Adobe Systems Drug interactions / Department of Pharmacology 1 Drug Interactions Alena Máchalová [USEMAP] Adobe Systems 2 Agenda •Drug interactions (DDI) - terminology •Pharmacokinetic DDI – examples •Absorption •Distribution •Metabolism •Elimination •Pharmacodynamic DDI - examples •Pharmaceutical DDI - examples •Drug interactions with food, beverages, herbs •Recommendation •Summary [USEMAP] Drug interactions / Department of Pharmacology Adobe Systems 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. Positive? Negative? Clinically significant Drug interactions / Department of Pharmacology 3 Definitions and Terms [USEMAP] Adobe Systems ̶Interactions of two or more different drugs that affect the action and effects of at least one of them ̶ ̶One-sided − combination of levodopa and carbidopa − combination of 5-fluorouracil and leucovorin − combination of glucocorticoids and setrons ̶ ̶Double-sided − combination of sulfamethoxazole and trimethoprim ̶ Drug interactions / Department of Pharmacology 4 Definition of drug-drug interaction [USEMAP] Adobe Systems ̶Antagonism is the opposite effect of two or more drugs administered (NSAIDs and ACEIs, methotrexate and leucovorin, heparine and protamine) ̶ ̶Receptor antagonism - naloxone with fentanyl ̶ ̶Synergism - The effects are magnified many times over (opioids and benzodiazepines, sulfamethoxazole with trimethoprim, amoxiciline and gentamicine) ̶Addition - the resulting effect corresponds to the sum of the effects of both substances (summation) (amoxicillin and clavulanic acid) ̶Potentiation – one drug has an effect, the other one not, but enhances effect of the first one (probenecid + penicillin). Drug interactions / Department of Pharmacology 5 Definition of drug-drug interaction [USEMAP] Adobe Systems Drug interactions / Department of Pharmacology 6 Drug interactions [USEMAP] Adobe Systems 7 Drug interactions [USEMAP] Drug interactions / Department of Pharmacology Adobe Systems ̶The side effects of the drugs are 4.-6. the most common cause of death (analysis of national registers of ARs, Lazaru J., JAMA, 1998) ̶Two-thirds of side effects are caused by drug interactions (US National Register Analysis, Philips KA, JAMA, 2001) ̶Behind most serious interactions is the background of polymorphism in the metabolism of several dozen "problematic" drugs (analysis of serious emergencies, McNamara, Circulation, 2001) ̶ ̶The risk of drug interactions increases with the number of drugs ̶ ̶Frequent polypharmacy in gerontological practice Drug interactions / Department of Pharmacology 8 Why are the drug interactions so important? [USEMAP] Adobe Systems ̶Polypharmacy - unjustified and irrational overuse of pharmacotherapy Drugs with a narrow therapeutic index and therapeutic range. Drugs that are metabolised via CYP3A4 9 The risk of polypharmacy Zobrazit zdrojový obrázek Cresswell, Kathrin & Fernando, Bernard & Mckinstry, Brian & Sheikh, Aziz. (2007). Adverse drug event in the elderly. British medical bulletin. 83. 259-74. 10.1093/bmb/ldm016. [USEMAP] Drug interactions / Department of Pharmacology Adobe Systems Non-relevant Minor Moderate (use with caution) Major (should be avoided) Contraindicated (prohibited) Drug interactions / Department of Pharmacology 10 Classifying drug interactions Zobrazit zdrojový obrázek [USEMAP] Adobe Systems ̶Desirable (beneficial for the patient) drug combination ̶ potentiating drug effect and decreasing the toxicity ̶ ̶combination of: cytostatics analgesics antihypertensives ATBs drugs for asthma… Drug interactions / Department of Pharmacology 11 Significance of drug interactions [USEMAP] Adobe Systems ̶Desirable (beneficial for the patient) - combination of the active substance suppressing/inhibiting the effect of another drug in the treatment of intoxication/poisoning organism Drug interactions / Department of Pharmacology 12 Significance of drug interactions Zobrazit zdrojový obrázek [USEMAP] Adobe Systems ̶Undesirable (for the patient harmful, potentially dangerous) ̶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 Always evaluate clinical significance Drug interactions / Department of Pharmacology 13 Significance of drug interactions [USEMAP] Adobe Systems Drug interactions / Department of Pharmacology 14 2. Pharmacokinetic DDIs Zobrazit zdrojový obrázek [USEMAP] Adobe Systems 1. altered pH 2. altered bacterial flora 3. formation of drug chelates or complexes 4. drug induced mucosal damage 5. altered GIT motility Drug interactions / Department of Pharmacology 15 Pharmacokinetic interactions - Absorption [USEMAP] Adobe Systems ̶The non-ionized form of a drug is more lipid soluble and more readily absorbed from GIT than the ionized form does. Drug interactions / Department of Pharmacology 16 1. Altered pH Decrease the tablet dissolution of p.o. azole antimycotics (e.g. Ketoconazole) Antacids H2 antagonists (acidic) PPI Therefore, these drugs must be separated by at least 2h in the time of administration of both. Effects of ranitidine and sucralfate on ketoconazole bioavailability. Piscitelli S., Antimicrob Agents Chemother. 1991 Sep; 35(9): 1765–1771. [USEMAP] Adobe Systems ̶40 % or more of the administered digoxin dose is under physiological conditions metabolized by the intestinal flora. Antibiotics kill a large number of the normal flora of the intestine ̶ Drug interactions / Department of Pharmacology 17 2. Altered intestinal bacterial flora Increase digoxin concentration and increase its toxicity [USEMAP] Adobe Systems •Sucralfate, some milk products, antacids, and oral iron preparations • •Medical coal (charcoal) • •Didanosine (given as a buffered tablet) •Cholestyramine Drug interactions / Department of Pharmacology 18 3. Formation of drug chelates or complexes Block absorption of quinolones, tetracycline, and azithromycin Reduces absorption of p.o. drugs (e.g. Metoprolole, delavirdine…) Reduces ketoconazole absorption Binds raloxifene, thyroid hormone, and digoxin DDIs Can Occur in the GI Tract [USEMAP] Adobe Systems ̶Tetracyclines, Quinolones interact with iron, calcium, magnesium, aluminium preparations (antacid - aluminum or magnesium hydroxide) or Drug interactions / Department of Pharmacology 19 Complexation or chelation Unabsorpable complex milk (Ca2+) Decrease absorption of ciprofloxacin by 85% due to chelation carbo medicinalis (coal), diosmectin – readsorption of other drugs [USEMAP] Adobe Systems Antineoplastic agents cyclophosphamide, vincristine, procarbazin Drug interactions / Department of Pharmacology 20 4. Drug-induced mucosal damage Inhibit absorption of several drugs such as digoxin [USEMAP] Adobe Systems Increased motility (diarrhea) • Prokinetic drugs - metoclopramide, domperidone, itopride Decreased motility (ileus, constipation) • Opioids, diphenoxylate, loperamide Drug interactions / Department of Pharmacology 21 5. Altered motility Reduced absorption Increase in AUC of drugs, toxicity [USEMAP] Adobe Systems The major plasma proteins to which most drugs bind are albumin - typically binds acidic, anionic drugs a1-acid glycoprotein - typically favors basic drugs Drug interactions / Department of Pharmacology 22 Pharmacokinetic interactions - Distribution Competitive protein binding by another drug will result in increase concentration of free drug, and that will yield more drug response [USEMAP] Adobe Systems ̶Depends on the affinity of the drug to plasma protein. The most likely bound drugs are capable to displace others. It is clinically important if displaced drug is highly PP binding , with LONG T ½, small Vd, narrow therapeutic range. ̶ ̶ ̶Aspirin, Phenylbutazone, Clofibrate displace: Oral Anti-coagulants (Dicumarol, Warfarin) Oral Hypoglycemics (Tolbutamide) Bilirubin in Neonate. Drug interactions / Department of Pharmacology 23 Displaced protein binding Bleeding Hypoglycemia Jaundice & Kernicterus [USEMAP] Adobe Systems ̶obr Drug interactions / Department of Pharmacology 24 Protein binding of drugs Zobrazit zdrojový obrázek [USEMAP] Adobe Systems ̶glycoprotein P - most important - works in tandem with CYP3A4 (mutual substrates, inductors and inhibitors) ̶ ̶ ̶ ̶ ̶OATP (organic anion transport protein) significant system ensuring the transfer of org. anions - risk of inhibition or competition or induction ̶ Drug interactions / Department of Pharmacology 25 Distribution reduced activity of P-gp (present in a quarter of the population) Increased absorption of drugs [USEMAP] Adobe Systems Useful mnemonics: P glycoprotein Increase Quantitative Absorption Very Effectively Ø Itraconazole Ø Quinidine Ø Amiodarone Ø Verapamil – most potent Pg inhibitor Ø Erythromycin Drug interactions / Department of Pharmacology 26 Distribution [USEMAP] Adobe Systems Drug interactions / Department of Pharmacology 27 Distribution of drugs in relation to P-glycoprotein http://m4.wyanokecdn.com/e33da2f864e1eb23c56ef2224b46e5fc.gif Adobe Systems 28 Influence of enterohepatic recirculation https://i1.wp.com/images.slideplayer.com/24/7039986/slides/slide_73.jpg Drug interactions / Department of Pharmacology [USEMAP] Adobe Systems ̶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 Drug interactions / Department of Pharmacology 29 Pharmacokinetic interactions - Metabolism [USEMAP] Adobe Systems ̶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 using this enzyme ̶ ̶Inducers of cytochrome P450 ̶increased degradation of the drug from the organism ̶subtherapeutic plasma levels of the drug ̶reduce the effect of drugs ̶ ̶Inhibitors of cytochrome P450 ̶accumulation of the drug in the body ̶increased plasma levels ̶Increased toxicity Drug interactions / Department of Pharmacology 30 CYP P450 https://upload.wikimedia.org/wikipedia/commons/thumb/0/08/Proportion_of_drugs_metabolized_by_differ ent_CYPs.png/300px-Proportion_of_drugs_metabolized_by_different_CYPs.png [USEMAP] Adobe Systems ̶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 Drug interactions / Department of Pharmacology 31 Polymorphism of enzymes [USEMAP] Adobe Systems Drug interactions / Department of Pharmacology 32 Drug interactions - induction ̶It may take seconds up to weeks in case of enzyme induction (weeks for protein synthesis), while enzyme inhibition occurs rapidly. [USEMAP] Adobe Systems Drug interactions / Department of Pharmacology 33 Basic mechanisms - inhibition [USEMAP] Adobe Systems 34 Mnemonics http://1.bp.blogspot.com/-9EKM5ZC2hSQ/VqKQ6Y6rxKI/AAAAAAAALaE/fdF4fx5HZSE/s1600/P450%2BInducers%2Ba nd%2BP450%2BInhibitors%2BMnemonics.PNG Zobrazit zdrojový obrázek Drug interactions / Department of Pharmacology [USEMAP] Adobe Systems Drug interactions / Department of Pharmacology 35 Zobrazit zdrojový obrázek High interindividual variability [USEMAP] Adobe Systems •glomerular filtration has only a limited effect on protein-bound substances •active tubular secretion - active transport of strong acids and bases in the proximal tubule •passive tubular resorption - is possible only for non-ionized forms •competition - reduction of the capacity for excretion of drugs eliminated exclusively by the kidneys •urine pH - alcalinisation / acidification Hepatic clearance - Enterohepatic recirculation Elimination by lungs, breast milk, sweat… Drug interactions / Department of Pharmacology 36 Elimination Zobrazit zdrojový obrázek [USEMAP] Adobe Systems Example: co-administering methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs), probenecid (Probalan, generics), penicillins, proton pump inhibitors, vitamin C, sulfa, and some other antibiotics 37 Elimination Toxicity (nausea, vomiting, diarrhea, mucositis, stomatitis, esophagitis, elevated hepatic enzymes, renal failure, rash, myelosuppression (leukopenia, pancytopenia, thrombocytopenia), acute lung injury, tachycardia, hypotension, and neurologic dysfunction (depression, headache, seizures, motor dysfunction, stroke-like symptoms, encephalopathy, coma) Why? Renal excretion is the major route of elimination for methotrexate (∼80% ); the drug being actively secreted in the renal tubule by the general organic acid transport system. The renal clearance of methotrexate is decreased by the co- administration of (organic) acids. Solution? With high dose methotrexate, routine administration of fluid and/or bicarbonate is recommended to prevent intratubular precipitation of the drug. The renal clearance of methotrexate is correlated with endogenous creatinine clearance which may provide a guideline to dosage adjustments according to renal function and age. [USEMAP] Adobe Systems 38 Summary of PK DDIs emDOCs.net – Emergency Medicine EducationCommon ED Medication Errors: Polypharmacy - emDOCs.net - Emergency Medicine Education Drug interactions / Department of Pharmacology Adobe Systems = alteration of the drug action without change in its serum concentration by pharmacokinetic factors. Drug interactions / Department of Pharmacology 39 Pharmacodynamics drug interactions Additive effect : 1 + 1 = 2 Synergistic effect : 1 + 1 > 2 Potentiation effect : 1 + 0 = 2 Antagonism : 1 – 1 = 0 [USEMAP] Adobe Systems Opioids x naloxone BDZ x flumazenil Tubocurarium x neostygmine Drug interactions / Department of Pharmacology 40 Receptor antagonism http://physiologicalmechanismsofopioids.weebly.com/uploads/2/8/0/6/28060847/3092981_orig.gif Zobrazit zdrojový obrázek Adobe Systems Drug interactions / Department of Pharmacology 41 Opposing or antagonistic interactions Adobe Systems 42 Pharmacodynamics drug interactions Drug interactions / Department of Pharmacology Adobe Systems 43 [USEMAP] Adobe Systems 44 Important Drug Interactions in the Elderly Louise Mallet, Anne Spinewine, Allen Huang, The challenge of managing drug interactions in elderly people, The Lancet, Volume 370, Issue 9582, 2007 Drug interactions / Department of Pharmacology [USEMAP] Adobe Systems Penicillins Do not administer concomitantly with other penicillins Digoxin - is metabolized by the intestinal microflora - TDM Oral contraceptives - inform about the use of other contraceptive methods Drug interactions / Department of Pharmacology 45 Clinically significant drug interactions Metronidazole Alcohol - disulfiram reaction Warfarin - risk of bleeding, INR control, dose adjustment Lithium - toxicity, do not administer simultaneously [USEMAP] Adobe Systems Clarithromycine Theophylline - risk of TDM toxicity, dose adjustment Carbamazepine - choice of another ATB Digoxin - TDM, dose adjustment Cyclosporine - TDM, dose adjustment Statins - choice of another ATB or replacement with lovastatin, pravastatin Oral contraceptives - informing about the use of other contraceptives Warfarin - risk of bleeding Midazolam - increased sedation Drug interactions / Department of Pharmacology 46 Clinically significant drug interactions [USEMAP] Adobe Systems Fluoroquinolones Antacids, minerals - ↓ absorption of ATB, do not administer together Caffeine - ↑ toxicity of caffeine Drug interactions / Department of Pharmacology 47 Clinically significant drug interactions Clindamycine Azole antifungals Neuromuscular blockers prolongation of their effect, toxicity [USEMAP] Adobe Systems Acetylsalicylic acid and NSAIDs Warfarin - increased risk of bleeding ACE inhibitors, beta-blockers, sartans - reduction of antihypertensive effect Furosemide - reduction of diuretic effect Drug interactions / Department of Pharmacology 48 Clinically significant drug interactions Paracetamol Alcohol Phenytoin, carbamazepine, isoniazid - increased risk of hepatotoxicity [USEMAP] Adobe Systems ̶St. John´s wort X immunosuppresants (tacrolimus, sirolimus, cyclosporine) ̶Tyramine X MAOI ̶ ̶Grapefruit juice X statins Drug interactions / Department of Pharmacology 49 Clinically significant drug - food interactions Zobrazit zdrojový obrázek [USEMAP] Adobe Systems ̶ 50 Drugs – food interactions Zobrazit zdrojový obrázek Drug interactions / Department of Pharmacology Adobe Systems 51 Drugs – food interactions Zobrazit zdrojový obrázek Drug interactions / Department of Pharmacology Adobe Systems ̶ Drug interactions / Department of Pharmacology 52 Pharmaceutical drug interactions Zobrazit zdrojový obrázek [USEMAP] Adobe Systems ̶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 ̶ ̶ ̶Amiodarone diluted in 5% glucose solution meets Norepinephrine reconstituted in saline solution - precipitation of amiodarone ̶ ̶ ̶Octreotide meets in one lumen with parenteral nutrition, octreotide is inactivated Drug interactions / Department of Pharmacology 53 Incompatibility do not mix in one fluid, split the route of administration, do not give in at the same time dilute NE in 5% glucose solution separate pathways for parenteral nutrition and octreotide [USEMAP] Adobe Systems Zobrazit zdrojový obrázek IV Drug Compatibility Chart www.ijccm.org Drug interactions / Department of Pharmacology 54 Adobe Systems ü Interactions are easily forgotten when prescribing ü Interactions are difficult to remember ü PD interactions can often be predicted across drug classes ü PK often cannot be predicted – experiments needed ü Many interactions probably remain undescribed ü The chances of interaction are 60 times higher in a patient taking 5 drugs than in a patient taking 2 55 Things to remember Drug interactions / Department of Pharmacology [USEMAP] Adobe Systems ̶SmPCs − Stockley’s Drug Interactions − ̶Micromedex − https://pubmed.ncbi.nlm.nih.gov/ − ̶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://www.uspharmacist.com − ̶www.QTdrugs.org (drug-induced arrhythmia) − ̶www.C-Path.org (drug development Drug interactions / Department of Pharmacology 56 References: Adobe Systems ̶ Drug interactions / Department of Pharmacology 57 Thanks for your attention [USEMAP]