Efek Non Terapi

(Adverse Drug Reaction)

Hasanul Arifin, Tri Widyawati

School of Medicine
Universitas Sumatera Utara

Paracelsus (1493-1541)
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

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 patients

Necessitates supportive care
Significantly complicates treatment
Decreases patients quality of life
Results 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 started
appears after a dosage increase
disappears when the drug is stopped
reappears when a drug is restarted (do not
deliberately rechallenge!)

Classification

ADR
PREDICTABLE

UNPREDICTABLE

Perpanjangan respons
farmakologik

Penyebab
imunologik (alergi
dan
hipersensitifitas)

Tipe I

Tipe II

Cytotoksisitas

Tipe III

Defek genetik

Tipe IV

Immunologic and Nonimmunologic Drug

Reactions
Immunologic
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
Non Immunologic

Predictable

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

UnPredictable

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

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, doseindependent

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

Phseutic

availab. at site of absorption : quantity & release

of dosage form

Decomposition products, additives,

excepients, etc

Phkinetic

level at site of action due to abnormalities of

ADME

Liberation of an abnormal metabolite

Phdynamic

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

Causes

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 drugs 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 preventable
Obvious interactions

Use

many drugs interact with warfarin

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)

PENCEGAHAN ROTD
PASIEN

Pemantauan pasien
Pengurangan dosis
DOKTER

Pemantauan kadar serum

Pemantauan kerja farmakologi

APOTEKER

PERAWAT

Evaluation and Management of Drug Reaction

Medical history: symptoms, detailed
medication list, temporal sequence
Physical examination
Clinical laboratory data
Yes

Is a drug reaction likely?

Other etiology likely

Is there a suspicion of
drug-induced hypersensitivity/
immunologic reaction?
Nonimmune mechanism
Pharmacologic side effect
Drug toxicity
Drug-drug interactions
Drug overdose
Pseudoallergic
Idiosyncratic
Intolerance

Immune mechanism
IgE-mediated
Cytotoxic
Immune complex
Delayed, cell-mediated
Other immune mechanism
Evaluate with appropriate
confirmatory tests.
Are tests supportive of
immune drug reaction?
Yes
Diagnosis of drug
hypersensitivity/
immunologic
reaction confirmed

No

Does test have high

negative predictive
value?
Yes

Administer drug with observation.

No

No

Evaluate and treat other

causes of symptoms.

Management
Consider desensitization (IgE) or
graded challenge (non-IgE) before
administration, as appropriate.*
Anaphylactic reactions require prompt
emergency treatment.
Avoid drug if possible.
Consider prophylactic regimen before
administration (if shown to be effective).
Prudent use of drugs in future
Patient education

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