NSAIDs PDF

Central nervous system Analgesic drugs 1-Central Analgesics: are drugs which relieve pain by Central action without Impairing Consciousness or other sensations. They are classified into: A) Non-Steroidal Anti-inflammatory (NSAIDs) = Analgesic Antipyretic drugs: Relieve Low Intensity pain (as Headach...

Central nervous system Analgesic drugs 1-Central Analgesics: are drugs which relieve pain by Central action without Impairing Consciousness or other sensations. They are classified into: A) Non-Steroidal Anti-inflammatory (NSAIDs) = Analgesic Antipyretic drugs: Relieve Low Intensity pain (as Headache, Neuralgia & Myalgia), act Subcortical on Thalamus, no Euphoria or Drowsiness and Non Addictive. B) Opioid (Narcotic) Analgesic drugs : Relieve any type of pain (except Itching), act Cortical and Subcortical, produce Euphoria and Addiction. 2-Peripheral analgesics: include Physical protectives, Local & Surface Anaesthetics and Counter-Irritants. A-Non-sterodal Anti-inflammatory drugs (NSAIDs) They inhibit Cyclo-Oxygenase (COX) Enzyme so inhibit Prostaglandins synthesis. Cycloxygenase Enzymes:COX-1: Mainly Constitutive (present normaly in Tissues regylating its physiologic functions), responsible for forming protective Prostaglandins in Gastrointestinal Tract and Kindney (Peripherally). COX-2: Inducible in Inflammation or Injury, Constitutive in Endothelium and Kidney (Peripherally). COX-3: Newly discovered (under Investigation, mainly in Brain), Centrally. (There are many PGs Synthesis and functions types of PGs) Stimuli activate Phospholipase A2 → release of Arachidonic Acid (Cyclo-Oxygenase Enzyme “COX” 90% / Lipo-Oxygenase Enzyme “LOX” 10%) 1) COX → Prostaglandins : * Induce Pain, Fever, Inflammation. * Contract Uterus → Dysmenorrhea “during Menstruation of Non Pregnant Woman”. * Prevent Peptic Ulcer → by Maintain of Muco-Protective Layer of Stomach “HCL protection”. * Maintain Patency of Ductus Arteriosus → vessel connecting Pulmonary Artery & Aorta of Fetus “since lungs are nonfunctioning”. * Increase Renal Blood Flow. * Thromboxane (released from platelets “COX-1”) → V.C. & increase Platelet Aggregation “released only during Injury → stop Bleeding”. * Prostacyclin (released from Endothelium) → V.D. & decrease Platelet Aggregation. 2)LOX → Leukotrienes : * Bronchospasm (Bronchial Asthma) + Inflammation. Therapeutic uses and side effects of Aspirin-like drugs "NSAIDs" :1. They are Analgesic, Antipyretic and Anti-inflammatory “inhibit Peripheral Prostaglandins synthesis”. However, Paracetamol (Acetaminophen) “because it’s selective COX-3 inhibitor/act centrally only” has no Anti-inflammatory action. 2. They can be used in Dysmenorrhea, Patent Ductus Arteriosus and Tocolytic (Relax Uterus) in Premature Labour. 3. They affect Platelet function and can be used as Antithrombotic (Low Dose NSAIDs). 4. They can induce Gastric or Intestinal Ulcerations. 5. They may induce Bronchospasm, Urticaria in Susceptible patients due to increase in Leukotriens the product of Lipoxygenase pathway. 6. They have little effect on Renal function in normal subjects but may decrease Renal Blood Flow and Glomerular Filtrate in Renal diseases & could lead to Nephropathy. They may produce Salt and Water Retention. 7. Use of Aspirin like drugs in Pregnant women is not recommended. If there is need, Aspirin may be the safest Antiinflammatory while Paracetamol is the safest Analgesic Antipyretic. Aspirin should be Discontinued before Labour to avoid its Prolongation, Postpartum Hemorrhage and Intrauterine Closure of Ductus Arteriosus. 8. Most of NSAIDs bind Firmly to Plasma Protein (Albumin) and can displace other drugs as Warfarin, Oral Hypoglycemics, Inducing Serious Drug Interactions. + Don’t give any drugs in the first 3 months + last 2 weeks, WHY? *Bleeding (Antithrombotic). *Birth Malformations (3 months). *Premature Closure of Ductus Arteriosus → Fetal Death. *Relax Uterus → prevent Labour. *Classification of Analgesic Antipyretic drugs :A) Non selective COX Inhibitors “inhibit COX-1, COX-2, COX3/acts Peripherally & Centrally”: 1.Salicylates: Aspirin/Indomethacin/Iboprufen/Ketoprofen/Diclofenac /Piroxicam. B) Selective COX-2 Inhibitors: Celecoxib “Indicated for Peptic Ulcer patients/No Plateletic action”. C)Selective COX-3 Inhibitors: Paracetamol “no Antiinflammatory”. I) Non selective COX Inhibitors 1. Salicylates :Derived from Salicylic Acid which itself is Highly Irritant. They include Aspirin. Pharmacokinetics: Effective Orally, Aspirin absorbed to Small Extent from Stomach being at Low pH in Non-Ionized form, Complete Absorption in Upper Part of Small Intestine and Bound to Plasma Proteins. Excreted in Urine (Alkaline Urine increases Excretion) → by Sodium Bicarbonate. Actions:*Local actions : Salicylic acid: Keratolytic, Antifungal and Antiseptic. Methyl salicylate (Oil of winter green): Counter-irritant. *Systemic actions :1. C.N.S.: a-Analgesic action by Inhibiting Prostaglandin synthesis (inhibit COX). They have Central action Elevating Pain and Peripheral action due to Anti-inflammatory effect. b-Antipyretic action: Centrally by Inhibiting Prostaglandins synthesis (decrease to normal). However, Salicylate in Large Dose may lead to Hyperthermia due to Uncoupling of Oxidative Phosphorylation. 2. Anti-inflammatory & Antirheumatic actions due to: Inhibition of Cyclo-Oxygenase Enzyme so Inhibit Prostaglandins synthesis. 3. C.V.S.: Therapeutic Dose → Little Effect. Large Doses produce Hypotension. 4. Uric Acid: Salicylate in Small Dose inhibits Uric Acid secretion. 5. Blood: “increase Uric Acid → Gout, So Aspirin/Salicylates are Contraincated for Gout Patients” *Aspirin in Small Dose inhibits Platelets Aggregation, and prolongs Bleeding time. (Respiration: Large Dose “increase Respiratory Centre”→ Washing CO2 → Respiratory Alkalosis / Kidney Excrete NaHCO3 → Compensated Respiratory Alkalosis / Decreased NaHCO3 in Blood → Metabolic Acidosis” *In Large Dose (Low 5g/day), they compete with Vit. K “in Liver” leading to Hypoprothrombinaemia → prolong Bleeding time. *In patients with G-6-PD Deficiency (Idiosyncrasy) they produce Haemolytic Anaemia 6. G.I.T.: Epigastric Distress, Nausea, Vomiting, Ulceration and Bleeding (due to Inhibition of Prostaglandin synthesis which have Cytoprotective action and directly Irritate stomach) 7. Renal & its effects: Salicylates “decrease Renal Blood Flow” can cause Sodium Retention and reduce Renal function especially in patients with H.F. or Hypovolemia. (Aspirin Toxicity → Uncoupling of Oxidative Phosphorylation → prevent Energy Storage/ATP production – Aspirin Toxicity stimulate Respiratory Centre → Hyperventilation → Loss of CO2 → Respiratory Alkalosis → Kidney increase Bicarbonate Excretion “in response” → Acidosis). Administration: Orally after meals to avoid Gastric Irritation. Sodium Salicylate should be given Enteric Coated. Uses:*Local :- Salicylic Acid as Keratolytic and Fungistatic. - Methyl Salicylate as Counter-Irritant. *Systemic :-Fever (Aspirin). -Analgesic in Headache, Arthritis, Neuralgia, Myalgia, common Cold. -Acute Rheumatic Fever. -Rheumatoid Arthritis. -Prevent Intravascular Thrombosis. Side effects:1-Gastric Irritation, Ulceration Perforation & Bleeding. 2-Allergic reaction: Urticaria, Skin Rash, Angioneurotic Edema. Precipitate an Attack of Asthma in Predisposed patients as it blocks Cyclo-Oxygenase pathway with increase in Leukotrienes which produce Bronchoconistriction. 3-Idiosyncrasy: In patient with G-6-PD Deficiency → Haemolytic Anaemia. 4-Reye’s Syndrome if used in children with Viral Infection (Increase Hepatic Necrosis with Virus Infection in children). 5- Prolonged use may lead to Hypoprothrombinaemia. 6-Salicylism (Chronic use): Headache, Mental Confusion, Vertigo, Ringing in Ears (Tinnitus), Sweating, Nausea & Vomiting. 7-Acute Toxicity: Hyperpyrexia, Convulsions, Hyperventilation, Dehydration, decrease Blood Pressure, Acidosis or Alkalosis & Hyperglycaemia which treated by Symptomatically. Contraindications:*Peptic Ulcer. *Bronchial Asthma. *Idiosyncrasy Allergy (in patients with G-6-PD Deficiency). *Virus Infection in Children, Bleeding Tendency. *Pregnancy Early & Late. *Small Dose in Gout. Interactions:*Ammonium Chloride enhances Toxicity (Acidify the Urine). *NaHCO3 increases Renal Excretion (Alkalinizes the Urine). *Alcohol & Glucocorticoids increase Gastrointestinal Tract Bleeding by Salicylates. *Can displace drugs from Plasma Proteins (as Oral Hypoglycemics & Oral Anticoagulant). *Antagonise effect of Angiotensin Converting Enzyme Inhibitors & increase Hyperkalemia. 2. Indole Derivatives :Indomethacin: Strong Anti-inflammatory & Serious side effects. +Ibuprofen & ketoprofen have Longer duration, 20 times more Potent than Aspirin. +Diclofenac “Voltaren” is Stronger than Ibuprofen. +Piroxicam is Strong Anti-inflammatory. II) Selective COX-2 Inhibitors Mechanism of action :*COX-2 Isoenzyme is induced at site of Inflammation, selective COX-2 Inhibitor as Clecoxib has Analgesic, Antipyretic and Antiinflammatory effect. *Weak effect on COX-1 Isoenzyme with Few Gastrointestinal side effects and without affecting Platelets. III) Selective COX-3 Inhibitors Selective COX-3 Inhibitor as Paracetamol. Pharmacokinetic: Orally Absorbed, Slightly bound to Plasma Proteins “No Drug To Drug Interaction”, Metabolized into Inactive and Less than 5% is converted into Hepatotoxic Metabolite which is Detoxificated by Glutathione. Actions: Analgesic, Antipyretic but not Anti-nflamrnatory. It decrease Prostaglandins synthesis Central NOT Peripheral (VERY SAFE). Selective COX-3 Inhibitor has NO effect on Uric Acid, NO Peptic Ulcer, NO effect on Platelets & NO Bronchospasm. Uses: Analgesic Antipyretic in :*Allergy or Intolerance to Aspirin. *In Pregnancy. *Patients with Hemophilia or Bleeding Tendancy of Peptic Ulcer. *Bronchial Asthma. *Viral Infection in Children. *Gout. (Max dose= 4g/day, if Low 4g/day → Toxicity “affect Liver & Kidney”) Side effects: It is Well Tolerated at Therapeutic Doses. If used in a dose Higher than 4 g/day, the Toxic Metabolite Accumulation leads to Hepatic Necrosis and Renal Tubular Necrosis. Acetyl Cysteine “increase synthesis of Glutathione” is used to Treat Toxicity (Antidote).