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DRUG REACTIONS
(prof. MUDr. Jiřina Martínková,PhD., done 2002)
DRUG REACTIONS- overview
• Reactions within the normal range
• Unwanted reactions
• Toxic reactions
DRUG REACTIONS- within the normal range
Desired: glycemia maintained within the normal range by
therapy with insulin in the diabetic patient
Hypersensitive :
hypoglycemia due to the usual dose of insulin in the diabetic
patient after a hard exercise
Hyposensitive:
hyperglycemia in the diabetic patient after a sweet meal even if
the usual dose of insulin was administered
DRUG REACTIONS - unwanted reactions-TYPE A
TYPE A - adverse reactions
• are consequences of the drug´s normal pharmacological effect
-----predictable
• dose-related with low mortalityare usually due to incorrect dosage
(too much or for too long)
• or disordered pharmacokinetics (usually a failure of drug
elimination)
• more frequent (80%), most severe in neonates or the elderly, in
women, patients with hepatic or renal disease. They occur most
commonly early in therapy (1-10 days)
example:
warfarin ---- bleeding
digoxin --- cardiac arrhythmia
thiazides --- hypokalemia
enalapril --- cough
DRUG REACTIONS - unwanted reactions-TYPE B
TYPE B - bad reactions
• are not predictable
• not dose-related and have considerable mortality
• they may have a genetic basis - idiosyncrasy
a immunological basis - allergic reactions
• occur infrequently (1:1000-1:10 000)
idiosyncrasy (see also pharmacogenetics)
is due to genetic polymorphism in pharmacokinetics or
pharmacodynamics:
isoniazid in „slow acetylators“ - (individuals deficient in acetylation
capacity).
„Slow acetylators“ may have prolonged or enhanced responses to
normal doses of isoniazid. They constitute about 50% of white and
African-American persons in the USA. The slow acetylation trait is
inherited as an autosomal recessive gene.
DRUG REACTIONS - unwanted reactions-TYPE B
Allergy
implies previous exposure to the drugs or to some very
closely related substance.
Most drugs are of low molecular weight (less than 1000)
and thus are not antigenic. They can, however, combine
with substances of high molecular weight, usually proteins,
acting as haptens
so that the conjugate thus formed is antigenic.
DRUG REACTIONS - unwanted reactions-TYPE B
Allergy
Type I reactions are due to the production of reaginic antibodies
known to consist predominantly of class IgE. The antigen-antibody
reaction on the surface of mast cells causes degranulation and release
of pharmacologically active substances. It occurs commonly with
penicillin, streptomycin.
Type II reactions: are due to antibodies of class IgG and IgM which
in contact with antibodies on the surface of cells are able to fix
complement, causing cell lysis,
for example :
thrombocytopenia after chinidine, thiazides, and chloramphenicol
agranulocytosis can be produced by: antithyroid drugs, clozapine,
and cytotoxic agents
DRUG REACTIONS - unwanted reactions-TYPE B
Allergy
to be continued
Type III reactions (IMMUNE COMPLEX):
circulating immune complexes can produce several clinical allergic
states including:
• serum sickness
• immune complex glomerulonephritis
• amiodarone lung
Type IV reactions
are delayed hypersensitivity reactions, the classical example of which
is contact dermatitis (e.g. to topical antibiotics such as penicillin).
DRUG REACTIONS - unwanted reactions TYPE C,D,E
TYPE C - continuous reactions
are due to long-term use „analgesic nephropathy“
TYPE D - delayed reactions
carcinogenesis or teratogenesis
TYPE E - end uf use reactions
withdrawal symptoms following discontinuation of
treatment with benzodiazepines, or beta-adrenoceptor
antagonists
DRUG REACTIONS - toxic reactions
are usually due to apoptosis and/or necrosis of cells.
Example: chronic cardiotoxicity of anthracyclines -doxorubicine
• there is strong evidence that the development of anthracyclineinduced congestive heart failure is mainly due to the progressive
formation of cardiotoxic free oxygen radicals, particularly
superoxide anion and hydroxyl radicals.
Very probably these hydroxyl radicals are primarily responsible for
severe DNA damage and lipid peroxidation within cardiac
tissue.
The high sensitivity of the heart tissue to such oxygen radicals can be
explained by its constitutive low amount of radical scavenging
enzymes, particularly superoxide dismutase and catalase. Highly
reactive radicals are formed particularly in the presence of ferric
ions (myoglobin, hemoglobin).
CARDIOTOXICITY OF CYTOTOXIC DRUGS
e(+2H+)
e-
O
OH
O
O
(-)
O
OH
Reactive superoxide radicals appear to play an important role in
cytostatic induced cardiotoxicity. In particular, quinone-containing
structures are able to release such reactive oxygen species via redox
cycling.
DRUG REACTIONS - toxic reactions
• the clinical symptoms of this cardiac insufficiency include:
tachycardia
arrhythmia
difficult breathing
unproductive cough
edemas, cardiomegaly
Its incidence can be strongly correlated with the cumulative total
dosage. It the total dose < 550 mg/m2, the incidence of congestive
cardiomyopathy in adult patients is supposed to be less than 1%.
Important risk factors: previous mediastinal irradiation,
advanced or younger age, female sex, preexisting heart disease,
hypertension, bolus injection rather than a prolonged infusion time
DRUG REACTIONS -monitoring
Monitoring/surveillance (pharmacovigilance)
continued surveillance is mandatory after a new drug has been
marked since it is inevitable that the testing of medicines during
drug development cannot identify uncommon unwanted effects.
For instance:
Yellow card scheme and postmarketing surveillance:
in the UK doctors were asked to report any unwanted effects on
prepaid yellow postcards.
Intensive monitoring:
based on programs usually used in hospital.
Patient questionnaires : self-administered questionnaires have
been used for outpatients attending hypertension and diabetic
clinics and have detected previously unsuspected unwanted events.
Feedback data are analyzed and important
information reported back to prescribing doctors