VARIATION IN DRUG RESONSIVNESS Decrease in drug effects

VARIATION IN DRUG RESONSIVNESS Decrease in drug effects. Development of side effects Between different individuals Within the same individual

ilos By the end of this lecture you will be able to : ØDistinguish difference between tolerance and desensitization ( tachyphylaxis ) and reasons for their development Ø Recognize patterns of adverse drug reactions (ADR) TOLERANCE / DESENSITIZATION & ADVERSE DRUG REACTIONS By Prof. Omnia Nayel Assoc. Prof. Osama Yousif

Phenomenon of variation in drug response, where by there is a gradual diminution of the response to the drug when given continuously or repeatedly TOLERANCE and DESENSITIZATION

DIMINUTION OF A RESPONSE Rapid, in the course of few minutes TACHYPHYLAXIS / DESENSITIZATION Gradual in the course of few days to weeks TOLERANCE These SHOULD BE DISTINGUISHED FROM Loss of effectiveness of antimicrobial agent Resistance

REASONS FOR DEVELOPMENT OF TOLERANCE PRE RECEPTOR EVENTS AT RECEPTORS ↓ drug availability at the relevant receptors due to pharmaco- kinetic variables Drug becomes: > metabolized or excreted < absorbed altered distribution to tissues eg. Barbiturates metabolism of Contraceptive pills = it availability POST RECEPTOR EVENTS Nullification of drug response by a physiological adaptative homeostatic Antihypertensive effects of response ACE Is become nullified by activation of renin angiotensin system by NSAIDs LOSS OF THERAPEUTIC EFFICACY Refractoriness

REASONS FOR DEVELOPMENT OF TOLERANCE PRE RECEPTOR EVENTS EXHUSTION OF MEDIATORS Depletion of mediator stores by amphetamine EVENTS AT RECEPTORS BINDING ALTERATI ON Phosphorylation of R i. e. ßadrenoceptors → ↓ activation of AC to related ionic channel [functional defect] DOWN REGULATION BINDING ALTERATION POST RECEPTOR EVENTS DOWN REGULATION ↓ number of receptors. Isoprenaline activation to b receptors →↑ R recycling by endocytosis [structural defect]

DOWN REGULATION

ADVERSE DRUG REACTIONS [ADR] Harmful or seriously unpleasant effects occurring at doses intended for therapeutic effects.

TYPES OF ADR Type A Type C Augmented Continuous PREDICTABL E Type E End-of. Use Occurs by sudden Occurs during chronic drug stop- page of chronic Occurs consequent administration chronic drug use due to but in excess of drug. Osteoporosis corticosteroid intake existing. . adaptive primary Withdrawal changes pharmacological syndrome effect. Hemorrhage Warfarin Type DMorphine Of quantitative nature Type B Bizzar UNPREDICTAB LE Delayed Occurs after long period of time even after drug stoppage -TERATOGENICITY Retinoids Occurs different [heterogenous / idiosyncrotic ] to known drug - CARCINOGENICIT pharmacological effect. Usually due to patient’s genetic defect or immunological Thrombocytopenia Quinidine

Type A Augmentation Type B Idiosyncrotic Pharmacological Yes No predictability Nature Dose dependent Onset of symptoms Quantitative [ Qualitative [ extension of immune or genetic pharmacology effect base] ] Yes (dose response No (dose response relationship present) relationship absent) Usually Rapid Usually delayed Incidence and morbidity High Low Mortality Low High Dose adjustment or Substitute by > selective + Antagonize Stop drug + Symptomatic treatment Treatment

Examples of TYPE A & B ADR Drug Type A Type B Chlorpromazine Sedation Cholestatic jaundice Naproxen GIT haemorrhage Agranulocytosis Phenytoin Ataxia Hepatitis, lymphadenopathy Thiazides Hypokalaemia Thrombocytopenia Quinine Warfarin Tinnitus Bleeding Thrombocytopenia Genetics Variation / defect Immunological Predisposition Breast necrosis

TYPE B Immunological Predisposition The drug or its bi-product [protein macromolecules or haptens] react as antigens and provoke immune Ig. E response that results in damage to the tissue Hypersensitivity Reaction 1 st exposure Sensitization to a drug Ig. G T killer cells Repeated exposure s HYPERSENSITIVITY REACTION

TYPE B 1 st exposure to a drug TYPE I Anaphylaxsi s Release of mediators from mast cells or blood basophils If due to immunological response Sensitization TYPE II Cytotoxi c Repeated exposures TYPE III Immune complex HYPERSENSITIVITY REACTION TYPE IV Cell mediated Antibody. Deposition of Interaction directed cell- soluble antigen– release mediated antibodycytokines that lysis complement attracts complexes in inflammatory small blood cell infiltrate vessels Urticaria Haemolytic Serum sickness Contact rhinitis, anaemia (fever arthritis dermatitis by bronchial thrombocytop enlarged lymph local asthma enia by anaesthetics nodes, urticaria) by Penicillin, Quinidine by Sulphonamides, creams

G G O O D D LL U U C C TOLERANCE / DESENSITIZATION & ADVERSE DRUG REACTIONS K K