DRUG REACTIONSDRUG REACTIONS

(prof. MUDr. Jiřina Martínková,PhD., done 2002)

DRUG REACTIONS-DRUG REACTIONS- overviewoverview

• Reactions within the normal rangeReactions within the normal range

• Unwanted reactionsUnwanted reactions

• Toxic reactionsToxic reactions

DRUG REACTIONS-DRUG REACTIONS- within the normal rangewithin the normal range

Desired: Desired: glycemia maintained within the normal range by therapy with insulin in the diabetic patient

HypersensitiveHypersensitive : :

hypoglycemia due to the usual dose of insulin in the diabetic patient after a hard exercise

Hyposensitive:Hyposensitive:hyperglycemia in the diabetic patient after a sweet meal even if the usual dose of insulin was administered

DRUG REACTIONS - DRUG REACTIONS - unwanted reactions-unwanted reactions-TYPE ATYPE A

TYPE A - TYPE A - adverse reactions adverse reactions • are consequences of the drug´s normal pharmacological effectnormal pharmacological effect -----predictablepredictable • dose-relateddose-related with low mortalitylow mortalityare usually due to incorrect dosageincorrect dosage (too much or for too long)• or disordered pharmacokineticsdisordered pharmacokinetics (usually a failure of drug elimination)• more frequentfrequent (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 - DRUG REACTIONS - unwanted reactions-unwanted reactions-TYPE BTYPE B

TYPE B - TYPE B - bad reactionsbad reactions• are not predictablenot predictable• not dose-related not dose-related and have considerable mortalityconsiderable mortality• they may have a genetic basis - idiosyncrasy- idiosyncrasy a immunological basis -- allergic reactionsallergic reactions• occur infrequently infrequently (1:1000-1:10 000)

idiosyncrasy 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 - DRUG REACTIONS - unwanted reactions-unwanted reactions-TYPE BTYPE B

A l l e r g yA l l e r g y implies previous exposureprevious 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 antigenicare 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.antigenic.

DRUG REACTIONS - DRUG REACTIONS - unwanted reactions-unwanted reactions-TYPE BTYPE B

Type IType I reactionsreactions are due to the production of reaginic antibodiesknown 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 IIType II reactions: reactions: are due to antibodies of class IgG IgG and IgM IgM whichin 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

A l l e r g yA l l e r g y

DRUG REACTIONS - DRUG REACTIONS - unwanted reactions-unwanted reactions-TYPE BTYPE B

A l l e r g y A l l e r g y to be continuedto be continued

Type IIIType III reactions (IMMUNE COMPLEX):reactions (IMMUNE COMPLEX):circulating immune complexes can produce several clinical allergic states including: • serum sickness• immune complex glomerulonephritis• amiodarone lung

Type IVType IV reactionsreactionsare delayed hypersensitivity reactions, the classical example of which is contact dermatitis (e.g. to topical antibiotics such as penicillin).

DRUG REACTIONS - DRUG REACTIONS - unwanted reactions unwanted reactions TYPE C,D,ETYPE C,D,E

TYPE C - TYPE C - continuous reactionscontinuous reactionsare due to long-term uselong-term use „analgesic nephropathy“

TYPE D - TYPE D - delayed reactionsdelayed reactionscarcinogenesis or teratogenesis

TYPE E - TYPE E - end uf use reactionsend uf use reactionswithdrawal symptoms following discontinuation of treatment with benzodiazepines, or beta-adrenoceptor antagonists

DRUG REACTIONS - toxic reactionsDRUG REACTIONS - toxic reactions

are usually due to apoptosis and/or necrosis of cells.

Example: chronic cardiotoxicitychronic 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).

O

O

O

O

OH

OH(-)

e- e-

(+2H+)

CARDIOTOXICITY OF CYTOTOXIC DRUGS

Reactive superoxide radicals appear to play an important role in cytostatic induced cardiotoxicity. In particular, quinone-containingstructures are able to release such reactive oxygen species via redoxcycling.

DRUG REACTIONS - toxic reactionsDRUG 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 -DRUG REACTIONS -monitoringmonitoring

Monitoring/surveillance (pharmacovigilance)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