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Nsaids Nsaids Presentation Transcript

  • DR.UMA KADAM M.B.B.S. MD ASSOCIATE PROFESSOR PHARMACOLOGY SKNMC
  • I: Pain and Analgesi cs
    • Pain ”an unpleasant sensory and emotional experience with actual or potential tissue damage or described in terms of such damage”
    • Analgesia absence of pain
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  • Pain pathways
    • Specialized receptors = free nerve endings
    • Stimulation
      • Mechanical damage
      • Extreme temperature
      • Chemical irritation
    • Two types of neurons
      • A-delta: first pain, sharp
      • C: second pain, dull
    • Four distinct processes
      • Transduction-conduction, transmission, modulation & perception.
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  • Pharmacological treatment of pain
      • Regional Anesthesia
      • NSAIDs
      • Opioids
      • NMDA-receptor agonists
      • Alpha-2-receptor agonists
      • Other agents
  • Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
    • Common therapeutic indications
    • Common adverse effects
    • Different pharmacokinetics and potency
    • Different chemical families
    • Common mechanism of action (cyclooxygenase inhibition)
    • Different selectivities to COX I and II
    • Similarities more striking than Differences
  • NSAIDs:
    • Large and chemically diverse group of drugs with the following properties:
      • Analgesic
      • Anti-inflammatory
      • Antipyretic
  • NSAIDs: Mechanism of Action
    • Inhibits cyclo-oxygenase (prostaglandin synthase) that is responsible for conversion of arachidonic acid to cyclic endoperoxides
    • 2 isoforms of enzyme
    • - COX-1 : beneficial prostaglandins synthesis
    • constitutive, present in platelets, blood vessel, stomach and kidney required for physiological functioning.
    • - COX-2 : harmful prostaglandins synthesis
    • inducible by cytokines & endotoxins at sites of inflammation e.g. joints, also found in kidney & brain responsible for pain-inflammation-fever.
  • COX Enzyme:Prostaglandin Effects vasodilation Kidney aggregation Platelets protect mucosa Stomach Modulate pain perception Promote fever (hypothalamus) Brain Inflammation Peripheral injury site COX-2: harmful COX-1: beneficial
  • Effects of COX Inhibition by Most NSAIDS NSAIDs : anti-platelet—decreases ability of blood to clot COX-1 Gastric ulcers Bleeding Acute renal failure COX-2 Reduce inflammation Reduce pain Reduce fever
  • CLASSIFICATION OF NSAIDs:
    • Nonselective COX-inhibitors:
    • Salicylates: Aspirin
    • Propionic acid derivatives: Ibuprofen, Ketoprofen.
    • Acetic acid derivatives: Diclofenac, Aceclofenac
    • Fenamic acid derivatives: mefenamic acid
    • Pyrrolo-pyrrole derivatives: Ketorolac
    • Oxicam derivatives: Piroxicam, Meloxicam
    • Indole derivatives: Sulindac, Indomethacin
    • Pyrazolone derivatives: Phenybutazone
    • Selective COX-2 inhibitors:
    • Celecoxib, Rofecoxib
    • Preferential selective Cox-inhibitors:
    • Nimesulide, Meloxicam, Nabumetone
    • Analgesic-antipyretic with poor anti-inflammatory effect: paracetamol
  • PROTOTYPE: Salicylates (Aspirin)
    • More potent effect on platelet aggregation and thermal regulatory center in the brain
      • analgesic
      • antipyretic
      • anti-inflammatory
    • Antithrombotic effect: used in the treatment of MI and other thromboembolic disorders
  • Pharmacokinetics: ASA
    • Absorption : from stomach and intestine
    • Distribution : readily, into most fluids/tissues
    • Metabolism : primarily hepatic
    • ASA contraindicated for use in children with viral fever –can lead to Reye’s Syndrome
    • Fatal overdose is possible
    • Similar pharmacokinetics for ibuprofen and related NSAIDs
  • PHARMACOLOGICAL ACTIONS: Aspirin
    • Analgesic: (300-600mg/day) Analgesia by peripheral inhibition of PG synthesis & increased pain threshold by acting on subcortical site . Analgesia without sedation, loss of consciousness or dependence.
    • Antipyretic: (300-600mg/day)
    • Reset hypothalamic thermostat by inhibition of PG synthesis, promote heat loss by vasodilation & sweating in fever.
    • Anti-inflammatory : (4-6 gm/day). Observed at high doses. By inhibition of PG & other mediators synthesis, T-cell modulation & inhibiting chemotaxis
  • PHARMACOLOGICAL ACTIONS: Aspirin
    • Antiplatelet:
    • PGI2 (vasodilation & inhibition of
    • platelet aggregation)
    • ASPIRIN
    • (2-3gm/day)
    • TXA2
    • (vasoconstriction & platelet aggregation)
    • Low dose aspirin
    • (50-325mg/day)
    • CVS : Prolonged use cause salt-water retention & precipitation of CCF.
    • Acid-base & electrolyte balance: in therapeutic doses compensatory respiratory alkalosis & in toxic doses respiratory acidosis.
  • PHARMACOLOGICAL ACTIONS: Aspirin
    • Gastrointestinal:
    • Urate excretion:
    • In therapeutic doses increase plasma Urate levels
    • In high doses uricosuric
    PGs HCl CTZ ASPIRIN SALICYLIC ACID PEPTIC ULCER EMESIS
    • Effect on Respiration: triphasic
    • Low doses: uncoupling Phosphorylation -> ↑ CO 2 -> 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
    PHARMACOLOGICAL ACTIONS: Aspirin
    • As analgesic: headache, myalgia, neuralgia, toothache, joint pain & dysmenorrhea etc. (300-600mg/day)
    • As antipyretic: any fever however paracetamol preferred for the same (300-600mg/day)
    • Acute rheumatic fever: first drug of choice
      • First 1-3 days 4-6 gm/day for symptomatic relief
      • From 4-7 days dose reduction
      • 2-3 weeks maintenance dose 50mg/kg/day
      • Withdrawal slowly over next 2 weeks.
    • Rheumatoid arthritis: 3-5gm/day beneficial*; delays progress but does not prevent it. Long-term treatment not tolerated hence other NSAIDs preferred.
    • Osteoarthritis: paracetamol is first drug of choice
    • Post MI & stroke: low dose i.e. 60-100mg/day prevent reinfarct & lowers incidences of stroke
    • Toxemia of pregnancy( preeclampsia): imbalance between TxA2 & PGI2 involved hence 80-100mg/day beneficial
    • Patent ductus arteriosus: brings about closure prevent surgery
    • Prevention of colonic cancers: since large quantities of COX-2 expressed in colonic tumors
    ASPIRIN (NSAIDS):THERAPEUTIC USES
  • NSAIDs: Side Effects
    • Gastrointestinal
    • Dyspepsia, heartburn, epigastric distress, nausea
    • GI bleeding
    • Mucosal lesions (erosions or ulcerations)
    • Misoprostol can be used to reduce these dangerous effects.
    • Dose dependent hepatitis
    • Reye’s syndrome
    • Renal
    • reductions in creatinine clearance
    • acute tubular necrosis with renal failure
    • Cardiovascular
    • noncardiogenic pulmonary edema
    • Metabolic
    • Uncoupling of Oxid. Phosphorylation
    • Hyperglycemia and depletion of muscle and hepatic glycogen
    • Endocrine:
    • Release of Corticosteroids, thyroid hormone due central stimulation.
    • Hypersensitivity:
    • Urticaria Skin rashes, Angioedema, Asthma.
    • Bleeding & delayed onset of labor
    Aspirin (NSAIDs): Side Effects
  • ASPIRIN (NSAIDs) INTERACTIONS: / Diuretics diuretic response& Probencid / NSAIDs inhibit tubular Antagonize uricosuric effect methotrexate uric acid secretion
  • NSAIDs: Salicylate Toxicity
    • Adults: tinnitus and hearing loss
    • Children: hyperventilation and CNS effects
    • Effects arise when serum levels exceed 300  g/mL.
    • Metabolic acidosis and respiratory alkalosis may be present.
    • Decrease absorption - activated charcoal, emetics, gastric lavage
    • Enhance excretion - alkalinize urine, forced diuresis, hemodialysis
    • Supportive measures - fluids, decrease temperature, bicarbonate, electrolytes, glucose, etc…
    Aspirin Toxicity - Treatment
  • ASPIRIN vs PARACETAMOL
    • Reversible nonselective Cox-inhibitor
    • Analgesic, antipyretic with poor anti-inflammatory* action
    • No Gastric irritation, peptic ulcer-bleeding
    • No acid-base & electrolyte imbalance
    • No Antiplatelet action
    • N-acetyl cysteine is antidote
    • Preferred analgesic-antipyretic in patient having asthma, peptic ulcer
    • Safe in children
    • Irreversible nonselective Cox-inhibitor
    • Analgesic, antipyretic with potent anti-inflammatory action
    • Gastric irritation, peptic ulcer-bleeding common
    • Cause acid-base & electrolyte imbalance
    • At low doses Antiplatelet action
    • No specific antidote
    • Contraindicated in patient having asthma, peptic ulcer
    • Not given in children: causes Reye’s syndrome
    Paracetamol (Para-amino phenol derivative) Aspirin (salicylate)
    • Metabolism
    • is conjugated in the liver as the inactive glucuronide and sulphate
    • a number of minor oxidation products inc.
    • N-acetylbenzoquinoneimine are also formed
    • NABQI is highly chemically reactive and is usually inactivated by conjugation with SH (thiol) groups of glutathione
    • Supply of glutathione is limited and exhausted in overdose
    • NABQI then reacts with cellular macromolecules and causes cell death
    PARACETAMOL/ acetaminophen (non-NSAID):
  • PARACETAMOL ( acetaminophen):
    • 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
  • PARACETAMOL POISONING:
    • Management
    • Blood for paracetamol at 4 hours post ingestion
    • Emesis, gastric lavage done. Activated charcoal given orally.
    • Supportive measures.
    • Specific antidote: N-acetylcysteine 150mg/kg infusion over 15 min followed by same dose IV over next 20 hrs. ( if in doubt of severe poisoning, don’t delay). Alternatively 75mg/kg orally 6 hrly for 2-3 days.
    • Check prothrombin time and plasma creatinine , pH
    • Acute renal (due to acute tubular necrosis) and hepatic failure and occur at 36-72 hours after ingestion
    • Indications for referral to liver unit are
    • - rapid development of Grade 2 encephalopathy
    • - PTT >45 secs at 48 hours or >50 secs at 72 hours
    • - rising plasma creatinine
    • - Arterial pH <7.3 more than 24 hours after ingestion
  • PHARMACOLOGICAL BASIS FOR USE OF N-ACETYLCYSTEINE IN TREATMENT OF PARACETAMOL POISONING:
    • N-acetylbenzoquinoneimine (toxic metabolite) usually inactivated by conjugation with SH (thiol) groups of glutathione
    • Supply of glutathione is limited and exhausted in overdose
    • NABQI then reacts with cellular macromolecules and causes cell death & necrosis
    • N-acetylcysteine replenish glutathione stores of liver & prevents binding of toxic metabolites to cellular macromolecules
  • COMPARATIVE PHARMACOLOGICAL PROFILE OF NSAIDS
    • Nonselective reversible COX-inhibitor
    • Potent anti-inflammatory ; poor & slower analgesic-antipyretic, uricosuric.
    • Sever GI-CNS-Renal toxic, bone marrow depression-cause fatal agranulocytosis.
    • Used in acute gout for short term
    • Oral
    • Dose:100-200mg bid
    1.Phenylbutazone/
    • Nonselective reversible COX-inhibitor
    • Potent anti-inflammatory
    • Concentrated in jt.spaces hence preferred in arthritis
    • More hepatotoxic
    • Diclofenac + Misoprostol reduce GI toxicity.
    • Oral, IM, rectal, topical, gel & eye drops
    • Dose:50-100mg bid
    Diclofenac
    • Nonselective reversible COX-inhibitor
    • Moderate anti-inflammatory
    • Better tolerated than aspirin
    • Can be used in children*
    • Oral, topical
    • Dose:400-600mg tid
    Ibuprofen /Ketoprofen Properties Route & formulations Drug Sr. no
  • COMPARATIVE PHARMACOLOGICAL PROFILE OF NSAIDS
    • Nonselective reversible COX-inhibitor
    • Potent analgesic# modest anti-inflammatory, equally effective as morphine but produce analgesia with out RS depression, hypotension & dependence
    • Used in renal colic, postoperative & cancer pain.
    • Oral, IM, IV, eye drops, Transdermal patch
    • Dose:50-100mg bid
    Ketorolac
    • Nonselective reversible COX-inhibitor
    • Potent anti-inflammatory**
    • Long acting
    • GIT side effects pronounced*
    • Oral, topical gel, IM
    • Dose:20 od
    Piroxicam
    • Nonselective reversible COX-inhibitor
    • Potent & promptly acting analgesic-antipyretic but poor anti-inflammatory .
    • No uricosuric effect
    • Useful as analgesic-antipyretic
    • Injection painful, agranulocytosis & GIT side effects.**
    • Oral, IM, IV
    • Dose:0.5- 1.5gm tid
    2.Metamizole Properties Route & formulations Drug Sr.no
  • COMPARATIVE PHARMACOLOGICAL PROFILE OF NSAIDS
    • Preferential COX2-inhibitor*
    • Useful in short lasting inflammatory pain e.g. sinusitis, bursitis.
    • ADRs Less than other NSAIDs.$
    • Oral
    • Dose:100mg bid
    Nimesulide
    • Nonselective reversible COX-inhibitor
    • Central as well as peripheral analgesic.
    • Useful in dysmenorrhea, joint & soft tissue pain
    • Diarrhea is most common adverse
    • Oral
    • Dose:250-500mg tid
    Mephenamic acid
    • Nonselective reversible COX-inhibitor, Potent PGs-I
    • Potent anti-inflammatory also Potent & promptly acting analgesic-antipyretic
    • Inhibit phospholipase-A & C; Inhibits migration of neutrophils in inflamed area
    • Useful in PDA, ankylosing spondilytis, acute gout, rh.arthritis resistant to aspirin
    • CNS** & GIT side effects pronounced
    • Contraindicated in drivers, machine operators, psychiatrics, epileptics & pregnant women
    • Oral, eye drops & suppositories
    • Dose:50mg tid
    • Indomethacin
    • /sulindac (prodrug#)
    • Extra MOAs
    • Extra uses
    • Extra adverse
    Properties Route & formulations Drug Sr. no.
  • COMPARATIVE PHARMACOLOGICAL PROFILE OF NSAIDS
    • Selective COX2-inhibitor
    • Potent anti-inflammatory analgesic-antipyretic
    • No antiplatelet actions.
    • Use as other NSAIDs
    • GIT side effects less
    • Nephrotoxic, Cardiotoxic.
    • Oral
    • Dose:50mg-200/day
    Coxibs (etorocoxib, rofecoxib, parecoxib) Properties Route & formulations Drug Sr. no.
  • Non selective Vs selective COX2 inhibitors
    • ↑ risk of cardiovascular adverse events with COX 2 inhibitors
    • Rofecoxib was withdrawn from the market
    • Higher BP, incidence of myocardial infarction, stroke
    • Mechanism _ ? Unopposed effect of Cox 1 action
    • - ? Block protective effect of COX2 on
    • ischemic myocardium or atherogenesis
  • NSAIDs: Nursing Implications
    • Before beginning therapy, assess for conditions that may be contraindications to therapy, especially:
      • GI lesions or peptic ulcer disease
      • Bleeding disorders
    • Assess also for conditions that require cautious use.
    • Perform lab studies as indicated (cardiac, renal, liver studies, CDC, platelet count).
  • NSAIDs: Nursing Implications
    • Perform a medication history to assess for potential drug interactions.
    • Several serious drug interactions exist:
      • alcohol
      • heparin
      • phenytoin
      • oral anticoagulants
      • steroids
      • sulfonamides
  • NSAIDs: Nursing Implications
    • Salicylates are NOT to be given to children under age 12 because of the risk of Reye’s syndrome.
    • Because these agents generally cause GI distress, they are often better tolerated if taken with food, milk or an antacid to avoid GI irritation.
    • Explain to patients that therapeutic effects may not be seen for 3 to 4 weeks.
  • NSAIDs: Nursing Implications
    • Educate patients about the various side effects of NSAIDs, and to notify their physician if these effects become severe or if bleeding or GI pain occur.
    • Patients should watch closely for the occurrence of any unusual bleeding, such as in the stool.
    • Enteric-coated tablets should not be crushed or chewed.
  • NSAIDs: Nursing Implications
    • Monitor for therapeutic effects, which vary according to the condition being treated:
      • decrease in swelling, pain, stiffness, and tenderness of a joint or muscle area
  • Summary
  • NSAIDs: Drug Effects
    • Analgesic (mild to moderate)
    • Antigout
    • Antiinflammatory
    • Antipyretic
    • Relief of vascular headaches
    • Platelet inhibition (ASA)
  •  
  • NSAIDs: Therapeutic Uses
    • Relief of mild to moderate pain
    • Acute gout
    • Various bone, joint, and muscle pain
    • Osteoarthritis
    • Rheumatoid arthritis
    • Juvenile rheumatoid arthritis
    • Dysmenorrhea
    • Fever
  • THANK YOU