Adverse drug reactions

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  • 1. BYASHUTOSH MISHRAResearch ScholarDepartment of PharmacologyKIET School of PharmacyTuesday, May 14, 2013ASHUTOSH MISHRA 1
  • 2. World health organization defines Adverse DrugReaction as:“Any response to a drug which isnoxious, unintended and occurs at doses usedin man for prophylaxis, diagnosis or therapy.”Tuesday, May 14, 2013ASHUTOSH MISHRA 2
  • 3.  From the earliest times, pharmaceuticalformulations have been recognized as beingpotentially dangerous. Indeed it is a truism that unless a drug iscapable of doing some harm it is unlikely todo much good. Public and professional concern about thesematters first arose in the late 19th century. In 1922, there was an enquiry into theJAUNDICE associated with the use ofSALVARSAN, an organic arsenical used in thetreatment of Syphillis.Tuesday, May 14, 2013ASHUTOSH MISHRA 3
  • 4.  In 1937 in the USA, 107 people died fromtaking an ELIXIR OF SULFANILAMIDE thatcontained the SOLVENT DIETHYLENEGLYCOL This led to the establishment of the FOODAND DRUG ADMINISTRATION (FDA), whichwas given the task of enquiring into thesafety of new drugs before allowing them tobe marketed. Major modern catastrophe that changedprofessional and public opinion towardsmedicines was the THALIDOMIDE INCIDENT.Tuesday, May 14, 2013ASHUTOSH MISHRA 4
  • 5.  In 1961, it was reported in West Germanythat there was an outbreak of PHOCOMELIA(hypoplastic and aplastic limb deformities)in the new born babies. It was shown subsequently thatthalidomide, a non barbiturate hypnotic, wasto blame. The crucial period of pregnancy during whichthalidomide is TERATOGENIC is the first threemonths.Tuesday, May 14, 2013ASHUTOSH MISHRA 5
  • 6.  The THALIDOMIDE INCIDENT led to a publicoutcry, to the institution all round the worldof DRUG REGULATORY AUTHORITIES, to thedevelopment of a much more sophisticatedapproach to the preclinical testing andclinical evaluation of drugs beforemarketing, and to a greatly increasedawareness of adverse effect of drugs andmethods of detecting them.Tuesday, May 14, 2013ASHUTOSH MISHRA 6
  • 7.  Many different figures have been publishedon the incidence of adverse drug reactions.The following are the representing figures. HOSPITAL IN-PATIENTS:10-20% suffer anadverse drug reaction. DEATHS IN HOSPITAL IN-PATIENTS: 0.24-2.9%are due to adverse drug reactions. HOSPITAL ADMISSIONS: 0.3-5% of hospitaladmissions are due to adverse drugreactions.Tuesday, May 14, 2013ASHUTOSH MISHRA 7
  • 8. Drug Year Adverse Reaction OutcomeSulfanilamide 1937 Liver damage dueto diethyleneglycolSolvent changed;FDA establishedThalidomide 1961 CongenitalMalformationsWithdrawnChloramphenicol 1966 Blood Dyscrasias Uses restrictedBenoxaprofan 1982 Liver damage WithdrawnAspirin 1986 Reye’s syndrome Uses restrictedFlecainide 1989 CardiacArrhythmiasUses restrictedNoscapine 1991 Gene toxicity WithdrawnTriazolam 1991 PsychiatricdisordersWithdrawnTuesday, May 14, 2013 8
  • 9. drug year AdversereactionOutcomeTemafloxacin 1992 Various seriousadverse effectsWithdrawnCo-trimoxazole 1995 Serious allergicreactionsUses restrictedTerfenadine 1997 Interactions(e.g. withgrapefruit juice)Withdrawn fromOTC saleSotalol 1997 CardiacarrhythmiasUses restrictedAstemizole 1998 Interactions WithdrawnCisapride 2000 CardiacarrhythmiasWithdrawnCerivastatin 2001 Rhabdomylosis WithdrawnTuesday, May 14, 2013ASHUTOSH MISHRA 9
  • 10. 1. DOSE-RELATED ADVERSE DRUGREACTIONS:a) PHARMACEUTICAL VARIATIONb) PHARMACOKINETIC VARIATIONi. Pharmacogenetic variationii. Hepatic diseaseiii. Renal diseaseiv. Cardiac diseasev. Thyroid diseasevi. Drug interactionsTuesday, May 14, 2013ASHUTOSH MISHRA 10
  • 11. c. PHARMACODYNAMIC VARIATIONi. Hepatic diseaseii. Altered fluid and electrolyte balanceiii. Drug interactions2. NON-DOSE RELATED ADVERSE DRUGREACTIONSa) IMMUNOLOGICAL REACTIONSb) PSEUDO ALLERGIC REACTIONSc) PHARMACOGENETIC VARIATION3. Long-term adverse drug reactionsa) ADAPTIVE CHANGESb) REBOUND PHENOMENATuesday, May 14, 2013ASHUTOSH MISHRA 11
  • 12. 4. Delayed adverse drug reactionsa) CARCINOGENESISb) EFFECTS CONCERNED WITH REPRODUCTIONi. Impaired infertilityii. Teratogenesisiii. Drugs in breast milkTuesday, May 14, 2013ASHUTOSH MISHRA 12
  • 13.  Dose related adverse reactions have led tothe concept of the THERAPEUTIC INDEX, orthe TOXIC:THERAPEUTIC RATIO. This indicate the margin between thetherapeutic dose and the toxic dose. The bigger the ratio, the better. Examples of drugs with a lowTOXIC:THERPEUTIC RATIO:Anticoagulants (warfarin, heparin)Hypoglycemic drugs (insulin, sulfonylurea)Antiarrythmic drugs (lidocaine, amiodarone)Tuesday, May 14, 2013ASHUTOSH MISHRA 13
  • 14. Cardiac glycosides(digoxin, digitoxin)Amino glycoside antibiotics(gentamicin, netilmicin)Oral contraceptivesCytotoxic and immunosuppressive drugs(cyclosporine, methotrexate, azathioprine)Antihypertensive drugs( beta adrenoceptors antagonists, ACEinhibitors) Dose-related adverse reactions can occurbecause of variations in thePharmaceutical, Pharmacokinetic, orPharmacodynamic properties of a drug, oftendue to Pharmacogenetic characteristic of apatient. Tuesday, May 14, 2013ASHUTOSH MISHRA 14
  • 15.  Adverse drug reactions occur because ofalterations in the systemic availability of aformulationEXAMPLE:Phenytoin Intoxication, by a change in oneof the excipients in the phenytoin capsulesfrom calcium sulfate to lactose, whichincrease the systemic availability ofphenytoin. Adverse reaction can occur because of thepresence of a contaminantEXAMPLE:Pyrogens or even Bacteria in intravenousformulations.Tuesday, May 14, 2013ASHUTOSH MISHRA 15
  • 16.  Out of date formulations can sometimes causeadverse reactions, because of degradationproductsEXAMPLE:out-dated Tetracycline can cause Fanconi’sSyndrome.Tuesday, May 14, 2013ASHUTOSH MISHRA 16
  • 17.  There is much variation among normalindividuals in the rate of elimination ofdrugs. This variation is most marked for drugs thatare cleared by hepatic metabolism. It is determined by several factors, whichmay be GENETIC, ENVIRONMENTAL, orHEPATIC.Tuesday, May 14, 2013ASHUTOSH MISHRA 17
  • 18. AcetylationOxidationSuccinylcholine hydrolysisAcetylation: Acetylation shows genetic variability. There are Fast and Slow acetylators. Several drugs are acetylated by N- ACETYLTRANSFERASE. Fast Acetylation is autosomal dominant andSlow Acetylation is autosomal recessive.Tuesday, May 14, 2013ASHUTOSH MISHRA 18
  • 19.  Drugs whose Acetylation is geneticallydetermined are:• Isoniazid• Hydralazine• Procainamide• Dapsone• Some sulfonamidesIncreased incidence of PERIPHERALNEUROPATHY is observed in slow acetylators ofIsoniazidTuesday, May 14, 2013ASHUTOSH MISHRA 19
  • 20. Oxidation: Oxidation also shows genetic variability. There are individuals with impaired oxidationand with normal oxidation. Impaired oxidation ones are called as POORMETBOLIZERS and the ones with normal arecalled EXTENSIVE METABOLIZERS.Debrisoquine type: CYP2D6 is a cytochrome P450 enzyme andcarries out Debrisoquine hydroxylation. Impaired hydroxylation of Debrisoquine is anAUTOSOMAL RECESSIVE DEFECT of thiscytochrome.Tuesday, May 14, 2013ASHUTOSH MISHRA 20
  • 21.  Drugs that are affected besides Debrisoquineare:• Captopril• Metoprolol• Phenformin• Perhexitine• Nortryptine Poor hydroxilators are more likely to showdose related adverse effect of these drugs. In case of toxic metabolites risk would begreater in extensive hydroxilators.Tuesday, May 14, 2013ASHUTOSH MISHRA 21
  • 22. Succinylcholine Hydrolysis: Succinylcholine is hydrolyzed byPSEUDOCHOLINESTRASE. In some individuals pseudocholinestrase isabnormal and does not metabolizesuccinylcholine rapidly. In such cases drug persist in blood and continueto produce neuro muscular blockade for severalhours. This result in respiratory paralysis calledSCOLINE APNOEA. There are three types of abnormalities ofpseudocholinestrase each inherited in anAUTOSOMAL RECESSIVE FASHION.Dibucaine resistant typeFluoride resistant typeSilent gene typeTuesday, May 14, 2013ASHUTOSH MISHRA 22
  • 23.  Adverse drug reaction due to impairedhepatic metabolism are not so common. Hepatocellular dysfunction, as in severalhepatitis or advanced cirrhosis, can reducethe clearance of drugs like phenytoin,theophylline and warfarin. A reduction in hepatic blood flow, as in heartfailure, can reduce the hepatic clearance ofdrugs that have an high extraction ratio fore.g. propranolol, morphine and pethidine. Reduced production of plasma proteins (fore.g. albumin) by the liver in cirrhosis canlead to reduced protein binding of drugs.Tuesday, May 14, 2013ASHUTOSH MISHRA 23
  • 24.  If a drug or active metabolite is excreted byglomerular filtration or tubular secretion, itwill accumulate in renal insufficiency andtoxicity will occur. Cardiac failure, particularly congestivecardiac failure, can alter thepharmacokinetic properties of drugs byseveral mechanisms:1) Impaired absorption, due to intestinalmucosal edema and a poor splanchniccirculation, can alter the efficacy of someoral diuretic, such as FUROSEMIDE;Tuesday, May 14, 2013ASHUTOSH MISHRA 24
  • 25. 2) Hepatic congestion and reduced liver bloodflow may impair the metabolism of somedrugs (e.g. Lidocaine).3) Poor renal perfusion may result in reducedrenal elimination (e.g. Procainamide).4) Reduction in the apparent volumes ofdistribution of some cardio active drugs, bymechanisms that are not understood causereduced loading dose requirements (e.g.Procainamide, Lidocaine, Quinidine)Tuesday, May 14, 2013ASHUTOSH MISHRA 25
  • 26.  Hepatic disease can alter pharmacodynamicresponses to drugs in several ways;1. Reduced Blood Clotting: In cirrhosis and acute hepatitis, production ofclotting factor is impaired and patients bleedmore readily. Drugs that impair blood clotting, that impairhomeostasis, or that predispose to bleeding bycausing gastric ulceration should be avoided orused with care for e.g. Anticoagulants andNSAIDS.Tuesday, May 14, 2013ASHUTOSH MISHRA 26
  • 27. 2. Hepatic Encephalopathy: In patients with, or on the border line of,hepatic encephalopathy, the brain is moresensitive to the effects of drugs with sedativeactions. If such drugs are used, coma canresult. It is therefore wise to avoid Opioids &other Narcotic Analgesics and Barbiturates.3. Sodium and Water Retention: In hepatic cirrhosis, sodium and waterretention can be exacerbated by certaindrugs. Drugs that should be avoided or usedwith care include NSAIDS, Corticosteroids,Carbamazepine and formulations containinglarge amount of sodium.Tuesday, May 14, 2013ASHUTOSH MISHRA 27
  • 28.  The pharmacodynamic effects of some drugsare altered by changes in fluid andelectrolyte balance.Example: The toxic effect of cardiac glycosides arepotentiated by both Hypokalaemia andHypercalcaemia. The Class1 of Antiarrhythmic drugs such asQuinidine, Procainamide and Disopyramideare more arrhythmogenic if there ishypokalaemia.Tuesday, May 14, 2013ASHUTOSH MISHRA 28
  • 29.  Includea) IMMUNOLOGICAL andb) PHARMACOGENETIC mechanisms of adversereactions.There is no relationship to the usualpharmacological effects of the drug;There is often a delay between the firstexposure to the drug and the occurrence of thesubsequent adverse reaction;There is no formal dose-response curve;The illness is often recognizable as a form ofimmunological reaction like rash, serumsickness, urticaria etc. Tuesday, May 14, 2013ASHUTOSH MISHRA 29
  • 30.  Factors involved in drug allergy concern theDrug and Patients:THE DRUG: Macromolecules such as PROTEINS (vaccinesand enzymes such as streptokinase),POLYPEPTIDES (insulin and dextrans) canthemselves be immunogenic.THE PATIENTS: There are genetic factors that make somepatients more likely to develop allergicreactions than others: A history of allergic disorders HLA status(antigens on human lymphocytes)Tuesday, May 14, 2013ASHUTOSH MISHRA 30
  • 31.  Classified acc. to the classification ofhypersensitivity reactions, i.e. into fourtypes, TYPES I-IV.Type 1 Reactions(anaphylaxis; immediate hypersensitivity): The drug or metabolite interacts with IgEmolecules fixed to cells, particularly tissuemast cells and basophiles leukocytes. This triggers a process that lead to therelease of pharmacological mediators likehistamine, 5-HT, kinins, and arachidonic acidderivatives, which cause allergic response.Tuesday, May 14, 2013ASHUTOSH MISHRA 31
  • 32.  Manifest as Urticaria, Rhinitis, BronchialAsthma, Angio-oedema and Anaphylactic Shock. Drugs likely to cause type 1 arePenicillins, Streptomycin, Local Anaestheticsetc.Type 11 Reactions (CytotoxicReactions): A circulating antibody of the IgG, IgM, or IgA classinteract with an antigen formed by hapten. Complement is then activated and cell lysisoccurs.Example: Thrombocytopenia, Haemolytic AnaemiaQuinidine or Quinine.Tuesday, May 14, 2013ASHUTOSH MISHRA 32
  • 33. Type 111 Reactions(Immune Complex Reactions): Antibody (IgG) combines with antigen i.e. thehapten-protein complex in circulation Complex thus formed is deposited in thetissues, complement is activated, and damageto capillary endothelium results. Serum sickness is the typical drug reactionof this type. Penicillins, Sulfonamides &Antithyroiddrugs may be responsible.Tuesday, May 14, 2013ASHUTOSH MISHRA 33
  • 34. Type 1V reactions(Cell Mediated): T-lymphocytes are sensitized by a hapten-protein antigenic complex. Inflammatory response ensues whenlymphocytes come in contact with the antigen. E.g. Dermatitis caused by local anestheticcreams, topical antibiotics and antifungalcreams.Pseudo Allergic Reactions: Term applied to reactions that resembleallergic reactions clinically but for which noimmunological basis can be found. Asthma and Skin Rashes caused by aspirin arethe examples.Tuesday, May 14, 2013ASHUTOSH MISHRA 34
  • 35.  Mechanistic approach does not fit in theclinical presentation so a clinical approach.Fever: Drug fever as an isolated phenomenon canoccur with penicillin, phenytoin, hydralazineand quinidine.Rashes: Different types of rashes are shown in thetable given.Tuesday, May 14, 2013ASHUTOSH MISHRA 35
  • 36. Type of rash Description Examples ofdrugs causingitErythemamultiformTarget like lesions on theextensor surface of the limbs.PenicillaminePenicillinSulphonamidesErythema nodosum Tender red nodules, sometimeswith bruising on the extensorsurface of the limbs.PhenobarbitalsSulphonamidesOralcontraceptivesExfoliativedermatitisRed, scaly, Exfoliative lesionssometimes involving extensiveareas of skinCarbamazepineGold saltsPhenylbutazonePemphigus Widespread blistering PenicillamineRifampicinUrticaria Red raised lesions surroundedby oedema often confluentCodieneDextransPenicillinTuesday, May 14, 2013ASHUTOSH MISHRA 36
  • 37. BLOOD DISORDERS: Thrombocytopenia, Neutropenia, HemolyticAnaemia, and Aplastic Anaemia can all occuras adverse drug reactions.RESPIRATORY DISORDERS: Asthma occurring as a pseudo allergicreaction to Aspirin, other NSAIDS andTartarzine is an e.g. adverse drug reaction.Tuesday, May 14, 2013ASHUTOSH MISHRA 37
  • 38. Red cell enzyme defectsPorphyriaMalignant hyperthermia RED CELL ENZYME DEFECTS: Unusual drug reaction occur in individuals whoseerythrocytes are deficient in any one of threedifferent but functionally related enzymes. Glucose-6-phosphate dehydrogenase Glutathione reductase Methaemoglobin reductaseTuesday, May 14, 2013ASHUTOSH MISHRA 38
  • 39. Tuesday, May 14, 2013ASHUTOSH MISHRA 39Methaemoglobin reductaseG6PDGlutathione reductase
  • 40. Glucose-6-phosphate dehydrogenasedeficiency: G6PD deficient erythrocytes when exposedto oxidizing agents undergoes Haemolysis. The prevalence of this defect varies withrace. There are two varieties of deficiency: Black variety Mediterranean variety Blacks have normal G6PD production but itsdegradation is accelerated. Mediterranean have abnormal G6PDproduction.Tuesday, May 14, 2013ASHUTOSH MISHRA 40
  • 41. Glutathione reductase deficiency Deficiency is autosomal dominant. Deficiency of enzyme directly causedeficiency of reduced glutathione.Methaemoglobin reductasedeficiency If Methaemoglobin is not reduced toHaemoglobin continously accumulation ofMethaemoglobin takes place resulting inimpairment of O2 delivery to tissues, causingHYPOXAEMIA. Inheritance of defect is autosomal recessive.Tuesday, May 14, 2013ASHUTOSH MISHRA 41
  • 42. Porphyria: Porphyrias constitute a group of disorders ofhaem-biosynthesis. Different types of porphyrias are there: Acute intermittent porphyrias Variegate porphyria Porphyria cutanea tarda Erythropoietic Porphyria Each type of Porphyria is associated with adifferent abnormality of an enzyme in haem-biosynthetic pathway. Drugs to be avoided in porphyria :Barbiturates, Dapsone, Chloramphenicol,Diclofenac etc.Tuesday, May 14, 2013ASHUTOSH MISHRA 42
  • 43. Tuesday, May 14, 2013 43Succinyl-CoA +GlycineALA SYNTHASEδ- aminolaevulinicacid(ALA)ALADEHYDRASEPropho-bilinogenDEAMINASEPorphrinshaemCyto-chromesEnzymatic defect in porphyrias
  • 44. Malignant hyperthermia: It is an autosomal dominant generic disorderof skeletal muscles that occurs in susceptibleindividuals undergoing General Anesthesiawith inhaled agents (halogenated) andmuscle relaxants like Succinylcholine. This rare condition of uncontrolled releaseof calcium by sarcoplasmic reticulum ofskeletal muscles leads to muscles spasm,hyperthermia and autonomic liability. Dantrolene is indicated in life threateningsituations.Tuesday, May 14, 2013ASHUTOSH MISHRA 44
  • 45.  Examples include development of toleranceto and physical dependence on theNARCOTIC ANALGESICS and the occurrenceof TARDIVE DYSKINESIA in some patientsreceiving long term neuroleptic drug therapyfor schizophrenia. During long term therapy sudden withdrawalof the drug can result in rebound reactions.Tuesday, May 14, 2013ASHUTOSH MISHRA 45
  • 46. Examples : Typical Syndromes occurring after suddenwithdrawal of narcotic analgesic or of alcohol(delirium tremens). Sudden withdrawal of Barbiturates result inrestlessness , mental confusion andconvulsions. Sudden withdrawal of β-adrenoceptorsantagonists result in rebound tachycardiawhich can precipitate myocardial ischemia. Sudden withdrawal of corticosteroids resultsin syndrome of adrenal insufficiency.Tuesday, May 14, 2013ASHUTOSH MISHRA 46
  • 47.  There are three major mechanisms ofcarcinogenesis:i. Hormonal: Incidence of VAGINAL ADENOCARCINOMA isincreased in daughters of women who havetaken STILBOESTROL during pregnancy forthe treatment of threatened abortions. Increased risk of BREAST CANCERS is about50% and woman taking HORMONEREPLACEMENT THERAPY (HRT) for more thanfive years.Tuesday, May 14, 2013ASHUTOSH MISHRA 47
  • 48. ii. Gene Toxicity: Occurs when certain molecules bind tonuclear DNA and produce changes in geneexpressions.Examples: BLADDER CANCER in patient taking long termCYCLOPHOSPHAMIDE Carcinomas of RENAL PELVIS associated withPHENACETIN abuse. Non lymphocytic LEUKEMIA in patientsreceiving ALKYLATING AGENTS such asmelphalan, chlorambucil etc.Tuesday, May 14, 2013ASHUTOSH MISHRA 48
  • 49. iii. Suppression of immuneresponses: Patients taking immunosuppressive drugssuch as AZATHIOPRINE withCORTICOSTEROIDS have increased risk ofdeveloping LYMPHOMAS.Tuesday, May 14, 2013ASHUTOSH MISHRA 49
  • 50. a. Impaired Fertilityb. TeratogenesisImpaired Fertility: Cytotoxic drugs can cause female infertilitythrough ovarian failure with amenorrhea. Male fertility can be reduced by impairmentof spermatozoal production or function andcan be either reversible or irreversible:Tuesday, May 14, 2013ASHUTOSH MISHRA 50
  • 51.  REVERSIBLE IMPAIRMENT can be caused bysulfasalazine, nitrofurantoin, MAO inhibitorsand antimalarial drugs; IRREVERSIBLE IMPAIRMENT, due to azospermia,can be caused by cytotoxic drugs, such asalkylating agents cyclophosphamide andchlorambucil.Tuesday, May 14, 2013ASHUTOSH MISHRA 51
  • 52. Teratogenesis: Teratogenesis occurs when a drug takenduring early stages of pregnancy causes adevelopmental abnormality in a fetus. Drugs can affect fetus at 3 stages:1) FERTILIZATION AND IMPLANTATION: Conception to 17 days Failure of pregnancy which often goesunnoticed.2) ORGANOGENESIS: 18 to 55 days of gestation Most vulnerable period, deformities areproducedTuesday, May 14, 2013ASHUTOSH MISHRA 52
  • 53. 3) GROWTH AND DEVELOPMENT: 55 days onwards development and functional abnormalitiescan occur ACE inhibitors can cause HYPOPLASIA oforgans NSAIDs may induce PREMATURE CLOSURE OFDUCTUS ARTERIOSUS Different teratogenic drugs are: Thalidomide, Methotrexate, Warfarin,Phenytoin, Phenobarbitone, ValproateSod.,Lithium, etc.Tuesday, May 14, 2013ASHUTOSH MISHRA 53
  • 54.  D.G.GRAHAME-SMITH & J.K.ARONSON Oxford Textbook of Clinical Pharmacology& Drug Therapy ROGER AND WALKAR Clinical Pharmacy and Therapeutics D.R. LAURENCE AND P.N. BENETT Clinical Pharmacology H.P.RANG AND M.M.DALE PharmacologyTuesday, May 14, 2013ASHUTOSH MISHRA 54
  • 55. Internet sources:www.medind.nic.inwww.fda.govwww.wikipedia.comwww.pharmpress.comwww.ncbi.nlm.nih.govTuesday, May 14, 2013ASHUTOSH MISHRA 55
  • 56. Tuesday, May 14, 2013ASHUTOSH MISHRA 56