NSAIDS.
Upcoming SlideShare
Loading in...5
×
 

NSAIDS.

on

  • 2,498 views

This is lecture on NSAIDS.

This is lecture on NSAIDS.
DO SEND YOUR FEEDBACKS.

Statistics

Views

Total Views
2,498
Views on SlideShare
2,489
Embed Views
9

Actions

Likes
0
Downloads
186
Comments
1

1 Embed 9

http://www.slideshare.net 9

Accessibility

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel

11 of 1

  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
  • i feel sorry that our doctor gives us the exact slideshow that u made in college , and he even changed your name and put his instead... , at least you should be mentioned .
    thank you for your work Dr.bhargav
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

    NSAIDS. NSAIDS. Presentation Transcript

    • 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 ?
    • 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
    • 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
    • II. PLATELETS
    • NORMALLY IN GIT… NSAIDS blocks this So PGS have PROTECTIVE effect on GIT
    • RESPIRATORY SYSTEM
    • GI TRACT
    • V. Reproductive Organs
      • 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 produce PAIN… how ?
    • 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
    • SALICYLATES
    • 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
    • GIT
    • KIDNEY
    • REYE’S SYNDROME
    • Aspirin Toxicity - Salicylism
    • 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%)
    • Selection of NSAID