5. Pharmacological actions of aspirin
and other NSAIDs
• Analgesic effect
– mainly used for relieving musculoskeletal pain.
– dysmenorrhoea and pain associated with
inflammation or tissue damage.
– Analgesic effect is mainly due to peripheral
inhibition of PG production.
– They also reduce pain by acting at subcortical
site. These drugs relieve pain without causing
sedation, tolerance or drug dependence
6. Pharmacological actions
• Antipyretic effect
– mainly due to inhibition of PGs in the hypothalamus.
– They promote heat loss by causing cutaneous
vasodilatation and sweating.
– They do not affect normal body temperature.
• Anti-inflammatory effect:
– These drugs produce only symptomatic relief. They
suppress signs and symptoms of inflammation such as
pain, tenderness, swelling, vasodilatation and
leukocyte infiltration but do not affect the
progression of underlying disease.
– mainly due to inhibition of PG, bradykinin, histamine,
serotonin, etc synthesis at the site of injury. thus
inhibit granulocyte adherence to the damaged
vasculature.
7. Pharmacological actions
• Antiplatelet (antithrombotic) effect
– Aspirin in low doses (50–325 mg/day) irreversibly
inhibits platelet TXA2 synthesis and produces
antiplatelet effect, which lasts for 8–10 days.
– Aspirin in high doses (2–3 g/day) inhibits both
PGI2 and TXA2 synthesis.
9. Pharmacological actions
• Cardiovascular system (CVS)
– Prolonged use of aspirin and other NSAIDs causes
sodium and water retention.
– They may precipitate congestive cardiac failure
(CCF) in patients with low cardiac output. They
may also decrease the effect of antihypertensive
drugs.
• For patients with cardiovascular disease or risk
factors for ischemic heart disease:
acetaminophen, aspirin, tramadol, opioidsare
recommended before moving to an NSAID
10. Adverse effects
• GIT
– Nausea, vomiting, dyspepsia, epigastric pain,
acute gastritis, ulceration and GI bleeding.
– Ulcerogenic effect is the major drawback of
NSAIDs, which is prevented/minimized by taking:
• NSAIDs after food.
• proton pump inhibitors/H2-blockers/misoprostol with
NSAIDs.
• Coated aspirin.
• selective COX-2 inhibitors.
11.
12. Adverse effects
• Hypersensitivity
– It is relatively more common with aspirin. The
manifestations are skin rashes, urticaria, rhinitis,
bronchospasm.
– Bronchospasm (aspirin-induced asthma) is due to
increased production of leukotrienes.
• Reye’s syndrome
– Use of salicylates in children with viral infection may
cause hepatic damage with fatty infiltration and
encephalopathy—Reye’s syndrome. Hence, salicylates
are contraindicated in children with viral infection.
13. Adverse effects
• Pregnancy
– These drugs inhibit PG synthesis, thereby delay onset
of labour and increase chances of postpartum
haemorrhage.
• Analgesic nephropathy
– Salt &water retention & edema of lower limbs
– Hyperkalemia
– Interstitial nephritis
– Slowly progressive renal failure may occur on chronic
use of high doses of NSAIDs. Renal failure is usually
reversible on stoppage of therapy but rarely, NSAIDs
may cause irreversible renal damage.
15. Clinical uses of NSAIDs
• As analgesic & Anti-inflammatory
– In painful conditions like toothache, headache,
backache, bodyache, muscle pain, other joint
pain, neuralgias, dysmenorrhoea, etc.
• As asntipyretic
– To reduce elevated body temperature in fever
paracetamol is preferred because:
• Gastrointestinal symptoms are rare.
• It does not cause Reye’s syndrome in children.
16. Clinical uses of NSAIDs
• Thromboembolic disorders
– The antiplatelet effect of low-dose aspirin is made
use of in the prophylactic treatment of various
thromboembolic disorders, such as:
• Transient ischaemic attacks (TIA)
• Myocardial infarction (MI)
– to reduce incidence of recurrent MI to decrease mortality in
post-MI patients
• Other uses:
– Colon and rectal cancer: Regular use of aspirin is
reported to reduce the risk of cancer.
– Reduce the risk and retard the onset of
Alzheimer’s disease.
17. Other NSAIDs
• They have similar mechanism of action,
pharmacological actions, therapeutic uses and
adverse effects.
• They vary mainly in their potency, duration of
action, analgesic and anti-inflammatory
effects.
24. Paracetamol
• Mechanism of Action
– The drug is only a weak COX-1 and COX-2 inhibitor in
peripheral tissues, which accounts for its lack of anti-
inflammatory effect.
– Evidence suggests that acetaminophen may inhibit a
third enzyme, COX-3, in the CNS.
• Uses
– As antipyretic
– As analgesic: To relieve headache, toothache,
dysmenorrhoea, etc.
– It is the preferred analgesic and antipyretic in patients
with peptic ulcer, bronchial asthma and children.
25. Paracetamol
• Adverse effects
– Side effects are rare, occasionally causes skin rashes and
nausea.
– Hepatotoxicity: with acute overdose or chronic use.
– Nephrotoxicity is commonly seen on chronic use
• Acute paracetamol poisoning
– Acute overdosage mainly causes hepatotoxicity—
symptoms are nausea, vomiting, diarrhoea, abdominal
pain, hypoglycaemia, hypotension, coma, etc.
– Death is usually due to hepatic necrosis.
• The usual adult dose is 2* 325-mg (regular-strength) tablets every 4-6 hours, 2
*650-mg (extra-strength) tablets every 6 hours, or 2* 500 mg caplets (extra-
strength) every 6 hours.
• No more than 10 regular-strength tablets or 6 extra-strength tablets should be
ingested by adults in 24 hours.
27. • The minimum toxic dose of acetaminophen for a
single ingestion is 7.5 to 10 g in adults and 150
mg/kg in children.
• The acute ingestion of more than 12 g of
acetaminophen in single ingestion is considered a
toxic dose and can poses a high risk for liver
damage.
• In children, the acute ingestion of 250 mg/kg
poses a high risk for liver damage, and the acute
ingestion of 350 mg/kg can cause severe
hepatotoxicity if not immediately treated.
28.
29. CLINICAL CASE STUDY
James Smith is 45 years old and is new to your practice. This is your first
meeting with him, and you would like to ask him some questions
regarding his medication/health history. During the course of your
conversation you learn that he has a history of coronary heart disease
and is currently taking a baby aspirin each day. He takes acetaminophen
for general aches and pains. During the course of his examination you
and the dentist find two cavities, which are filled that day. Mr. Smith is
experiencing some mild pain after the procedure.
1. What is the rationale for using acetaminophen instead of an NSAID instead
to treat Mr. Smith’s pain?
2. What dose and duration of therapy should be recommended for Mr. Smith?
3. At what doses does hepatotoxicity occur with acetaminophen?
4. How can acetaminophen toxicity be avoided in Mr. Smith?
5. Compare and contrast acetaminophen to aspirin in terms of pharmacology,
adverse effects, and therapeutic effects.
6. What is the role of aspirin in the prevention of heart attack or stroke?
7. Are any dental concerns associated with low-dose aspirin therapy?
8. Can Mr. Smith take a drug like ibuprofen?
9. What should be said to Mr. Smith during a counseling session regarding
acetaminophen?
30. Case
1. A 64-year-old male presents with mild to moderate
musculoskeletal back pain after playing golf. He states
he has tried acetaminophen and that it did not help.
His past medical history includes diabetes,
hypertension, hyperlipidemia, gastric ulcer (resolved),
and coronary artery disease. Which of the following is
the most appropriate NSAID regimen to treat this
patient’s pain?
A. Celecoxib.
B. Indomethacin and omeprazole.
C. Naproxen and omeprazole.
D. Naproxen.
Prostaglandins
Prostaglandins (PGs) are products of long-chain fatty acids. Arachidonic acid is the precursor for
the biosynthesis of all PGs. The enzyme involved in the formation of PGs from arachidonic acid is
cyclooxygenase (COX). The main PGs in humans are prostaglandin E2 (PGE2), prostaglandin F2 (PGF2)
and prostacyclin (PGI2). Another class of substances obtained from arachidonic acid by the action of
lipoxygenase is leukotrienes.
There are two forms of COX, COX-1 and COX-2 (Fig. 7.2). COX-1 is constitutive (it is always
present) and is widely distributed. It participates in various physiological functions such as protection
of gastric mucosa, homeostasis, regulation of cell division, etc. COX-2 is induced during infl ammation
by cytokines and endotoxins.
Gastrointestinal tract (GIT): Aspirin irritates the gastric mucosa and produces nausea, vomiting and dyspepsia. The salicylic acid formed from aspirin also contributes to these effects. Aspirin also stimulates chemoreceptor trigger zone (CTZ) and produces vomiting
The increased risk of arterial thrombosis
is believed to be due to the COX-2 inhibitors having a greater
inhibitory effect on endothelial prostacyclin (PGI2) formation
than on platelet TXA2 formation. Prostacyclin promotes vasodilation
and inhibits platelet aggregation, whereas TXA2 has the
opposite effects
Autacoids and Respiratory System
Mechanism of toxicity and treatment (Fig. 7.5) The toxic metabolite of paracetamol is detoxified by conjugation with glutathione and gets elimi- nated.
High doses of paracetamol cause depletion of glutathione levels. In the absence of glutathione, toxic metabolite binds covalently with proteins in the liver and kidney and causes necrosis.
Alcoholics and premature infants are more prone to hepatotoxicity.
N-acetylcysteine or oral methionine replenishes the glutathione stores of liver and protects the liver cells.
Activated charcoal is administered to decrease the absorption of paracetamol from the gut.
Charcoal haemoperfusion is effective in severe liver failure.
Haemodialysis may be required in cases with acute renal failure.
1. Correct answer = C. This patient is at high risk of future
ulcers, due to the history of gastric ulcer. Therefore, using a
regimen that includes an agent that is more COX-2 selective
or a proton pump inhibitor is warranted. Therefore,
D is incorrect. Choices A and B are incorrect because this
patient has significant cardiovascular risk and a history
of coronary artery disease. Naproxen is thought of as the
safest NSAID regarding cardiovascular disease, though it
still can present risks. Therefore, C is correct as it uses the
first-choice NSAID with the GI protection of a proton pump
inhibitor.