Efek Non Terapi(Adverse Drug Reaction)

School of MedicineUniversitas Sumatera Utara2010

Hasanul Arifin, Tri Widyawati

• “All substances are poisons; there is none which is not a poison; the right dose differentiates a poison and a remedy.”

• Key Principle of Pharmacology

Paracelsus (1493-1541)

No drug has a single action.

1956 Talidomid obat yang sangat aman

5 tahun kemudian

8000 bayi di 46 negara cacat

• Medicines Control Agency (MCA) : Inggris• Food and Drug Administration (FDA) : AS• Badan Pengawas Obat dan Makanan (Badan POM) : Indonesia

Mengevaluasi obat baru yang belum / sudah beredar di masyarakat

Drugs removed from or restricted in Europe an USA

Terfenadine (1998) Mibefradil (1998) Astemizole (1999) Grepafloxacin (1999) Cisapride (2000) Cerivastatin (2001) Troglitazone (Rezulin) (2000) Rofecoxib (Vioxx) (2004)

ADRs are important

USA : - Over 2 million serious ADRs/year - 100.000 deaths/year from ADRs - ADRs are fourth leading cause of death more than lung disease, Diabetes, AIDS, and accidents - 3-5% are preventable in-hospital ADRs due to drug interactions(Lazarou J et al.JAMA.1998; 279(15):1200-1205. Gurwitz JH et al.Am.J.Med. 2000;109(2):87-94.)

Only heart disease, cancer, and stroke kill more Americans than ADRs

The number of deaths from ADRs is three times the number of deaths from people killed by automobile accidents

Adverse drug reactions may lead to complications:Prevents optimal drug use in some patientsNecessitates supportive careSignificantly complicates treatmentDecreases patient’s quality of lifeResults in temporary or permanent harm,

disability, or death

What is an Adverse Drug Reaction (ADR)?

“an unwanted or harmful reaction experienced following the administration of a drug or combination of drugs under normal conditions of use and suspected to be related to the drug”

Ref. MCA/CSM Suspected adverse drug reaction (ADR) reporting and the Yellow Card Scheme, Guidance notes

Who might get an ADR?

Anyone who takes a medicine Differential diagnosis should include the

possibility of an ADR if the patient is taking any form of medication

Examples of ADRs

Common ADRs Constipation with opioids Sedation with antihistamines Nausea when starting fluoxetine Gastrointestinal upset with non steroidal anti-inflammatory drugs

• Uncommon but well recognised ADRs– Achilles tendonitis caused by quinolone antibiotics– Visual field defects with vigabatrin

What should raise our suspicion of an ADR?

A symptom : appears soon after a new drug is startedappears after a dosage increasedisappears when the drug is stoppedreappears when a drug is restarted (do not

deliberately rechallenge!)

Classification

ADRPREDICTABLE

Perpanjangan respons farmakologik

UNPREDICTABLE

Penyebab imunologik (alergi dan hipersensitifitas)

Cytotoksisitas Defek genetik

Tipe I Tipe II Tipe III Tipe IV

Type I reaction (IgE-mediated) Anaphylaxis from lactam antibiotic

Type II reaction (cytotoxic) Hemolytic anemia from penicillin

Type III reaction (immune complex) Serum sickness from anti-thymocyte globulin

Type IV reaction (delayed, cell-mediated) Contact dermatitis from topical antihistamine

Specific T-cell activation Morbilliform rash from sulfonamides

Immunologic and Nonimmunologic Drug Reactions

Immunologic

Pharmacologic side effect Dry mouth from antihistamines

Secondary pharmacologic side effect Thrush while taking antibiotics

Drug toxicity Hepatotoxicity from methotrexate

Drug-drug interactions

Seizure from theophylline while taking erythromycin

Drug overdose

Seizure from excessive lidocaine (Xylocaine)

Immunologic and Nonimmunologic Drug Reactions

Non Immunologic Predictable

Pseudoallergic Anaphylactoid reaction after radiocontrast media

Idiosyncratic

Hemolytic anemia in a patient with G6PD deficiency after primaquine therapy

Intolerance Tinnitus after a single, small dose of aspirin

Immunologic and Nonimmunologic Drug Reactions

Non Immunologic UnPredictable

Obat Efek yang mungkin

Gol ACE inhibitor Gagal ginjal pada janin dan neonatus

Obat antitiroid Hipertirodisme pada janin

Benzodiazepin Ketergantungan obat pada janin

Barbiturat Ketregantungan Obat

AINS Konstriksi pada ductus arterious

Tetrasiklin Pewarnaan gigi, hambatan pertumbuhan tulang

Warfarin Pendarahan dalam otak jantung

Penggunaan Obat bagi yang menyusui juga perlu mendapat perhatian untuk meminimal ROTD

Obat Efek yang mungkin

Tetrasiklin Resiko perwarnaan gigi

Karbimazol Hipotiroidisme

Benzodiazepin Letargia

Aspirin Resiko sindroma reye

Barbiturat Mengantuk

PREDICTABLE UNPREDICTABLE

Synonyms Augmented, toxic, quantitative, dose-related Bizarre, allergic, idiosyncratic, or drug intolerance, qualitative, dose-independent

Mechanism Predictable, understood Usually poorly understood

Site 1.Same site of primary drug action

2.Another site for primary & secondary action

Unrelated to the site of action

Incidence High (70%) Low(30%)

Morbidity Mild Severe

Mortality Low High

Causes

Ph’seutic availab. at site of absorption : quantity & release of dosage form

Decomposition products, additives, excepients, etc

Ph’kinetic level at site of action due to abnormalities of ADME

Liberation of an abnormal metabolite

Ph’dynamic 1.Enhanced organ or tissue responsiveness

due to enhanced number or sensitivity of

receptors

2.Homeostatic imbalance

3.Disease state

1. Genetic

2. Immunologic

3. Neoplastic

4. Teratologic

Reproducibility Reproducible Not reproducible

Treatment Adjust the dose Stop treatment

Risk Factors for Developing an ADR

Multiple drug therapy Over the counter medications Alcohol Drugs of abuse Number of drugs

Age - Very young

Very old Pregnancy

Risk to fetal development (first trimester, phenytoin) Co-morbidity/chronic diseases – can alter a drug’s absorption,

distribution, metabolism or elimination Hereditary factors – slow acetylators Have a history of allergy or a previous reaction to drugs

Are ADRs avoidable?

30-50% are preventableObvious interactions

– many drugs interact with warfarinUse of contra-indicated drugs

– use of a non-selective beta-blocker in an asthmatic bronchospasm

Drug use in an inappropriate clinical indication or medically unnecessary

– antibiotics for a viral infection

Prevention of ADRs

• Avoid inappropriate in the context of clinical condition

• Use right dose, route, frequency, based on patient variables

• Elicit medication history; consider untoward incidents

• Elicit history of allergies ( in patients with allergic disease)

• Rule out drug interactions

• Adopt right tehnique, eg. Slow iv injection of Aminophylline

• Carry out appropriate monitoring (eg. PT with warfarin, Li level)

DOKTER

APOTEKER

PERAWAT

PASIEN

Pemantauan pasien

Pengurangan dosis

Pemantauan kadar serum

Pemantauan kerja farmakologi

PENCEGAHAN ROTD

Evaluation and Management of Drug Reaction

Medical history: symptoms, detailedmedication list, temporal sequencePhysical examinationClinical laboratory data

Is a drug reaction likely?Yes No

Other etiology likely

Evaluate and treat othercauses of symptoms.

Is there a suspicion ofdrug-induced hypersensitivity/immunologic reaction?

Immune mechanism• IgE-mediated• Cytotoxic• Immune complex• Delayed, cell-mediated• Other immune mechanism

Nonimmune mechanism• Pharmacologic side effect• Drug toxicity• Drug-drug interactions• Drug overdose• Pseudoallergic• Idiosyncratic• Intolerance

Evaluate with appropriateconfirmatory tests.

Are tests supportive ofimmune drug reaction?

Diagnosis of drughypersensitivity/immunologicreaction confirmed

Management• Consider desensitization (IgE) orgraded challenge (non-IgE) beforeadministration, as appropriate.*• Anaphylactic reactions require promptemergency treatment.• Avoid drug if possible.• Consider prophylactic regimen beforeadministration (if shown to be effective).• Prudent use of drugs in future• Patient education

Does test have highnegative predictive value?

Yes

No No

Yes

Administer drug with observation.

Remember!

“All health-care professionals have a responsibility to inform colleagues about clinically important adverse drug reactions that they detect, even if a well-recognised or causal link is uncertain.”

Edwards IR and Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000; 356: 1255-59