ADVERSE DRUG REACTIONS

DEFINATIONS

Adverse drug reactions (WHO):

Any response to a drug that is noxious and unintended

and that occurs at doses used in man for prophylaxis,

diagnosis or therapy of disease or modification of

physiological states.

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

Epidemiology

4% of hospital admissions1 in 1000 deaths in medical wards10 to 20 % of in-patients5% of patients in general practice

More frequent in elderly:erratic drug takingmultiple pathologyaltered pharmacokineticsincreased sensitivity of CNS

and CVS

Drugs - anti-coagulants, NSAIDs,corticosteroids, anti-hypertensives, anti-biotics, diuretics and insulin.

Occur in circumstances related to drug’s pharmacology, predisposing factors in the patient and care taken in choosing the drug and the dose.

SIDE EFFECTS-Pharmacological effects produced with therapeutic dose of drug.Troublesome in one condition but useful in others.Ex. atropine

UNTOWARD EFFECTS-Undesirable effects with therapeutic dose of the drug ,if severe requires

caessation of treatment.Ex.tetracyclines,aspirin

TOXIC EFFECTS-Effects produced by large & / repeated dosesEx. morphine

TYPES ADR

QUANTITATIVE QUALITATIVE(Type A) (Type B)

IDIOSYNCRASY ALLERGY Genetic Unknown I II III

IV (HYPERSENSITIVITY)

Comparison –type A &BType A Type B

1.Nature

2.Mechanism

3. Predictable

4.Incidence

5.Mortality

6. Treatment

7.Dose dependent

augmented/ attenuated normal

Hyper/ hypo response

Yes

high

Low

Adjust dose

Yes

Totally abnormal, bizarre response

Genetic, immunological,UK

No

Low

High

Stop the drug

No

IDIOSYNCRASY

GENETIC• G6PD DEFECIENCY• ATYPICAL PSEUDOCHOLINESTRASES

UNKNOWNChloramphenicol –Aplastic anaemia

ALLERGIC REACTION

FEATURES1. Ranges from mild- severe (anaphylaxis)2. Prior sensitization requried3. Immunologically mediated4. Low incidence , unpredictable, dose

independent.

Hypersensitivity

Hypersensitivity is an immune reaction to innocuous antigens that results in tissue injury and/or diseaseAn antigen that causes allergy is an allergen

TYPES OF ALLERGIC REACTIONS

I.IgE MEDIATED REACTION AND ANAPHYLAXIS-(immediate hypersensitivity)

• Systemic anaphylaxis- ex.penicillin. Antigen + IgE antibodies—influx of ca++ ----degranulation of mast

cells ,basophiles—release of histamine---anaphylaxis• Local anaphylaxis -Hay fever -Asthma -Diarrhea, gi.Pain. -Skin rash

Allergy (type I hypersensitivity mediated by IgE on mast cells)

Mast cell degranulation by antigen (allergen) cross-linking of FceR-bound IgE

Mast cell activation has many effects

TYPE II ALLRGIC REACTIONCytotoxic type reaction- Antibodies binds to antigen present on the cell surface

promotes phagocytosis of cell or cell destruction by polymorphs, macrophages or by lymphoid killer cells.

Examples-Transfusion reactionsRh incompatibility• drugs-antigenic complex with blood cells----increase

humoral antibodies----cytotoxic – haemolysis / agranulocytosis / thrombocytopenia

Type II hypersensitivityType II hypersensitivity (IgG-mediated anti-

cell-associated antigen response) is rare

Immune response to certain drugs (e.g.,

penicillin) where drug binds to cell surface and

antibody cause removal of the cells (usually

by macrophages).

TYPE III

IMMUNE COMPLEX MEDIATED REACTIONS ANTIGEN+HUMORAL ANTIBODIES

IMMUNE COMPLEXES

Ab EXCESS Ag EXCESS

Ppt.NEAR SITE OF ENTRY DEPOSIT IN SKIN, JOINTS SKIN-ERYTHEMA,EDEMA, ETC. KIDNEY

ARTHUS REACTION SERUM SICKNESS

Arthus Reaction: acute antibody-mediated hypersensitivity to soluble

antigens

TYPE IV

CELL MEDIATED REACTION-(Delayed hypersensitivity) Inflammatory reaction initiated by T cells. Delayed-secondary cellular response occurs after 48

hrs of antigen exposure. Examples-1.montoux reaction-i.d. tuberculin inj.2.Sulphonamides

Four Types of Hypersensitivities

MANIFESTATION OF ADR

1. Haemopoetic toxicity2. Hepatotoxicity –direct / immunological3. Nephrotoxicity4. Abnormality in taste & smell5. Occular toxicity6. Ototoxicity7. Behavioural toxicity8. Iatrogenic diseases9.Teratogenicity

32

Risk Factors for Adverse Drug Reactions

Simultaneous use of several different drugs– Drug-drug interactions

Very young, or very old in agePregnancyBreast FeedingHereditary FactorsDisease states which may effect drug absorption, metabolism, and/or elimination

33

Risk Factors Examples: Simultaneous Drug Use or Drug-Drug Interactions

Cerivastatin-Gemfibrozil interactions in hypercholesterolemia patients (rhabdomyolysis)

Coumadin-NSAID interactions (increased inhibition of platelet aggregation)

Venlafaxine-indinavir interactions in depressed HIV-infected patients (decreased indinavir concentrations)

34

Risk Factors Examples: Age Related Issues

Children are often at risk because their capacity to metabolize drugs is usually not fully developed– Newborns cannot metabolize or eliminate chloramphenicol, an

antibiotic– Children younger than 18 may be at risk of developing Reye’s

syndrome if given acetylsalicylic acid (aspirin) while infected with chickenpox or influenza

– Central nervous system effects of topiramate in children (seizures, tremor, and dizziness)

35

Risk Factors Examples: Age Related Issues

ADRs, including drug interactions, are a common cause of admission to hospitals in the elderly

Reasons for ADRs in the elderly:– Concomitant use of several medications– Disease states leading to drug ADME changes– Decreased drug ADME activity due to age

These conditions are exacerbated by malnutrition and dehydration, common in the elderly

36

Risk Factors Examples: Pregnancy

Use of sulfonamides (antibiotic) can lead to jaundice and brain damage in the fetus

Warfarin use for anticoagulation can lead to birth defects, and increased risk of bleeding problems in newborns and mothers

Lithium, for bipolar disorder, can lead to defects of the heart, lethargy, reduced muscle tone, and underactivity of the thyroid gland

37

Risk Factors Examples: Breastfeeding

Similar concerns, as for other children with underdeveloped capability to metabolize or excrete xenobiotics

Many drugs can be passed from mother to infant via breast milk– Amantadine (antiviral)– Cyclophosphamide (antineoplastic)– Cocaine (Schedule 2 FDA drug)– Carisoprodol (skeletal muscle relaxant)

38

Risk Factors Examples: Hereditary Factors

Genetic polymorphisms may play a role– Evident in CYP2C9 and 2C19, especially in the Asian population

(phenytoin)– May lead to impaired metabolism in mutation of enzymes

Higher risk of hemolysis in some populations, such as African, Middle Eastern, and South East Asian races– Quinolones– Antimalarials

39

Risk Factors Examples: Disease States

Metabolism (Phase I or II) may be impaired with hepatic disease – Cirrhosis– Hepatic Carcinoma

Renal Insufficiency– Acute or Chronic Renal Failure– Decreased glomerular filtration rate (GFR)

Drug levels may become toxic if too high, so dosing modifications may be indicated