MUNI MED Drug Interactions Alena Machalová 1 Drug interactions / Department of Pharmacology 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 HUH I 2 Drug interactions / Department of Pharmacology med 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 " Uatro DS (Ed.) Drug Interaction Facts. J.B. Lippincott Co. St. Louis 1992. Positive? Negative? Clinically significant 3 Drug interactions / Department of Pharmacology MUM I med,>" Definition of drug-drug interaction - 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 4 Drug interactions / Department of Pharmacology MUM I med,>" Definition of drug-drug interaction - 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). MUNI 5 Drug interactions / Department of Pharmacology . . _ Drug interactions Pharmaceutical Incompatibilities Pharmacological Pharmacodynamics Pharmacokinetics Metabolism 6 Drug interactions / Department of Pharmacology MUM I med,>" Drug interactions Change in the expected properties of the drug caused Drug interaction 7 Drug interactions / Department of Pharmacology Drug Food and beverage Alcohol Food supplement Smoking MUM I ed- Why are the drug interactions so important? - 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 8 Drug interactions / Department of Pharmacology MUM I med,>" The risk of polypharmacy - Polypharmacy - unjustified and irrational overuse of pharmacotherapy Drugs with a narrow therapeutic index and therapeutic range. Drugs that are metabolised via CYP3A4 Classifying drug interactions Non-relevant Minor Moderate (use with caution) Major (should be avoided) Contraindicated (prohibited) Risk rating Description Action A Data have not demonstrated either pharmacodynamic or pharmacokinetic interactions between the specified agents No interaction B Data demonstrate that the specific agents may interact which each other, but there is little to no evidence of clinical concern resulting from their concomitant use No action needed c Data demonstrate that the specific agents may interact which each other in a clinically significant manner. The benefits of concomitant use of these two medications usuaHy outweigh the risk Monitor therapy D A patient-specific assessment must be conducted to determine whether the benefits of concomitant therapy outweigh the risks Modify regimen X The risks associated with concomitant use of these agents usually outweigh the benefits Avoid combination MUNI 10 Drug interactions / Department of Pharmacology ed 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... 11 Drug interactions / Department of Pharmacology MU!H med ANTIDOTES 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 12 Drug interactions / Department of Pharmacology Coumadin.........................................................Vitamin K Benzodiazepines....................Romazicon (Flumazenil) Magnesium Sulfate.......................Calcium Gluconate Heparin.................................................Protamine Sulfate Tylenol...............................................................Mucomyst Opiates........Narcotic analgesics, heroin morphine, Narcan Cholinergic Meds.........Atropine, pralidoxime (2-PAM) Digoxin................................................................Digiband Acetaminophen..................................n-Acetylcysteine Iron.................................................................Deferoxamine Alcohol Withdrawal........................................Librium Anticholinergics....................................Physostigmine Beta Blockers...................................................Glucagon Methotrexate................................................Leucovorin Anticoagulants.......................................Vitamin K, FFP Aspirin................................................Sodium bicarbonate CCB..............................................Calcium, glucagon, insulin Cyanide..................Tydroxycobalamin, sodium thiosulfate Hydrofluoric acid............................Calcium Gluconate Insulin....................................................................Glucose Isoniazid......................................................Deferoxamine Methanol..............................................................Ethanol Ethylene glycol.............................Fomepizole, ethanol Methemoglobin..................................Methylene blue Tricyclic antidepressant..........Sodium bicarbonate -*- -—-IUI l_—C7 I Significance of drug interactions - 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 13 Drug interactions / Department of Pharmacology MUM I 2. Pharmacokinetic DDIs 14 Drug interactions / Department of Pharmacology Pharmacokinetic interactions - Absorption 1. altered pH 2. altered bacterial flora 3. formation of drug chelates or complexes 4. drug induced mucosal damage 5. altered GIT motility 15 Drug interactions / Department of Pharmacology MU»'I 1. 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 H2 antagonists (acidic) PPI Decrease the tablet dissolution of p.o. azole antimycotics (e.g. Ketoconazole) Therefore, these drugs must be separated by at least 2h in the time of administration of both. 16 Drug interactions / Department of Pharmacology I I a s □ KETD t keto/sjcc a KtTG/luui FIG. 1. Mean ketoconazole scrum concentraunn for eath sluJy ptiase. Effects of ranitidine and sucralfate on ketoconazole bioavailability. Piscitelli S., Antimicrob Agents Chemother. 1991 Sep; 35(9): 1765-1771. MUM I ed- 2. Altered intestinal bacterial flora - 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 Increase digoxin concentration and increase its toxicity Drug interactions / Department of Pharmacology MU*> med 3. Formation of drug chelates or complexes DDIs Can Occur in the Gl Tract > Sucralfate, some milk products, antacids, and oral iron preparations • Medical coal (charcoal) • Didanosine (given as a buffered tablet) • Cholestyramine 18 Drug interactions / Department of Pharmacology 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 Ml V e n*'" s Complexation or chelation -Tetracyclines, Quinolones interact with iron, calcium, magnesium, aluminium preparations (antacid - aluminum or magnesium hydroxide) or milk (Ca2+) Unabsorpable complex Decrease absorption of ciprofloxacin by 85% due to chelation carbo medicinalis (coal), diosmectin -readsorption of other drugs Drug interactions / Department of Pharmacology MUM e d 4. Drug-induced mucosal damage Antineoplastic agents cyclophosphamide, vincristine, procarbazin Inhibit absorption of several drugs such as digoxin 20 Drug interactions / Department of Pharmacology MUM I med,>" 5. Altered motility Increased motility (diarrhea) • Prokinetic drugs - metoclopramide, domperidone, itopride Reduced absorption Decreased motility (ileus, constipation) • Opioids, diphenoxylate, loperamide Increase in AUC of drugs, toxicity 21 Drug interactions / Department of Pharmacology MU^> I ed Pharmacokinetic interactions - Distribution The major plasma proteins to which most drugs bind are albumin - typically binds acidic, anionic drugs a 1-acid glycoprotein - 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 22 Drug interactions / Department of Pharmacology Maximum Fraction Bound in Plasma Fraction of Total Drug Bound in the Body Maximum Possible Increase in PI tarmac odynami c Effect Due to Complete Binding Displacement 50% 10% 10% 00% 49.6% ~ twofold 00% 013% Displaced protein binding - 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 1/2, 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 Bleeding Hypoglycemia Jaundice & Kernicterus MU" i ed- Examples of medications that are >90% protein-bound (not inclusive) Category Medication(s) Antibiotics Ceftriaxone, doxycycline, ertapenem Antidepressants Duloxetine, fluoxetine, nortriptyline, sertraline Antipsychotics Chlorpromazine, clozapine, haloperidol Anxiolytics Chlordiazepoxide, diazepam, lorazepam Cardiac Amiodarone, bumetanide, furosemide, nicardipine, verapamil, warfarin Chemotherapy Paclitaxel, tamoxifen Diabetes Glipizide Pain Bupivacaine, buprenorphine, Ibuprofen Seizure Phenytoin, valproic acid Source: Reference 1 24 Drug interactions / Department of Pharmacology MUM I Distribution - glycoprotein P - most important - works in tandem with CYP3A4 (mutual substrates, inductors and inhibitors) reduced activity of P-gp (present in a quarter of the population) Increased absorption of drugs - 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 MUM e d Distribution Useful mnemonics: P glycoprotein Increase Quantitative Absorption Very Effectively > Itraconazole > Quinidine > Amiodarone > Verapamil - most potent Pg inhibitor > Erythromycin MUNI 26 Drug interactions / Department of Pharmacology . . _ Distribution of drugs in relation to P-glycoprotein 27 Drug interactions / Departi Medications that act as substrates, inhibitors or inducers of P-gp Substrate Inhibitors Inducers Cyclosporine Amiloride Aspirin Dipyridamole Amiodarone Cyclosporine Digoxin Atorvastatin Paclitaxel Diltiazem Carvedilol Reserpine Losartan Cyclosporine Quinidine Digoxin Tacrolimus Diltiazem Dipyridamole Doxazosin Felodipine Lidocaine Lovastatin Nifedipine Propafenone Propranolol Quinidino Simvastatin Spiroanlactone Verapmil MUNI ED Influence of enterohepatic recirculation IB 22 26 30 T ni* I Mr I Effect of Interruption of Enterohepatic Cycling on Drug Elimination Condition fM-tffe Digitoxin 6 days Digitoxin + cholestyramine 4.5 days Dapsone 20.5 hr Daps one + charcoal 10,8 hr Gallbladder— 28 Drug interactions / Department of Pharmaco EXAMPLES OF XENOBIOT1CS EXCRETED INTO RILE AND SUBJECT TO ENTEROHEPATIC Rf CIRCULATION Compound Cefoperazone Estradiol Valproic acid Chloramphenicol Digitoxin Spironolactone Imipramine Species in bift unknown conjugates glucuronlde glucuronide conjugates metabolites parent and desm ethyl MUM I ed- 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 MIH! e d 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 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 16% CYP1A2 11% CYP2D6 19% CYP3A4/5 36% CYP2C19 8% CYP2E1 4% CYP2B6 3% CYP2A6 3% Drug interactions / Department of Pharmacology MU^> I med 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 31 Drug interactions / Department of Pharmacology MUM I med,>" Drug interactions - induction - '*maytakesecondsupto weeks in case of enzyme 32 Basic mechanisms - inhibition P450 Inhibitors CYP450 inducers Mnemonics SICKFACES.COM Group Sodium valproate Isoniazid Cimetidine Ketoconazole Fluconazole Alcohol..binge drinking Chloramphenicol Erythromycin Sulfonamides Ciprofloxacin Omeprazole Metronidazole Grapefruit juice P450 Inducers CRAP GPS induce me to madness!! Carbe maze pines Rifampicin Alcohol (chronic) Phenytoin Griseofuhin Phenobarbitone Sulp ho ny lure as Barb's: PheNOBarbitol Funny: Phenytoin Mom: Modafinil Refuses: Rifampin Greasy: Griseo Ivin Carb: Carbamazepine Shakes: St. John's wort Liver P450 INDUCERS 34 Drug interactions / Department of Pharmacology Bullshit CRAP GPS induces my rage! Barbituates St. John's wort Carbamazepine Rifampin Alcohol (chronic) Phenytoin Griseofulvin Phenobarbital Sulfonylureas CYP450 inhibitors VICK'S FACE All Over GQ stops ladies in their tracks. Valproate Isoniazid Cimetidine Ketoconazole Sulfonamides Fluconazole Alcohol (acute) Chloramphenicol Erythromycin (macrolides) Amiodarone Omeprazole Grapefruit juice Quinidine ■ VI W má med Becomes Enzyme active at Substrates Inhibitors Inducers High interindividual variability CYP 1A2 1-3 months Caffeine Paracetamol CYP2D6) Hours, days Amphetamines Codeine Flecainide Lignocaine Metoclopramide CYP2C9J First weeks Ibuprofen Phenytoin CYP2C19 First weeks Omeprazole Phenytoin Indomethacin CYP3A4J First weeks Steroids Clarithromycin Ciprofloxacin Cocaine Methadone Ranitidine Tobacco Insulin Omeprazole Phenobarbitone Phenytoin Fluconazole Rifampicin Sulfamethoxazole Omeprazole Carbamazepine Indomethacin Prednisone Fluconazole Phenobarbitone Grapefruit Juice Phenytoin 35 Drug interactions / Department of Pharmacology CYP2E1 Hours Midazolam Ethanol Paracetamol disulfiram Ethanol _ Isoniazid ) N Elimination • 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... 36 Drug interactions / Department of Pharmacology THE NEPHRON COLLECTING j PERITUBULAR "CAPILIMIES F - FIITRATION R ■ REA850RPTION S - SECRETION MU^> I ed Elimination Example: co-administering methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs), probenecid (Probalan, generics), penicillins, proton pump inhibitors, vitamin C, sulfa, and some other antibiotics 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. 37 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. MUM I ed- Summary of PK DDIs emDOCs.net- Emergency Medicine Education Common ED Medication Errors: Polypharmacy - emDOCs.net -Emergency Medicine Education 38 Drug interactions / Department of Pharmacology Pharmacokinetic property example changes with age Drug effects Example pharmacodynamic complication Absorption Decreased gastric blood flow Decreased bioavailability Chronic salicylate toxicity (aspirin requires acidic gastric pH; decreased absorption may lead to delayed drug accumulation with daily dosing) Decreased gastric acid secretion, increased gastric pi i Prolonged gastric emptying (e.g. due lo anticholinergic drugs) Distribution Decreased muscle mass Volume of distribution (Vd) of fat-soluble drugs increases; Vdof water-soluble drugs decreases; increased free (non-protein bound) drug levels Benzodiazepine accumulation in tissues with chronic use (fat-soluble); increased bleeding with warfarin use (highly protein bound) Increased body fat Decreased protein binding Metabolism Decreased hepatic mass Decreased clearance of drugs that undergo considerable first-pass metabolism (leading to increased bioavailability) Beta blocker toxicity {e.g. metoprolol, propranolol) Decreased hepatic blood flow Reduced cytochrome P4S0 enzyme activity Excretion Decreased renal blood flow Reduced drug clearance Digoxin toxicity (narrow therapeutic index, primarily renally excreted) Decreased glomerular filtration rale (GFR) Decreased tubular secretion MUNI ed Pharmacodynamics drug interactions = alteration of the drug 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 Drug interactions / Department of Pharmacology MU»> med Receptor antagonism Opioids x naloxone BDZ x flumazenil Tubocurarium x neostygmine Agonists and Antagonists Agonists Drugs that occupy receptors and activate them. Antagonists Drugs that occupy receptors out do not activate them. Antagonists block receptor activation by agonists AgeriM ■ orw Agonist * antagonist V Antagonist alone [*) [i] [_] Full act.vator Less activation No activation Drug interactions / Department of Pharmacology B Competitive Inhibition Noncompetitive Inhibition 100 Isoproterenol + Propranolol (Antagonist) Isoproterenol + 2X Propranolol Parallel Shift No A Maximum Q. co g 1.0 10 [Isoproterenol] (ng/ml) NorEpi Decreased Response No change In EC„ ...... / — NorEpi + / / Phenoxybenzamine / y _ — NorEpi + A : i 2 X Phenoxybenzamine l 1 0.1 1.0 10 100 [Norepinephrine] (ng/ml) t u Opposing or antagonistic interactions Drug affected Anticoagulants Carbenoxolone Hypoglycaemic agents Hypnotic drugs Levodopa 41 Drug interactions / Department of Pharmacology Interacting drugs Vitamin K Spironolactone Glucocorticoids Caffeine Antipsychotics (those with Parkinsonian side effects) Results of interaction Anticoagulant effects opposed Ulcer-healing effects opposed Hypoglycaemic effects opposed Hypnosis opposed Antiparkinsonian effects opposed Pharmacodynamics drug interactions Drugs Anticholinergics + anticholinergics (antiparkinsonian agents, butyrophenones, phenothiazines, tricyclic antidepressants, etc.) Antihypertensives + drugs causing hypotension (anti-anginals, vasodilators, phenothiazines) CNS depressants + CN5 depressants (alcohol, antiemetics, antihistamines, hypnosedatives, etc.) QI prolonging drugs + other QT prolonging drugs {Amiodarone + Disopyramide) Methotrexate + co-trimoxazole Nephrotoxic drugs + nephrotoxic drugs (genta-micin or tobramycin with cefalotin (cephalothin) Neuromuscular blockers + drugs with neuromuscular blocking effects (e.g. aminoglycoside antibacterials) 42 Drug intera^^^i^^^^^^ potassjum_sparirig diuretics (triamterene) Result of interactio Increased anticholinergic effects; heat stroke in hot and humid conditions; adynamic ileus; toxic psychoses Increased antihypertensive effects; orthostasis Impaired psychomotor skills, reduced alertness, drowsiness, stupor, respiratory depression, coma, death Additive prolongation of QJ interval, increased risk of torsade de pointes Bone marrow megaloblastosis due to folic acid antagonism Increased nephrotoxicity Increased neuromuscular blockade; delayed recovery, prolonged apnoea Marked hyperkataemia 1U N I ed QT interval prolongation Sorafenib Sunitinib Pazopanib Dasatinib Nilotinib + CYP 3A4 Inhibitors claritromycin ciprofloxacin Deterioral ADRs on me heart, including QT prolongation and torsades de ointes amiodaron sotalol ondansetron propafenon chlorpromazine haloperidol cisapride domperidon pimozide T~ I MIX 4.*.U 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 Example Mechanism of action Outcome Drug-drug, PK Gatifloxadn+cakium and antacid Ciprofloxacin+olanzapine Decrease in absorption of gatifloxacin Ciprofloxacin inhibits CYP1A2 leading to an increase in Cp of olanzapine Treatment failure26 Rigidity, falls Drug-drug, PD Ciprofloxacin+glibenclamide Anticholinergic drug+donepezil Synergy (hypog lycaemic effect) Antagonism Profound hypoglycemia" Decreased effect of donepezil Drug-nutritional status Low albumin+phenytoin Increase in freephenytoin concentration Confusion, somnolence, ataxia38 Drug-herbaJ product Gingko+aspirin Decrease in platelet function and adhesion Increased risk of bleedings Drug-alcohol Alcohol+chronic use of bromazepam Synergy Increased risk of falls Drug-disease or drug-patient Metoctopramide for gastric dysmotility in a patient with Parkinson's disease Increase in dopamine receptor blockade Worsening Parkinson's disease30 Cp=plasma concentration. CYP=cytochrome P450. PD=pharmacodynamic. PK=pharmacokinetic. Pharmar.olonv- tions in elderly patients ed<>* Clinically significant drug interactions 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 45 Drug interactions / Department of Pharmacology Metronidazole Alcohol - disulfiram reaction Warfarin - risk of bleeding, INR control, dose adjustment Lithium - toxicity, do not administer simultaneously MUNI MED** Clinically significant drug interactions 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 46 Drug interactions / Department of Pharmacology MUM I med,>" Clinically significant drug interactions Fluoroquinolones Antacids, minerals - [ absorption of ATB, do not administer together Caffeine -1 toxicity of caffeine Clindamycine Azole antifungals Neuromuscular blockers prolongation of their effect, toxicity 47 Drug interactions / Department of Pharmacology MUNI Clinically significant drug interactions Acetylsalicylic acid and NSAIDs Warfarin - increased risk of bleeding ACE inhibitors, beta-blockers, sartans - reduction of antihypertensive effect Furosemide - reduction of diuretic effect Paracetamol Alcohol Phenytoin, carbamazepine, isoniazid - increased risk of hepatotoxicity 48 Drug interactions / Department of Pharmacology MUNI meln>- Clinically significant drug - food interactions -St. John's wortX immunosuppresants (tacrolimus, sirolimus, cyclosporine) -TyramineX MAOI - Grapefruit juice X statins 49 Drug interactions / Department of Pharmacology M U fl I ed Druqs - food interactions Common Food-Drug Interactions Food Drug What happens? Kale, broccoli (vitamin K) blood thinners auch as warfarin Poods that are rich, in vitamin K can reduce the effectiveness of blood thinners. Grapefruit Bananas (potassium) Walnuts, soybean flour (high fiber) Dairy products (calcium) Salami, aged cheese (tyramine) 50 Drug interactions / Department of Pharmacology statins such as atorvastatin, lovastatin, simvastatin A CK inhibitors such as Captopril, ertaJaprii and llslnoprtl thyroid medications such as levothyroxlne Grapefruit can increase statin levels in your body, thereby increasing statin-related side effects. ACE inhibitors increase potassium in your body. Too much potassium can cause an irregular heartheat and heart palpitations. High-fiber foods can prevent the body from absorbing thyroid medications. (luinolone antibiotics such &s ciprofloxacin and levofloxacin oxazoiidiitone antibiotics (such, as linezolid) and MAOI-type antidepressants (such as phenelzine) Calcium reduces the level of these antibiotics in your blood. Avoid eating dairy and calcium-fortified products alone. Eating a tyramine-rich diet while taking certain meds can cause a sudden, dangerous increase in blood pressure. MUNI ed Drugs - food interactions Drug-Food interactions ■ A drug-food interaction happens when the food you eat affects the ingredients in a medicine you are takine so die medicine cannot work the way it should. 1 Bisphosphonates4- Any drug Reduced effectiveness of drug1 1 Benzodiazepines + grapefruit metabolism Inhabit enzymes involved in drug .v Digoxin I Oatmeal Decreased adsorption of drug 4 Aspirin ■■ Milk Upset stomach Acetaminophen i Alcohol Liver damage (i. MAO Inhibitors + food(ryramine) Severe headache 7. Tetracycline's i calcium food Reduced absorption of drug s. Warfarin j Vi la nun K Reduced effect of drug 'i Celecoxib ; Milk Upset stomach 10, Naproxen + fatty food Upset stomach ii Oxycodon + Alcohol Coma, asthma Caffeine + food Rapid heart beat 51 Drug interactions / Department of Pharmacology MUNI med Pharmaceutical drug interactions 52 Drug interactions / Department of Pharmacology Incompatibility 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 do not mix in one fluid, split the route of administration, do not give in at the same time Amiodarone diluted in 5% glucose solution meets Norepinephrine reconstituted in saline solution - precipitation of amiodarone dilute NE in 5% glucose solution Octreotide meets in one lumen with parenteral nutrition, octreotide is inactivated separate pathways for parenteral nutrition and octreotide Drug interactions / Department of Pharmacology TJ1JI ed- IV Drug Compatibility Chart Acyclovir ,VI,.T..ilmi- Amiodaron <5 S lue >< n E £ um 'R m < 4» s ■ň C = 3 I i Amphotericin 6 Aiithromycin Calcium Gluconate Cefapima C Otu rosíme Dopamin» Fentanyl Fluconazole Furosemide Heparin Imiporiom-Cltastatln Insulin Lidocains UneEolid Magnesium Sulfate Mnnnitol Mcropcncm Me-thyl Prednisolone Metoclopramide Midazolam Morphine Noradrenaline Ondansetron Pantoprazolc Phonytoln Kipcraciinn - lazoDactum Potassium Chloride Sodium Bicarbonate ^"Dfú'g interactions Vasopressin Vecuronium j Compatible Drugs j Incompatible Dilta« j No in Form at ion Aval I Able Mote: This (Able cm be u srtl for Y-SII* compatibility at the usual manufacturer's concentration. This table gives Informal Inn for two drug combinations only, IF any drug combination is found lo be Incompatible (hen. administer through different IV access site or clarify with the clinical pharmacist. www.ijccm.org Things to remember S Interactions are easily forgotten when prescribing S Interactions are difficult to remember S PD interactions can often be predicted across drug classes S PK often cannot be predicted - experiments needed S Many interactions probably remain undescribed S The chances of interaction are 60 times higher in a patient taking 5 drugs than in a patient taking 2 MUNI 55 Drug interactions / Department of Pharmacology _ _ _ References - 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 MUNI 56 Drug interactions / Department of Pharmacology *" e d Thanks for your attention 57 Drug interactions / Department of Pharmacology