Drug toxicity and safety

Drug toxicity and safety
Therapeutic index
The therapeutic index is a quantitative measurement of the relative safety of a drug. It is a comparison of the
amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity.
Therapeutic index = Median lethal dose (LD 50)/median effective dose (ED 50)
Adverse drug reaction
 Any undesirable or unintended consequence of drug administration.

 It is defined as any noxious change which is suspected to be due to a drug, occurs at doses
normally used in man, requires treatment or decrease in dose or indicates caution in the
future use of the same drug.
 Two types of adverse reaction are:
1. Predictable reaction/Type A
 Expected
 Side effects, toxic effects and consequences of drug withdrawal.
 They are more common, dose related and mostly preventable and reversible.
Eg:
2. Unpredictable reaction/Type B
 Unexpected
 These are based on peculiarities of the patient and not on drug’s known actions; include
allergy and idiosyncrasy.
 They are less common, often non-dose related, generally more serious and require
withdrawal of the drug
Eg:
Type A Type B
Incidence rate is high Incidence rate is lower
Mortality rate is rare or very low Mortality rate is higher
Reduction in dose can minimize these adverse Reduction in dose can’t minimize these adverse
effects effects
Preventable and reversible Can be predicted and prevented if their genetic

basis is known
Side effects
 These are undesirable effects which are observed even with the therapeutic doses of the
drug. These ADRs are usually mild and manageable.
 E.g.:
o Dicyclomine causes dryness of mouth at therapeutic doses
o Promethazine produces sedation which is unrelated to its antiallergic action
o Estrogens cause nausea which is unrelated to their antiovulatory action
o Codeine used for cough produces constipation
Toxic effects
 These are exaggerated form of side effects which occur either due to overdoses or after
prolonged use of the drug.
Eg: Hyperpyrexia, hallucination, delirium due to atropine
Hepatic necrosis due to paracetamol
Nephrotoxicity, ototoxicity due to streptomycin
Respiratory failure due to morphine
Idiosyncrasy
 These are harmful and sometimes fatal reactions that occur in a small minority of
individuals.
 It is genetically determined abnormal reactivity to a chemical substance.
 e.g.: Barbiturates cause excitement and mental confusion in some individuals.
Quinine/quinidine cause cramps, diarrhoea, purpura, asthma and vascular collapse in some
patients.
Hypersensitivity reactions/Drug allergy
 Allergic responses to drug occur when there has been previous exposure to drug and when
this sensitized individual is re-exposed to the same drug again. Eg: Penicillin, salicylates
 Immunologically mediated reaction
 occurs even with much smaller doses
o E.g.: Penicillins, cephalosporins, sulfonamides, tetracyclines, quinolones,
antitubercular drugs, phenothiazines, salicylates, carbamazepine, allopurinol, ACE
inhibitors, methyldopa, hydralazine, local anaesthetics
 Two types: Humoral and Cell mediated
o A. Humoral: Three types
 Type-I (anaphylactic) reactions:
 Mediated by IgE
 Antibodies (IgE) are produced which get fixed to the mast cells.
 On exposure to the drug, AG: AB reaction takes place on the mast
cell surface
 Release of mediators like histamine, 5-HT, leukotrienes, PGs, etc
 Results in urticaria, itching, angioedema, bronchospasm, rhinitis or
anaphylactic shock
 Type-II (cytolytic) reactions:
 Mediated by IgG or IgM
 Drug + component of a specific tissue cell act as AG.
 The resulting antibodies (IgG, IgM) bind to the target cells
 on re-exposure, AG: AB reaction takes place on the surface of these
cells, complement is activated, and cytolysis occurs
 e.g., thrombocytopenia, agranulocytosis, aplastic anaemia,
haemolysis, organ damage (liver, kidney, muscle), systemic lupus
erythematosus
 Type-III (retarded, Arthus) reactions:
 Immune complex mediated
 AG:AB complex gets deposited on vascular endothelium.
 Manifestations are rashes, serum sickness (fever, arthralgia,
lymphadenopathy), polyarteritis nodosa, Stevens-Johnson
syndrome.
o Cell mediated:
 Type-IV (delayed hypersensitivity) reactions:
 mediated through production of sensitized T-lymphocytes carrying
receptors for the AG.
 On contact with the AG these T cells produce lymphokines which
attract granulocytes and generate an inflammatory response
 e.g., contact dermatitis, some rashes, fever, photosensitization.
 The reaction generally takes > 12 hours to develop.
Tetratogenecity
 Capacity of a drug to cause fetal abnormalities when administered to the pregnant mother
 Drugs can affect the foetus at 3 stages—
o (i) Fertilization and implantation—conception to 17 days—failure of pregnancy
which often goes unnoticed.
o (ii) Organogenesis—18 to 55 days of gestation—deformities are produced.
o (iii) Growth and development—56 days onwards — developmental and functional
abnormalities can occur
 It is, therefore, wise to avoid all drugs during pregnancy
Iatrogenic disease/Drug induced disease
 These are the diseases induced by drug therapy. These also occur when a drug is suddenly
discontinued.
 Functional disturbances (disease) caused by drugs which persist even after the offending
drug has been withdrawn and largely eliminated
 e.g.: Peptic ulcer by salicylates and corticosteroids.
 Parkinsonism by phenothiazines and other antipsychotics.
 Hepatitis by isoniazid.
 DLE by hydralazine.
Photosensitivity
 Phototoxic reactions in response to drugs is known as drug-induced photosensitivity

 It is a cutaneous reaction resulting from drug induced sensitization of the skin to UV
radiation.
 The reactions are of two types:
o Phototoxic:
 Drug or its metabolite accumulates in the skin, absorbs light and undergoes
a photochemical reaction followed by a photobiological reaction resulting in
local tissue damage.
 Erythema, edema, blistering, hyperpigmentation and desquamation.
 Drugs involved in acute phototoxic reactions are tetracyclines (especially
demeclocycline) and tar products.
o Photoallergic:
 Drug or its metabolite induces 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 appearance.
 Rarely antibodies mediate photoallergy and the reaction takes the form of
immediate flare and wheal on exposure to sun.
 Drugs involved are sulfonamides, sulfonylureas, griseofulvin, chloroquine,
chlorpromazine
Drug dependence
 A physiological state of neuroadaptation resulting from repeated administration of the drug,

necessitating its continued use to prevent the appearance of distressing withdrawal
syndrome which is manifested as opposite to the pharmacological effects of the drug.
 Physical dependence:
o Altered physiological state produced by repeated administration of a drug
o Drug is necessary to maintain physiological equilibrium.
o Discontinuation of the drug results in a characteristic withdrawal (abstinence)
syndrome.
o Drugs producing physical dependence are— opioids, barbiturates and other
depressants including alcohol and benzodiazepines.
 Psychological dependence:
o When the individual believes that optimal state of wellbeing is achieved only
through the action of the drug.
o Subject feels emotionally distressed if the drug is not taken.
o Reinforcement is the ability of the drug to produce effects that make the user wish
to take it again or to induce drug seeing behaviour. Certain drugs (opioids, cocaine)
are strong reinforcers, while others (benzodiazepines) are weak reinforcers. Faster
the drug acts, more reinforcing it is.

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Drug toxicity and safety

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Drug toxicity and safety

Adverse drug reaction

 Any undesirable or unintended consequence of drug administration.

Preventable and reversible Can be predicted and prevented if their genetic

Hypersensitivity reactions/Drug allergy

 Phototoxic reactions in response to drugs is known as drug-induced photosensitivity

 A physiological state of neuroadaptation resulting from repeated administration of the drug,

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