce
a) Inflammation (anti-inflammation),
b) Pain (analgesia), and
c) Fever (antipyrexia).
 However, not all NSAIDs are equally effective in
each of these actions.

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a) Anti-inflammatory actions of Aspirin:
• Inhibits the formation of prostaglandins __ thus,
modulates those aspects of inflammation in which
prostaglandins act as mediators.
• Aspirin inhibits inflammation in arthritis, but it
neither arrests the progress of the disease nor induces
remission.

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b) Analgesic action:
• PGE2 is thought to sensitize nerve endings to the
action of bradykinin, histamine, and other chemical
mediators released locally by the inflammatory
process___ repress the sensation of pain.
• Used for management of low to moderate intensity
pain arising from musculoskeletal disorders rather than
that arising from the viscera.
• Combinations of opioids and NSAIDs are effective in
treating pain caused by malignancy.
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Antipyretic action:
• Fever occurs when the set-point of the anterior
hypothalamic thermoregulatory center is elevated by
PGE2 synthesis.
– PGE2 synthesis stimulated when endogenous fever-
producing agents (pyrogens), such as cytokines, are
released from WBCs that are activated by infection,
hypersensitivity, malignancy, or inflammation.
• The salicylates imped PGE2 synthesis and release.
• Aspirin has no effect on normal body temperature.

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Respiratory actions:
• At therapeutic doses, aspirin increases alveolar
ventilation. [Note: Salicylates uncouple oxidative
phosphorylation, which leads to elevated CO2 and
increased respiration.]
• Higher doses work directly on the respiratory
center in the medulla, resulting in hyperventilation
and respiratory alkalosis that usually is adequately
compensated for by the kidney.
• At toxic levels, central respiratory paralysis occurs,
and respiratory acidosis ensues due to continued
production of CO2. 13
Gastrointestinal effects:
• Normally, prostacyclin (PGI2) inhibits gastric acid
secretion, whereas PGE2 and PGF2α stimulate
synthesis of protective mucus in both the stomach and
small intestine.
• Aspirin inhibits these prostanoids _ resulting in
increased gastric acid secretion and diminished
mucus protection.
• This may cause epigastric distress, ulceration,
hemorrhage, and iron-deficiency anemia.
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• These GI effects can be managed by:
– Use of buffered and enteric-coated aspirin preparations
– PGE1-derivative misoprostol and the proton-pump
inhibitors (PPIs)
– H2-antihistamines relieve dyspepsia due to NSAIDS,
but they may mask serious GI complaints and may not
be as effective as PPIs for healing and preventing ulcer
formation.

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Effect on platelets:
– Low doses (81 to 325 mg daily) of aspirin can
irreversibly inhibit thromboxane production in platelets
via acetylation of cyclooxygenase.
– Because platelets lack nuclei, they cannot synthesize new
enzyme ___ producing an antiplatelet effect with a
prolonged bleeding time.
– Finally, aspirin also inhibits cyclooxygenase in
endothelial cells, resulting in reduced PGI2 formation.__
However, endothelial cells possess nuclei and are able to
re-synthesize new cyclooxygenase.
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Actions on the kidney:
– Cyclooxygenase inhibitors prevent the synthesis of PGE2
and PGI2, prostaglandins that are responsible for
maintaining renal blood flow, particularly in the presence
of circulating vasoconstrictors.
– Decreased synthesis of prostaglandins can result in
retention of sodium and water and may cause edema and
hyperkalemia in some patients.

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Therapeutic uses:
 Anti-inflammatory, antipyretic, and analgesic uses:
• The salicylic acid derivatives are used in the treatment
of
– Gout, rheumatic fever, osteoarthritis, and
Reumathoid Arthritis.
– common conditions (headache, arthralgia, and
myalgia) requiring analgesia.

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Cardiovascular applications:
• Aspirin is used to inhibit platelet aggregation.
• Low doses are used prophylactically to reduce the risk
of
– recurring transient ischemic attacks (TIAs) and stroke
or death
– death in those having an acute Myocardial Infraction
(MI),.
– recurrent nonfatal MI and/or death in patients with
previous MI or unstable angina pectoris,
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 Pharmacokinetics:
 Administration and distribution:
– Absorbed partly from the stomach and mostly from the
upper small intestine.
– Rectal absorption is slow and unreliable.
– Salicylates cross both the blood-brain barrier and the
placenta and are absorbed through intact skin
(especially methyl salicylate).

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 Adverse effects:
a) Gastrointestinal:
• Epigastric distress, nausea, and vomiting.
• Microscopic GI bleeding is almost universal in patients
treated with salicylates.
– Aspirin should be taken with food and large volumes of
fluids to diminish dyspepsia.
– Additionally, misoprostol or a PPI may be taken
concurrently.

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• Blood:
– Inhibition of platelet aggregation and a prolonged
bleeding time.
– Aspirin should not be taken for at least 1 week
prior to surgery.

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 Metabolic processes:
– The energy is dissipated as heat
– Which explains the hyperthermia caused by
salicylates when taken in toxic quantities.
 Hypersensitivity: __ 15%
– Symptoms of true allergy include urticaria,
bronchoconstriction, and angioedema.
– Fatal anaphylactic shock is rare.

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• Reye syndrome: swelling in liver and brain
– Aspirin and other salicylates given during viral
infections have been associated with an increased
incidence of Reye syndrome__characterized by the
acute onset of encephalopathy, liver dysfunction, and
fatty infiltration of the liver and other viscera .
– contraindicated in children and young adults <20 years
of age with viral illness–associated fever
– acetaminophen used instead of aspirin when
medication is required to reduce fever.
– Ibuprofen is also appropriate.
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• In pregnancy:
– Aspirin is classified as FDA pregnancy category C risk
during the first and second trimesters and category D
during the third trimester.
– Because salicylates are excreted in breast milk, aspirin
should be avoided during pregnancy and while
breastfeeding.

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 Toxicity
Salicylate intoxication
• The mild form__ is called salicylism
– Characterized by nausea, vomiting, marked
hyperventilation, headache, mental confusion,
dizziness, and tinnitus.
• Management
– Symptomatic treatment is usually sufficient.
– Increasing the urinary pH enhances the elimination of
salicylate.

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• Severe salicylate intoxication
– When large doses of salicylate are administered
– The symptoms listed above are followed by
restlessness, delirium, hallucinations, convulsions,
coma, respiratory and metabolic acidosis, and death
from respiratory failure
• Management
– IV administration of fluid,
– dialysis (hemodialysis or peritoneal dialysis), and
– frequent assessment and correction of acid-base and
electrolyte balances.
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 Propionic acid derivatives
• Agents includes:
– Ibuprofen ,naproxen,
• All of these drugs possess anti-inflammatory,
analgesic, and anti-pyretic activity.
• Reversible inhibitors of the cyclooxygenases
• Inhibit the synthesis of PG but not of LK like aspirin
• Chronic treatment of RA and osteoarthritis, because
their GI effects are generally less intense than those
of aspirin.

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Uses
1. As an analgesic in painful conditions.
2. In fever.
3. Soft tissue injuries, fractures, following tooth
extraction, to relieve postoperative pain,
dysmenorrhoea and osteoarthritis.
4. Gout.
5. Surgical removal of impacted tooth-
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 Acetic acid derivatives
• group of drugs includes:
– Indomethacin sulindac, and etodolac .
• All have anti-inflammatory, analgesic, and antipyretic
activity.
• Reversibly inhibiting cyclooxygenase.
• They are generally not used to lower fever.
• Indomethacin use
– acute gouty arthritis__toxicity limits its use
– To close a PDA in neonates
– Ankylosing spondylitis, and
– Osteoarthritis of the hip 30
 Oxicam derivatives
 The groups include: Piroxicam and meloxicam
 Are used to treat RA, ankylosing spondylitis, and OA.
 Long half lives_once-daily administration,
 The parent drug as well as its metabolites are renally
excreted in the urine
• Meloxicam
– Preferential bind to COX-2, and
– At low to moderate doses shows less GI irritation
than piroxicam.

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 Heteroaryl acetic acids
• The groups include:
– Diclofenac, Tolmetin, Ketorolac.
• Diclofenac
– Approved for long-term use in the treatment of RA,
OA, and ankylosing spondylitis.
– It is more potent than indomethacin or naproxen
– Its tissue penetrability is good and attains good
concentration in synovial fluid which is maintained for
a long time.

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Uses of Diclofenac
– Treatment of chronic inflammatory conditions like
rheumatoid arthritis and osteoarthritis.
– Acute musculoskeletal pain, painful dental lesions.
– Postoperatively for relief of pain and inflammation.

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 SELECTIVE COX-2 INHIBITORS_ Celecoxib,
rofecoxib and valdecoxib
• More selective for inhibition of COX-2__ which is
time dependent and reversible.
• Does not inhibit platelet aggregation and does not
increase bleeding time.
• Less GI bleeding and dyspepsia_ when used without
concomitant aspirin
• In patients at high risk for ulcers (that is, history of peptic
ulcer disease), use of PPIs with celecoxib and aspirin may
be necessary to avoid gastric ulcers

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• They have good anti-inflammatory, analgesic and
antipyretic properties but do not affect platelet
aggregation
Disadvantages
• The COXIBs can cause hypertension and oedema
which can be troublesome in patients with
cardiovascular problems.
• Studies have shown that use of coxibs can increase the
risk of myocardial infarction and stroke.
• The exact cause is not known but could be because of
inhibition of PGI2 production without inhibiting TXA235
 ACETAMINOPHEN
• Acetaminophen, (N-acetyl-p-aminophenol)
• Inhibits prostaglandin synthesis in the CNS.
– This explains its antipyretic and analgesic properties.
• Less effect on cyclooxygenase in peripheral tissues,
– accounts for its weak anti-inflammatory activity.
• Does not affect platelet function or increase blood-
clotting time.
• Not considered to be an NSAID

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Therapeutic uses Acetaminophen
• suitable substitute for the analgesic and antipyretic
effects of aspirin for those patients with
– gastric complaints,
– prolongation of bleeding time would be a
disadvantage,
– who do not require the anti-inflammatory action of
aspirin.
– for children with viral infections or chickenpox
(recall that aspirin increases the risk of Reye
syndrome).
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• .
Pharmacokinetics
– Acetaminophen is rapidly absorbed from the GI tract.
– significant first pass metabolism
– A portion of acetaminophen is hydroxylated to form N-
acetylbenzoiminoquinone, (N-acetyl-p-
benzoquinoneimine, or NAPQI), a highly reactive and
potentially dangerous metabolite that reacts with
sulfhydryl groups and causes liver damage.
– At normal doses of acetaminophen, NAPQI reacts with
glutathione, forming a nontoxic substance
– Acetaminophen and its metabolites are excreted in urine.
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 Adverse effects
 With normal therapeutic doses, free of any
significant adverse effects.
 Skin rash and minor allergic reactions (infrequently)
 Renal tubular necrosis (rare)- long and large dose
 Hepatic necrosis__ due to NAPQI at In adults,
ingestion of a single dose of 10-15 g (150-250
mg/kg) of acetaminophen; doses of 20-25 g or
more are potentially fatal
– Administration of N-acetylcysteine, can be
lifesaving if administered within 10 hours of the
overdose. 39