NSAIDs.pdf

NONSTEROIDAL ANTI-INFLAmMATORY DRUGS NSAIDs by dr –hamida albarasi Nonsteroidal anti-inflammatory drugs (NSAIDs) are a heterogeneous group having anti-inflammatory, analgesic &antipyretic effects. Classification of Nonsteroidal anti inflammatory drugs NSAIDs 1-Non selective C...

NONSTEROIDAL ANTI-INFLAmMATORY DRUGS NSAIDs by dr –hamida albarasi Nonsteroidal anti-inflammatory drugs (NSAIDs) are a heterogeneous group having anti-inflammatory, analgesic &antipyretic effects. Classification of Nonsteroidal anti inflammatory drugs NSAIDs 1-Non selective COX inhibitors: a- Salicylates– Aspirin, diflunisal b-Propionic acid derivatives – Ibuprofen, Naproxen , Ketoprofen c-Fenamic acid derivatives– Mefenamic acid, flufenamic acid d-Acetic acid derivatives-- Ketorolac, indomethacin e-Enolic acid deravatives– Piroxicam, tenoxicam,Lornoxicam 2-Preferential COX2 inhibitors: Diclofenac , aceclofenac 3- Highly selective COX2 inhibitors : Etoricoxib, Parecoxib 4-Analgesic & antipyretic with poor anti-inflamatory effect: Paracetamol , nefopam Cyclooxygenase Enzymes COX-1: Mainly constitutive (present normally in tissues regulating its physiologic functions), responsible for forming protective PGs in GIT & kidney. COX-2: Inducible in inflammation, constitutive in endothelium &kidney. COX-3: Newly discovered (its role is still under investigation) Mechanism of action: Aspirin & most of NSAIDs inhibit both COX1 & COX2 isoforms thereby reduce PGs & thromboxane synthesis The anti-inflammatory effect of NSAIDs is mainly due to inhibition of COX2.Aspirin cause irreversible inhibition of COX activity. Rest of NSAIDs cause reversible inhibition of the enzyme  Membrane phospholipid Phospholipase2 PL2 Arachidonic acid Cycloxygenase Lipoxygenase (COX) (LOX) COX1 COX2 Leukotriens Is responsible for Inducible during biosynthesis of most inflammation by cytokines PGs & infl. mediators  COX1 found in most tissues Kidney,plt.,BVs,stomach PGI2 PGf2 PGE2 PGD2 TXA2 Vasodilatation lower IOP GI protection vasodilation Plt. agregation Inhibit Plt. Agregation Plt. bronchoconstriction regulation of kidney blood flow regulate blood flow (vasoconstrictor)  COX2 inducible during inflammation by cytokines & inflammatory mediators in brain & kidney PGE2 PGI2 TXA2 others TNF ILs, bradykinin -pain -inflammation - fever Pharmacological action of NSAIDs: 1- Analgesic effect: produced mainly by peripheral inhibition of PGs production 2- Antipyretic effect: they produce antipyretic effect by causing cutaneous vasodilatation & sweating 3- Anti-inflammatory effect: is seen in high doses , NSAIDs cause only symptomatic relieve by inhibition of PGs at site of injury 4-Antiplatelets:Aspirin in low doses irreversibly inhibit Plt. & TXA2 synthesis. Aspirin in high doses inhibit both PGI2 & TXA2 hence antiplt. effect is lost It should be withdrawn one week before surgery to prevent bleeding 5- Aspirin irritates gastric mucosa & cause nausea,vomiting gastric dyspepsia 6-In therapeutic doses aspirin causes respiratory alkalosis & in toxic doses it causes respiratory acidosis. 7-CVS prolonged use of aspirin & other NSAIDs causes sodium & water retention 8-urate excretion: salicylates in therapeutic doses inhibit urate secretion into renal tubules, in high doses inhibit reabsorption of uric acid in the renal tubules Pharmacokinetics: Salicylates are rapidly absorbed from upper GIT ,they are highly pound to plasma protiens but the binding is saturable they are well distributed throughout the tissues & metabolized in the liver by glycine & glucuronide conjugation Dosage regimen of aspirin: 1-Analgesic dose: 2-3g / day in divided doses 2-Anti-inflammatory dose : 4-6g/day in divided doses 3-Antiplatelet: 50-325mg/day (low dose aspirin) Adverse effect: 1-GIT: nausea , vomiting ,dyspepsia , gastritis & ulceration & bleeding these effects are minimized by a- taking them after food b-using buffered aspirin(aspirin with antacid) c-use of proton pump inhibitor, H2 blockers , misoprostol with NSAIDs d-selective COX2 inhibitors 2-Hypersensitivity: more common with aspirin manifested by rash, urticaria , rhinitis, bronchospasm , angioneurotic edema 3-use of salicylates in children with viral infection may cause hepatic damage with encephalopathy (Reye~s syndrom) 4- in pregnancy they inhibit PGs synthesis thereby delay onset of labour 5-analgesic nephropathy: slowly progressive may occur on chronic use of high doses of NSAIDs which is usually reversible on drug stoppage Clinical uses of NSAIDs: 1-Analgesic: in painful conditions like headache , toothache , bodyache, joint pain, dysmenorrhea 2-Antipyretic : paracetamol is preferred as GIT symptoms are rare & cause no Reyes syndrome in children 3-Osteoarthritis 4-Rheumatoid arthritis : they have anti-inflamatory effects but don’t alter disease progression 5-Acute rheumatic fever : Aspirin is the preferred drug it reduces fever relieves swelling & joint pain 6- Thromboembolic disorders: This is low dose effect a-stroke & transient ischemic attacks b-myocardial infarction 7-Patent ductus arteriosus (PDA) closure(indomethacin is preferred) Acute salicylate poisning: It is common in children manifests as vomiting, dehydration , acid-base & electrolytes imbalance , hyperpnoea, restlessness confusion , coma convulsion, cardiovascular collapse & death Treatment of salicylate poisoning: There is no specific antidote for salicylate & treatment is symptomatic 1-Hospitalization 2- gastric lavage & administration of activated charcoal(physical antagonism) 3-correct acid-base balance & maintain adequate fluid intake IV NaHCO3 to treat metabolic acidosis , it also alkalinize the urine & enhances renal excretion of salicylate 4-Haemodialysis in sever cases 5-Vitamin K & blood transfusion if there is bleeding Paracetamol: Effective by oral & parenteral routes , well absorbed widely distributed all over the body metabolized in the liver by sulphate & glucuronide conjugation Uses: 1-antipyretic 2-analgesic It is preferred in Pt. with peptic ulcer & Br. Asthma & in children Adverse effects: 1-Hepatotoxicity: in acute over dose 2-Nephrotoxicity: mostly on chronic use Acute paracetamol poisoning: Acute overdosage mainly causes hepatotoxicity , causing nausea, vomiting, abd. Pain, hypoglycemia, hypotension , hypoprothrompenia , coma & death is usually due to hepatic necrosis Some differences between Paracetamol & Aspirin Aspirin Paracetamol 1-its salicylate derivative 1-its para-aminophenol derivative 2-has analgesic , antipyretic & potent anti- 2-it has potent antipyretic & analgesic effects with inflammatory effects poor anti-inflammatory activities 3-it causes GIT irritation , peptic ulcer & bleeding 3-it doesn’t produce gastric irritation 4-in large doses produces acid-base & electrolytes 4-it doesn’t produce acid-base imbalance imbalance 5-it has antiplatelet action 5-it has no antiplatelet action 6-it has no specific antidote 6-N-acetyl cysteine is the antidote 7-contraindicated in patient with peptic ulcer 7-paracetamol is preferred analgesic & antipyretic ,bleeding tendency, bronchial asthma & in in pt. with peptic ulcer & bronchial asthma & in children with viral infection children Mechanism of paracetamol toxicity: -The toxic metabolite of paracetamol is detoxified by conjugation with glutathione & gets eliminated -High doses of paracetamol causes depletion of glutathione levels. -In the absence glutathione toxic metabolite binds covalently with protiens in the liver & kidneys & causes necrosis -Alcoholic & premature infants are more prone to hepatotoxicity. Treatment of paracetamol hepatotoxicity: -N-acetyl cysteine & or oral methionine replenishes the glutathione stores of the liver & protects liver cells -Activated charcoal is administered to decrease the absorption of paracetamol from the gut. -Haemodialysis may be required in cases with acute renal failure. Indomethacin Strong anti-inflammatory. Due to serious adverse effects its use is limited to: 1. Acute gouty arthritis. 2. Rheumatoid arthritis, ankylosing spondylitis. 3. Postoperative pain. 4. Patent ductus arteriosus (inhibits PG synthesis closing the ductus). Adverse Effects 1. Adverse effects common with other NSAIDs. 2. CNS: dizziness, confusion, ataxia, severe headache (cerebral VD). 3. Aplastic anemia. Migraine An attack of migraine starts by a prodroma (irritability, fatigue, muscle aches), followed by an aura (visual disturbances; scotoma) Migraine is triggered by stress, hormonal changes (menstruation), disturbed sleep pattern, weather changes & alcohol. Treatment of migraine I. Mild analgesics: NSAIDs & acetaminophen (for mild infrequent attacks). II. Triptans: "specific" antimigraine therapy: therapy for outpatients with moderate to severe migraine is begun with a triptan. Mechanism of action (selective 5HT1B/1D agonists) Sumatriptan 1. Activate 5HT1B/1D receptors on presynaptic trigeminal nerve endings to inhibit release of vasodilatory neuropeptides. 2. Vasoconstriction of dural vessels preventing stretching of pain nerve endings. Adverse effects: 1. Injection site reaction (with SC) or unpleasant taste (with intranasal). 2. Chest pressure (resolves spontaneously in 30 minutes). 3. Paresthesias , warmth, drowsiness, dizziness, weakness, malaise. Contraindications: 1.Uncontrolled hypertension, ischemic stroke & IHD , 1st dose given cautiously in diabetics, hypertensives, men over 40 & in postmenopausals. 2. Pregnancy. 3. With serotoninergic drugs III- Ergots: 5HT agonists similar to triptans 1. Ergotamine tartrate (sublingual, oral, rectal); of choice in prolonged or frequent headaches. 2. Dihydro ergotamine (IV, IM, SC & intranasal). Adverse effects & contraindication: 1-Nausea, vomiting, diarrhea. 2-Chest pressure. 3-Vasospasm causing gangrene (CI peripheral vascular disease). 4-CI. Pregnancy. 5-GIT: Nausea, Should not be used IV-Benzodiazepines & opioids Used in resistant cases (may lead to habituation & rebound headache). Drugs for migraine prophylaxis: Anti-migraine therapy should not exceed 10 days /month to avoid medication overuse headache "MOH". Prophylactic drugs should then be administered: 1. Beta blockers: propranolol and timolol: are of choice 2. Antidepressants: amitriptyline 3. Anticonvulsants: valproate & topiramate. (reduce Excess firing of trigeminal nerve). 4. Calcium channel blockers: nifedipine, verapamil.