Nonsteroidal Anti-inflammatory Drugs and Antipyretic - Analgesics PDF

Nonsteroidal Antiinflammatory Drugs and Antipyretic - Analgesics Dr. Anuroop Singhai Oral Surgery Division Non Steroidal Antiinflammatory Drugs and Antipyretic-Analgesics Introduction Analgesic is a drug that selec-vely relieves pain by ac-ng in the CNS or on peripheral pain mechanisms, witho...

Nonsteroidal Antiinflammatory Drugs and Antipyretic - Analgesics Dr. Anuroop Singhai Oral Surgery Division Non Steroidal Antiinflammatory Drugs and Antipyretic-Analgesics Introduction Analgesic is a drug that selec-vely relieves pain by ac-ng in the CNS or on peripheral pain mechanisms, without significantly altering consciousness. Analgesics relieve pain as a symptom without affec-ng its cause. They are used when the noxious s-mulus (evoking pain) cannot be removed, or as an adjuvant to more e-ologic approach to pain, such as an-bio-c treatment of apical tooth abscess. Analgesics are divided into two groups: A. Opioid / narco-c / morphine like analgesics. B. Nonopioid / non-narco-c / an-pyre-c / aspirin-like analgesics or nonsteroidal an-inflammatory drugs (NSAIDs). Classification NSAID Antiinflammatory Drugs / Antipyretic-Analgesics Nonselec9ve COX inhibitors Analgesic-antipyretics with Selec9ve COX-2 poor anti-inflammatory action Preferential inhibitor COX-2 inhibitors Salicylates Enolic acid derivatives Celecoxib Para aminophenol derivative Nimesulide Paracetamol Etoricoxib Diclofenac (Acetoaminofen) Parecoxib Propionic acid Aceclofenac derivatives Acetic acid derivatives Benzoxazocine deriva9ve Meloxicam Nefopam Etodolac Fenamate Pyrazolone derivatives  Slow-reacting substance of anaphylaxis (SRS-A) is an import- that either one or both play a role in the bronchial constriction and ant mediator of anaphylactic and other immediate allergic reactions. mucosal edema of asthma. Leukotriene B4 can enhance chemotactic Mechanism of Action SRS-A can be found in most tissues, especially in the lung, after appro- priate antigenic challenge. It is released along with histamine and other and chemokinetic responses in human neutrophils, monocytes, and eosinophils. These findings suggest that leukotrienes are involved Cell membrane phospholipids Steroids inhibit Phospholipases Other Arachidonic acid HPETEs HETEs lipoxygenases COX-1 and COX-2 inhibitors, aspirin, Cyclooxygenase 5-Lipoxygenase ibuprofen, naproxen and celecoxib inhibit Prostaglandin G2 (PGG2) 5-HPETE 5-HETE 12-Lipoxygenase Chemotaxis Prostaglandin H2 (PGH2) Leukotriene A4 (LTA4) Leukotriene B4 (LTB4) Endothelium Platelets Leukotriene C4 (LTC4) Vasoconstriction Prostacyclin Thromboxane A2 Bronchospasm (PGI2) (TXA2) Leukotriene D4 (LTD4) Increased vascular Vasodilation, Vasoconstriction, permeability inhibits platelet promotes platelet Leukotriene E4 (LTE4) aggregation aggregation Lipoxin A4 Lipoxin B4 PGD2 PGE2 PGF2 (LXA4) (LXB4) Smooth muscle Vasodilation, Inhibit neutrophil adhesion and chemotaxis Vasodilation, Increased vascular permeability-edema FIG 17-1 Pathways of arachidonic acid metabolism to prostaglandins and leukotrienes and their subsequent PG Synthesis Inhibition Beneficial Actions: 1. Analgesia: prevention of pain nerve ending sensitization 2. Antipyresis 3. Antiinflammatory 4. Antithrombotic 5. Closure of ductus arteriosus in newborn Shared Toxicities: 1. Gastric mucosal damage 2. Bleeding: inhibition of platelet function 3. Limitation of renal blood flow : Na+ and water retention 4. Delay/prolongation of labour 5. Asthma and anaphylactoid reactions in susceptible individuals Features of nonselective COX inhibitors and selective COX-2 inhibitors Nonselective COX Action COX-2 inhibitors inhibitors 1. Analgesic + + 2. Antipyretic + + 3. Antiinflammatory + + 4. Antiplatelet aggregatory + – 5. Gastric mucosal damage + – 6. Renal salt/water retention + + 7. Delay/prolongation of labour + + 8. Ductus arteriosus closure + ? 9. Aspirin sensitive asthma precipitation + – Adverse effects of NSAIDS CNS Headache, mental confusion, ver@go, behavioural disturbances, seizure precipita@on CVS Rise in BP, risk of myocardial Hepatic infarc@on (especially with COX-2 Raised transaminases, hepatic failure inhibitors) (rare) Renal Gastrointestinal Na+ and water retention, chronic Nausea, anorexia, gastric irritation, renal failure, nephropathy, papillary erosions, peptic ulceration, gastric necrosis (rare) bleeding/perforation, esophagitis Haematological Others Bleeding, thrombocytopenia, Asthma exacerbation, nasal haemolytic anaemia, agranulocytosis polyposis, skin rashes, pruritus, angioedema Drug interactions with NSAIDS Fenamate (Anthranilic Acid Derivative) 3 Drug interactions with NSAIDs Pharmacodynamic Pharmacokinetic ] Diuretics : ↓ diuresis Oral anticoagulants Metabolism β blocker : ↓ antihypertensive effect Sulfonylureas inhibited; ACE inhibitors : ↓ antihypertensive effect Phenytoin Competition Anticoagulants : ↑ risk of g.i. bleed Valproate for plasma protein binding Sulfonylureas : ↑ risk of hypoglycaemia ] Alcohol : ↑ risk of g.i. bleed Digoxin ↓ Renal Cyclosporine : ↑ nephrotoxicity Lithium excretion of Corticosteroids : ↑ risk of g.i. bleed Aminoglycosides interacting drug Selective serotonin : ↑ risk of g.i. bleed Methotrexate reuptake inhibitors orally, highly bound to plasma proteins adverse drug reporting system in UK. (90–99%), but displacement interactions Ibuprofen (400 mg) has been found equally Salicylates Aspirin Aspirin is acetylsalicylic acid. It is rapidly converted in the body to salicylic acid which is responsible for most of the actions. Pharmacological actions 1. Aspirin has analgesic, antipyretic and antiinflammatory action. 2. Aspirin as well as the salicylic acid released from it irritate gastric mucosa → cause epigastric distress, nausea and vomiting. Aspirin – Pharmacological Actions 3. Aspirin, even in small doses, irreversibly inhibits thromboxane A2 (TXA2) synthesis by platelets. Interferes with platelet aggregation, Bleeding time is prolonged to nearly twice the normal value. This effect lasts for about a week (turnover time of platelets). Long-term intake of large doses decrease synthesis of clotting factors in liver and predisposes to bleeding. This can be prevented by prophylactic vit - K therapy. 4. The analgesic doses of aspirin (0.3–0.6 g) employed in dentistry or for headache, fever, etc. have practically no other action. Aspirin – Pharmacokinetics Absorption: Stomach and small intestines. Its poor water solubility is the limiting factor in absorption. Plasma t1⁄2: Of aspirin as such is 15–20 min, but taken together with that of released salicylic acid, it is 3–5 hours. Aspirin – Adverse effects Aspirin – Adverse effects 1. Hypersensitivity and idiosyncrasy though infrequent, these can be serious. Reactions include rashes, fixed drug eruption, urticaria, rhinorrhoea, angioedema, asthma and anaphylactoid reaction. 2. Antiinflammatory doses (3–5 g/ day) produce the syndrome called salicylism— dizziness, tinnitus, vertigo, reversible impairment of hearing and vision, excitement and mental confusion, hyperventilation and electrolyte imbalance. Salt and water retention occurs in a dose-dependent manner. 3. An association between salicylate therapy and ‘Reye’s syndrome’, a rare form of hepatic encephalopathy seen in children having viral (varicella, influenza) infection, has been noted. Long-term therapy with high dose aspirin can cause insidious onset hepatic injury. Aspirin – Adverse effects 4. Acute salicylate poisoning: It is more common in children. Coma and death due to respiratory failure + cardiovascular collapse. Treatment: a. Symptoma