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

1. DRUG REACTIONS (prof. MUDr. Jiřina Martínková,PhD., done 2002)

2. DRUG REACTIONS-overview • Reactions within the normal range • Unwanted reactions • Toxic reactions

3. DRUG REACTIONS-within the normal range Desired: glycemiamaintainedwithin the normal range by therapy with insulin in the diabetic patient Hypersensitive : hypoglycemiadue 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

4. DRUG REACTIONS - unwanted reactions-TYPE A • TYPE A - adverse reactions • are consequences of the drug´snormal pharmacological effect • -----predictable • dose-relatedwithlow 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 --- cardiacarrhythmia • thiazides --- hypokalemia • enalapril --- cough

5. 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: • isoniazidin„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.

6. 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.

7. DRUG REACTIONS - unwanted reactions-TYPE B A l l e r g y Type Ireactionsare due to the production of reaginic antibodies known to consist predominantly of class IgE. The antigen-antibody reactionon the surface of mast cellscauses degranulation and release of pharmacologically active substances. It occurs commonly with penicillin, streptomycin. Type IIreactions: 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

8. DRUG REACTIONS - unwanted reactions-TYPE B • A l l e r g y to be continued • Type IIIreactions (IMMUNE COMPLEX): • circulating immune complexes can produce several clinical allergic states including: • serum sickness • immune complex glomerulonephritis • amiodarone lung • Type IVreactions • are delayed hypersensitivity reactions, the classical example of which is contact dermatitis (e.g. to topical antibiotics such as penicillin).

9. 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

10. 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).

11. 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.

12. 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

13. 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 dataare analyzed and important information reported back to prescribing doctors