Adverse drug Reaction

• Drug toxicity refers to the level of damage that a compound can cause
to an organism. The toxic effects of a drug are dose-dependent and can
affect an entire system as in the CNS or a specific organ such as the
liver.
• Drug toxicity takes place when a person accumulate too much of a drug
in blood, which may leads to adverse effects on the body. This may also
occur when the dose of a drug is too high which are unable to remove
the drug from the blood. Drug toxicity may occur a result of over dose
of a medication which have too much of a drug in a persons system at
once. This may happen when the dose taken exceeds the prescribed
dose, either accidentally and intentionally. However the drug toxicity
may also occur as an adverse drug reaction
contd.,
• Toxicology is the science that deals with the amount of an agent that
causes an adverse action in some living system.All substances are
poisons there is none which is not a poison. The right dose
differentiates a poison from a remedy.- Paracelus (16th century
physician-alchemist)
Factors influencing toxicity absorption
Absorption

• pulmonary
• sublingual
• Injection (I.V., I.P., subcut, I.A.)
• Topical
Distribution
• Binding plasma proteins, tissue (liver, bone,fat)
Metabolism
• Mainly liver (some in GI tract, kidneys, lungs)
• Phase I introduce or expose a functional group on the parent compound losing
pharmacological effect
• Phase II produces polar conjugates generally inactive and easily excreted in urine
and/or faeces
 Excretion
• All these factors determine the drug/toxin
• Bioavailability
Pharmacokinetics
• Clearance (Cl)
• Ratio relating to the rate of elimination(usually in ml/min)
• High values for efficient clearance
Contd.,
• Most important index of the capacity of an organ to remove a drug
• Volume of Distribution (Vd)
• Relates the amount of drug in the body to the concentration of drug in
the plasma
• Reflects the extent to which it is present in the extravascular tissue and
not in the plasma
• Half life (t1/2)The time it take for the plasma concentration of drug in
the body to be reduced by 50
contd.,
• For practical purposes the drug is considered eliminated after 7 half-
lives.
• Bioavailability (F)The fraction of the dose that reaches the systemic
circulation
• Absorption rate can be by zero-order kinetics rate is constant and
independent of amount ofdrug absorbede.g continuous intravenous drip
or rate can be by first-order kinetics diminishing and always in
proportion to the amount of drug still to be absorbed most drug
absorption follows first-order kinetics
• If drug is injected then consider drug is absorbed instantaneously
contd.,
• Clearance plasma concentration time curves
• Drug eliminated from a single compartment by a first order process half life 4hrs
• If sample before 2 hrs, reveals drug elimination is a multiexponential process
Principle causes of drug toxicity/side effects

• a. the predictable
• b. the less predictable
• c. the unpredictable
predictable
• Excessive action at a primary site (overdosage)e.g. anaesthetics, warfarin
• non-selectivity acting at unrelated sites (morelikely with overdosage)e.g.
chlorpromazine
contd.,
• Incomplete selective toxicity acts against the host as well as the target
organism or cell e.g. protein synthesis inhibitors,antimicrobials,
antifungals
• tolerance (dependence abuse potential) e.g. benzodiazepines, opioids
• unavoidable side-effects e.g. immunosuppression by corticosteroids
• Opportunistic infections The predictable Pharmacokinectic Drug
interactions - absorptione.g. gastric emptying, gut motilityAtropine and
metoclopramide
• Distribution e.g. displacement from plasma proteins aspirin and
warfarin
• Metabolism e.g. increased by enzyme induction