NSAIDS.

NSAIDS Dr.B.M.PUROHIT Assistant Professor (Pharmacology) P.D.U.MEDICAL COLLEGE, Rajkot (GUJARAT). 360001 [email_address]

INTRODUCTION NSAIDs means.. “ N on S teroidal A nti I nflammatory D rugs” If you want to study ANTI INFLAMMATORY drugs , you should know …… What is inflammation ?... “ Response of the body to injurious stimuli” So it is beneficial. Than why it is required to be suppressed ? Because at times it can be in EXAGGERATED form and can be…. Harmful to body Extremely disturbing to the patient

Which are the features of inflammation… ? Heat/fever Swelling Pain Redness Loss of function NSAIDS addresses mainly FEVER, PAIN AND SWELLING. Redness is not a problem from functional point of view . Loss of function is usually restored when FEVER , PAIN and SWELLING are taken care of “if” it is due to those features. . Loss of function because of permanent fibrosis can not be reversed. IN ONE WAY, fever and pain are beneficial ….. HOW ?

So both phenomenon are beneficial

But when these reflexes are EXAGGERATED it is required to be suppressed because …… RAISED TEMPERATURE …. May make a person incapable for doing his job. May inactivate several enzymes required to maintain normal metabolism. In extreme cases…interfere with the state of consciousness. EXCESSIVE PAIN … May interfere with the quality of life. May frighten the patient. In extreme cases …may produce shock …

We will study both pathways … Now get ready for a LONG CHAIN OF CHEMICAL REACTIONS … This chemical reactions are IMPORTANT. . Products of this pathway PRODUCE NUMEROUS ACTIONS . They are the sites of pharmacological intervention.

PGG2 MEMBRANE PHOSPHOLIPID ARACHIDONIC ACID 12-HPETE PHOSPHOLIPASE CHEMICAL AND MECHANICAL STIMULIE 5-HPETE PGH2 ISOMERASE THROMBOXANE SYNTHEASE PROSTACYCLINE SYNTHEASE CYCLOXYGENASE PATHWAY LIPOXYGENASE PATHWAY 15-HPETE PGD2 PGE2 PGF2 α TXA2 TXB2 PGI2 LTB4 LTA4 LTC4 LTD4 LTE4 LTF4

Was it frightening…. ? DEFINATETLY NEED A REVISION…….. RIGHT ?

Summary of the chart… Cycloxygenase pathway generates … TXA2. PGD2 PGE2 PGF2 α PGI2. How to remember it ? Alphabetical order is … DEFGH Here first … G & H and then D E F. Lipoxygenase pathway generates 12 HPETE through 12-lipoxygenase 15 HPETE through 15-lipoxygenase 5-HETE through 5-Lipoxygenase 5-HETE subsequently produces … LTA4  LTB4 LTA4  LTC4  LTD4  LTE4

So that was CHEMISTRY part of inflammation… Now their FUNCTIONAL part…. There are so many mediators of inflammation.. Which causes numerous effects….

They are Opposite !!! Store it in your mind !!!

It is not possible to remember everything !! Don’t worry !!

Its not possible to remember ALL THE EFFECTS of ALL THE MEDIATORS . Just try to remember the NAMES OF MEDIATORS and MAJOR EFFECT produced by it.

PAIN Unpleasant experience Protective reflex Warning bell of tissue damage !! Interferes with Quality Of Life. Two components Sensations  peripheral component Perception  central component

CLASSIFICATION Superficial or cutaneus pain Deep pain from muscle,joints,ligaments and bones. Visceral pain-(spasm,infla.,ischemia,stim. Of nerve endings) Deafferentiation pain /neuropathic pain- (damage to axons or nerve membranes) Psychological/Functional

Now move ahead for “ PAIN PATHWAY ” 1 ST Slide shows afferent pathway . ( periphery to centre ). 2 nd Slide shows efferent pathway .( centre to periphery ). Again you are not expected to remember it , but you should have an idea about nuts and bolts of pain circuits.

SOMATIC SENSORY CORTEX ` Amygdala Hypothalamus Midbrain periaqueductal gray matter Parabrachial nucleus Medullary Reticular formation Locus cerulous Raphe nuclei Dorsal horn of the spinal cord Anterolateral System

Prostaglandins (PGS) sensitize the nerve endings…. To the nociceptive stimuli ……. Caused by ……. Histamine…… and Bradykinin.

Pharmacological/Physiological Effects I. Cardiovascular System

NORMALLY IN GIT… NSAIDS blocks this So PGS have PROTECTIVE effect on GIT

VI. Pain and Inflammation PGE 2 , PGI 2 , LTB 4 : sensitize nerve endings to painful stimuli. Hyperemia, Edema, Hotness due to increased eicosanoids at inflammation sites. LTB 4 : chemotactic factor for neutrophils and mononuclear cells. Promotes aggregation and degranulation of PMN’s, adhesion to vessel wall and migration Pharmacological/Physiological Effects

PGS produces FEVER….. How ? Hypothalamus contains thermoregulatory centre Maintains balance between heat production and heat loss It regulates heat dissipating mechanisms

PGs PRODUCES INFLAMMATION … HOW ? INFLAMMATION

Mechanism Of Action : NSAIDS MOST IMPORTANT MECHANISM Efficacy of these mechanisms is doubtful.. So you are not required to remember everything!! Just keep in mind that such mechanisms exist !!

COX-1 Physiologically expressed Maintains the normal (house keeping) function. Expressed in .. Platelets GIT COX-2 Induced in pathological states (mostly) Physiologically expressed in kidney. So NON SPECIFIC NSAIDS produces bleeding tendency and peptiuc ulcer

Analgesic activity No impairment of mental activity. No hypnosis Major component  peripheral action Minor component  central action Can be combined with opioids ONLY NSAID THAT BLOCKS THE COX ENZYME IRRERVERSIBLY NSAIDS suppresses the pain arising out of bones and joints  exception DYSMENORRHEA

NSAIDS blocks.. REDUCES THE INTENSITY OF PAIN

ANTIPYRETIC ACTIVITY Hypothalamus contains thermoregulatory centre Maintains balance between heat production and heat loss It regulates heat dissipating mechanisms Reduces fever due to inflammation. But not due to… Heat stroke Exercise induced/Physiological diurnal variation in temperature NSAIDS inhibits PGE2 synthesis and reduces fever

GIT So Use aspirin with Plenty of water or after food Milk Alkali Soluble of buffered aspirin

ANTIINFLAMMATORY ACTIVITY Decrease PG in peripheral tissue Reduce capillary permeability Inhibition of neutrophil aggregation and activation Inhibition of activated kallikrein from inactive plasma and leucocyte kallikrein. Inhibite mucopolysaccheride biosynthesis  reduce edema.

BLOOD AND PLATELETS Antiplatelet action Irreversibe COX inhibition 75-150 mg OD Platelet activity starts after 7-10 days when new platelets are synthesized. IN RHEU. FEVER  aspirin reduces WBC count and ESR. Decrease fibrinogen level

URICOSURIC ACTION Urate present in glomerular filtrate is reabsorbed by proximal tubule Excretion occurs because of tubular secretion.

PHARMACOKINETICS ABSORPTION : Skin GIT Particle size pH Solubility of salicylate preparation Presence of food DISTRIBUTION: 80% Albumin Achieves significant concentration in saliva,milk,spinal,synovial fluid, peritoneal fluid and in RBCs. HIGH AMOUNT  liver, heart and muscle SMALL AMOUNT  brain. So little central action.

Metabolism Aspirin 300-600 mg dose : 1 st order kinetics 1-2 gm dose : zero order kinetics  toxicity PHARMACOKINETICS Salicylate Deacetylation Salicylic acid

EXCRETION : PHARMACOKINETICS Salicylate Glycine conjugation Glucuronic acid conjugation Oxidized to Gentisic acid

INTOLERANCE : HS reaction. Angioedema & anaphylactic symptoms  adrenalin G6PD deficiency  hemolytic anaemia ADVERSE REACTION Cell Membrane Phospholipids Arachidonic Acid Prostaglandin H 2 Phospholipase A 2 Cyclooxygenase I&II Leucotriens Inflammation Bronchospasm NSAIDS

MANAGEMENT OF SALICYLISM Hospitalization Gastric lavage Rx of Hyperthermia Dehydration Hypokalamia Acid base disturbances Ketosis Alkalization Vit,K, BLOOD TRANSFUSION

USES LOCAL APPLICATION Keratolytic Fungistatic Antiseptic Counter irritant IBS

ANALGESIC Musculoskeletal pain Dysmenorrhea ANTIPYRETIC Remember, it reduces fever due to inflammation but not due to ….????? ANTIINFLAMMATORY Arthritis Fibromyositis

ANTIRHEUMATIC Antirheumatic action

ANTIPLATELET ACTION Platelets aggregates and provides the nidus for thrombus formation. Platelet aggregation is prevented by PGI2 in circulation and promoted by TXA2 . Inhibition of TXA2 by Aspirin at LOWER DOSES (75-150 mg)  reduce platelet aggregation. Platelet TXA2 remains irreversibly inhibited Only when new platelets are synthesized , platelet activity restarts (approx. 7-10 days ) Stop aspirin one week prior to surgery. Useful in …..thromboembolic disorders ( MI, TIA, Ischemic stroke, atherosclerotic PVDs) Avoid aspirin in ….. Liver damage Hypo prothombinemia Vit. K deficiency Haemophilia

PDA : PG mediadted IV administration of 0.1 to 0.2 mg/kg every 12 hours for three doses. 70% success.. Primarily in premature infants who weigh between 500 and 1750 g, Who have a hemodynamically significant patent ductus arteriosus, and In whom other supportive maneuvers have been attempted. Several food allergy PG mediadted Radiation induced diarrhoea PGmediadted Local application  in sunburn  PG mediadted Systemic mastocytosis Use with antihistaminics C0lon carcinoma Familial adenomatous polyposis (fap) Pgs involved in carcinogenesis Inhibits angiogenesis Dysmenorrhoea : Increase d PG in menstrual blood  uterine cramps.

NOW IT’S TIME TO REVISE What is inflammation ? Why it is required to be suppressed >? How PAIN and FEVER and beneficial and how they are harmful ? Following injury which chemical reactions are set off ? What are the effects of PGD2,PGE2,PGF2 α , PGI2, TXA2, LTA4 ? How will you classify pain ? Do your remember pain pathway ? If yes … good …if no … it’s ok. What is the effect of different mediators on I.blood vessels, II. platelets, III. GIT, IV. respiratory system and V. reproductive system ? How PGS produces PAIN, FEVER and INFLAMMATION ? Which are the mechanisms of action of NSAIDS ? Which are the local actions of NSAIDS ? How NSAIDS produces ANALGESIC, ANTIPYRETIC and ANTIINFLAMMATORY actions ? How it produces anti platelet action ? What is the effect of aspirin on urate levels ? Which are the main ADRs of NSAIDS ? What are the pharmacological basis of the same ? How they produces reye’ s syndrome ? What is salicylism ? How will you treat it ? Which are the uses of aspirin ? Which are the pharmacological basis of the same ?

Diflunisal Cancer pain with bone metastases For pain control in dental (third molar) surgery. 2% diflunisal oral ointment is a clinically useful analgesic for painful oral lesions.

PARACETAMOL Analgesic Antipyretic Central action> Peripheral action 10–15 mg/kg every 4 hours (maximum of 5 doses/24 hours) NO GI disturbances Acid-base imbalance Electrolyte imbalance Impairment of clotting ADR : Extremely safe drug. But rarely produces …. Hepatic toxicity

Paracetamol overdose Ingestion of >10g of paracetamol may be fatal May be lower in chronic alcoholics or subjects with underlying liver disease. Clinical features In severe poisoning Up to 24 hours - none or nausea and vomiting > 24 hours - nausea and vomiting, right upper quadrant pain, jaundice, encephalopathy

NAC SUPPLIES GLUTATHIONES so detoxifies toxic metabolites !! NAC “MAY”directly conjugates with quinones/epoxide. MAY BE… NAC has additional antioxidant and antiinflammatory activity

Management Repeat blood paracetamol estimatations. PARACETAMOL ( acetaminophen)

Now we will discuss all the remaining NSAIDs.. Their MOA, ADR, USES are more or less same. So we will only discuss differentiating points. Or something UNIQUE about that particular drug. You are not required to remember ALL THE DETAILS of ALL THE DRUGS. This list has been added only so that …. Presentation does not look incomplete !!!! ????

PHENYLBUTAZONE & OXYPHENBUTAZONE Now almost obsolated ANALGIN : Fatal blood dyscrasias DICLOFENAC SODIUM: Neutrophil chomotaxis and superoxide production is reduced Hepatotoxicity more common than other NSAIDS. Eye drops/Gel for solar keratosis (3%)/Rectal suppository for post op. analgesia/Oral mouthwash/IM injection ACECLOFENAC More GI friendly Some what selective on COX-2. Enhancement of glycosaminoglycan synthesis  chondroprotective property. MELOXICAM Preferential COX-2 inhibitor

ETODOLAC Postoperative pain relief after coronary artery bypass operations IBUPROFEN Oral Topical cream preparation -primary knee osteoarthritis Patent ductus arteriosus in preterm infants FENOPROFEN The NSAID most closely associated with interstitial nephritis FLURBIPROFEN Also affect TNF-a and nitric oxide synthesis?? 200-400 mg/d Ophthalmic formulation for inhibition of intraoperative miosis Flurbiprofen intravenously has been found to be effective for perioperative analgesia in minor ear, neck, and nose surgery and in lozenge form for sore throat. Rarely with cogwheel rigidity, ataxia, tremor, and myoclonus

PIROXICAM A nonselective COX inhibitor that at high concentrations also inhibits polymorphonuclear leukocyte migration, decreases oxygen radical production, and inhibits lymphocyte function. Decreases the production of IgM rheumatoid factor. USES : Same TENOXICAM SAME …. INDOMETHACIN PDA – 0.1-0.2 mg/kg /12 hr X 3 times. Ophthalmic preparation -- conjunctival inflammation reduce pain after traumatic corneal abrasion Gingival inflammation is reduced after administration of indomethacin oral rinse. Malignancy induced fever. frontal headache & other CNS side effects. C/I in psychiatric illness or epilepsy. HYPERKALAMIA KETOROLAC Replace morphine in some situations involving mild to moderate postsurgical pain. ORAL/IM/IV/EYE DROP

NABUMETONE Pseudoporphyria and photosensitivity NAPROXEN Oral suspension/SR preperation/Eye drops SULINDAC : Suppresses familial intestinal polyposis It may inhibit the development of colon, breast, and prostate cancer Sulfa like reaction NIMESULIDE Weak PG synthesis inhibitor. Relative COX-2 inhibitor Other mechanisms like … inhibition of neutrophil activation Reduced generation of superoxide Inhibition of PAF synthesis & TNF α release. Free radicle scavanging Inhibition of metalloproteinase activity. possibly activation of glucocorticoid receptors???

SELECTIVE COX-2 INHIBITORS CELECOXIB ROFECOXIB VALDECOXIB ETOROCOXIB LUMERACOXIB PARACOXIB– only selective COX-2 inhibitor for parental use. BANNED BECAUSE OF CARDIOVASCULAR MORATLITY

Advantages No ADR like GI ulceration Bleeding tendency Disadvantage Increases cardio vascular mortality because of inhibition of endothelial PGI2 production without effect on platelet TXA2 synthesis. ??Incomplete suppression of inflammation. COX-2 is constitutively expressed in kidney so nephrotoxicity can not be avoided. Na+ and Water retention,edema,HT,CHF may be ppted.

CELECOXIB GI friendly Sulfalike reaction Edema and HT ETOROCOXIB Maximum COX2: COX 1 activity ration OA – 60 mg OD RA - 90 mg OD Acute gouty arthritis 120 mg OD Acute musculoskeletal pain- 60 mg OD ADR : Dry mouth Aphthous ulcer Taste disturbnaces Paraesthesia Lumiracoxib : Its acidic nature allows it to penetrate well into areas of inflammation The half-life in synovial fluid is considerably longer than in plasma. Once-daily dosing. 900-mg dose. Cardiovascular safety questionable…. Gi safety promised…

TOPICAL NSAIDS Used for RA,OA,musculoskeletal pain,Soft Tissue Injury etc. Advantage (???): ??? High local levels?????  may be better therapeutic efficacy. Low systemic levels  GI safety. DILEMMA , whether the effect is …. Due to drug ? Due to placebo ? Due to irritant present in ointments ? Due to concomitant oral NSAID? EVIDENCES AVAILABLE SO FAR …. Slow topical absorption (~10 times than oral) Highest blood levels remains 15% below the same dose given orally. Upto 4-6 mm( Dermis)  high concentraion. At 25 mm (muscle )  concentration is low and same as blood. MARKED INTERINDIVIDUAL VARIATION( 18-92%)

NSAIDS.

More Related Content

NSAIDS.