nsaids - drdhriti


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A power point presentation on NSAIDs (Part 1- salicylates) useful for 2nd Professional medical undergraduate students


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Nonsteroidal Antiinflammatory Drugs and Antipyretics-analgesics:

Nonsteroidal Antiinflammatory Drugs and Antipyretics-analgesics Department of Pharmacology NEIGRIHMS, Shillong

Introduction to NSAIDs:

Introduction to NSAIDs Chemically diverse, but most are organic acids Grouped together as these drugs have common analgesic and antipyretic (fever-reducing) effects and which have, in higher doses, anti-inflammatory effects Also called non-narcotic, nonopioid and aspirin-like analgesics Primarily act on periphera l pain mechanism, and also in CNS


History Salix alba or White Willow bark Sodium salicylate – 1875 Acetylsalicylic acid – 1899 Also phenacetin and antipyrine Phenylbutazone – 1949 Indomethacin - 1963

Classification – Traditional :

Classification – Traditional Salicylic acids Aspirin Propionic acids Naproxen, Ibuprofen, Ketoprofen, Oxaprozin and Flurbiprofen Anthranilic acid Mefenamic acid and Meclofenamate Aryl-acetic acid derivative Diclofenac and Aceclofenac Oxicam derivatives Piroxicam and Tenoxicam Pyrrolo-pyrrole derivative Ketorolac Indole derivatives Sulindac and Indomethacin Pyrazolone derivative Phenylbutazone

Classification – contd.:

Classification – contd. Preferential COX-2 inhibitors Nimesulide, Meloxicam and Nabumetone Selective COX-2 inhibitors Celecoxib, Rofecoxib, Etoricoxib and Parecoxib Analgesic-antipyretic with poor antiinflammatory action: Paraaminophenol derivative Pyrazolone derivative Benzoxazocine derivative Paracetamol (acetaminophen) Metamizole and propiphenazone Nefopam

NSAIDs and Prostaglandin:

NSAIDs and Prostaglandin All NSAIDs inhibit PG synthesis Prostaglandins, prostacyclines (PGI 2 ) and Tromboxane A2 (TXA 2 ) are produced from Arachidonic acid The enzyme responsible is prostaglandin synthase , also known as cyclooxygenase or COX COX exists in 2 (two) isoforms: constitutive - COX-1 and inducible COX-2 COX-1 serves house keeping functions COX-2 is generated by cytokines and others during inflammation (constitutive in brain and JG cells) Most NSAIDs inhibit COX-1 and COX-2 non-selectively and inhibit PG synthesis

Proposed Mechanism: COX-1, COX-2, & COX-3:

Proposed Mechanism: COX-1, COX-2, & COX-3 Arachidonic acid COX-2 (inducible) Body homeostasis Stomach Intestine Kidney Platelet Inflammatory Site Macrophages Synoviocytes Endothelial cells X X Selective COX-2 inhibitor COX-1 (normal constituent) X Normal Constituent CNS Kidney Female U/G tract Glucocorticoids (block mRNA expression) X X Acetaminophen COX-3 (normal constituent) Pain Fever ?HTN ?GI CNS, Heart, Aorta Nonselective NSAID

NSAIDs and Prostaglandin :

NSAIDs and Prostaglandin Mediate inflammation, pain, and fever COX-2 – specific inhibitors Protect gastroduodenal mucosa Supports platelet function COX-1 COX-2 Nonspecific NSAIDs Prostaglandins Thromboxane Prostaglandins Arachidonic Acid Membrane Phospholipid Phospholipase A

Benefits of PG synthesis inhibition:

Benefits of PG synthesis inhibition Analgesia: Prevention of pain nerve ending sensitization Antipyresis: Reduction of Body temperature in hyperthermia Anti-inflammatory action: reduction in signs of inflammation (pain, tenderness, swelling and vasodilatation) Antithrombotic action: Inhibition of platelet aggregation Closure of Ductus arteriosus in Newborn

1. Analgesia:

1. Analgesia Pain: An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (IASP) Duration: Acute Pain and Chronic Pain

Classification of Pain:

Nociceptive Neuropathic Classification of Pain Pain that arises from a stimulus that is outside of the nervous system Proportionate to the stimulation of the receptor When acute serves a protective function Musculoskeletal disorders are a very common cause of nociceptive pain Examples - Postoperative pain, arthritis, mechanical low back pain Pain initiated or caused by a primary lesion or dysfunction in the nervous system No nociceptive stimulation required Disproportionate to the stimulation of receptor Examples - Post herpetic neuralgia (PHN), and diabetic neuropathy vs Diabetic foot

Peripheral & Central Sensitization Peripherally & Centrally Induced COX-2:

Peripheral & Central Sensitization Peripherally & Centrally Induced COX-2 Peripheral Central Trauma/inflammation Release of arachidonic acid COX-2 Prostaglandins E2 Pain Peripheral sensitization COX-2 Prostaglandins Central sensitization Pain IL-1ß IL-6?

Slide 13:

Transduction Transmission Modulation Perception Interpretation Pain Behavior Peripheral Nerve Ascending Pathways Injury Descending Pathway Dorsal Root Ganglion C-Fiber A-beta Fiber A-delta Fiber Dorsal Horn Brain Spinal Cord NSAIDs and Analgesia

NSAIDs and Prostaglandin - Summary :

NSAIDs and Prostaglandin - Summary The first enzyme in the prostaglandin (PG) synthetic pathway is prostaglandin synthase, also known as cyclooxygenase or COX Converted to unstable PGG 2 and PGH 2 and a variety of PGs and TXA2 Pain results from inflammation due to local stimulation of pain fibers enhanced pain sensitivity (hyperalgesia) - ↑excitability of central neurons in the spinal cord Antihyperalgesic (analgesic) effects through inhibition of spinal PGs release NSAIDs is usually classified as mild analgesics, particularly effective when inflammation has caused sensitization of pain receptors to normally painless mechanical or chemical stimuli

2. Antipyresis:

2. Antipyresis Reduction in body temperature in case of hyperthermia by acting in Hypothalumus Not in normothermic individuals Fever during infection generates pyrogens, including TNF-alpha, interferones which induce PGE 2 COX-2 and COX-3 (?) isoforms Temperature threshold is raised NSAIDs blocks the action of PG production in hypothalumus and reduce temperature

3. Antiinflammatory :

3. Antiinflammatory NSAIDs inhibit PG synthesis at the site of injury The decrease in vasodilator prostaglandins (PGE 2 , PGI 2 ) means less vasodilatation and, indirectly, less oedema PGs are not sole mediators of inflammation LTs, PAF and cytokines etc. are also targets of anti-inflammatory action The inhibition of activity of adhesion molecule - ECAM Accumulation of inflammatory cells is also reduced (WBCs) – superoxide generation inhibition Some NSAIDs may act via these additional mechanisms also


Dysmenorrhoea Severe pain during menstruation – may precede menstruation or during menstruation Caused by increased release of PGs (PGF-alpha) due to increased destruction of endometrial cells and release of their contents Intermittent ischaemia of myometrium – cramps NSAIDs are effective by decreasing the PG release Secondary Primary

Antiplatelet aggregator:

Antiplatelet aggregator TXA 2 is pro-aggregator (COX-1) PGI 2 is anti-aggregator Effects on TXA 2 predominates and inhibits aggregation – prolonged bleeding time Aspirin is highly active and acetylates COX in circulation – before hepatic one Antithrombotic effect – Myocardial Infarction

Ductus arteriosus:

Ductus arteriosus It is a shunt connecting the pulmonary artery to the aortic arch Maintained by local PGE 2 and PGI 2 Closes at birth Failure to close – small doses of NSAIDs (aspirin or indomethacin) – closes (No NSAIDs in late pregnancy – premature closure)

Gastric Mucosa:

Gastric Mucosa All NSAIDs produce gastric mucosal damage, ulceration and blood loss – varying extent Due to inhibition of COX-1 mediated synthesis of gastro protective PG (PGE 2 and PGI 2 ) Also back diffusion of H+ in gastric mucosa Deficiency of PGs reduces HCO3 secretion – promote mucosal ischaemia Enhance aggressive factors over defensive factors Paracetamol – free of gastric toxicities Selective COX-2 inhibitors Misoprostol

Renal Effects:

Renal Effects PGs cause: (Intrarenal regulator) Renal vasodilatation and inhibition of tubular reabsorption Frusemide like effect – inhibition of Cl- reabsorption Increased excretion of Na+, K+ and water NSAIDs block these renal effects by inhibition PGs Impairment of renal blood flow Na+ and water retention Papillary necrosis on prolonged use Particularly important in conditions of CHF, hypovolaemia, cirrhosis and renal impairment (Na+ retention and edema) Patent under antihypertensives and diuretics


Salicylates ASPIRIN is the Prototype Converted in the Body to Salicylic acid Other important salicylate – Sulfasalazine, Diflunisal

Aspirin Pharmacological Actions:

Aspirin Pharmacological Actions Aspirin irreversibly inhibiting COX-1 & COX-2 activity Inhibits COX irreversibly by acetylating one of its serine residues (at 530) – fresh enzyme synthesis requires for return Also inhibits the transcription of the COX-2 gene, preventing more enzyme from being produced Mainly effective in pains related to inflammation, tissue injury, connective tissue and integument pain Not much effective in visceral and ischemic pain Other mechanisms: Raising of pain threshold by acting centrally – morphine like Resetting of hypothalamic thermostat – fever reduction Anti-inflammatory doses are higher than analgesic doses

Aspirin Pharmacological Actions – contd.:

Aspirin Pharmacological Actions – contd. Metabolic effects: Increased cellular metabolism uncoupling phosphorylation → increased heat production Increased utilization of glucose – decreased blood sugar and glycogen depletion Negative Nitrogen balance (increased protein to carbohydrate) Toxic doses: Hyperglycaemia Respiration: Low doses: uncoupling phosphorylation → ↑ CO2 → stimulates respiration Direct stimulation of respiratory center → Hyperventilation → resp. alkalosis → renal compensation Depression of respiratory center and cardiovascular center → ↓ BP, respiratory acidosis, no compensation + metabolic acidosis also

Aspirin Pharmacological Actions – Acid- base and Electrolyte balance: :

Aspirin Pharmacological Actions – Acid- base and Electrolyte balance: Anti-inflammatory doses ( 4 - 5 gm/day ) – very important changes in acid-base balance Initially Respiratory alkalosis (low CO2) – due to stimulation of respiration and hyperventilation Increased expelling of CO2 – shift in dynamics of chemical equilibrium of CO2 in circulatory system Shift of H+ and HCO3- for more production of CO2 via carbonic anhydrase Net result is decrease in H+ resulting in increased pH Increase pH stimulates kidneys to excrete HCO3 (also Na+, K+ and water) – patients remain in compensated respiratory alkalosis Still Higher doses: Respiratory depression leading to CO2 accumulation CO2 production continues due to increased burning of energy leading to Respiratory acidosis Added burden of metabolic products – lactate, pyruvate, sulphuric and phosphoric acids etc. – Uncompensated metabolic acidosis

Actions of Aspirin – contd.:

Actions of Aspirin – contd. GIT: Salicylic acid – irritant to mucosa causing nausea and vomiting Unionized in stomach and absorbed but upon absorption – ionizes and and indiffusible (Ion trapping) Locally – back diffusion of acid – necrosis of mucosa and arteries – ulceration, erosive gastritis etc Occult blood loss – haematemesis Salicylate-induced gastric bleeding is painless and may lead to an iron deficiency anemia CVS: Therapeutic doses have no significant cardiovascular effect High doses may cause peripheral vasodilation by exerting a direct effect on smooth muscle Toxic doses - depress circulation directly and by central vasomotor paralysis CCF – low cardiac reserve patients

Aspirin Pharmacological Actions – contd.:

Aspirin Pharmacological Actions – contd. Hematologic effects : It inhibits the platelet aggregation by decreasing the production of TXA2 – lasts for a week In doses greater than 6 gm/d, aspirin may reduce plasma prothrombin levels Prolonged use – decrease in synthesis of clotting factors Urate Excretion: Dose less than 2 gm/day – urate retention 2-5 gm/day – variable effects More than 5 gm/day – increased urate excretion

Aspirin - Pharmacokinetics:

Aspirin - Pharmacokinetics Absorbed from stomach and SI Poorly water soluble – limitation Solubility can be increased by alkalizations – but ??? Converted to salicylic acid in gut, liver and plasma 80-85% bound to plasma protein Can cross placenta and CSF Metabolized in liver by conjugation with glycine – salicyluric acid Excreted as glomerular filtration and tubular secretion T1/2 life is 15-20 minutes 8 – 12 Hrs due to metabolic process saturation High doses have long t1/2

Aspirin – Adverse Effects:

Aspirin – Adverse Effects Gastrointestinal disturbances Nausea, vomiting, epigastric distress and gastric mucosal damage Hypersensitivity and Idiosyncrasy: FDE, rash, urticaria, asthma (bronchospasm – aspirin sensitive asthmatics) Salicylism: on repeated administration (3-5 gm/day) headache, mental confusion, lassitude, and drowsiness tinnitus and difficulty in hearing hyperthermia, sweating, thirst, hyperventilation, vomiting, and diarrhea Hepatotoxicity: Rise in serum transaminases – hepatotoxic Reye`s Syndrome – rare disease of hepatic encephalopathy when given in viral conditions of influenza and varicella Prolongation of bleed time or reduce prothrombin level Reye`s FDE

Treatment of Aspirin poisoning:

Treatment of Aspirin poisoning Fatal dose: 15 – 30 gm Low in case of children Features: Vomiting, dehydration, acidosis, petechial haemorrhage, hyperglycaemia, hyperpyrexia, confusion and coma etc. Management: Inducing emesis or administering gastric lavage Appropriate infusion measures to correct abnormal electrolyte balance and dehydration – Na+, K+, HCO 3 etc. as per need Alkalinization of the urine Dialysis as required Vit.K injection

Aspirin – Therapeutic uses:

Aspirin – Therapeutic uses Analgesic: Headache, migraine, backache, tothache, dysmenorrhea etc (300 to 600 mg 8 Hrly) Rheumatoid arthritis: (3-5 gm/day) Used to be standard first line of drug Poorly tolerated – newer NSAIDS Acute Rheumatic Fever: (4-5 gm/day) First drug of choice – other drugs are added when it fails Dose is reduced after 1 week therapy Continued for 3-4 weeks gradual withdrawal for over 2 weeks Osteoarthritis Antipyrretic Rheumatic Valve

Aspirin and Myocardial infarction:

Aspirin and Myocardial infarction Routinely prescribed for post myocardial infarction patients – prophylaxis purpose to prevent re-infarction MOA - TXA 2 (pro-aggregator) inhibition Dose is very low (60 – 100 mg/day) High doses inhibit PGI 2 (anti-aggregator) Primary prophylaxis (100 to 150 mg – more useful Reduces TIA and lowers incidence of stroke Aspirin preparations: Tablets of various strength – 75 mg, 100 mg, 325 mg, 650 mg etc. Aspirin, Disprin, Loprin, Ecospirin etc.

Aspirin – Contraindications:

Aspirin – Contraindications Sensitive Persons Children with viral diseases Peptic ulcer disease and bleeding disorders Chronic liver diseases Diabetes, CHF and juvenile Rh. Arthritis G-6-PD deficient persons Stop prior to surgery, near term pregnancy, breast feeding mothers etc

Drug Interactions of Aspirin:

Drug Interactions of Aspirin Aspirin and Probenecid: Antagonize Uricosuric action of probenecid Probenecid become ineffective in Gout Aspirin and anti-hypertensive: NSAIDs cause fluid retention and oedema – antihypertensive effects are decreased Aspirin and Diuretics: ( furosemide and thiazides ) Blunting of Furosemide effects Aspirin and oral anticoagulants ( warfarin and sulfonylureas ) Toxicity (increased tendency of bleeding)

What to Remember ?:

What to Remember ? Classifications (at least 10 Drugs) Inhibition of COX-1 and COX-2 by NSAIDS and benefits related to analgesic, antipyretic and anti-inflammatory actions Other clinical beneficial effects of PG inhibition by NSAIDs Pharmacological actions of Salicylates Adverse effects of salicylates Therapeutic uses of salicylates – dose related effects Contraindications of salicylates

Thank You:

Thank You Other NSAIDs in Next Class