Pharmacology – Drug interactions/Department of Pharmacology1 Drug Interactions Agenda Drug interactions (DDI) • Definition • Significance Pharmacokinetic DI - examples Pharmacodynamic DI - examples Pharmaceutical DI - examples Drug interactions with food, beverages, herbs Drug interactions among smokers Recommendation Summary Definitions and Terms Drug Interactions:“ The pharmacologic or clinical response to the administration of a drug combination different from that anticipated from the known effects of the two agents when given alone ” 1Tatro DS (Ed.) Drug Interaction Facts. J.B. Lippincott Co. St. Louis 1992. Negative? Positive ? Clinically relevant! Drug Interaction Classification • Interrelationship 2 or more drugs at the level of: • Pharmaceuticals - physico-chemical and chemical interactions of the components • Pharmacokinetics – Involves absorption, distribution, metabolism and excretion, all of them being associated with both treatment failure or toxicity • Pharmacodynamics - interaction of active ingredients at the level • direct effect at receptor function, • interference with a biological or physiological control process and • additive/opposed pharmacological effect.. Drug interactions - classification Pharmaceutical Incompatibilities Pharmacological Pharmacodynamics Pharmacokinetics Absorption Metabolisms Distribution Excretion Drug interactions - classification Drug interaction Drug Food and beverage Alcohol Nutritional supplements Smoking Change of expected drug properties caused by Classifying drug interactions Grade Relevance 1 – A Nonrelevant 2 – B Minor 3 – C Moderate 4 – D Major 5 – X Contraindicated (?) Significance of drug interactions Desirable (beneficial for the patient) • drug combination potentiating drug effect and decreasing the toxicity combination of: cytostatics analgesics antihypertensives ATBs drugs for asthma Significance of drug interactions Desirable (beneficial for the patient) • combination of the active substance suppressing/inhibiting the effect of another drug • in the treatment of intoxication/poisoning organism toxic substance Antidote amanita phalloides Silibin, N-acetylcystein opiates naloxon atropine fysostigmin benzodiazepines flumazenil digitalis antidigitalisová globulin glycoles ethanol, fomepizol carbamates atropine kumarini vitamin K cyanides amylium nitrosum, hydroxycobalamin, aniline methylene blue lead EDTA, DMSA organophosphate atropine, oximy paracetamol N-acetylcystein Significance of drug interactions Undesirable (for the patient harmful, potentially dangerous) Major - life threatening Moderate - clinically significant Minor This may result in: increase or decrease (loss) effect increasing or reducing the incidence of side effects other changes in effect injury or even death clinically insignificant Why are the drug interactions so important? • are one of the commonest causes of ADRs • particularly in the elderly due to polypharmacy • with a prevalence of 20-40% in population • 75 % are preventable • ADR are 4th most frequent cause of death Leape LL et al. JAMA 1995;274(1):35–43. Raschetti R et al. Eur J Clin Pharmacol 1999;54(12):959–963. DDI risk factors • Poly pharmacy • Multiple prescribers • Multiple pharmacies • Genetic • Specific population like elderly, obese, critically ill patient • Specific illness e.g. Hepatic disease, • Renal dysfunction… • Narrow therapeutic index drugs Digoxin, Warfarin, Insulin, Antidepressant, Lithium The risk of polypharmacy May F.E., Stewart R.B., Cluff L.E.: Drug interactions and multiple drug administration. Clin.Pharmac.Ther. 1977, 22:322 prescribing cascade - which occurs when an ADR is misunderstood and new potentially unnecessary drugs are administered; therefore the patient is at risk to develop further ADRs Consequences of drug interactions 1. Loss of therapeutic effect 2. Toxicity 3. Unexpected increase in pharmacological activity 4. Beneficial effects e.g additive & potentiation (intended) or antagonism (unintended). 5. Chemical or physical interaction e.g I.V incompatibility in fluid or syringes mixture Pharmacokinetics drug interactions Pharmacokinetics drug interactions Pharmacokinetics drug interactions • are often considered on the basis of knowledge of each drug and are identified by controlling the patient's clinical manifestations as well as the changes in serum drug concentrations. They involved all the processes from absorption up to excretion. Pharmacokinetic interactions - Absorption ▪ altered pH ▪ altered bacterial flora ▪ formation of drug chelates or complexes ▪ drug induced mucosal damage ▪ altered GIT motility Altered pH The non-ionized form of a drug is more lipid soluble and more readily absorbed from GIT than the ionized form does. Antacids Decrease the tablet dissolution of Ketoconazole (acidic)H2 antagonists Therefore, these drugs must be separated by at least 2h in the time of administration of both. PPI https://www.ncbi.nlm.nih.gov/pmc/articles/PMC245265/?page=2 They Can Occur in the GI Tract Sucralfate, some milk products, antacids, and oral iron preparations Omeprazole, lansoprazole, H2-antagonists Didanosine (given as a buffered tablet) Cholestyramine ▪ Block absorption of quinolones, tetracycline, and azithromycin ▪ Reduce absorption of ketoconazole, delavirdine ▪ Reduces ketoconazole absorption ▪ Binds raloxifene, thyroid hormone, and digoxin Tyrosinkinase inhibitors/azole antimycotics And drugs lowering gastric pH TKI/azole antimycotics sunitinib Gefitinib Sorafenib Bosutinib imatinib Drugs lowering gastric pH omeprazol ranitidin Antacids Decreased absorption and availability of TKI/azole antimycotics Voriconazole Fluconazole pantoprazol famotidin Altered intestinal bacterial flora • 40% or more of the administered digoxin dose is metabolised by the intestinal flora. • Antibiotics kill a large number of the normal flora of the intestine Increase digoxin conc. and increase its toxicity Complexation or chelation Tetracyclines, Quinolones interact with iron, calcium, magnesium, aluminium preparations or Milk (Ca2+ ) Unabsorpable complex Antacid (aluminum or magnesium) hydroxide Decrease absorption of ciprofloxacin by 85% due to chelation carbo medicinalis (coal), diosmectin – readsorption of other drugs Drug-induced mucosal damage Antineoplastic agents cyclophosphamide, vincristine, procarbazine Altered motility Increased motility • Diarrhea - reduce absorption • Prokinetic drugs - metoclopramide, domperidone, itopride Decreased motility • Ileus, constipation - increase in AUC of drugs, toxicity • Opioids, diphenoxylate, loperamide Pharmacokinetic interactions - Distribution • The major plasma proteins to which most drugs bind are albumin and a1-acid glycoprotein; the former typically binds acidic, anionic drugs whereas the latter typically favors basic drugs • Competitive protein binding by another drug will result in increase concentration of free drug, and that will yield more drug response Displaced protein binding • It depends on the affinity of the drug to plasma protein. The most likely bound drugs is capable to displace others. • It is clinically important if displaced drug is highly PP binding , with LONG T ½, small Vd, narrow therapeutic range. • The free drug is increased by displacement by another drug with higher affinity. Aspirin, Phenylbutazone, Clofibrate Displace: • Oral Anti-coagulants (Dicumarol, Warfarin) • Bleeding • Oral Hypoglycemics (Tolbutamide) • Hypoglycemia • Bilirubin in Neonate • Jaundice & Kernictrus. • Phenytoin Drugs binding to protein 28 29 http://www.vetfolio.com/pharmacology/adverse-drug-reactions-in-herding-breed-dogs-the-role-of-p-glycoprotein Pharmacokinetic interactions - Metabolism The effect of one drug on the metabolism of the other is well documented. The liver is the major site of drug metabolism but other organs can also do e.g., WBC, skin, lung, and GIT. CYP450 family is the major metabolizing enzyme in phase I (oxidation process). Therefore, the effect of drugs on the rate of metabolism of others can involve the following examples 50% 30% 10% 4% 2% 2% 3A4 2D6 2C9 1A2 2A6 2C19 Polymorphism of enzymes • slow metabolizer - all defective alleles • medium metabolizer - an intact allele • rapid metabolizer - all intact allele (wild type) • ultrarapid metabolizer - multiplication of a gene or a higher enzyme activity CYP P450 a key enzyme in the metabolism of xenobiotics mainly responsible for Phase I biotransformation processes occurring in the liver, lungs, kidneys, brain, skin, small intestine and other organs ▪ Substrates P450 ▪ drug metabolizing by this enzyme ▪ Inhibitors of cytochrome P450 ▪ accumulation of the drug in the body ▪ increased plasma levels ▪ Increased toxicity ▪ Inducers of Cytochrome P450 ▪ increased degradation of the drug from the organism ▪ subtherapeutic plasma levels of the drug ▪ reduce the effect of drugs Substrates high interindividual variability high interindividual variability high interindividual variability Basic mechanisms - inhibition 10 1 time time 10 1 inhibition exposure Significant drug interactions - inhibition 4.900% 18.400% 3.500%3.300% 19.000% 0 20 40 60 80 100 120 140 160 180 200 ramelteon tizanidin lovastatin tilidin vardenafil fluvoxamin itrakonazol ritonavir násobekexpozice Different inhibiting ability of drugs from the same ATC 37 22 10 4,4 19 9 3,53,3 5 2,5 0 5 10 15 20 25 itrakonazol ketokonazol flukonazol EXPECTED MULTIPLE INCREASE IN AUC alprazolam simvastatin atorvastatin Inhibitors 10 1 čas čas 10 1 induction expozice Basic mechanisms - induction 261% -86%-87% 75% -89% 121% -150% -100% -50% 0% 50% 100% 150% 200% 250% 300% vorikonazol rifampicin oxykodon noroxykodon noroxymorfon Drug interactions - induction AUC (%) Drug interactions – slow onset of induction 145% -16% -48% -78% -82% -100% -50% 0% 50% 100% 150% 200% 24 hodin 48 hodin 72 hodin 96 hodin 120 hodin AUC (%) Inductors It may be seconds up to weeks for example in case of enzyme induction, it needs weeks for protein synthesis, while enzyme inhibition occurs rapidly. Pharmacodynamics drug interactions Pharmacodynamics drug interactions It means alteration of the dug action without change in its serum concentration by pharmacokinetic factors. Additive effect : 1 + 1 =2 Synergistic effect : 1 +1 > 2 Potentiation effect : 1 + 0 =2 Antagonism : 1-1 = 0 Pharmacodynamics drug interactions - examples QT interval prolongation Deterioration of ADRs on the heart, including QT prolongation and torsades de pointes Sorafenib Sunitinib Pazopanib Dasatinib Nilotinib CYP 3A4 Inhibitors claritromycin ciprofloxacin amiodaron sotalol ondansetron propafenon chlorpromazine haloperidol cisapride domperidon pimozide TKI Opposing or antagonistic interactions Important Drug Interactions in the Elderly Drug interactions with food, drinks, herbs49 50 Drugs in which food reduces bioavailability -78% -90% -80% -70% -60% -50% -40% -30% -20% -10% 0% atorvastatin cefaklor ciprofloxacin erythromycin furosemid ketokonazol kyselina alendronová lansoprazol melfalan methotrexát takrolimus (normální jídlo) takrolimus (tučnéjídlo) AUC (%) Define footer – presentation title / department51 Furosemide before or after a meal? ̶ Furon® does not mentioned in SPC ̶ Furorese® fasting ̶ Slovakofarma® furosemide after meal ̶ Food in healthy volunteers (n = 18) resulted in a 45% reduction in the furosemide (40 mg) curve, a 78% reduction in peak plasma concentrations and a reduction in absolute bioavailability from 76% to 43% and a decrease in diuretic effect. ̶ Furosemide should be administered one hour before or 2 hours after a meal. 52 Inhibition of alcohol metabolism ̶ Disulfiram reaction: ̶ facial flushing associated with nausea, palpitations and hot flashes, collapse, arrhythmia, syncope, unconsciousness, convulsions ̶ disulfiram ̶ griseofulvin ̶ metronidazole ̶ co-trimoxazole (Biseptol®) ̶ cephalosporins (eg cefamandole, cefmenoxime, cefoperazone, cefotetan) ̶ ketoconazole ̶ tolbutamide ̶ furazolidone ̶ levamisol Define footer – presentation title / department53 Coca-Cola® phenomenon -49% -66% -1% -3% -70% -60% -50% -40% -30% -20% -10% 0% itrakonazol +ranitidin itrakonazol + omeprazol itrakonazol +ranitidin+ CocaCola itrakonazol + omeprazol +CocaCola ACU (%) Define footer – presentation title / department54 Foods as CYP modulators ̶ St John's wort ̶ CYP3A4 inducer ̶ CYP2C19 inducer ̶ CYP2C9 inducer ̶ P-glycoprotein inducer ̶ affecting (reducing to loss) the effect of many drugs that are substrates of CYP3A4 or P-glycoprotein Define footer – presentation title / department55 St John's wort -87% -100% -90% -80% -70% -60% -50% -40% -30% -20% -10% 0% ciklosporin desogestrel digoxin fexofenadin imatinib ivabradin midazolam nifedipin norethisteron simvastatin takrolimus verapamil vorikonazol plocha pod křivkou maximální plazmatické koncentrace Define footer – presentation title / department56 Foods as CYP modulators ̶ Garlic ̶ CYP3A4 inducer ̶ CYP2C9 inhibitor ̶ P-glycoprotein inducer ̶ increase in bleeding after warfarin ̶ Paprica, cauliflower nárůst závažnosti změn Citrus juice + felodipine 25% 32% 61% 88% 173% 303% 0% 50% 100% 150% 200% 250% 300% 350% citronová šťáva pomerančová šťáva sevilská pomerančová šťáva zředěná grapefruitová šťáva grapefruitová šťáva pomelová šťáva AUC (%) Drug interactions in smokers59 60 Influencing the effect of drugs by smoking ̶ Pharmacodynamic ̶ mainly nicotine in the CNS and periphery, has sympathomimetic effects (cardiovascular system, reduces insulin sensitivity) ̶ Pharmacokinetic ̶ in the absorption phase - nicotine, other products ̶ in the metabolic phase - especially polycyclic hydrocarbons Define footer – presentation title / department61 Pharmacodynamic interactions of nicotine ̶ Beta-blockers ̶ Less decrease in BP and Heart rate ̶ Benzodiazepines ̶ Less sedative effect ̶ Discontinuation of smoking on prolonged use of benzodiazepines may cause depression ̶ Opioids ̶ Reduction of analgesia ̶ Oral Contraceptives ̶ smoking increases the risk of complications p.o. contraception ̶ in women over 35 who smoke more than 15 cigarettes a day the risk of death is 19: 100,000 vs. 3: 100,000 Define footer – presentation title / department62 Effect of smoking on CYP1A2 induction ̶ Smokers have 1.5 x increased CYP1A activity compared to non-smokers ̶ Polycyclic aromatic hydrocarbons cause metabolic induction ̶ Induction already occurs when smoking 10 cigarettes/day ̶ Typically, higher dosages of some drugs are required for smokers ̶ After smoking discontinuation, the enzyme activity is reduced to 7.3x per week ̶ Interrupting smoking requires doses to reduce ̶ High risk NÚL after smoking interruption (extrapyramidal symptoms, cramps…) Define footer – presentation title / department63 Increased CYP450 activity in smoking ̶ CYP1A2 amitriptylin, kofein, clozapin, duloxetin, fluvoxamin, haloperidol, imipramin, olanzapin, ondansetron, paracetamol, propranolol, teofylin, warfarin (R-isomer) ̶ CYP2B6 bupropion, clopidogrel, cyclophosphamid, ifosfamid, methadon, nevirapin Pharmaceutical drug interactions 65 Incompatibility ̶ The incompatibility occurs outside the body, inside the infusion bottles, bags, syringe, or infusion tubes, sometimes visible to the eye. ̶ Physical Reaction ̶ In the event of physical reactions to the bath, it is usually a separation or precipitation (eg, dilution of alcoholic solutions) due to a change in the relationship between ionization, non-ionization and solubility. ̶ Chemical reaction ̶ Chemical incompatibility means that it is chemically degraded by oxidation, reduction, hydrolysis or decomposition. Chemical reactions can be manifested by turbidity, precipitation, and color changes. ̶ The result is a reduction in the amount of the medicinal agent or the formation of toxic by-products Incompatibility • Amiodarone diluted in 5% glucose solution meets NE reconstituted in FR precipitation of amiodarone Management - dilute NA to 5% glucose solution • Octreotide meets in one lumen with parenteral nutrition, octreotide is inactivated Management - Separate pathways for parenteral nutrition and octreotide • Administration of aminoglycosides and beta-lactams meeting in one of the lumens inactivation of the free -NH2 in the free aminoglycosides and -COOH in beta-lactams Management - do not mix in one fluid, split the route of administration, do not give in t the same hour IV Drug Compatibility Chart In-vitro: 1-Drug-laboratory tests interaction: Recommended links https://www.drugs.com/drug_interactions.html https://www.webmd.com/interaction-checker/default.htm https://reference.medscape.com/drug-interactionchecker www.arizonacert.org (drug interactions) www.drug-interactions.com (P450-mediated drug interactions) http://www.drugwatch.com/drug-interactions/ http://drugagency.cz/lekove-interakce.php?id=9 http://www.uspharmacist.com www.QTdrugs.org (drug-induced arrhythmia) www.C-Path.org (drug development) Things to remember Thank you for attention