M6: Non-Narcotic Analgesics (Antipyretics)

Question 1

Cyclooxygenase (COX) Enzyme

Answer 1

3 Isoenzymes:

1. COX-1: widely distributed
2. COX-2: limited distribution
   - macrophages and at sites of inflammation
3. COX-3: mainly in brain

Question 1

(3) Types of Antipyretics

Answer 1

1. Non-steroidal anti-inflammatory drugs (NSAIDs):

DRUGS = Acetylsalicylic acid (ASA, Aspirin®), Ibuprofen, Naproxen, Diclofenac, Ketorolac, Indomethacin

2. Acetaminophen:
   DRUGS = Tylenol® – Paracetamol®
3. Selective COX-2 inhibitors:
   DRUGS = celecoxib

Question 2

ACETYLSALICYLIC ACID
- Mechanism of Action
- Therapeutic Indications
- Adverse Effects
- Contraindications
- Pharmacokinetics
- Acute Aspirin Toxicity

Answer 2

MECHANISM OF ACTION:
1. Irreversible* inhibition of COX-1 and -2 = decrease production of prostaglandins (PGs) and thromboxanes (Txs)

2. Pharmacological actions:
   - Analgesic
   - Antipyretic
   - Anti-platelet
   - Anti-inflammatory (high dose)

**Other NSAIDs cause reversible inhibition of COX enzyme

THERAPEUTIC INDICATIONS:
1. Pain:
- Mild to moderate (less effective than opioids)

• Mechanism (through inhibition of PGs synthesis):

(1) Peripheral action (main action): prevents sensitization of pain-transmitting nerve fibres to chemical mediators released by tissue injury

(2) Central action: inhibits action of transmitters involved in pain pathways

• Different types of pain including headaches and migraine
• No tolerance, addiction, or dependence

2. Fever:
   Mechanism (through inhibition of PGs synthesis):
   - Reset temperature center in hypothalamus
   0 No effect on normal body temperature
3. Thromboembolic Disease:
   - Through antiplatelet effect
   - Treatment or prophylaxis
4. Inflammation: (high dose)
   - Rheumatic fever
   - Rheumatoid arthritis
   - Gout (high dose!)

ADVERSE EFFECTS:
1. Bleeding: e.g., GI bleeding

2. GI Upset: e.g., dyspepsia, gastritis, peptic ulcer
3. Bronchial Asthma
4. Tinnitus (ringing in the ears)
5. Acid base imbalance:
   - Metabolic acidosis
   - Respiratory alkalosis
6. Chronic Nephritis: with long term use
   - Hypersensitivity reactions
7. Reye’s Syndrome:
   - Brain and liver damage (can be fatal)
   - Occurs in children or adolescents who have viral infection and take aspirin
8. Bright red/ black or tarry blood in stools
9. Cold, clammy skin
10. Hives/Rash
11. Swelling of the face
12. Ringing in the ears, loss of hearing
13. Fast heart rate, heartburn
14. Stomach pain, vomiting

CONTRAINDICATIONS
1. Bleeding tendencies
2. Peptic ulcer
3. Bronchial asthma
4. Allergy to aspirin or other NSAIDs
5. Chronic renal disease
6. Children or adolescents with fever & viral infection

PHARMACOKINETICS:
1. Absorption: stomach, small intestine

2. Protein Bound: 50-80%
3. Metabolism: liver (80%)
4. Excretion: kidney

ACUTE ASPIRIN TOXICITY:
- Vomiting, abdominal pain
- Tinnitus
- Hypoglycemia, hypokalemia
- Hyperthermia, hyperventilation
- Metabolic acidosis, respiratory alkalosis
- Confusion, seizures, coma
- Pulmonary edema, hypotension, CV collapse

TREATMENT:
- No specific antidote

• Supportive measures:
  Stabilize airway, breathing, and circulation
• Fluids and electrolytes (e.g., potassium)
• Restore pH
• Glucose
• Alkalinization of urine
  +/- charcoal ingestion
  +/- gastric lavage
  +/- dialysis

Question 3

ACETAMINOPHEN
- Mechanism of Action
- Pharmacokinetics
- Adverse Effects
- Metabolism & Toxicity
- Acute Toxicity

Answer 3

MECHANISM OF ACTION:
1. Not fully understood!
2. Inhibits COX enzyme (like NSAIDs) … BUT:
- +/- more COX-2 selective
- ?? COX-3 inhibition
3. NO anti-inflammatory or anti-platelet action

PHARMACOKINETICS:
1. Absorption: GIT
2. Metabolism: Liver
3. Excretion: Kidney

ADVERSE EFFECTS:
1. Usually safe if taken in proper dose

2. Safe during pregnancy
3. Main adverse effect:
   - Liver damage
   - Renal damage

METABOLISM & TOXICITY:
1. NAPQI: N-acetyl-p-benzoquinoneimine
2. GSH: Glutathione

ACUTE TOXICITY:
1. Commonly due to suicide
2. Acute liver damage (may be fatal)
3. Treatment:
- Antidote: N-acetylcysteine (NAC)
- Supportive measures …
+/- charcoal ingestion
+/- gastric lavage

Question 4

N-ACETYLCYSTEINE (NAC)

Answer 4

1. Antidote of acetaminophen
2. Source of glutathione → decrease NAPQI → decrease liver damage
3. Most effective within 8 hours of exposure
4. Oral or IV

Question 5

ASPIRIN vs. ACETAMINOPHEN

Answer 5

ASPIRIN:
1. Anti-inflammatory (+)
2. Anti-platelet (+)
3. Peptic Ulcer (+)
4. Bronchial Asthma (+)
5. Reye’s Syndrome (+)
6. Specific Antidote (-)
7. Pregnancy: Avoid

ACETAMINOPHEN:
1. Anti-inflammatory (-)
2. Anti-platelet (-)
3. Peptic Ulcer (-)
4. Bronchial Asthma (-)
5. Reye’s Syndrome (-)
6. Specific Antidote: N-acetylcysteine
7. Pregnancy: Safe

Question 6

COX-2 INHIBITORS

Answer 6

1. Selective inhibitors of COX-2 isozyme
2. Less COX-1 induced side effects:
   - e.g., asthma, gastric irritation & bleeding
   - more theoretical!!
3. More risk of thrombosis and cardiovascular morbidity and mortality
   e.g., celecoxib
4. Vioxx: Rofecoxib
   - Cause: inhibition of COX2 in - blood vessels → reduction of prostacyclin (PGI2) synthesis. Prostacyclin inhibits platelet aggregation and vasoconstriction