Bez nadpisu

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DRUG REACTIONS (prof.
MUDr. Jirina Martínková,PhD., done 2002)
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DRUG REACTIONS- overview

• Reactions within the normal range
• Unwanted reactions
• Toxic reactions

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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 hyperglycemi
a in the diabetic patient after a sweet meal even
if the usual dose of insulin was administered
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DRUG REACTIONS - unwanted reactions-TYPE A

• TYPE A - adverse reactions
• are consequences of the drugs 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

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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 (11000-110 000)
• 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.

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DRUG REACTIONS - unwanted reactions-TYPE B
A l l e r g y 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.
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DRUG REACTIONS - unwanted reactions-TYPE B
A l l e r g y
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
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DRUG REACTIONS - unwanted reactions-TYPE B

• A l l e r g y 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).

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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
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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
  anthracycline-induced 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).

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CARDIOTOXICITY OF CYTOTOXIC DRUGS
OH
O
O
e-
e-
(2H)
O
OH
O
(-)
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.
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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 lt
  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

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DRUG REACTIONS -monitoring
Monitoring/surveillance (pharmacovigilance) contin
ued 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