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

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

3. DRUG REACTIONS- within the normal range DRUG REACTIONS- within the normal range Desired: 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 exerciseHyposensitive: 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 DRUG REACTIONS - unwanted reactions-TYPE A TYPE A - adverse reactions normal pharmacological effect are consequences of the drug´s normal pharmacological effect predictable -----predictable dose-relatedlow mortalityincorrect dosage dose-related with low mortalityare usually due to incorrect dosage (too much or for too long) disordered pharmacokinetics or disordered pharmacokinetics (usually a failure of drug elimination) frequent 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

5. DRUG REACTIONS - unwanted reactions-TYPE B DRUG REACTIONS - unwanted reactions-TYPE B TYPE B - bad reactions not predictable are not predictable not dose-related considerable mortality not dose-related and have considerable mortality - idiosyncrasy they may have a genetic basis - idiosyncrasy -allergic reactions a immunological basis - allergic reactions infrequently occur 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.

6. DRUG REACTIONS - unwanted reactions-TYPE B A l l e r g y previous exposure implies previous exposure to the drugs or to some very closely related substance. are not antigenic 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 antigenic. so that the conjugate thus formed is antigenic.

7. DRUG REACTIONS - unwanted reactions-TYPE B Type Ireactions 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 IIreactions: IgG IgM 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 A l l e r g y

8. DRUG REACTIONS - unwanted reactions-TYPE B DRUG REACTIONS - unwanted reactions-TYPE B A l l e r g y to be continued A l l e r g y to be continued Type IIIreactions (IMMUNE COMPLEX): Type III reactions (IMMUNE COMPLEX): circulating immune complexes can produce several clinical allergic states including: serum sickness immune complex glomerulonephritis amiodarone lung Type IVreactions Type IV reactions 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 DRUG REACTIONS - unwanted reactions TYPE C,D,E TYPE C - continuous reactions long-term use 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 DRUG REACTIONS - toxic reactions are usually due to apoptosis and/or necrosis of cells. chronic cardiotoxicity 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. O O O O OH (-) e-e- e-e- (+2H + ) CARDIOTOXICITY OF CYTOTOXIC DRUGS 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 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/m 2, 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 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