ADVERSE DRUG REACTIONS

ADVERSE DRUG REACTION
Any noxious change in the body which is suspected to be due to a drug at doses normally used in man. It may requires treatment or decrease in dose or caution in the future use of the same drug



GRADING OF SEVERITY OF ADVERSE DRUG REACTIONS :

Minor : No therapy, antidote or prolongation of hospitalization is required.

Moderate: Requires change in drug therapy, specific treatment or prolongs hospital stay.

Severe: Potentially life-threatening, causes permanent damage or requires intensive medical treatment.

Lethal : Directly or indirectly contributes to death of the patient.


CLASSIFICATIONS OF ADR


A (Augmented)
B (Bizarre)
C (Continuous)
D (Delayed)
E (Ending Use)
F (Failure of Efficacy)
Broadly
Type- A (Predictable)- Based on pharmacological properties
Type- B (Non-predictable) – Based on Immunological response
and genetic makeup of person




TYPE A- AUGMENTED



These are based on the pharmacological properties of the drug so can be predicted.

They are common and account for 75% of ADRs

Dose related and preventable mostly reversible.

Examples:-
Anticoagulants (e.g., warfarin, heparin) – bleeding
Anti-hypertensives (e.g.. α1-antagonists) – hypotension
Anti-diabetics (e.g. insulin) - hypoglycemia


TYPE B- BIZZARE OR UNPREDICTABLE


Have no direct relationship to the dose of the drug or the pharmacological mechanism of drug action.

Develop on the basis of:
Immunological reaction on a drug (Allergy)
Genetic predisposition (Idiosyncratic reactions

More serious clinical outcomes with higher mortality and morbidity.

Mostly require immediate withdrawal of the drug.



TYPE C – CHRONIC (CONTINOUS) USE


They are mostly associated with cumulative-long term exposure

Example:-
Analgesic (NSAID)– interstitial nephritis, papillary sclerosis, necrosis


TYPE D – DELAYED



They manifest themselves with significant delay

Teratogenesis -Thalidomide – Phocomelia (flipper-like fore limbs)

Mutagenesis/Cancerogenesis

Others:

Tardive dyskinesis – during L-DOPA Parkinson disease treatment

TYPE E – END OF USE

Drug withdrawal syndromes and rebound phenomenons

Example – sudden withdrawal of long term therapy with -blockers can induce rebound tachycardia and hypertension


Identifying and Managing ADRs

Premarketing clinical trials
Animal studies
Human studies—Phases I, II, III
Cannot identify ADRs with incidence < 1%


Postmarketing surveillance
Postmarketing clinical trials—Phase IV
Other methods—observational studies, meta-analysis, case reports
Determining causality
Actions taken to manage new ADRs



PHARMACOVIGILANCE (DAUP)


The 'science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug related problems’

The information generated is useful in educating doctors and in the official regulation of drug use.
It has an important role in rational use of medicines, as it provides the basis for assessing safety of medicines.



PREVENTION OF ADVERSE EFFECTS TO DRUGS

Avoid inappropriate use of drugs .
Appropriate drug administration (Rational Therapeutics)
Dose
Dosage form
Duration
Route
Frequency
Technique


Ask for previous history of drug reactions and allergies
Ask for laboratory findings like serum creatinine etc.




Categorized into:


Side effects-
Secondary effects
Toxic effects
Intolerance
Idiosyncrasy
Drug allergy
Photosensitivity
Drug dependence
Drug withdrawal reactions
Teratogenicity
Mutagenicity and Carcinogenicity
Drug induced diseases (Iatrogenic disorders or Iatrogenicity)




SIDE EFFECTS

Unwanted often unavoidable Pharmaco-dynamic effects.
Occur at therapeutic doses.
Predictable
Examples.
Benzodiazepines- Motor in coordination
H1 Anti-histaminics- Sedation


SECONDARY EFFECTS

Indirect consequences of a primary action of the drug.
E.g. corticosteroids weaken host defence
mechanisms so that latent tuberculosis gets activated.



TOXIC EFFECTS (Poisonous effect)


It is the dose and duration which makes a poison.... Paracelsus
Over dose or prolonged use.
The effects are predictable and dose related.

The CNS, CVS, kidney, liver, lung, skin and bone marrow are most commonly involved in drug toxicity.


Toxicity may result from extension of the therapeutic effect itself, e.g. complete A-V block by digoxin, bleeding due to heparin.

Poisoning: Poison is a substance which endangers life by severely affecting one or more vital functions

Specific antidotes such as receptor antagonists, chelating agents or specific antibodies are available for few poisons.

For others as well as for those poisons which have a selective antagonist general supportive and symptomatic treatment should be done.



INTOLERANCE

It is the appearance of characteristic toxic effects of a drug in an individual at therapeutic doses
It indicates a low threshold of the individual to the action of a drug
Example:- Only few doses of carbamazepine may cause ataxia in some people


IDIOSYNCRASY


It is genetically determined abnormal reactivity to a chemical.
The drug interacts with some unique feature of the individual, not found in majority of subjects, and produces the uncharacteristic reaction.
Example :-
Chloramphenicol produces nondose-related

serious aplastic anaemia in rare individuals.
Barbiturates cause excitement and mental confusion in some individuals



DRUG ALLERGY

It is also called drug hypersensitivity.
It is an immunologically mediated reaction producing stereotype symptoms which are unrelated to the pharmacodynamic profile of the drug.

It generally occur even with much smaller doses and have a different time course of onset and duration.

Allergic reactions occur only in a small proportion of the population exposed to the drug .

History of prior sensitization may or may not be evident.

The drug or its metabolite acts as antigen (AG) or more commonly hapten (incomplete antigen) and induce production of antibody (AB)/sensitized lymphocytes.



TYPES OF ALLERGIC REACTIONS

A) HUMORAL

1. Type I/ anaphylactic reactions.
2. Type-II / cytolytic reactions.
3. Type-Ill / retarded or Arthus reactions.


B) CELL MEDIATED

Type-IV (delayed hypersensitivity) reactions.


PHOTOSENSITIVITY

It is a cutaneous reaction resulting from drug induced sensitization of the skin to UV radiation.



The reactions are of two types:

Photo-toxic :


Drug or its metabolite Accumulates in the skin,

absorbs light and undergoes a Photochemical reaction followed by

Photobiological reaction resulting in Tissue damage (sunburn-like),

i.e. erythema, edema, blistering , hyper pigmentation, desquamation.

The shorter wave lengths (290-320 nm, UVB) are responsible



(b) Photo-allergic:



Drug or its metabolites induce a cell mediated immune response which on exposure to

Light of longer wave lengths (320-400 nm, UV -A)

Produces a papular or eczematous contact dermatitis like picture.

Drugs involved are sulfonamides, sulfonylureas, griseofulvin,

chloroquine, chlorpromazine

DRUG DEPENDENCE


Use of drugs for personal satisfaction

Higher priority than other basic needs, often in the face of known risks to health.

Physical dependence It is an altered physiological state produced by repeated administration of a drug which necessitates the continued presence of the drug to maintain physiological equilibrium.

Discontinuation of the drug results in a characteristic withdrawal (abstinence) syndrome.

Drugs producing physical dependence are opioids, barbiturates and other depressants including alcohol and benzodiazepines Drug habituation (Psychological dependence)

It denotes less intensive involvement with the drug, so that its withdrawal produces only mild discomfort.

Consumption of tea, coffee, tobacco, social drinking are regarded habituating, physical dependence is absent



DRUG WITHDRAWAL REACTIONS


Sudden interruption of therapy with certain other drugs results in adverse consequences, mostly in the form of worsening of the clinical condition for which the drug was being used

Example: Acute adrenal insufficiency may be precipitated by abrupt cessation of corticosteroid therapy.



TERATOGENICITY (Teratos- Monster)


Drug to cause foetal abnormalities when administered to the pregnant mother.

Drugs can affect the foetus at 3 stages-

(i) Fertilization and implantation-conception to
17 days-failure of pregnancy which often goes unnoticed.
(ii) Organogenesis-18 to 55 days of gestation most vulnerable period, deformities are produced.

(iii) Growth and development-56 days onwards
developmental and functional abnormalities can occur,
e.g. ACE inhibitors , Thalidomide, Warfarin, Barbiturates,...............................



MUTAGENICITY AND CARCINOGENICITY


Cause genetic defects and cancer respectively.

Reactive intermediates which affect genes and may cause structural changes in the chromosomes

Even without interacting directly with DNA, certain chemicals can promote malignant change in genetically damaged cells, resulting in carcinogenesis.

Examples- anticancer drugs, radioisotopes, estrogens, tobacco...................................................



DRUG INDUCED DISEASES

These are also called iatrogenic (physician induced) diseases, and are functional disturbances (disease) caused by drugs .

Hepatitis by isoniazid and Rifampicin
Peptic ulcer by salicylates and corticosteroids
Retinal damage by chloroquine