Analgesics & Antipyretics

Classifications pharmacokinetics pharmacodynamics & applied knowledge of analgesics & antipyretics with special emphasis on NSAIDS.

1. ANALGESICS & ANTIPYRETICS DR TARAK NATH CHATTOPADHYAY MBBS, MD GENERAL MEDICINE

2. Let’s start 65 female presented with pain in both knees, more on left side. Pain worsens while walking or standing. X-ray shows joint space narrowing, mild effusion & osteophytic projection. She had a heart attack 1y back & treated with angioplasty. She is taking aspirin 75mg regularly What analgesic to be given? Which analgesic should be avoided?

3. PAIN & FEVER Pain: Pain is a symptom of inflammation Fever: When the temperature is above 100.4 F Analgesic: A drug that selectively relieves pain by acting on CNS or on peripheral pain mechanisms without significantly altering consciousness. Antipyretic: A drug that reduces fever by lowering body temperature

4. Pain RECEPTOR Free nerve endings located in various body tissues responding to thermal, mechanical, chemical stimuli Injured tissue releases chemicals Prostaglandins & Leucotrienes that make pain receptor more sensitive

5. PHYSIOLOGY OF PAIN Source (Injury/ Inflammation/Heat/Cold) Pain receptors Discharge impulse Electrical activity to spinal cord & brain In brain: electrical activity becomes experience of pain

6. CLASSIFICATIONS OPIOIDS: Morphine & morphine like substance Non Opioid: NSAIDS, ACETAMINOPHEN,

7. NSAIDS

8. Mechanism of action Analgesia: PG induces analgesia by altering transduction property of free nerve endings. NSAIDs inhibit PG synthesis in Brain & spinal cord(Central mechanism). Also they block pain sensitisation by Bradykinin, TNF@, Interleukins (Perpheral mechanism). Anti inflammatory : Inhibition of COX2>COX1 at site of injury. However inflammation is the result of concerted participation of vasoactive, chemotactic & proliferation factors at different stages. Apart from PG there are other mediators like LT, PAF, Cytokines. Antiplatelet: By inhibiting proaggregatory TXA2 & antiaggregatory PGI2 through COX1 inhibition. Low dose Aspirin inhibits platelet aggregation but at high anti inflammatory dose this advantage get lost. NSAID increases bleeding tendency by this mechanism

9. Mechanism of action Parturition: sudden spurt of PG synthesis occurs before labour begins which trigger & facilitate labour. NSAIDS can delay labour Ductus arteriosus closure: In foetal circulation DA is kept patent by local elaboration of PGE2. It gets closed during birth spontaneously. When it fails small dose of Indomethacin given to cause this. Administration of NSAID near term can cause premature closure of DA & thus should be avoided

10. Mechanism of action Gastric mucosal damage: COX1 mediated synthesis of PGE2 & PGI2 protects gastric mucosa. Deficiency of PG causes reduction of mucus, HCO3, increases H+ secretion thus causing gastric erosion. Selective COX 2 inhibitor & paracetamol is free from this adverse effect. Also PG analogue can be administered to counteract NSAID induced gastric toxicity. Renal effect: Hypovolaemia causes PG synthesis which causes it rare all adjustments by vasodilation, inhibits tubular Cl- absorption( Na, H2O accompany). NSAID causes renal blood flow reduction, juxtaglomerular COX2 inhibition causes Na & H2O retention, papillary necrosis. These changes are marked in patients with CHF, Cirrhosis of liver, CKD. Diuretic & antihypertensive action reduced.

11. Classification Nonselective COX inhibitor: Salicylate ( Aspirin), Propionic acid derivative( Ibuprofen, Naproxen), Acetic acid derivative ( Indomethacin, ketorolac), Fenamate( Mephenamic acid), Enolic acid ( Piroxicam), Pyrazolone (Phenylbutazone) Preferential COX 2 inhibitor: Diclofenac, Aceclofenac, Nimesulide Selective COX2 inhibitors: Celecoxib, Etoricoxib, Parecoxib

12. Aspirin Acetyl salicylic acid Acetylation of COX Weak analgesic. .(3-.6 g 6-8 hourly) Ineffective in visceral pain Potent anti inflammatory at high dose 3-6 gm/day Acute rheumatic fever, RA Antiplatelet action at low dose 75-150 mg/day. Action lasts for about a week T1/2 15-20 min. Together with salicylic acid 3-5 hour. T1/2 of anti inflammatory dose 8-12 hour while during poisoning may be up to 30 hours Adverse effects: Gastric mucosal damage & PUD, Hypersensitivity! Reye’s syndrome in children

13. Contraindications PUD Children with chicken pox/ influenza CLD Frank heart failure with low output status 1 week before surgery Breast feeding mother Repeated dose in pregnancy causes LBW baby, delayed/ prolonged labour, premature closure of DA

14. Other NSAIDS Ibuprofen: Better tolerated than aspirin . Not to be given in pregnancy. Used as analgesic 400-600 mg 2-3 times a day Naproxen: Longer duration of action12-16 hour. Effective in Gout, RA, Migraine,Ankylosing spondylosis. Gastric bleed more common but lower thrombotic risk. Mephenamic acid: Effective in Dysmenorrhea. Diarrhoea is major AE. Ketorolac: Potent analgesic, comparable to opioids. Used in post operative , dental pain. Not to be used for more than 5 days Indomethacin: Potent analgesic, anti inflammatory. Malignancy associated fever, Reactive arthrithritis, GI side effects are more prominent. Leukopenia, hypersensitivity reaction are more common. Causes dizziness, hallucinations psychosis. Contraindicated in driver, machinery worker, psychiatric/epilepsy patients, women children Nimesulide: weaker analgesic. Completely absorbed orally. Effective in sinusitis, sport injuries, . Withdrawn due to high incidence of fulminant hepatic failure. Used in patients having bronchospasm/ intolerance to other NSAID Diclofenac: somewhat COX2 selective. Good tissue permeability, stays 3 times longer in synovial fluid. Increased hepatic dysfunction, high incidence of cardiac events.

15. COX2 inhibitor Less gastric mucosal damage, lower incidence of PUD Does not suppress TXA2. No Antiplatelet function But reduces PGI2. High incidence of cardiac events Used in Gout, RA, AnkSpon, Dental pain

16. Acetaminophen Potent antipyretic, negligible anti inflammatory, weak analgesic. Analgesic action is additive with aspirin Poorly understood MOA. Weak Inhibitor of Pg synthesis in peripheral tissue but inhibits COX in brain. Postulated to be inhibitor of COX3 T1/2 2-3 hours Well tolerated. GI side effects are negligible Poisoning: occurs specially in children with hepatic dysfunction. Occurs in > 150mg/kg or > 10g/day in adult. Fatal dose 250mg/kg. N acetyl p benzoquinoneimine ( metabolite of PCM ) gets detoxified in liver by conjugation with glutathione. With high dose glucoronidation capacity saturated, hepatic glutathione depleted, metabolite binds to hepatic cells causing necrosis. In chronic alcoholic CYP2E1 is induced causing more production of NABQI. Hepatic toxicity can occur with 5gm/day dosage. Not recommended in infants < 2kg. Antidote: N. acetyl cysteine replenishes hepatic glutathione storage. Ineffective if started > 16 hours

17. Local NSAID Diclofenac 1% Ibuprofen 10% Naproxen10% Nimesulide1% Ketoprofen 2.5% Flurbiprofen5% Piroxicam.5%

18. Choice of drugs Mild/moderate pain with little inflammation: paracetamol/ low dose ibuprofen Postoperative, short lasting: injectable Diclofenac, ketorolac Renal colic, dental pain, fracture, trauma: injectable PCM/NSAID Inflammatory pain( RA, AS, GOUT, ARF): naproxen, Indomethacin, high dose aspirin Gastric intolerance, Asthma, : COX2 inhibitor (avoid if cardiac comorbidities)

19. 65 female presented with pain in both knees, more on left side. Pain worsens while walking or standing. X-ray shows joint space narrowing, mild effusion & osteophytic projection. She had a heart attack 1y back & treated with angioplasty. She is taking aspirin 75mg regularly What analgesic to be given? Which analgesic should be avoided?

20. Thank you For not sleeping!!