Adobe Systems Factors influencing drug effects. Influence of accompanying diseases on drugs effects. [USEMAP] Adobe Systems Copyright notice The presentation is copyrighted work created by employees of Masaryk university. Students are allowed to make copies for learning purposes only. Any unauthorised reproduction or distribution of the presentation or individual slidesis against the law. Adobe Systems Overview of factors ̶A. Factors related to drug: ̶Physical and chemical properties ̶Dose ̶Drug form ̶Combination of drugs ̶Food administered together with a drug ̶Repeated administration ̶ ̶ ̶B. Factors related to organism: ̶Age ̶Gender ̶Weight and body constitution ̶Circadian rhytms ̶Pathological state of organism ̶Genotype/fenotype ̶(Race group/ethnic group) ̶ Adobe Systems A. Factors related to drug ̶ I.Physical and chemical properties II.Drug dose III. Drug dosage form IV. Drug combination with other drugs V. Food administered together with a drug [USEMAP] Adobe Systems I. Physical and chemical properties of drug Influence on the transport trough membranes ̶Chemical configuration ̶Size and shape of the molecule ̶Solubility in water and fats ̶Acidobasic properties ̶ [USEMAP] Relationship of chemical structure to PK Isosorbide_dinitrate_svg ISDN is more lipophilic than ISMN ISDN may be administrated sublingually ISMN is almost not subject to the hepatic FPE Another example: atenolol x metoprolol 200px-Monosorbitrate_svg ISDN ISMN [USEMAP] Adobe Systems Stereoisomerism ̶Cis-trans isomerism: only the cis form of chlorprothixene is efficient ̶ ̶ ̶ [USEMAP] Adobe Systems II. Drug dose - dosage ̶In preclinical trials ̶ ̶In clinical trials phase I: MTD (maximal tolerated dose) ̶ [USEMAP] Adobe Systems Drug information sources ̶SPC = summarizing information about MP (Summary of Product Characteristics) part of the marketing authorisation of a medicinal product ̶AISLP - electronic drug information database for MP ̶ ̶SÚKL MP database (state authority for control of drugs) ̶Czech pharmacopoeia Adobe Systems III. Drug dosage form ̶definition: a substance or combination of substances presented as having therapeutic or preventive properties administered to set the medical diagnosis. [USEMAP] Adobe Systems III. Drug dosage forms ̶1st generation – conventional DDF ̶2nd generation with controlled release ̶with prolongated release (SR,XR...)* ̶transdermal therapeutic system (TTS) ̶gastrointestinal therapeutic system ̶3rd generation with targeted drug delivery *SR=sustained release, slow release LA=long acting, SA=slow acting, XR=extended release CR=continuous (controlled) release, retard atd. [USEMAP] Adobe Systems IV. Combinations of drugs The effect is S y n e r g i s m ̶Summation: both drugs have the same (similar) effect and, if we combine them, the final effect is a sum of all effects, which the drugs would have when administered in monotherapy one-sided : analgetics anodynes + narcotics two-sided : combination of cytostatics ̶Potentiation one-sided : Ca2+ + digoxin two-sided : digoxin + thiazide diuretics [USEMAP] Adobe Systems IV. Combinations of drugs The effect is A n t a g o n i s m ̶ pharmacological (histamine x cetirizine) ̶ physiological (histamine x salbutamol) ̶ chemical (heparin x protamin sulfate) (metals x dimerkaprol, EDTA) [USEMAP] Adobe Systems V. Food intake PD interactions - non-selective inhibitors of monoaminooxidase increase the bioavailability of tyramine from food (fermented food is risky, e.g. some cheese, red wine, smoked meat, bananas) -> risk of excessive wash out of catecholamines and hypertensive crisis - food with high content of vitamin K (e.g. broccoli) can decrease the effect of warfarin (vitamin K antagonist) PK interactions - more often- influence at the level of absorption, but also in metabolism and excretion [USEMAP] Adobe Systems V. Pharmacokinetic interactions with food Food can: ̶slow down drug absorption without changing its bioavailability (inappropriate in analgetics, hypnotics…) ̶decrease bioavailability ̶increase bioavailability [USEMAP] Adobe Systems B. Factors related to organism ̶Age ̶Gender ̶Weight and body constitution ̶Circadian rhythms ̶Pathological conditions of organism ̶Genotype/phenotype [USEMAP] Adobe Systems Age Administration of medicinal product (MP) ̶to children ̶to elderly people ̶ [USEMAP] Administration of MP to children approximate dose for children = body surface area (m2) x dose for adult/1,7 (m2) [USEMAP] Administration of MP to children A child is not a miniature of an adult particularities of PD particularities of PK [USEMAP] Particularities of PK of drugs in child Particularly on newborns (especially premature): relatively bigger volume of extracellular liquor lower binding on plasma proteins unfinished development of hematoencephalic barrier immaturity of enzymatic systems Immaturity of renal functions [USEMAP] Adobe Systems Administration of MP to old people ̶60 – 74 older person ̶75 – 89 elderly ̶> 90 longevity ̶ ̶physiological changes ̶multimorbidity ̶polypragmasia (administration of many drugs together, risk of drug interactions is increasing) ̶higher incidence and severity of adverse effects ̶ [USEMAP] Adobe Systems 90% Changes of PK of drugs in old age ̶absorption (passive diffusion of subacid substances thanks to hypoacidity, active transport is decreasing) ̶binding on plasma proteins ̶elimination: decrease of blood flow through kidneys and GFR, flow through liver and activity of redox enzymes ̶ => Prolongation of t1/2 (e.g. digoxin, aminoglykoside atb) [USEMAP] Adobe Systems Changes of PD in old age ̶Very variable ̶Tissue hypoxia ̶Dysfunction of regulatory mechanisms ̶Change of sensibility of target structures = hyperergic reaction [USEMAP] Adobe Systems Changes of PD in old age Examples: ̶ATB aminoglycosides: lower doses in case of lower GF ̶ ̶Antihypertensives: orthostatic hypotension, psychical alternations (confusion) ̶ ̶Anticoagulants: bleeding from GIT (decreased absorption of vitamin K and decreased synthesis of prothrombin) ̶ ̶NSAID: in 25% hematemesis ̶ ̶Anticholinergic drugs: higher toxicity, depression, confusion [USEMAP] Adobe Systems Gender ̶Women are in general more sensitive to effects of some drugs, e.g. because of lower weight, but also of lower CL ̶ ̶Specific periods are: ̶menstruation ̶gravidity ̶lactation ̶menopause ̶ ̶ [USEMAP] Adobe Systems Pregnancy ̶slowed stomach and intestinal motility ̶ ̶increased volume of plasma, body water can be raised up to 8 litres ̶ ̶hypoalbuminemia, occupancy rate of plasma proteins by hormones ̶ ̶increased blood flow through kidneys and increase of GFR ̶ [USEMAP] Adobe Systems Weight and body constitution ̶In many cases drugs are dosed in consideration to the weight of the patient (it’s recommended to use dosing per 1kg of body weight, respecting the patient’s age) ̶ [USEMAP] Adobe Systems Pathological state of organism ̶Influence of lesion/renal dysfunction, liver and thyroid gland on pharmacokinetics ̶Influence of pathological state on pharmacodynamics [USEMAP] Adobe Systems Hypofunction of kidneys ̶The most common reason for a drug dose adjustment ̶Customisations of dosage in accordance to the tables – GFR is a clue ̶For the majority of drugs, the customisation of the dosage means prolongation of intervals (AMG, vancomycin) ̶In drugs with very long t1/2 we keep the same interval, but administer a lower dose (digoxin) [USEMAP] Adobe Systems Influence of liver diseases ̶No reliable quantitative criteria is available for measuring impaired liver elimination capacity (analogy CLcr in kidney dysfunctions) ̶ ̶Liver function tests (aminotransferases, albumin, blood coagulation factors) are not a good clue for the dosage of drugs ̶ [USEMAP] Adobe Systems In persons with liver diseases ̶Prefer drugs eliminated mostly by kidneys, if possible (or those whose kinetics is not disturbed by liver hypofunction) e.g. atenolol ̶ ̶Prefer drugs acting directly – without activation of biotransformations in liver (lisinopril x enalapril) ̶ ̶Think about the possibility of increased biol. availability when drugs with high first-pass effect are administered orally (e.g. metoprolol) [USEMAP] Adobe Systems Genetic factors ̶The drug response varies among individuals qualitatively and quantitatively ̶ interindividual variability – polymorphism ̶ ̶Genetic factors influence PD and also PK [USEMAP] Adobe Systems Genetic factors ̶Genetic polymorphism = existence of several (at least two) alleles for a concrete gene, the least frequent one of which has the population frequency at least 1% ̶ ̶Pharmacogenetics focused on studies of genetically conditioned variability in response of the organism to a drug (Pharmacogenomics investigates the relationship of drug effect at the level of the whole genome) [USEMAP]