NSAIDs, Acetaminophen, & Drugs

Used in Rheumatoid Arthritis & Gout

Aspirin
 Pharmacokinetics
• Aspirin is readily absorbed and is hydrolyzed in blood and
tissues to acetate and salicylic acid.
• Salicylate is a reversible nonselective inhibitor of
cyclooxygenase.
• Elimination of salicylate is first order at low doses, with a half-
life of 3–5 h.
• At high (anti-inflammatory) doses, half-life increases to 15 h
or more and elimination becomes zero order. Excretion is via
the kidney.
 Mechanism of action
• Aspirin is a weak organic acid that is unique among the
NSAIDs in that it irreversibly acetylates (and, thus, inactivates)
cyclooxygenase

• Aspirin is rapidly deacetylated by esterases in the body

producing salicylate, which has anti-inflammatory, antipyretic,
and analgesic effects
The other NSAIDs,
including salicylate,
are allreversible
inhibitors of
cyclooxygenase
 Actions
• The NSAIDs, including aspirin, have major
therapeutic actions—namely, they reduce
1. inflammation (anti-inflammation)
2. pain (analgesia)
3. fever (antipyrexia)
4. Anti platelet
 Anti inflammatory action
• aspirin inhibits cyclooxygenase activity
• it diminishes the formation of prostaglandins
• thus, modulates those aspects of
inflammation in which prostaglandins act as
mediators
NSAIDs have no effect on lipoxygenase and
therefore do not inhibit the production of
leukotrienes
 Analgesic effect
• a. PGE2 and PGI2 are the most important prostaglandins
involved in pain. Inhibition of their synthesis is a primary
mechanism of NSAID-mediated analgesia.
• b. Prostaglandins sensitize pain receptors .NSAIDs prevent the
potentiating action of prostaglandins on endogenous
mediators of peripheral nerve stimulation (e.g., bradykinin).
 Antipyretic
• Fever occurs when the set-point of the anterior hypothalamic
thermoregulatory center is elevated.
• This can be caused by PGE2 synthesis, which is stimulated when an
endogenous fever-producing agent (pyrogen), such as a cytokine, is
released from white cells that are activated by infection, hypersensitivity,
malignancy, or inflammation.
• The salicylates lower body temperature in patients with fever by impeding
PGE2 synthesis and release
 Antiplatelet effect
• At low dose NSAIDs irreversibly inhibit
thromboxane A2 produced by the platelets.As
result of decrease in thromboxane A2 platelet
aggregation effect is reduced

. Low doses (60–81 mg daily) of

aspirin can irreversibly inhibit
thromboxane production in
platelets
 So you will always give
aspirin in lower dose for
antiplatelet action…
Therapeutic uses
• treatment of gout
• rheumatic fever
• Osteoarthritis
• RA
• Headache
• Arthralgia
• myalgia.
Dosage
• two 325-mg aspirin tablets administered four times daily produce
analgesia

• 12 to 20 tablets per day produce both analgesic and anti-inflammatory

activity

• . For longterm myocardial infarction prophylaxis, the dose is 81 to 162

mg/day

• In RA or osteoarthritis, the initial dose is 3 grams/day

• for stroke prophylaxis, the dose is 50 to 325 mg/day

Adverse effects
• Gastrointestinal(epigastric distress, nausea, ulcer and vomiting)
• Blood ( Donot use atleast 1 week prior to surgery and reduce the dosage of anticoagulant when
given with aspirin)
• Respiration(In toxic doses, salicylates cause respiratory depression and a combination of
uncompensated respiratory and metabolic acidosis)
• Metabolic processes: Large doses of salicylates uncouple oxidative phosphorylation. The
energy normally used for the production of adenosine triphosphate is dissipated as heat, which explains
the hyperthermia caused by salicylates when taken in toxic quantities)

• Hypersensitivity
• Salicylism: tinnitus, vertigo, decrease hearing-often first signs of toxicity
• Bronchoconstriction: exacerbation of asthma (Bcz leukotrine increase)
• REYES SYNDROME

• children with viral infections who are treated with aspirin

have an increased risk for developing Reye’s syndrome

Acetaminophen instead of aspirin

when such medication is required
to reduce fever. Ibuprofen is also
appropriate.
 Drug Interection
• Salicylate is 90 to 95 percent protein bound and can be displaced from its
protein-binding sites, resulting in increased concentration of free salicylate;
alternatively, aspirin could displace other highly protein-bound drugs, such as
warfarin, phenytoin, or valproic acid

• Chronic aspirin use should be avoided in patients receiving probenecid or

sulfinpyrazone, because these agents cause increased renal excretion of uric
acid

• Concomitant use of ketorolac and aspirin is contraindicated because of

increased risk of GI bleeding and platelet aggregation inhibition

• Children who have received live varicella virus vaccine should avoid aspirin for
at least 6 weeks after vaccination to prevent Reye's syndrome
 IMPORTANT
• Aspirin decreases the incidence of
• transient ischemic attacks
• unstable angina
• coronary artery thrombosis with myocardial infarction
• thrombosis after coronary artery bypass grafting
• The most plausible mechanism for a cardioprotective effect
of aspirin derives from its ability to decrease platelet
aggregation and thereby reduce the risk of thrombotic
vascular events.
Other NSAIDS
 Ketorelac greater analgessia.
Indomethacin greater
antinflammatory
It’s only NSAID in perentral form
COX-2 inhibitors
 COX 2 inhibitors have
Rofecoxib and valdecoxib shown higher incidence of
increase the risk of MI cardiovascular
thrombocytic events than
non selective drugs
Acetaminophin
DRUGS USED IN GOUT
 What is Gout?
• Gout is associated with increased serum
concentrations of uric acid.
• Acute attacks involve joint inflammation
initiated by precipitation of uric acid crystals
 Treatment strategies in Gout
• (1) reducing inflammation during acute attacks (with
colchicine, NSAIDs, or glucocorticoids
• (2) accelerating renal excretion of uric acid with uricosuric
drugs (probenecid or sulfinpyrazone)
• (3) reducing (with allopurinol or febuxostat) the conversion of
purines to uric acid by xanthine oxidase
Management of acute Gout
attack
• NSAIDs such as indomethacin are effective in inhibiting the inflammation
of acute gouty arthritis.
• These agents act through the reduction of prostaglandin formation and
the inhibition of crystal phagocytosis by macrophages

• Glucocorticoids are also effective in inhibiting the inflammation of acute

gouty arthritis
• Colchicine, a selective inhibitor of microtubule assembly, reduces
leukocyte migration and phagocytosis; the drug may also reduce
production of leukotriene B4 and decrease free radical formation.
 Pharmacokinetics
• An NSAID or a glucocorticoid is preferred for the treatment of
acute gouty arthritis.

• h colchicine can be used for acute attacks, the doses required

cause significant gastrointestinal disturbance, particularly
diarrhea(proff mcqs)
 Toxicity
• NSAIDs can cause renal damage, and indomethacin can
additionally cause bone marrow depression.
• Short courses of glucocorticoids can cause behavioral changes
and impaired glucose control.
• Because colchicine can severely damage the liver and kidney,
dosage must be carefully limited and monitored and can
cause severe diarrhea
Management of chronic gout
• Chronic gout can be caused by
• 1) a genetic defect, such as one resulting in an
increase in the rate of purine synthesis
• 2) renal deficiency
• 3) Lesch-Nyhan syndrome
• 4) excessive productionof uric acid associated
with cancer chemotherapy
 Uricosuric Agents
• Normally, over 90% of the uric acid filtered by the kidney is
reabsorbed in the proximal tubules.
• Uricosuric agents (probenecid, sulfinpyrazone) are weak acids
that compete with uric acid for reabsorption by the weak acid
transport mechanism in the proximal tubules and thereby
increase uric acid excretion
At low doses, these agents
may also compete with uric
acid for secretion by the
tubule and occasionally
can elevate, rather than
reduce, serum uric acid
concentration
 Toxicity
• Uricosuric drugs can precipitate an attack of acute gout during
the early phase of their action.
• This can be avoided by simultaneously administering
colchicine or indomethacin.
• Because they are sulfonamides, the uricosuric drugs may
share allergenicity with other classes of sulfonamide drugs
(diuretics, antimicrobials, oral hypoglycemic drugs)
Xanthine Oxidase Inhibitors

. Clinical trials suggest that

febuxostat is more effective than
allopurinol in lowering serum uric
acid
 Adverse effects
• Allopurinol causes gastrointestinal upset
• Rash

• Like uricosuric agents, these drugs are usually

withheld for 1–2 wk after an acute episode of
gouty arthritis and are administered in
combination with colchicine or an NSAID to avoid
an acute attack
Interection
DMARDS
• Toxic effects
• CHLOROQUINE & HYDROXYCHLOROQUINE
• ocular toxicity
• ophthalmologic monitoring every 12 months is advised.
• Other toxicities include
• Dyspepsia
• Nausea
• Vomiting
• abdominal pain,
• Rashes
• and nightmares
• Methotrexate
• Nausea and mucosal ulcers are the most common toxicities.
• Leukopenia
• Anemia
• Stomatitis
• GI ulcerations,
• alopecia are probably the result of inhibiting cellular proliferation
• Rare hypersensitivity-like lung reaction with acute shortness of
breath has been documented, as have pseudo-lymphomatous
reactions.