Drug

Pharmacodynamics

Pharmacokinetics

Toxicity/Contraindications

Clinical Use

Para-aminophenol group:

·        Paracetamol.

Propionic acids:

·        Ibuprofen

·        Naproxen

Fenamic acids:

·        Mefenamic acid

Salicylic acids:

·        Aspirin

·        Salsalate

Acetic acids:

·        Diclofenac

·        Indomethacin

·        Sulindac

Enolic acids:

·        Piroxicam

·        Phenylbutazone

·        Azapropazone

·        Inhibits cyclooxygenase & prostaglandin (PG) synthesis.

COX-1:

·        Produces prostanoids that mediate homeostatic functions.

·        Important in gastric mucosa, kidney, platelets & vascular endothelium.

·        Protects gastric mucosa.

·        Support platelet function.

COX-2:

·        Mediate inflammation, pain & fever.

·        Induced at sites of inflammation by cytokines.

·        PG lowers threshold to pain & raises temperature set-point in hypothalamus.

·        Well absorbed from GI tract.

·        Tend not to undergo first-pass elimination.

·        Highly bound to plasma albumin.

·        Have small volumes of distribution.

·        Majority are acidic drugs that localized preferentially in the synovial tissue of inflamed joints.

·         

·        Gastric intolerance: dyspepsia, gastric ulceration & haemorrhage.

·        Prolonged bleeding time.

·        Analgesic nephropathy: papillary necrosis, tubular atrophy & renal fibrosis.

·        Urticaria, severe rhinitis & asthma.

Interactions:

·        Diuretics: increased risk of renal impairment.

·        Methotrexate & lithium: elimination is reduced by NSAIDs.

·        ACE inhibitors & potassium retaining diuretics: hyperkalaemia.

·        Inhibition of metabolism by phenylbutazone increases plasma concentration of phenytoin, sodium valproate, sulphonylureas & oral anticoagulants.

·        4-aminoquinolone antimicromials: convulsions.

·        Analgesic: effective against pain of mild to moderate intensity.

·        Anti-inflammatory: useful in rheumatoid arthritis, osteoarthritis & musculoskeletal disorders.

·        Anti-pyretic: block PG synthesis in the hypothalamus.

·        Protect against vascular occlusion.

·        Prolongation of gestation & labor.

·        Maintain patency of ductus arteriosus.

Drug

Pharmacokinetics

Toxicity/contraindications

Clinical use

Paracetamol

·        Weak acid: does not produce gastrointestinal or platelet adverse effects.

·        Weak inhibitor of COX in many tissues.

·        Good inhibitor of PG synthesis in low-peroxide environment of hypothalamus.

·        Half-life: 2-3 h.

·        Protein binding is negligible.

·        Well absorbed from GI tract.

·        95% inactivated in liver by conjugation as glucuronide & sulphate.

·        5% oxidized by cytochrome P450 to toxic NABQI inactivated by hepatic glutathione.

Adverse effects:

·        Skin rash.

·        Allergy.

·        Heavy, long-term use may predispose to chronic renal failure.

Toxicity:

·        Occurred when glutathione stores are depleted.

·        NABQI oxidizes –SH group of hepatic enzymes, causing cell death.

·        Severe hepatic & renal damage can result from taking 150mg/kg (10 – 20 tablets) in one dose.

·        Clinical signs: jaundice, abdominal pain, hepatic tenderness do not become apparent for 24-48h.

·        Liver failure occurs between 2 – 7 days after overdose.

Therapy:

·        Prothrombin time: monitor liver damage.

·        Plasma creatinine: monitor renal impairment.

·        Activated charcoal.

·        N-acetylcysteine (NAC) or methionine to replenish glutathione stores.

·        Popular analgesic & antipyretic for adults and children.

·        Analgesic efficacy is equal to that of aspirin but in therapeutic doses it has only weak anti-inflammatory effects.

·        Effective in mild to moderate pain as that of headache or dysmenorrhoea.

·        Useful in patients who should avoid aspirin because of age<12, gastric intolerance or a bleeding tendency.

Aspirin

·        Irreversibly inhibits COX by acylating active site of enzyme.

·        Half-life: 15 min.

·        Well absorbed from stomach & upper intestinal tract.

·        Considerable first-pass effect.

·        Hydrolyzed in many tissues to salicylic acid which is inactivated largely by conjugation with glycine.

·        Low doses: first-order kinetics with a half-life of 4h, zero-order kinetics at higher therapeutic doses.

·        Protein binding of salicylate is 85%.

·        Renal excretion accounts for 10% of salicylate elimination.

·        Gastrointestinal effects: dyspepsia, heartburn, epigastric distress, vomiting, gastric erosions & bleeding.

·        Salicylism: tinnitus & hearing difficulties, dizziness, headache & confusion.

·        Allergy: severe rhinitis, urticaria, angioedema, asthma or shock.

·        Decrease uric excretion at low doses.

·        Reye’s syndrome: encephalopathy & liver injury in children recovering from febrile viral infections.

Overdose:

·        Nausea, vomiting, epigastric discomfort.

·        Tinnitus, deafness.

·        Hyperpnoea, headache, sweating.

·        Pyrexia, hypokalaemia & restlessness.

·        Pulmonary edema, convulsions, coma with severe dehydration & ketosis.

Metabolic derangements:

·        Respiratory alkalosis due to salicylate stimulation of respiratory center, leading to rise in blood pH compensated by renal loss of bicarbonate.

·        Metabolic acidosis due to accumulation of lactic & pyruvic acids.

·        End-result: mixed acid-base disturbance.

Therapeutic measures:

·        Gastric lavage: up to 12h after overdose.

·        Activated charcoal adsorbs salicylate.

·        Correction of dehydration: dextrose 5% i.v. with added potassium.

·        Acid-base disturbance: sodium bicarbonate to correct acidosis & alkalinize urine to remove salicylate.

·        Haemodialysis: plasma salicylate exceeds 750mg/l.

·        Analgesic effect: mild; aspirin is most effective against mild pain of somatic as opposed to visceral origin, e.g. headache, dysmenorrhoea, osteoarthritis, myalgia & painful bony metastases.

·        Anti-platelet: protects ‘at risk’ patients against stroke and myocardial infarct.

·        Anti-pyretic: acts in hypothalamus to lower set point of temperature regulation controlled by prostaglandin synthesis.

·        Anti-inflammatory: rheumatoid disease, Still’s disease & acute rheumatic fever.

Ibuprofen

·        Half-life: 2h

·        Well absorbed after oral dose.

·        Inactivated by metabolism.

·        Lower incidence of adverse effects particularly in the GI tract.

·        Epigastric discomfort, activation of peptic ulcer & bleeding.

·        Headaches.

·        Dizziness.

·        Fever.

·        Rashes.

·        Most useful in painful conditions such as mild rheumatoid disease & musculoskeletal disorders.

Mefenamic acid (Ponstan)

·        Half-life: 3h

·        Slowly absorbed from the small intestine.

·        Eliminated mainly as metabolites in the urine & faeces.

·        Diarrhoea.

·        Upper abdominal discomfort.

·        Peptic ulcer.

·        Haemolytic anaemia.

·        Drug should be avoided or used with close supervision in the elderly.

·        Used for mild to moderate pain where inflammation is not marked, e.g. muscular, dental & traumatic pain & headache, dysmenorrhoea & menorrhagia due to uterine dysfunction.

Indomethacin

·        Half-life: 4h.

·        Absorption from gut is rapid and complete.

·        Inactivated by metabolism.

·        Gastric irritation with ulcer formation, bleeding & perforation.

·        May cause salt & fluid retention, reducing the effectiveness of diuretics.

·        Antagonize the anti-hypertensive action of beta-blockers.

·        Frontal headache similar to migraine is common.

·        Dizziness.

·        Vomiting.

·        Ataxia.

·        Highly effective anti-inflammatory, analgesic & antipyretic agent.

·        Relieve moderate to severe pain due to pericardial & pleuritic inflammation, for pain following minor operations & to reduce opioid requirements after major surgery.

·        Rheumatic diseases: rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, gout).

·        Refractory fever: Hodgkin’s disease.

Sulindac (Clinoril)

·        Structurally related but less toxic than indomethacin.

·        Pro-drug, converted to active sulphide metabolite (half-life: 16h) in the body & by gut flora.

·        Less adverse effects in kidney due to selective inhibition of only extra-renal COX.

·        Used for pain & inflammation in rheumatoid disease, musculoskeletal disorders & in gout.

Diclofenac (Voltarol)

·        Half-life: 2h

·        GI & CNS effects.

·        Used for moderate pain & inflammation due to rheumatoid disease, musculoskeletal disorders, renal colic & postoperative pain.

Piroxicam (Feldene)

·        Half-life: 45h

·        Completely absorbed from GI tract.

·        Rheumatoid disease, musculoskeltal disorders, gout & dysmenorrhoea.

Phenylbutazone

·         

·        Relatively toxic.

·        Exfoliative dermatits, hepatic & renal tubular necrosis, fatal blood dyscrasias.

·        Considered as last resort & only for short-term therapy.

·        Rarely indicated except in ankylosing spondylitis under specialist supervision.

Ketorolac

·        Half-life: 5h

·         

·        Given by i.m. injection to provide short-term relief of acute post-operative pain.

Azapropazone (Rheumox)

·         

·        Adverse reactions are frequent.

·        Rheumatoid arthritis.

·        Ankylosing spondylitis.

·        Acute gout.