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ADVERSE DRUG REACTIONS

Adverse effects of drugs2

PredictablePharmacologic side effectDry mouth from antihistaminicsSecondary pharmacologic side effectThrush while taking antibioticsDrug toxicityHepatotoxicity from diclofenac Drug-drug interactionsSeizure from theophylline while taking erythromycin (increased thephylline level)Drug overdoseSeizure from excessive lidocaine (Xylocaine)

UnpredictablePseudoallergicAnaphylactoid reaction after ASPIRINIdiosyncraticHemolytic anemia in a patient with G6PD deficiency after ciprofloxacin therapyIntoleranceTinnitus after a single, small dose of aspirin

What are Adverse Drug Reactions (ADRs)?any response to a drug which is noxious and unintended and which occurs at doses used in man for prophylaxis, diagnosis or therapy

ADRs: 4th Leading Cause of DeathStudy: Drug reactions kill an estimated 100,000 a year5% of adults are allergic to one or more medications6 10% of ADRs result from a drug allergy3% of hospital admissions are due to ADRs28% of ADRs are preventableDrugs associated with ADRs: 29% analgesics, 10% sedatives, 9% antibiotics, and 7% antipsychotics.PGH: Antibiotics (35%), anti-TB meds (34%), anticonvulsants and ASA/NSAIDS (10% each)

Key points to rememberADRs

are undesirableare unintentionalare suspected (not necessarily proven)may develop as a consequence of therapy (or other procedures)

Common Causes of ADRsFailing to take the correct dosages at the correct times Overdosing Allergies to chemical components of the medicine Combining the medicine with alcohol Taking other drugs or preparations that interact with the medicine Taking a medicine that was prescribed for someone else.

Causes of ADRPharmaceutical causesdecreasing particle size or changing excipients Pharmacokinetic causesdiazepam aminoglycosidesPharmacodynamic causesincreased sensitivity of target organs in the body to drugs

Factors affecting Adverse Drug Reactions :Patient-related factors Age Sex Genetic influences Concurrent diseases (renal,liver, cardiac) Previous adverse drug reactions Compliance with dosing regimen Total number of medications Misc. (diet, smoking, environmental exposure)

Factors affecting Adverse Drug Reactions : Drug-related factors:DoseDurationInherent toxicity of the agentPharmacodynamic propertiesPharmacokinetic properties

Six Classifications of ADRType AType BType CType DType EType F(Augmented)(Bizarre)(Continuous)(Delayed)(Ending of Use)(Failure of Efficacy)

CLASSIFICATION OF ADRs~According to SEVERITY~MildNo therapy , antidote or prolongation of hospitalization is required.Does not affect patients day-to-day activityModerateAffects patients day-to-day activity to some extentIt requires change in drug therapy, specific treatment or prolongs hospital stay by at least one day.Severe It is life threatening, cause permanent damage or requires intensive medical treatment.Adversely affects patients life and is Potentially life threateningLethal: Directly or indirectly leads to death

CATEGORIES OF ADVERSE DRUG EFFECT

Side effectsSecondary effectsIntoleranceIdiosyncrasyDrug allergyPhotosensitivityDrug dependenceDrug withdrawal reactionsMutagenicity & CarcinogenicityDrug induced diseasesTeratogenicity

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ADVERSE DRUG EFFECTS[1] Side EffectsUnwanted but unavoidable pharmacodynamic effects occuring at therapeutic doses.Side effect may be based on same action as therapeutic effect.Eg. Atropine and dry mouthCodeine and constipation[2] Secondary effectsIndirect consequences of a primary action of the drug.Super infection due to tetracyclines.Latent tuberculosis activated by corticosteroids.

[3] Intolerance: Opposite of tolerance: sensitivity to low dosesfew doses of carbamazepine ataxia [ defective movement/gait]single dose of triflupromazine muscular dystonia.Failure to tolerate even a single dose of the drug.Appearance of characteristic toxic effects of a drug in an individual at therapeutic doses.Aspirin gastric bleeding

[4] Idiosyncrasy: genetically determined atypical / bizarre effect Chloramphenicol aplastic anemia.Barbiturate excitement & mental confusion.Streptomycin deafness with single dose[5] Drug allergy: [ or hypersensitivity] Immunologically mediated Independent of doseOccurs in a small proportion;Prior sensitization required1-2 weeks required after first doseDrug acts as an antigen or HaptenChemically related drugs may show cross sensitivitySame drug can cause diff allergic reactions in diff individuals

Immune reactionMechanismClinical manifestationTiming of reactionsType I (IgE-mediated)Drug-IgE complex binding to mast cells with release of histamine, inflammatory mediatorsUrticaria, angioedema, bronchospasm, pruritus, vomiting, diarrhea, anaphylaxisMinutes to hours after drug exposureType II (cytotoxic)Specific IgG or IgM antibodies directed at drug-hapten coated cellsHemolytic anemia, neutropenia, thrombocytopeniaVariableType III (immune complex)Tissue deposition of drug-antibody complexes with complement activation and inflammationSerum sickness, fever, rash, arthralgias, lymphadenopathy, urticaria, glomerulonephritis, vasculitis1 to 3 weeks after drug exposureType IV (delayed, cell-mediated)MHC presentation of drug molecules to T cells with cytokine and inflammatory mediator releaseAllergic contact dermatitis, 2 to 7 days after cutaneous drug exposure

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[6]Photosensitivity:: Phototoxic: Drug accumulates in skin absorbs light photochemical reaction photobiological reaction tissue damage [Eg erythema, edema, blistering etc] Eg tetracyclines

Photoallergic: drug cell mediated immune response contact dermatitis on exposure to light. Eg sulfonamides, griseofulvin etc.

[7]Drug Dependence: Psychological: Physical dependence[8] Drug withdrawal reactionPropranolol hypertension ,worsening of MIAcute adrenal insufficiency following withdrawal of corticosteroidsSevere hypertension, restlessness, sympathetic over activity may occur shortly after discontinuing Clonidine

[9] Drug induced deseases, Iatrogenic diseases : Salicylates peptic ulcer; Phenothiazines parkinsonism; INH hepatitis

[10]Carcinogenicity & mutagenicity: Anticancer drugs, estrogens

It refers to capacity of a drug to cause genetic defects & cancer respectively.Usually oxidation of drug results in the production of reactive intermediates, which effects genes & may cause structural changes in the chromosome.Drugs implicated in these adverse effects are -Anticancer drug , radio isotopes, tobacco.

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[11] Teratogenicity: Drug use in pregnancy affects offspring Eg Thalidomide phocomelia; phenytoin cleft palateIt refers to capacity of a drug to cause abnormalities when administered to the pregnant mother.The placenta does not strictly constitute a barrier and any drug can cross it to a greater or lesser extent.The embryo is one of the most dynamic biological systems and in contrast to adults, drug effects are often irreversible.

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Why report ADRs?To prevent drug-induced human sufferingTo avoid financial risks associated with unexpected risks

Who can report ADRs?Doctors, pharmacists, dentists, nurses, herbalists, general public. anyone!

What ADRs can be reported?SeriousUnexpectedNewReports are sent to WHO - data added to world-wide data base

MedicineHerbVaccineDeviceBlood product

How do we report ADRs?STEP 1 : Fill out the RED ALERT CARDSSTEP 2: Complete the ADR REPORT FORM

The Resident - in - charge of the patient shall complete the necessary report of ADR circumstances.

STEP 3: Submit the red alert card and the ADR report form to the Central Block Pharmacy for proper referral.

STEP 4: The Pharmacy will then compile the reports for review of the ADR Subcommittee and submission to the Bureau of Food and Drugs (BFAD).

IMPORTANT!!!!

The ADR Report Form should include the following:

brand name of the suspect drug

the manufacturer (if generic)

the lot and batch number.

It should be done in duplicate. ALL REPORTS ARE CONFIDENTIALExamples of Reported ADRs Common reports rash caused by Oxacillin red face, fever secondary to Vancomycin

Uncommon reports hair loss due to anti thyroid agents neuroleptic malignant syndrome with risperidone

Prevention of ADR:[1] Avoid inappropriate drugs in the context of clinical condition[2] Use right dose, route, frequency based on patient variables[3] Elicit medication history; consider untoward incidents[4] Elicit history of allergies [in patients with allergic diseases][5] Rule out drug interactions[6] Adopt right technique: Eg slow iv injection of aminophylline[7] Carry out appropriate monitoring [Eg PT with warfarin; Li levels]