Lecture 3 Adverse Drug reactions Flashcards
Has the incidence of deaths or adverse reactions doubled in the last couple of years ?
Incidence of death or adverse reactions to drugs
more than doubled between 1998 and 2005
What is Adverse Drug reactions ?
Harmful or seriously unpleasant action of a drug at
a dose intended for therapeutic use (Lawrence ,
Bennett and Brown, 1997)
toxicity
secondary effects
intolerance
How is it caused by the drug ?
Harmful or seriously unpleasant action of a drug at
a dose intended for therapeutic use (Lawrence ,
Bennett and Brown, 1997)
toxicity
secondary effects
intolerance
What are the Types of ADR?
Predictable (Type A)
Not predictable (Type B)
unrelated to dose
only occurs in susceptible individuals
not proportionally related to dose
What is Predictable ( Type A ) ?
Predictable (Type A)
related (proportional) to dose
will happen in everyone at a certain dose
~80 of ADRs
Type A are predictable, dose-related toxicities, often identified in preclinical or clinical trials, and usually occur in overdose settings or with pre-existing hepatic impairment.
What is Predictable Type B?
Not predictable (Type B)
unrelated to dose
only occurs in susceptible individuals
not proportionally related to dose
Type B are not clearly related to increasing dose and are associated with drug-specific and patient-specific characteristics and environmental risks.
Rare Type B reactions are often identified postmarketing. Identification and management, including electronic resources, has evolved.
Which one occurs the most and why ?
Predictable ADR Basis of reaction Pharmacokinetic Pharmacodynamic Pharmaceutical up to 80% of ADRs
Variations according to
inherited characteristics
Slow/Fast acetylators Isoniazid Glucose-6-phosphate dehydrogenase deficiency Integrity of red blood cell Possible haemolysis if exposed to oxidants Pseudocholinesterase deficiency
Variability due to age
Neonates Absorption from GI tract, distribution, metabolism, excretion The elderly Polypharmacy Compliance Absorption from GI tract, distribution, metabolism, excretion
Pharmaceutical ADR
An adverse drug reaction (ADR) is an injury caused by taking medication.
What causes some pharmaceutical ADR ?
Drug given after expiry date deterioration of therapeutic effect toxicity Compliance when sole responsibility of patient Change in formulation by manufacturer Imported drugs
How Pharmokinectics affected by ADR ?
Pharmacokinetic ADR 1
Overdose leads to high drug concentration at sites of action Variation in absorption from GI tract rate of gastric emptying GI disease Drugs affecting GI flora Decreased protein binding reduced production, increased loss two drugs competing for binding sites
Pharmacokinetic ADR 2
Abnormal metabolism genetic variation liver disease drug inhibition/potentiation of metabolism Abnormal excretion renal impairment NB drug competition for renal tubules Variation in diet affecting urinary pH
Pharmacodynamics ADR
Congenital causes Disease-related respiratory CVD neurological Drug interaction Indirect effects
Long(er) term CAUSES because of ADR
Rebound long term steroid therapy Prozac Delayed effects carcinogenesis depressed fertility teratogenesis immunosuppression gene toxicity hormonal
Non-predictable ADR
~20% of ADRs usually related to immune response type I, II, III, IV hypersensitivity reaction not dose dependent concomitant with therapy sometimes cause unknown chloramphenicol aplastic anaemia
Type I hypersensitivity
Type I hypersensitivity (or immediate hypersensitivity) is an allergic reaction provoked by re-exposure to a specific type of antigen referred to as an allergen.
Allergic response Involves IgE and mast cells mast cells release chemical mediators of inflammation when IgE on surface binds drug Chemical mediators of inflammation GI mucosa D & V bronchioles blood vessels
How is caused ?
Type I hypersensitivity reactions occur when allergens cross-link IgE molecules that are bound to receptors on mast cells and basophils and trigger degranulation.
Type II hypersensitivity
Type II hypersensitivity, in the Gell and Coombs classification of allergic reactions, is an antibody mediated process in which IgG and IgM antibodies are directed against antigens on cells (such as circulating red blood cells) or extracellular material (such as basement membrane).
A type II hypersensitivity is said to occur when damage to the host tissues is caused by cellular lysis induced by the direct binding of antibody to cell surface antigens
Type III hypersensitivity
Type III hypersensitivity occurs when there is accumulation of immune complexes (antigen-antibody complexes) that have not been adequately cleared by innate immune cells, giving rise to an inflammatory response and attraction of leukocyte
Antibody and complement response Drug/Ab/complement complex lodges in tissues giving rise to inflammation, tissue injury and dysfunction e.g Penicillamine nephrotic syndrome
Type IV hypersensitivity
Type IV hypersensitivity is a cell-mediated immune reaction. In other words, it does not involve the participation of antibodies but is due primarily to the interaction of T cells with antigens.
Cellular response
e.g. contact dermatitis in response to
topical application of drug
Drug-drug interactions
Type Pharmacodynamic Pharmacokinetic Result Synergism- the interaction or cooperation of two or more organizations, substances, or other agents to produce a combined effect greater than the sum of their separate effects.
antagonism- An interaction between two or more drugs that have opposite effects on the body. Drug antagonism may block or reduce the effectiveness of one or more of the drugs.
