K10 Adverse Drug Reaction

transcript

14032012 Adverse Drug Reaction

Dr.Datten Bangun MSc,SpFK&

Dr.Zulkarnain Rangkuty,MS

Dept.Farmakologi & TherapeutikFak.Kedokteran USU

M E D A N

All Drugs are Dangerous

No Drugs are Dangerous if used properly

How dangerous a drug is depends on the skill of the prescriber

The most dangerous drugs have the greatest potential for benefit

Some drugs are dangerous in acute poisoning but not when used therapeutically

Some drugs have a low therapeutic ratio

Some drugs have a low incidence of horrendous effects

Some adverse effects can be predicted if you know the pharmacology (Type A); some are not (Type B)

Some adverse effects occur after a delay or after stopping

BADGOOD

RISK BENEFIT

When prescribing drugs a doctor must assess risk to benefit ratio in the individual patient by

•Choosing an appropriate class of drug then an appropriate individual agent

•Is it effective ?

•What are the chances of adverse effect ?

•Are there features in this patient which affect choice eg other drugs, organ failure, aged

•Tailoring the dose

•Considering duration of treatment

The Risk to Benefit Ratio

Adverse Drug Reaction

• Response to a drug which is noxious, unintended and occurs at doses used in man for prophylaxis, diagnosis and therapy (WHO)

• Unwanted or harmful reaction experienced after the administration of a drug or combination of drugs under normal conditions of use and suspected to be related to drug

Type of adverse reactions

• Type A (Augmented)• Type B (Bizarre)• Type C (Chronic)• Type D (Delayed)• Type E (End of use)• Type F (Therapeutic failure)• Type G (Genetic/genomic)

CLASSIFICATION OF ADRS• Type A (Augmented ) reactions

– Reactions which can be predicted from the known pharmacology of the drug

– Dose dependent, can be alleviated by a dose reduction

– E.g. Bleeding with anticoagulants, bradycardia with beta blockers, headache with nitrates, postural hypotension with prazosin

CLASSIFICATION OF ADRS

• Type B (Bizarre) reactions– Cannot be predicted from the

pharmacology of the drug– Not dose dependent, host dependent

factors important in pre-disposition– E.g. anaphylaxis with penicillin,

anticonvulsant hypersensitivity

• Type C (Chemical) reactions– Biological characteristics can be predicted from the

chemical structure of the drug/metabolite– E.g. paracetamol hepatotoxicity

• Type D (Delayed) reactions– Occur after many years of treatment. Can be due to

accumulation– E.g. Secondary tumours after treatment with

chemotherapy, teratogenic effects of phenytoin taken during pregnancy, analgesic nephropathy, tardive dyskinesia with antipsychotic agents,

– Genital Ca after dietilstilbesterol in pregnant woman

CLASSIFICATION OF ADRS

• Type E ( End of treatment) reactions– Occur on withdrawal especially when drug

is stopped abruptly– E.g. withdrawal seizures on stopping

phenytoin, adrenocortical insufficiency on withdrawal of steroids

Type A Type B

Associated with the pharmacology of the product

Predictable

Dose related

Common

Serious

1. Type I hypersensitivity (Anaphylactic type)

Immediate hypersensitivity reaction, resulting from release of pharmacologically active mediators.

2. Type II Hypersensitivity

Cytolytic or cytotoxic reactions (1) Mechanism:① Complement-dependent reactionsTransfusion reactionsErythroblastosis fetal Autoimmune hemolytic anemiaCertain drug reactions

3. Type Hypersensitivity Ⅲ(Immune complex-mediated)

(1) Reaction types(1) Reaction types ① Arthus reaction ② serum sickness ③ Collagen diseases

4. Type HypersensitivityⅣ (Cell-Mediated )

Delayed hypersensitivity reaction (1) TissueTissue reactionreaction: Consist of

parenchymal destruction associated with perivascular lymphocytic and macrophage reaction.

②Antibody-dependent cell-mediated cytotoxicit (ADCC).

May be relevant to: Graft rejection The destruction of targets too large to be

phagocytosed, such as parasites or tumor cells.

4. Type HypersensitivityⅣ (Cell-Mediated )

③Antibody-mediated cellular dysfunction

Myasthenia gravis: muscle weakness

Graves’ disease:Graves’ disease: hyperthyroidism

Preventing ADRs cont’d

• Age, hepatic and renal disease may impair clearance of drugs so smaller doses may be needed. Genetic factors may also predispose to certain ADRs

• Prescribe as few drugs as possible and give clear instructions

• Where possible use familiar drugs. With new drugs be particularly alert for ADRs and unexpected event.

• If serious ADRs are liable to occur warn the patient

Prevention of Adverse Drug reactions

• Never use any drug unless there is good indication. If the patient is pregnant do not use the drug unless the need is imperative.

• Allergy and idiosyncrasy are important causes of ADRs. Ask if the patient had previous reactions.

• Ask if the patient is already taking other drugs including self medication

teratogenic

Teratogenicity is based on…

• Substance ----thalidomide• Dose relatedness,length of exposure• Time course --1st semester• Susceptibility

Type AType A Type BType B

PharmacologicaPharmacologically predictablelly predictable

Yes Yes NoNo

Dose Dose dependentdependent

Yes Yes NoNo

IncidenceIncidence HighHigh LowLow

MorbidityMorbidity HighHigh LowLow

MortalityMortality LowLow HighHigh

ManagementManagement Dosage Dosage adjustmentadjustment

STOPSTOP

• Type A ADRs – intrinsic to the drug effects• Type B ADRs - idiosyncratic

Mechanisms of non dose-related (Type B) ADR

• Pharmacodynamic causes-target organs – genetic, immunologic,

neoplastic or teratogenic

Erythrocyte glucose-6-phosphate (G6PD) deficiency

• Sex-linked inherited deficiency • Weakened red cell membrane • Hemolysis from primaquine, sulfonamides,

sulfones and nitrofurantoin• African type-mild, Mediterranean type-

severe

Drugs that should be avoided with G6PD deficiency

• Dapsone• Niridazole• Methylene blue (methylthioninium Cl) • Primaquine• Quinolones (ciprofloxacin, nalidixic acid,

norfloxacin, ofloxacin)• Sulfonamides (Cotrimoxazole)

Malignant hyperthermia

• Rapid rise in body temperature (at least 2 C per hour)

• Associated with anesthetics and muscle relaxants (succinylcholine)

• Stiffness of skeletal muscle, hyperventilation, acidosis, hyperkalemia, increased activity of sympathetic NS outcome?Associated with a sudden release of intracellular ionized Ca

Antidote: Dantrolene

Predisposing factors

• Multiple drug therapy• Age1.Elderly- hypnotics, diuretics, NSAIDS, anti-

hypertensives, psychotropics, digoxin2.Adults- polypharmacy3.Children- antiepileptics, cytotoxic agents,

anesthetic gases, antibiotics (associated with hepatic failure), Na valproate

• Age4. Neonates- chloramphenicol, morphine,

antiarrhythmicsReye’s syndrome - ?Hepatotoxicity – Na valproate

• Gender- Females have 1.5-1.7 folds of developing ADR

than males- Women are prone to develop blood

dyscrasias with phenylbutazone & chloramphenicol

- Histaminoid reactions with neuromuscular blocking drugs

Prevention of Adverse Drug reactions

• Never use any drug unless there is good indication. If the patient is pregnant do not use the drug unless the need is imperative.

• Allergy and idiosyncrasy are important causes of ADRs. Ask if the patient had previous reactions.

• Ask if the patient is already taking other drugs including self medication

Drug administered

Pt develops a new condition/symptoms

Drug suspected?

Check literature

Documented ?– (for the product or similar class of products)

Highly suggestive of ADR

Not documented in literature

Drug continued Drug discontinued

Worsening of symptoms Symptoms improve (+ve dechallenge)

Drug restarted

Symptoms recur(+ve rechallenge)

Any other possible causes?• Concomitant therapy• Underlying conditions

K10 Adverse Drug Reaction

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