NONSTEROIDAL ANTIINFLAMMATORY DRUGS AND ANTIPYRETIC-ANALGESICS
MS.NAGESWARARAO DEPT OF MEDICAL PHARMACOLOGY All drugs grouped in this class have analgesic, antipyretic and anti-inflammatory actions in different measures. In contrast to morphine they areweaker analgesics, do notdepress CNS, do not produce physical dependence and have no abuse liability.They act primarily on peripheralpain mechanisms, but alsoin the CNS to raise pain threshold . They are more commonlyuseddrugs. CLASSIFICATION Nonselective COX inhibitors ( traditional NSAIDs )
1. Salicylates: Aspirin. 2. Propionic acid derivatives:Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen Anthranilic acid derivatives: Mephenamic acid Aryl-acetic acid derivatives:Diclofenac, Aceclofenac Oxicam derivatives: Piroxicam, Tenoxicam Pyrrolo-pyrrole derivative:Ketorolac Indole derivative: Indomethacin Pyrazolone derivatives: Phenylbutazone, Oxyphenbutazone. B. Preferential COX-2 inhibitors: Nimesulide, Meloxicam,
Nabumetone. C. Selective COX-2 inhibitors: Celecoxib, Etoricoxib, Parecoxib. D. Analgesic- antipyretics with poor anti-inflammatory action Paraaminophenol derivative:Paracetamol (Acetaminophen). 2. Pyrazolone derivatives: Metamizol (Dipyrone), Propiphenazone. 3. Benzoxazocine derivative: Nefopam. MECHANISM OF ACTION: Prostaglandins, Prostacyclin (PG I2) and thromboxane A2(TXA2)are produced from arachidonic acid by the enzyme cyclooxygenase which exists in a constitutive(COX-1) and an inducible (COX-2 ) isoforms. Cox-1 isconstitutive, found in most tissues such as blood vessels, stomach and kidney. PGs have important physiological role in many tissues.(GI protection, platelet function, kidney function , regulation of blood flow and lowers IOP etc COX-2 is induced during inflammation by cytokines and endotoxins, and is responsible for the production of prostanoid mediators of inflammation, pain and fever. Most NSAIDs inhibit COX-1 and COX-2 nonselectively, , but some preferential and selective COX-2 inhibitors have been produced SALICYLATES ASPIRIN (PROTOTYPE) Aspirin is acetyl salicylic acid
SALICYLATES ASPIRIN (PROTOTYPE) Aspirin is acetyl salicylic acid. It is rapidly converted in the body to salicylic acid which is responsible for most of theactionsIt is one of the oldest analgesic- anti-inflammatory drugs and is stillwidely used MOA: Inhibits irreversibly both the COX nonselectively PHARMACOLOGICAL ACTIONS:
Analgesia- Due toperipheral inhibition of prostaglandin synthesis. Relieve pain without causing sedation, tolerance or drug dependence. They are mainly relieving musculoskeletal pain , dysmenorrhea and pain associated with inflammation or tissue damage. Antipyresis :Inflammation, bacterial infection Increase in PGE2 Hypothalamus Raises its temperature set point Aspirin by inhibiting PG synthesis decreases temperature They promote heat loss by causing cutaneous vasodilatation and swatting. Anti-inflammatory: Inhibits PG synthesis at the site of injury . And also affect other mediators of inflammation bradykinin , histamine , serotonin etc. Other mechanisms Produce symptomatic relief Suppress Pain swelling, vasodilatation. But they do not affect the progression of underlying disease. Antiplatelet aggregation (Antithrombotic effect ):
PGI Platelet aggregation TXA2 vasodilatation Vasoconstriction inhibit platelet aggregation promote platelet aggregation Aspirin (low doses mg ) by inhibitingTXA2itprevents platelet aggregation . Aspirin in high doses (2-3g/day) inhibits both PGI2 and TXA2 synthesis, hence beneficial effects of PGI2 is lost. Respiration and Acid-base, electrolyte balance:
Anti-inflammatory doses (therapeutic dose) Stimulation of respiration Hyperventilation Respiratory Alkalosis (which is compensated by excretion of alkaline urine ) Respiratory depression CO2 retention
At toxic doses Respiratory depression CO2 retention Respiratory acidosis (later, there is uncompensated metabolic acidosis ) Gastrointestinal tract:
Aspirin irritates the gastric mucosa and produces nausea , vomiting and dyspepsia. Aspirin also stimulates CTZ and produces vomiting. Cardiovascular system: Prolonged use of these drugs Causes sodium and water retention.(inhibit COX-2 in kidney) Thus can precipitate CCF and they may also compromise the effect of antihypertensive drugs. Urate excretion: Salicylates in therapeutic doses inhibit urate secretion into the renal tubules and increase the plasma urate levels. In high doses, salicylates inhibit the reabsorption of uric acid in the renal tubules and produceuricosuric effect. PHARMACOKINETICS Absorbed from stomach and small intestines
Poor water solubility-micro fining enhances absorption 80 % bound to plasma proteins Volume of distribution 0.17L/Kg - 11L Conjugated with glucuronic acid and glycine Excreted by glomerular filtration and tubular secretion In low doses , elimination follows 1st order kinetics and with high doses as the metabolizing enzymes get saturated ,it switches over to zero order kinetics. Analgesic dose( g /day)- t 3-5 hours Antiinflammatory dose(3-5 g /day)-t 8-12 hours Anti platelet dose : mg/day. ADVERSE EFFECTS Side effects-analgesic dose-nausea, vomiting,epigastric distress, increased occult blood in stools-gastric mucosal damage, peptic ulceration. Ulcerogenic effect is the major drawback of NSAIDs which is prevented / minimized by taking: -After food - buffered aspirin (preparation of aspirin with antacid) - Misoprostol/H2 blockers /PPIs with NSAIDs - selective COX-2 inhibitors Hypersensitivity and idiosyncrasy are more common with aspirin-
rashes, urticaria, rhinorrhoea, nasal polyps ,angioedema, bronchospasm and anaphylactoid reaction. Aspirin induced asthma(due to incresesd production of LT ) LT antagonists are effective to treat aspirin induced asthma. Anti-inflammatory doses-salicysm-dizziness, tinnitus, vertigo, reversible impairment of hearing and vision, excitement and mental confusion, hyperventilation and electrolyte imbalance. these symptoms are reversible on stoppage of therapy. Reyes syndrome- Use of salicylates in children'swith viral infection may cause hepatic damage with fatty infiltration and encephalopathy. Hence these drugs are contraindicated . In Pregnancy: These drugs inhibit PG synthesis, there by delaying
onset of labour. andIncrease chances of PPH. In new-borns inhibition of PG s synthesis results inPremature closure ofductus arteriosus. Haemostatic effects: Prolonged use of salicylates interfere with action of vitamin K in the liver Decreased synthesis of clotting factors (hypoprothrombinaemia) Predisposes to bleeding (can be treated by administration of vit K) Analgesic nephropathy: mainly seen in renal disease patients.
Slowly progressive renal failure / chronic nephritis occurs on chronic use of high doses of NSAIDs. This is mainly due to inhibition of PGE2 mediated compensatory vasodilatation that occurs in response to angiotensin-2 ACUTE SALICYLATE POISONING
More common in children Fatal dose in adults is g Vomiting, dehydration, electrolyte imbalance, acidotic breathing, petechial haemorrhages, restlessness,, hallucinations, hyperpyrexia, convulsions, coma - death due to respiratory failure + cardiovascular collapse TREATMENT symptomatic and supportive IV fluids with Na, K, HCO3 and glucose Gastric lavage-alkaline diuresis-haemodialysis Bleeding-blood transfusion- vit k External cooling PRECAUTIONS AND CONTRAINDICATIONS
Hypersensitivity, peptic ulcer, bleeding tendencies, children suffering from chicken pox or influenza Chronic liver disease-may cause hepatic necrosis CHF sodium and water retention Stopped one week before surgery bleeding Taken at or near term may cause- prolonged labour-greater postpartum blood loss-premature closure of ductus arteriosus (PGE2 &PGI2) Bronchial asthma patients Avoid high doses in G-6-PD deficiency-may cause haemolysis Interactions Displaces warfarin, phenytoin from protein binding sites
Alcohol and glucocorticoids increase the risk of gastritis Increase risk of bleeding in patients on oral anticoagulant Clinical uses of NSAIDS:
Analgesic-( g 6-8 hourly)-headache,toothahe, joint pains etc Antipyretic-Paracetamol preferred (no Reyes syndrome in children's and GIT symptoms are less) Acute rheumatic fever-4-5 g/day in divided doses-dose reduction after 4-7 days- it reduce fiver , swelling and joint pain. Rheumatoid arthritis-(3-5 g/day) Osteoarthritis-Paracetamol is first choice drug.in severe cases NSAIDs are effective Post myocardial infarction and post stroke patients mg/day inhibit platelet aggregation. Primary prevention of myocardial infarction Other uses: Medical closure of patent ductus arteriosus (indomethacin is preferred) Colon and rectal cancer: regular use of aspirin is reported to reduce the risk of cancer (COX-2 inhibition in colon) To control pruritus and flushing associated with the use of nicotinic acid (Aspirin will inhibit PGD2 in he skin) PROPIONIC ACID DERIVATIVES
OTHER NSAIDS HAVE SIMILAR MECHANISAM OF ACTION, PHARMACOLOGICAL ACTIONS, THERAPEUTIC USES AND ADVERSE EFFECTS. THEY VARY MAINLY IN THEIR POTENCY, DURATION OF ACTION, ANALGESIC AND ANTIINFLAMMATORY EFFECTS. PROPIONIC ACID DERIVATIVES Ibuprofen-Naproxen-Ketoprofen-Flurbiprofen Side effects are milder and incidence is lower Ibuprofen rated as the safest conventional NSAID Naproxen more efficacious-better tolerated-longer lasting Ibuprofen-200,400,600mg tab, 100mg/ml susp mg TDS Naproxen-250,500mg tab mg BD-TDS Ketoprofen-50,100,200mg tab, 100mg/ml amp mg BD-TDS Flurbiprofen-50,100,200mg tab mg BD-QID 0.03% eye drops-1 drop 6 hourly ANTHRANILIC ACID DERIVATIVE
MEPHENAMIC ACID-An analgesic, antipyretic with potent anti-inflammatory action Diarrhoea is the most important dose related side effect Haemolytic anaemia is a rare but serious complication Used primarily as analgesic in muscle, joint and soft tissue pain where strong anti-inflammatory action is needed 125,250,500 mg tab, mg TDS 50 mg/ml syrp, 100 mg/5 ml susp ARYL-ACETIC ACID DERIVATIVES
DICLOFENAC SODIUM-Similar in efficacy to Naproxen Most extensively used NSAID Used in osteoarthritis, bursitis, ankylosing spondylitis,toothache, dysmenorrhoea, post-traumatic and postoperative inflammatory conditions Affords quick relief of pain and wound edema 25,50 mg tab-50 mg TDS then BD oral, mg/ml in 3ml amp given deep i.m % topical gel and 0.1% eye drops ACECLOFENAC-Congener of Diclofenac-longer acting 100 mg tab-100 mg BD OXICAM DERIVATIVES PIROXICAM-long acting potent NSAID
Antiinflammatory efficacy similar to Indomethacin Good analgesic-anti-inflammatory action Better tolerated than Indomethacin and aspirin Used in rheumatoid and osteo-arthritis, ankylosing spondylitis, acute gout, musculoskeletal injuries, dentistry, episiotomy, dysmenorrhoea, etc 10,20 mg cap-20 mg BD for two days followed by 20 mg OD mg/ml inj in 1 and 2ml amps TENOXICAM-a congener of Piroxicam similar properties uses 20 mg tab-20 mg OD PYRROLO-PYRROLE DERIVATIVE
KETOROLAC-A novel NSAID with potent analgesic and modest anti-inflammatory activity In post operative pain it has equalled the efficacy of morphine Does not interact with opioid receptors and is free of opioid side effects Used in postoperative, dental and acute musculoskeletal pain May also be used for renal colic, migraine and pain due to metastasis 30 mg in 1 ml amp mg im or iv every 4-6 hours (maximum 90mg/day) 10 mg tab mg 6 hourly Use for more than 5 days continuously not recommended INDOLE DERIVATIVE INDOMETHACIN-It is a potent anti-inflammatory drug with prompt antipyretic action A high incidence (up to 50%) ofgastrointestinal and CNS side effects is produced Gastric irritation, nausea, anorexia, gastric bleeding and diarrhoea are produced Frontal headache, dizziness, ataxia, mental confusion, hallucination, depression and psychosis can occur Because of prominent adverse effects, Indomethacin is used as a reserve drug in conditions requiring potent anti-inflammatory action like ankylosing spondylitis, acute exacerbations of destructive arthropathies, and acute gout 25,75 mg cap mg BD-QID 1% eye drops 50 mg suppository PYRAZOLONES METAMIZOL(DIPYRONE-ANALGIN)
It is a prompt acting analgesic and antipyretic with poor anti-inflammatory action It can be given orally, im as well as iv Few cases of agranulocytosis were reported g oral/im/iv 0.5 g tab, 0.5 g/ml in 2 ml and 5 ml amps PROPIPHENAZONE-Claimed to be better tolerated Agranulocytosis not reported SARIDON-Propiphenazone 150 mg +Paracetamol 250 mg tab DART-Propiphenazone 150 mg + Paracetamol 300 mg Caffeine 50 mg tab PREFERENTIAL COX-2 INHIBITORS
NIMESULIDE-has relative COX-2 selectivity Instances of fulminant hepatic failure reported Withdrawn in Tanzania and many countries 100 mg tab 100 mg BD, 50 mg/5 ml susp MELOXICAM-newer congener of Piroxicam Long acting can be given once daily Gastric side effects are milder compared to Piroxicam Used in osteo arthritis and rheumatoid arthritis 7.5, 15 mg tab mg od NABUMETONE-effective in the treatment of rheumatoid arthritis, osteo arthritis and soft tissue injury 500 mg tab-1 tab daily SELECTIVE COX-2 INHIBITORS
Cause little gastric mucosal damage Do not inhibit platelet aggregation-platelet TXA2 not affected Reduces anti aggregatory endothelial PGI2 Rofecoxib and Valdecoxib withdrawn for increasing cardiovascular risk (Due to inhibit PGI2 with out effecting TXA2) CELECOXIB-gastric tolerability better than nonselective NSAIDs Used in osteo arthritis and rheumatoid arthritis 100, 200 mg caps, mg BD ETORICOXIB-newer COX-2 inhibitor - for once a day treatment 60, 90, 120 mg, mg OD PARECOXIB-suitable for injection-efficacy similar to Ketorolac 40 mg/vial inj, 40 mg tab 40 mg oral/ im/ iv, repeated after 6-12 hours PARA-AMINO PHENOL DERIVATIVE
PARACETAMOL(ACETAMINOPHEN) Recentevidences suggests that paracetamol may act by inhibiting cox-3 in CNS. cox-3 is involved in painperception and fever but not in inflammation. Has analgesic, antipyretic actions Weak anti-inflammatory action Does not stimulate respiration or affect acid base balance Does not increase cellular metabolism Has no effect on CVS Gastric irritation is insignificant Does not affect platelet function PARACETAMOL Well absorbed on oral administration 1/4this plasma protein bound Uniformly distributed in body Metabolismmainly conjugation with glucuronic acid and sulfate Conjugates excreted rapidly in urine Plasma t is 2-3 hours Effects after an oral dose lasts 3-5 hours ADVERSE EFFECTS-Safe and well tolerated Nausea and rashes occur occasionally Hepatotoxicity and nephrotoxicity is seen on chronic use. ACUTE PARACETAMOL POISONING
Occurs commonly in small children having low glucuronide conjugating capacity 15-20 g in an adult fatal Hepatic necrosis, renal tubular necrosis, hypoglycemia may progress to coma and death Minor metabolite N-acetyl-p-benzoquinoneimine is detoxified by conjugation with glutathione Toxicity manifests when glutathione is depleted Specific antidote N-acetylcysteine replenishes glutathione stores of liver and prevents binding of toxic metabolite to proteins in the liver and kidney. Activated charcoal is administered to decrease the absorption of paracetamol from the GIT Hemodialysis may be required in case with acute renal failure. PARACETAMOL-USES One of the most commonly used over the counter analgesic Used for headache, mild migraine, musculoskeletal pain, dysmenorrhoea First choice analgesic for osteo arthritis Is best drug to be used as antipyretic 500 mg tab g TDS 125 mg/ 5 ml syrup, infants 50 mg, 1-3 years mg, 4-9 years mg, 9-12 years300=600 mg TDS TOPICAL NSAIDs Topical formulations for application over painful muscles or joints Believed that drug penetrates subjacent tissues attaining high concentrations in the affected muscles/joints, while maintaining low blood levels Strong placebo effect of local application-massaging Presence of counter irritants like menthol, methyl salicylate, etc. Diclofenac 1% gel, Ibuprofen 10% gel, Naproxen 10% gel, Ketoprofen 2.5% gel,Flurbiprofen 5% gel, Nimesulide 1% gel, Piroxicam 0.5% gel CHOICE - NONSTEROIDAL ANTIINFLAMMATORY DRUG
Mild to moderate pain with little inflammation: Paracetamol or low dose Ibuprofen Postoperative or similar acute but short lasting pain: Ketorolac, Propionic acid derivative, Diclofenac, Nimesulide, Aspirin Acute musculoskeletal, osteoarthritic, injury associated pain: Paracetamol, propionic acid derivative, Diclofenac Exacerbation of rheumatoid arthritis, ankylosing spondylitis, acute gout, acute rheumatic fever: Naproxen, Piroxicam, Indomethacin, high dose aspirin Gastric intolerance to traditional NSAIDs or predisposed patients:a selective COX-2 inhibitor or paracetamol CHOICE NONSTEROIDAL ANTIINFLAMMATORY DRUG
Patients with history of asthma or anaphylactoid reaction to aspirin/other NSAIDs: Nimesulide, COX-2 inhibitor Paediatric patients: Only Paracetamol, Aspirin, Ibuprofen, Naproxen have been adequately evaluated in children. Due to risk ofReyes syndrome Aspirin should be avoided Pregnancy: Paracetamol is the safest; Low dose Aspirin is probably the second best Hypertensive, diabetic, ischaemic heart disease, epileptic and other patients receiving long term regular medication: possibility of drug interaction with NSAIDs should be considered ANALGESIC COMBINATIONS
Additive synergism Aspirin + Paracetamol Ibuprofen + Paracetamol Diclofenac + Paracetamol Aspirin + Codeine Paracetamol + Codeine THANK YOU