Efek Non Terapi

(Adverse Drug Reaction)

Hasanul Arifin, Tri Widyawati

School of Medicine
Universitas Sumatera Utara
2010

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 antiinflammatory 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
many drugs interact with warfarin
Use 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?

No
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

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