Adverse drug reaction

A person was admitted with fever. He was

prescribed ceftriaxone, paracetamol and vitamin B

complex. After taking the drugs he developed

rash,and macular lesion on fore arm. When he

consulted prescribing doctor ,ceftraixone was

replaced with ampicillin and lesion disappeared after

that. What could be the reason for this?

ADVERSE DRUG REACTIONDr Bikash MeherMBBS,MDAsst ProfessorAIIMS,Bhubaneswar

Learning Objectives

Definition of Adverse Drug Reaction(ADR)

Definition of Pharmacovigilance

Types of ADR

Difference between Type A and B

Characteristics of each type with suitable examples

Adverse drug reaction (ADR)

Response to a drug that is noxious and unintended, and

which occurs at doses normally used in man for prophylaxis,

diagnosis or therapy of disease or for the modification of

physiological function

Adverse Drug Events

Any untoward medical occurrence that may present during

treatment with a pharmaceutical products but which does

not necessarily have a causal relationship with this treatment.

Ex .Road accident

Clinical Significance

ADR is responsible for significant morbidity and mortality

It is fourth to sixth leading cause of death in USA

Responsible for 0.2 to 24% of hospital admission

ADR also has a significant impact on health care cost

Most of the adverse effects are reversible initially

Types of ADR

ABCDE

A-Augmented

B-Bizzare

C-Continuous

D-Delayed

E-End of Use

Intensity of ADR

Mild

Transient in nature, Not interfering with normal activities

Moderate

Discomforting in nature, interfering with normal activities

Severe

Incapacitating and prevent normal activities

Type A(Augmented) Type B(Bizzare)

Due to extension of Pharmacological action

Immunological basis

Predictable Not predictable

Quantitative Qualitative

High incidence but less mortality

Low incidence but high mortality

Dose reduction is needed Has to be discontinued

Hypoglycemia Anaphylactic reaction

Type A

About 80% of ADR----Type A reactions

Based on pharmacological effects

Dose related

Different types included in this are

1.Side effects

Undesired but unavoidable effects at therapeutic doses

Predicted from pharmacologic profile of drug

Reduction in dose relieves the symptoms

Therapeutic in one context but side effect in another context

Ex. Dry mouth with atropine

Hypokalemia with thiazide

Postural Hypotension by Prazosin

May be on different basis

Ex Promethazine cause sedation and also anti allergic reaction

Effect may be therapeutic in one context but side effect in

another context

Codeine used in cough causes constipation

Can be used in diarrhea

2.Secondary effect

Secondary to pharmacodynamic effect of drug

Super infection with antibiotic therapy

Pseudo membranous colitis with clindamycin

Orthostatic hypotension with a phenothiazine

3.Toxic effect

Excessive pharmacological effect

May be due to over dose or prolong use

Extension of pharmacological effect

Significant for drug with narrow therapeutic effect

Drug is not toxic but active metabolites may be toxic

Drug is toxic but active metabolite is not

3.Toxic effect

Over dose may be absolute

Homicidal,Accidental or suicidal

Relative

Gentamicin cause severe renal toxicity in kidney disese

Paracetamol in liver toxicity

Drug (Safe) Metabolite ( Toxic)

Paracetamol NABQI

Halothane Trifluroacetic acid

Isoniazid Acetylhydrazine

Methoxyflurane Fluoride

Cyclophosphamide Acrolein

Drug(Toxic) Active metabolite(Safe)Phenacetin ParacetamolTerfenadine FexofenadinePhenylbutazone Oxybutazpone

4.Intolerance

Failure to tolerate drug

Exaggerated pharmacological response at therapeutic dose

Lower threshold to normal pharmacodynamic action

Few are intolerant

Ex.

Carbamazepine induced ataxia

Chloroquine induced vomiting

Triflupromazine induced acute muscular dystonia

Q.Type A (augmented ) adverse drug reaction are characterized

by all EXCEPT.

A. Qualitatively abnormal responses to the drug

B.Predictable from drug’s known pharmacological or toxicological

effects.

C.Generally dose dependent

D.Usually common

Type B

Unrelated to known pharmacological actions of drug

Unpredictable

Caused by immunological & pharmacogenetic mechanisms

Unrelated to dosage

Comparatively rare & cause serious illness or death

Drug Allergy

Allergy-Altered state of reactivity

Immunologically mediated reaction

Occur to drug or metabolite or inert compound

Unrelated to pharmacodynamic profile of drug

Not dose dependent

Affect small no. of patients

Disappear on discontinuation and reappear on re exposure

Induction period is required for primary exposure

Prior sensitization is required

Similar to food or other allergic conditions

Drug Allergy

Cross allergy

Allergy to one drug may lead to allergy to other drug with

similar chemical structure

Type I

Immediate hypersensitivity

Develop within minutes

Formation of IgE antibodies

Attached to mast cell

Subsequent exposure drug conjugates with these antibodies

and activate mast cell

Release of pharmacologically active substance

Responsible for allergic manifestations

1.Anphylaxis reaction

Without protection

Hypotension,Laryngospasm,Angioedema

Fatal condition

Ex. Penicilli,Contrast dye

2.Mild reaction(Atopy)

Management

1.Adrenaline

0.3-0.5ml of 1:1000 by IM or SC route

Repeat after 10-20 min.(if required)

2.Corticosteroid

100mg IV every 6hrs

3.H1 antihistamine

Chlorpheniramine 10-20mg slow IV

4.Colloid

Type II reaction(Antibody dependent cytotoxic reaction)

Drug combine with tissue protein

Body consider it as foreign antigen

Ex.When drug combine with RBC

Antigen antibody reaction trigger lysis of RBC

Type III(Immune Complex mediated )

Antigen antibody form complex

Activates complement

Release pharmacologically active substance

Ex.Glomerulonephritis,Pneumonotis,

Ampicillin,Sulfonamides

Type IV reaction (Cell mediated)

Manifestations after 2-3days

Mediated by sensitized T cells

Released cytokines activate macrophase,NK cells to induce

infalmmatory response

Ex.Contact dermatitis

Idiosyncratic Reactions

Interaction of drugs with unique host factor

Genetically determined abnormal reaction

Inherited abnormal response to due to single gene defect

Restricted to particular group

Ex

G6PD deficiency-Hemolytic anemia

Malignant hyperthermia

Pseudochoiline esterase deficiency

Q.Characteristic unwanted reaction which isn’t related to a

dose or to a pharmacodynamic property of a drug is called:

a) Idiosyncrasy

b) Hypersensitivity

c) Tolerance

d) Teratogenic action

Idiosyncratic reaction of a drug is:

a) A type of hypersensitivity reaction

b) A type of drug antagonism

c) Unpredictable, inherent, qualitatively abnormal reaction to

a drug

d) Quantitatively exaggerated response

Type C (Continuous Use )

Hepatotoxicity-INH,Rifampicin

Nephrotoxicity-NSAIDs

Cumulative toxicity-Cloroquine induced retinal toxicity

Physical dependence

Altered physiological state

Discontinuation lead to withdrawal syndrome

Ex.Alcohol,Opioid

Type D(Delayed effects)

Mutagenicity and carcinogenicity

Cause genetic defect and cancer

Altered Gene,DNA

Ex.Secondary carcinoma by alkylating agent

Type E(End of Use)

Drug of addiction

Withdrawal syndrome

Corticosteroid-Acute adrenal insufficiency

Clonidine –Rebound hypertension

B blocker-Rebound sympathetic over activity

Drug addiction

Compulsive drug use

Overwhelming desire to get the drug

Ex.Cocaine,Amphetamine

Drug Habituation

Less intensive involvement with drug intake

Ex.Tea,Cofee

Drug Dependence

Psychological

Optimal state of well being can be achieved by drugs

Desire to craving

Drug seeking behavior

Physical

Altered physiological state which require drugs presence to

maintain physiological equilibrium

Discontinuation results in with drawl syndromes

Photo sensitivity

Cutaneous reaction adverse reaction in presence of light

Developed reaction on body part exposed to UV light

Phototoxic

Photochemical reaction followed by photo biological reaction

Ex.Tetracycline,Sulfones,Phenothiazines

Photo allergic reaction

Cell mediated immune response

Dermatitis

Ex. Sulfonamides

Iatrogenic/Drug induced disease

Induced by physician

DM due to glucocorticoids

Parkinsonism due to narcoleptics

Glaucoma due to glucocorticoids

SLE due to hydralazine and procainamide

Manifestations of ADR

Allergy

Others

GIT-Nausea,Vomiting,Constipation,Organ Toxicities

Hepatotoxicity-INH,Rifampicin

Nephrotoxicity-Aminoglycoside,Vancomycin

Cardiac-Theophylline,Digitalis

Occular –Chloroquine,Ethambutol

Oto toxicity-Aminoglycoside,Vancomycin

Manifestations of ADR

CNS toxicity-Reserpine,Neuroleptic

Endocrine-Spironolactone

Dermatological toxicity-Many drugs

Disorder of taste-ACE inhibitors

Teratogenicity

Ability of drug to cause fetal anomalies

Single exposure can affect fetal structure

Affect at 3 different stages

Fertilization and implantation

Organogenesis

Growth and development phase

Teratogenic drugsThalidomide PhocomeliaAlcohol Fetal alcohol syndromeCarbamazepine NTDPhenytoin Cleft PalateWarfarin Growth retardation, Eye and hand defectLithium Ebstein anomaly

Pharmacovigilance

Pharmacovigilance is defined by WHO as the science and

activities relating to the detection, understanding and

prevention of adverse effects or any other drug related

problems

How to prevent ADR

Rational use of drug

Proper drug history and drug allergy history

To check the possibility of drug interaction

Assessment of risk benefit ratio

Advice patient ,not to take drug without advice

Restricted use of OTC drug

Criteria CriteriaDefinite Probable Possible Conditional

Reasonable Time sequence

Yes Yes Yes Yes

Dechallenge Yes Yes Yes No

Rechallange Yes Yes

Event could explained by patients disease

No Yes No

Thank You