Factors Influencing Drug Effects (Pharmacology Lecture 2023 PDF)

FACTORS INFLUENCING DRUF EFFECT Pharmacology Lecture, 2023  Overview of factors A. Factors related to drug: ̶ Physical and chemical properties ̶ Dose ̶ Drug form ̶ Combination of drugs ̶ Food administered together with a drug (drug-food interactions) B. Factors related to orga...

FACTORS INFLUENCING DRUF EFFECT Pharmacology Lecture, 2023  Overview of factors A. Factors related to drug: ̶ Physical and chemical properties ̶ Dose ̶ Drug form ̶ Combination of drugs ̶ Food administered together with a drug (drug-food interactions) B. Factors related to organism: ̶ Age ̶ Gender ̶ Weight and body constitution ̶ Circadian rhytms ̶ Pathological state of organism ̶ Genotype/fenotype A. Factors related to the drug 1. Physical and chemical properties 2. Drug dose 3. Drug dosage form 4. Drug combination with other drugs 5. Food administered together with a drug 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 …relationship of chemical structure ISMN ISDN ISDN is more lipophilic than ISMN ISDN may be administrated sublingually ISMN is almost not subject to the hepatic FPE Stereoisomerism ̶ Cis-trans isomerism: only the cis form of chlorprothixene is efficient II. Drug dose - dosis ̶ In preclinical trials ̶ In clinical trials phase I: MTD (maximal tolerated dose) ̶ SPC = summarizing information about MP (Summary of Product Characteristics) part of the marketing authorisation of a medicinal product ̶ Czech pharmacopoeia III. Drug dosage form ̶ definition: a substance or combination of substances presented as having therapeutic or preventive properties administered to set the medical diagnosis. 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. IV. Combinations of drugs The effect is Synergism ̶ 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 IV. Combinations of drugs The effect is Antagonism ̶ pharmacological (ACH + atropin) ̶ physiological (ACH + adrenalin) ̶ chemical (heparin + protamin sulfate) 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 V. Pharmacokinetic drug- food interactions Food can: ̶ slow down drug absorption without changing its bioavailability (inappropriate in analgetics, hypnotics…) ̶ decrease bioavailability ̶ increase bioavailability B. Factors related to the host organism ̶ Age ̶ Gender ̶ Wight / body constitution ̶ Pathological comorbitites ̶ Genotype / phenotype – pharmacogenetics/genomics I. Age Administration of medicinal product (MP) ̶ to children ̶ to elderly people Administration of MP to children approximate dose for children = body surface area (m2) x dose for adult 1,7 (m2) 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 Administration of MP to elderly 60 – 74 older person 75 – 89 elderly People aged 90 or more…. ̶ physiological changes ̶ multimorbidity ̶ polypragmasia (administration of many drugs together, risk of drug interactions is increasing) ̶ higher incidence and severity of adverse effects Changes of PK of drugs in elderly ̶ 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, aminoglycoside atb) Changes of PD in elderly ̶ Dysfunction of regulatory mechanisms ̶ Change of sensibility of target structures = hyperergic reaction ̶ Tissue hypoxia Changes of PD in elderly Examples: ̶ ATB aminoglycosides: lower doses in case of lower GF (correction according to CL CR) ̶ 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 II. Gender ̶ Women are in general more sensitive to effects of some drugs, e.g. because of lower weight, but also of lower CL (olanzapine) ̶ Specific periods are: ̶ menstruation ̶ gravidity ̶ lactation ̶ menopause Pregnancy ̶ slowed stomach and intestinal motility ̶ increased volume of plasma, body water can be raised up to 8 litres more ̶ hypoalbuminemia, occupancy rate of plasma proteins by hormones ̶ increased blood flow through kidneys and increase of GFR III. 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) ̶ Dosage mode: dose per time period ̶ Dose: mg/kg, mg/kg/age, mg/m2 IV. Comorbities ̶ Influence of lesion/renal dysfunction, liver and thyroid gland on pharmacokinetics ̶ Influence of pathological state on pharmacodynamics 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) Influence of liver diseases ̶ No reliable quantitative criteria is available for measuring impaired liver elimination capacity (analogy CLcr in kidney dysfunctions) empirical attitude ̶ Liver function tests (aminotransferases, albumin, blood coagulation factors) are not a good clue for the dosage of drugs 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) V. Genetic factors ̶ The drug response varies among individuals qualitatively and quantitatively interindividual variability – genetic polymorphism ̶ Genetic factors influence PD and also PK  DEFINITION PHARMACOGENETICS and PHARMACOGENOMICS are Both disciplines focus on pharmacology issues from the view of genetics or genomics respectivelly PHARMACOGENETICS PHARMACOGENOMICS Study of particular genes involved Study of the whole genome in pharmacological processes affected by a drug  DEFINITION PHARMACOGENETICS focuses on genetic variability of patients. An item of interest is a studying of variant gene allels = gene polymorphism and their impact on pharmacological processes. It´s a tool for a personalised medicine. PHARMACOGENOMICS focuses on variability of potential (new) drugs and compare their gene expression profile. An item of interest is to choose the best drugs without serious adverse effects. It´s a tool for selection for new efficient and safe drug.  Molecular-biological basis of GENE/GENETIC POLYMORPHISM Almost each of human gene exists in several allele variants, that are created by MUTATION and passed (handed down) from parents to children. ALLELE VARIANT of gene with the frequency > 1%  COMMON GENE POLYMORPHISM ALLELE VARIANT of gene with the frequency < 1%  RARE GENE MUTATION  OCCURENCE of allele gene variants differ … AMONG AMONG INDIVIDUALS POPULATIONS Persons differ in the variant Populations differ in the alleles occurrence – variant alleles occurrence INDIVIDUAL DIVERSITY – ETHNIC DIVERSITY It is a big complication for pharmacogenetic clinical studies  Example of ethnic diversity Relative allele frequency of CYP2D6 variant alel (v %) Schimizu et al. Drug Metab. Pharmacokinet. 18 (1): 48-70, 2003. Ingelman-Sundberg. Pharmacogenomics J. 5(1): 6-13, 2005.  Example of ethnic diversity And higher aktivity of enzymes? The causes of ultrarapid metabolism lie in the presence duplicated to multiplied CYP2D6 genes. (2,3,4,5, up to 13) Frequency of occurence : Ethiopia………….... 21% Saudi Arabia ……... 29% Central Europe …… 4%  SUMMARY Different genetic equipment is responsible for individual differences in pharmacokinetics/pharmacodynamics: ▪ Efficacy/inefficacy of administered drugs ▪ Occurrence/non-occurrence of serious adverse effects Common Gene (Genetic) polymorphism A lot of genes are polymorphic, but NOT each of gene polymorphism has an apparent impact in clinical practise  Genes affected PHARMACOKINETICS ABSORPTION, DISTRIBUTION and EXCRETION of DRUGS Genes coding membrane transporters ▪ Anionic, cationic and peptide transporters e.g. OAT1, 2, 3 up to 3, OATP8, OCTN2, PepT1, OATP1B1 (SLCO1B1) ▪ Protein transporters with multidrug resistance MRP1 - MRP6 ▪ P-glycoprotein transporters with multidrug resistance MDR1 (ABCB1 gene), MDR3, SPGP... CLINICAL IMPACT of variant alleles: ▪ creation of modified non-functional transporters ▪ Insufficient amount of transport proteins ▪ Alteration of the binding affinity of transporters to substrat Genes affected PHARMACOKINETICS DRUG METABOLISM Genes coding biotransformation enzymes Phase I of biotransformation ▪ Enzymes of cytochrome P 450: CYP2D6, CYP2C9, CYP2C19, CYP3A4 ▪ MTHFR (methylene tetrahydrofolate reductase) ▪ DPD (dihydropyrimidine dehydrogenase) (5-FU) Phase II of biotransformation ▪ TPMT (thiopurine S-methyl transferase) ▪ NAT1, NAT2 (N-acetyl transferase) ▪ UGT1A1 (uridine diphosphate glucuronosyl transferase 1A1)  CLINICAL IMPACT of gene polymorphisms: ▪ Decreased / increased enzyme activity ▪ Binding afinity to certain substrates can be changed DECREASE enzyme activity INCREASE enzyme activity Slowdown of the metabolism → Acceleration of the metabolism → → drug accumulation in organism → → rapid elimination of the drug from → increase adverse effects organism → up to intoxication → insufficient pharmacological effect BEWARE !! The PRODRUG needs enzyme for creation of active metabolite. Enzyme with decreased activity  less pharmacological effect (efficacy decreased)  CLINICAL USE OF PHARMACOGENETICS 1. PERSONALISED MEDICINE „Personalised medicine, precision medicine“ = a multidisciplinary branch of science dealing with the THE RIGHT DIAGNOSIS optimization of therapeutic and THE RIGHT TREATMENT diagnostic procedures for a FOR THE RIGHT PATIENT particular patient using modern AT THE RIGHT TIME methods. 2. INDIVIDUALISATION OF PHARMACOTHERAPY = pharmacotherapy "fitted" for a particular patient. ONE DRUG IS RARELY EFFECTIVE AND SAFE FOR ALL PATIENTS PHARMACOGENETICS could help us to choose the best one for an individual person Selection of an appropriate drug or combination at a ▪ maximum efficiency ▪ minimum adverse effects ▪ reduction of the risk of drug interactions ▪ correction of the dosage adjustment…. 42 International „organisations“ dealing with incorporation pharmacogenetic knowledge to the clinical practise: Pharmacogenetic and Pharmacogenomic Knowledge Base (PharmGKB) GOAL: to establish the definitive source of information about the interaction of genetic variability and drug response – www.pharmgkb.org Clinical Pharmacogenetics Implementation Consortium (CPIC) GOAL: to create freely-available, peer-reviewed DRUG-DOSING GUIDELINES FOR CLINICIANS who have access to pre-emptive genetic testing results CLINOMICS is the study of genomics data along with its associated clinical data ENZYMES of CYTOCHROME P 450 They affect pharmacokinetic processes (drug metabolism) CYP2D6 CYP2D6 is responsible for the metabolism and elimination of almost 25% of clinically used drugs Gene polymorphisms have more clinical impact, in case the metabolism hasn´t alternative way (used by other isoenzymes) In CYP2D6 gene were identified over 100 polymorphisms, that caused total enzyme deficiency or decreased enzyme activity or increased activity. CYP2D6 Classification according to CYP2D6 PHENOTYPE Rapid (extensive) metabolisers Poor metabolisers: Homozygotes for variant alleles that decrease enzyme activity + carriers of Poor Ultra-rapid metabolisers variant alleles metaboliser Ultra-rapid s (one or two) metabolisers causing enzyme Metabolic rate debrisoquin: 4-hydroxydebrisoquin Carriers of inactivation duplicated or Extensive (rapid) metabolisers multiplicated Majority population, carriers of standard (wild) alleles + genes heterozygotes for variant alleles that decrease enzyme activity Clinical consequences of the presence of variant alleles CYP2D6 7% of people has low activity approx. 1% high activity of enzyme CYP2D6 Clinical consequencies of increased activity of CYP2D6 A higher percentage of codein metabolisation to morphine  intoxication risk. Risk of relapse in patients with breast cancer taking tamoxifen due to rapid metabolization of this drug CYP2D6 gene polymorphisms can have the impact on seriousness of poisons by amphetamines, opioid analgesics and antidepressants (Haufroid V, Hantson P. 2015) CYP2C9 This isoenzyme involves in the metabolism of warfarin (S-isoform)*, phenytoin, NSAIDs, losartan, carbamazepine, diclofenac… Wild allele: Variant allele: CYP2C9*1 *2 - reduction of the enzyme affinity for the substrate Occurrence: 8-13 % Caucasians *3 - substrate specificity to the enzyme is changed Occurrence: 6-9 % Caucasians S-warfarin is metabolised via CYP2C9 R-warfarin is metabolised via CYP3A4 a CYP1A2 R-warfarin has only 30% activity of the S isomer, but there is more of it in plasma  CYP2C9 Initial dose of WARFARIN according to CYP2C9 mg 5 4,6 and VKORC1 genotypes. It´s recommended by 4.5 CPIC and adjusted on the basis of FDA materials 4 3,7 3.5 3,1 3 2.5 2,2 2,1 2 1.5 1,1 1 0.5 0 The ranges are derived from many published *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 clinical studies Pacients with polymorphisms in CYP2C9 gene need lower doses of WARFARIN for the keeping the same INR 2-3. This doses can be lower 5–6 times.  Pharmacogenetics of warfarin VKORC1 gene encodes „the vitamin K epoxide reductase VKORC1 enzyme“ – subunit C1 (= VKORC1) = the target of warfarin. Patients who carry the polymorphism -1639G>A (in the promoter region) are more sensitive to warfarin and require lower doses. Homozygous carriers of variant alleles AA have more than 10 times higher risk of warfarin overdosing. Standard (wild) allele: -1639 GG Variant allele: -1639 GA; -1639 AA 20 % of populations belongs to high risk group – carriers of AA alleles or GA alleles of VKORC1 gene and at the same time at carriers least one variant allele (*2 or *3) in CYP2C9 gene This effect is potentiated by the presence of variant alleles in CYP2C9 gene or by the drug interactions Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends that this dosing table should only be used when electronic access is not possible. The pharmacogenetic algorithms available on http://www.warfarindosing.org should be used to predict the optimal warfarin dose, because also non-genetic factors are important.  CYP2C19 is involved in metabolism of omeprazol (minority also CYP3A4) citalopram (from 60 %), diazepam…also it takes a part in conversion prodrug clopidogrel to its active metabolite Wild allele: Variant alles: CYP2C19*1 CYP2C19*2 - inactive enzyme (aberant splicing) rs4244285 Occurrence: Caucasians 15 % Asians 12-23% CYP2C19*3 - inactive enzyme (* stop codon) Approximately 3% Europeans rs4986893 Occurrence: Caucasians 0,4 % Asians 1% have complete deficit of CYP2C19 = carriers of both CYP2C19*17 ultra-rapid metabolism variant alleles (*2 *2) rs12248560 Occurrence: Caucasians up to 21 % Asians 2.7 %  N-acetyl transferase 2 (NAT2) More than 22 variant alleles were found in NAT2 gene. ▪ Carriers of *4 a *12C alleles are rapid metabolisers ▪ Carriers of other allels are poor metabolisers Clinical consequences of decreased NAT2 activity  risk of adverse effects increases isoniazid  peripheral neuropathy sulfonamides  hypersensitive reaction hydralazines  Lupus like syndrome amonafide (prodrug - topoisomerase II inhibitor)  rapid acetylators are in risk of strong leukopenia DPD (dihydropyrimidine-dehydrogenase)- gen DPYD Major elimination route for fluoropyrimidine chemotherapeutics e.g. 5-FU, capecitabine, tegafur. DPD enzyme is relevant for efficacy and toxicity as well. Wild allele: *1 Variant alleles: *2A - Splicing defect  short protein  inactive enzym *13 - SNP  decreased enzyme activity The most commonly observed variant allele is 2A Occurrence: about 2 % in Caucasian population (for all variant alleles)  UGT1A1 (uridindifosfate glucuronosyltransferase) Enzyme detoxifies different endogenous substances including bilirubin and takes a part in detoxification of IRINOTECAN Polymorphism was found in gene promoter  decrease gene expression  DECREASE CATALYTIC ACTIVITY OF UGT1A1 FAMILIAL HYPERBILIRUBINEMIA (approx. 12% population are PMs) Gilbert syndrome (mutation in „TATA box“ - aff. transcription)  HIGH RISK OF TOXICITY (myelotoxicity, diarrhea) in patients taking IRINOTECAN IRINOTECAN is used in cancer therapy e.g. colorectal carcinoma  TPMT (thiopurin S-methyl transferáza) TPMT is important for metabolizing thiopurine drugs (azathioprine, merkaptopurine (6-MP), thioguanines). Wild allele: They are used to treat cancer TPMT*1 (acute lymphoblastic leukemia) or autoimmune inflammation Variant alleles are SNP (Crohn Disease). TPMT*2 G238C TPMT*3B G460A TPMT*3C A719G TPMT*3A combination G460A + A719G TPMT Presence of variant alleles causes in decreased TPMT enzyme activity Dosage of azathioprine Adjusting of dosage according to Severe, life- threatening toxicities of genotype in TPMT gene you can see thiopurine drugs in CPIC guidelines Wild allele *1 TPMT: Toxicity for BLOOD STEM CELLS Therapeutic dosage according to SPC Variant alleles (*2, *3A, *3C…) TPMT : Heterozygote carriers: 65 % of standard therapeutic dosage MYELOSUPPRESSION Homozygote carriers: 6-10 % of standard therapeutic dosage FATAL LEUCOPENIA Genetic testing for TPMT is a routine practise nowadays  TRANSPORTERS ▪ ABC transporters: e.g. MDR, MRP, BCRP, P-gp, LRP) ▪ SLC transporters: e.g. SLC2A1, OAT, OATP, OCT,OCTN ABC transporters play an important role in absorption, distribution and elimination of many drugs Gene polymorphisms can affect the drug penetration through membranes to the cell / out the cell (tumor cells) LOW LEVEL of cancer HIGH LEVEL of cancer drug in tumor cell drug in tumor cell RELAPSE OF SERIOUS ADVERSE EFFECT CANCER INCREASED Genetic predisposition can neither be overestimated nor underestimated! THE INDIVIDUAL RISK OF CLINICAL COMPLICATIONS is a result of the ENVIRONMENT + GENES interactions  GENETIC FACTORS Create conditions GENOTYPE: genes encoding receptors , ion channels, drug-metabolising enzymes , drug transporters ….. and others NON GENETIC FACTORS Trigger patogenic process Environmental Non genetic changes of Factors the DNA, RNA o proteins NUTRITIONAL FACTORS, lifestyle (smoking, alcohol EPIGENETIC CHANGES IN DNA consumption, sport aktivity) (methylation, acetylation) pozitive thinking… DIFFERENT INACTIVATION OF X CHR. POSTTRANSLATIONAL MODIFICATION DRUG-DRUG INTERACTIONS of proteins (alternative splicing) (concomitantly administered drugs) Thank you for your attention