Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSORDEPT. OF PHARMACOLOGYSSIMS & RC.

An adverse drug reaction (ADR) is any untowardmedical occurrence in a patient administered apharmaceutical product, which is suspected to havea causal relationship with this treatment.

A response to a drug which is noxious andunintended, and which occurs at doses normallyused in man.

Spontaneous reports from consumers andhealthcare professionals should be regarded assuspected ADRs.

Adverse Event (AE) – any untoward medicaloccurrence that may present during treatment witha pharmaceutical product but which does notnecessarily have a casual relationship with thistreatment

Serious Adverse Event (SAE) – AE that is either life-threatening, fatal, cause of prolong hospitaladmission, cause persistent disability or concernmisuse or dependence

Adverse Drug Reaction(event attributed to drug)

Adverse Event

All Spontaneousreports

Events not attributed to drug

Diseases

Other Drugs

Environment

Diet

Genetics

Compliance

Otherfactors

Normal larynx Laryngeal oedema

ADR databaseNo of reports: more than 3.5 millionEach year increase ~160,000 / year

Withdrawn Drugs From the Market

Drug Year ReasonLumiracoxib 2008 HepatotoxicityAprotinin 2008 Kidney and cardiovascular toxicityTegaserod 2007 Cardiovascular ischemic eventsXimelagatran 2006 HepatotoxicityValdecoxib 2005 Dermatology adverse eventsPemoline 2005 HepatotoxicityRofecoxib 2004 Thrombotic cardiovascular eventsLevomethadyl 2003 Fatal ArrhytmiaRapacuronium 2001 Risk of fatal bronchospasmCerivastatin 2001 RhabdomyolosisTrovafloxacin 2001 HepatotoxicityAmineptine 2000 Hepatotoxicity, dermatological side effects, abuse potentialCisapride 2000 Cardiac arrhythmiasTroglitazone 2000 Hepatotoxicity

Drug Year Adverse Reaction Outcome

Sulfanilamide 1937 Liver damage due todiethylene glycol

Solvent changed; FDAestablished

Thalidomide 1961 Congenital Malformations Withdrawn

Chloramphenicol 1966 Blood Dyscrasias Uses restricted

Benoxaprofan 1982 Liver damage Withdrawn

Aspirin 1986 Reye’s syndrome Uses restricted

Flecainide 1989 Cardiac Arrhythmias Uses restricted

Noscapine 1991 Gene toxicity Withdrawn

Triazolam 1991 Psychiatric disorders Withdrawn

Withdrawn Drugs From the Market

drug year Adverse reaction Outcome

Temafloxacin 1992 Various seriousadverse effects

Withdrawn

Co-trimoxazole 1995 Serious allergicreactions

Uses restricted

Terfenadine 1997 Interactions(e.g. with grapefruitjuice)

Withdrawn from OTCsale

Sotalol 1997 Cardiac arrhythmias Uses restricted

Astemizole 1998 Interactions Withdrawn

Cisapride 2000 Cardiac arrhythmias Withdrawn

Cerivastatin 2001 Rhabdomylosis Withdrawn

Withdrawn Drugs From the Market

Type A (Augumented):Common->1%Pharmacological mechanism based reactionsSuggestivetime relationship and Dose relationshipReproducible Ex- side effects, toxic effectsType B (Bizzare): (“Patient Reactions”)Immuno allergic reactions peculiarities related to patientsIdiosyncrasy. Less common, non-dose related, Unexpected,Causality uncertain, Not reproducible experimentallyCharacteristic-serious, Rare <1%Anaphylaxis with penicillin

Type C adverse effects (Statistical effects)Often long latencyMechanism unknownDifficult to reproduce experimentallyAssociated with long term drug therapyE.g., Benzodiazepines dependence

Analgesic Nephropathy

Classification of adverse effects

Type DThese reactions refers to teratogenic & carcinogenic effectsThese reactions are delayed in onset of actionThey are well known and can be anticipated

Type EEnd of dose effectse.g. Abrupt cessation of corticosteroids produces acute

adrenal insufficiencyPropanolol – hypertension

Type FFailure of therapy

E.g. Anti tubercular therapy

MINOR No need of therapyMODERATE requires drug change, specific treatment,hospitalizationSEVERE Potentially life threatening, permanentdamage, prolonged hospitalizationLETHAL Directly or indirectly lead to death

Type of rash Description Examples of drugscausing it

Erythema multiform Target like lesions on the extensor surfaceof the limbs.

PenicillaminePenicillinSulphonamides

Erythema nodosum Tender red nodules, sometimes withbruising on the extensor surface of thelimbs.

PhenobarbitalsSulphonamidesOral contraceptives

Exfoliative dermatitis Red, scaly, Exfoliative lesions sometimesinvolving extensive areas of skin

CarbamazepineGold saltsPhenylbutazone

Pemphigus Widespread blistering PenicillamineRifampicin

Urticaria Red raised lesions surrounded by oedemaoften confluent

CodieneDextransPenicillin

SIDE EFFECTSUnavoidable, predictableOccur at extension of same therapeutic effectE.g. Atropine - Dry mouth

Promethazine – SedationEstrogen (Antiovulatory) - NauseaCodeine (antitussive) –Constipation

Indirect consequences of primary effect of therapyE.g. microflora killed by tetracycline super infectionCorticosteroids' (immunity) –Oral candidiasis

Over dose or prolonged use of drugsThe manifestations are predictable and dose relatedThey result from functional alteration or drug inducedtissue damageAtropine – deliriumParacetamol – hepatic necrosisBarbiturates – comaMorphine – Respiratory failure

Appearance of characteristic toxic effects of a drug inan individual at therapeutic doses.

Opposite to tolerance –sensitive to low dosesFew doses of Carbamazipines causes ataxia, defectivemovement, goiter

Single dose of Triflupromazine –Muscular dystonia

Genetically determinedabnormal reactivity to a chemicalatypical, bizarre effectsBarbiturates- excitement & mental confusionStreptomycin –Deafness with single doseDeficiency of glucose 6 phosphate enzyme inindividual, causes Haemorhoidal necrosis

Immunologically mediated reactions producingstereotype symptoms which are unrelated topharmacodynamic profile of the drugIndependent of doseOccur in small proportionPrior sensitization required1-2 weeks required after 1st doseDrug acts as a AntigenSame drug may cause different allergy in differentindividuals

Classification (Gell & Coombs)Type I reactions (IgE-mediated)

Type II reactions (cytotoxic)Type III reactions (immune complex)Type IV (delayed, cell mediated)

(anaphylaxis; immediate hypersensitivity):The drug or metabolite interacts with IgE molecules fixedto cells, particularly tissue mast cells and basophilesleukocytes.This triggers a process that lead to the release ofpharmacological mediators like histamine, 5-HT, kinins,and arachidonic acid derivatives, which cause allergicresponse.Manifest as Urticaria, Rhinitis, Bronchial Asthma, Angio-oedema and Anaphylactic Shock.Drugs likely to cause type 1 are Penicillins, Streptomycin,Local Anaesthetics

Serious allergic reactions i.e. rapid inonset & may cause deathIt typically results in a no. of symptoms including anitchy, rashes , throat swelling & low B. P.On a pathologic level, anaphylaxis is due to Release ofmediators or non immunologic mechanismPrimary treatment is injection of Epinephrine withother complementary measures

Skin –Generalized hivesItchiness, Flushing

AngiodemaSwelling of tongue and throat

Respiratory –Shortness of breathWheezeStrider ( upper respiratory obstructions)

Can occur in response to almost any foreignsubstancesCommon trigger includes venom from insect bites &stings , food and medicationLess common causesPhysical factor - ExerciseBiological agent , Latexhormonal changes,food additives (mono sodium glutamate)

topical medications

It is due to release of inflammatory mediators &cytokines from mast cells & basophiles , typically dueto immunological responseIg E + Antigens activates

FcRi receptor on mast cells & basophil

Lead to release of Histamines causes contraction ofbronchial smooth muscle

Epinephrine (Adrenaline) -Is primary treatment for anaphylaxis with no absolutecontra indicationsIt is given I. m. into mid anterolateral thigh as soon asdiagnosedThe injection is repeated every 10- 20 min. if there isinsufficiency responseA second dose is administered 16- 30 % of episode

People on beta b can blockers may be resistant to theeffectIn that case I.v. glucagon can be administeredAntihistamines (both H1 & H2)CorticosteroidsNebulized Salbutamol

Use the Airway ,Breathing , Circulation, Disability,Exposure (ABCDE) approach to treat at primary level

Cytotoxic ReactionsA circulating antibody of the IgG, IgM, or IgA classinteract with an antigen formed by hapten.Complement is then activated and cell lysis occurs.Example: Thrombocytopenia, Haemolytic AnaemiaQuinidine or Quinine.

Immune Complex ReactionsAntibody (IgG) combines with antigen i.e. the hapten-protein complex in circulationComplex thus formed is deposited in the tissues,complement is activated, and damage to capillaryendothelium results.Serum sickness is the typical drug reaction of this type.Penicillin, Sulfonamides & Anti-thyroiddrugs may beresponsible.

Cell MediatedT-lymphocytes are sensitized by a hapten-proteinantigenic complex.Inflammatory response ensues when lymphocytes comein contact with the antigen.E.g. Dermatitis caused by local anesthetic creams, topicalantibiotics and antifungal creams.Pseudo Allergic Reactions:Term applied to reactions that resemble allergicreactions clinically but for which no immunological basiscan be found.Asthma and Skin Rashes caused by aspirin are theexamples

Phototoxic – drugs accumulates in skin absorbs lightto give photochemical reactions, photo biologicreactionsEg. Erythma edema blistering

Photo allergic- drugs with cell mediated immuneresponse, contact dermatitis on exposure to lightEg. Sulfonamides, Griseofulvin

Drugs used in pregnancy affects offspring'sEg. Thalidomide - phocomaliaPhenytoine – cleft palateOral hypoglycemic- neonatal hypoglycemiaTetracycline– Anomaly of teeth & bonesValproic acid – neural tube disorderWarfarin - skeletal & CNS defectsCarcinogenicity/ MutagenicityAnt cancerous drugsEstrogen

Avoid inappropriate drugs in the context of clinicalconditionsUse right dose, route ,frequency based on patientvariablesElicit medication historyElicit history of allergyRule out drug interactionsAdopt right technique of medicationCarry out adequate monitoring-pharmacovigilance,Periodic Safety Update Reports (PSURs)

“All substances are poisons;there is none which is not a poison.The right dose differentiates a poison from a remedy.”

Paracelsus (1493-1541)

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