Drug Interactions PDF

Clinically Significant Drug Interactions Prof. Mohamed Abdel-Latif Drug Interactions Most drug interactions happen after the medication is taken, but some are physical or chemical reactions when drugs come in contact with each other. Not all drug interactions result in adverse drug events...

Clinically Significant Drug Interactions Prof. Mohamed Abdel-Latif Drug Interactions Most drug interactions happen after the medication is taken, but some are physical or chemical reactions when drugs come in contact with each other. Not all drug interactions result in adverse drug events. Some drug interactions are actually intentional (have positive health effects). Interactions between drugs (drug–drug interactions) may be beneficial or harmful. Drug Interactions: Definition Defined as the modification of the effect of a drug by prior or concomitant administration of another drug. A clinically meaningful alteration in the effect of one drug as a result of co-administration of another drug. Risk Factors The use of more than one prescribed drug is the role. The use of non-prescribed drugs (OTC drugs). Additives and preservatives used in canned food are also a medium for interaction. Multiple prescribers: (go to more than one physician or to other health care professionals (e.g. a dentist). Multiple pharmacological effects of many drugs that have the capacity to influence many physiological systems. Patient non-compliance: Confusion may happen from taking several medications (especially elderly patients). Risk Factors High risk drugs ▫ Drugs that show narrow therapeutic index. High risk patients ▫ Groups of patients that should be treated with caution due to specific health condition.  Drug Interaction Risk Factors Patient Factors ▫ Number of medications (polypharmacy) ▫ Severity of the diseases being treated ▫ Age (the very young and elderly) ▫ Renal and hepatic dysfunction ▫ Acute medical condition (eg, dehydration, infection) ▫ Pharmacogenetics Patients in high risk of drug interactions Polypharmacy people (elderly patients) Hepatic disorders Renal disorders Genetic factors  Drug Interaction Risk Factors Drug Factors ▫ Higher dose ▫ Narrow therapeutic range (e.g.digoxin) ▫ NSAIDs ▫ Anticoagulants ▫ Hypoglycemics ▫ Antiarrythmics ▫ Anticonvulsants ▫ Antibiotics ▫ Antiretrovirals  Drug Interaction Risk Factors Other Considerations ▫ Increasing use of prescription drugs ▫ Increasing complexity of medication regimens ▫ Fragmented health care system  Incomplete problem or med lists  Multiple prescribers managing  Multiple pharmacies dispensing  Self-medication with OTC or herbals Seriousness and Severity of Drug Interaction FDA define a serious adverse event as one when the patient outcome is one of the following: ▫ Death ▫ Life-threatening ▫ Hospitalization (initial or prolonged) ▫ Disability—significant, persistent, or permanent change, impairment, damage or disruption in the Types of Drug Interactions Drug-drug Drug-disease Drug-herbal Drug-alcohol Drug-food Drug-nutrition Drug-laboratory  Mechanisms of Drug Interactions Pharmacokinetic interactions ▫ Precipitant drug affects the absorption, distribution, metabolism or excretion of object drug.  Alteration of gastrointestinal absorption  Alteration of drug distribution  Interactions in drug metabolism  Changes in hepatic blood flow  Interactions due to changes in renal excretion Pharmacodynamic interactions ▫ Effect of object drug is modified by the precipitant without changes in pharmacokinetics of object drug.  Drugs having opposing pharmacological actions (Antagosim)  Drugs having similar pharmacological actions (Synergism)  Indirect pharmacodynamic interactions Pharmaceutical interactions ▫ Outside the body Pharmacokinetic Drug Interactions A. Absorption Mechanism Examples Drug binding in GIT Iron may chelate ciprofloxacin, resulting in decreased absorption GI motility Increased GI motility caused by metoclopramide may decrease cefprozil absorption GI pH GI alkalinization by omeprazole may decrease absorption of ketoconazole GI flora Decreased GI bacterial flora caused by antibiotic administration could decrease bacterial production of vitamin K, augmenting the anticoagulant effect of warfarin Pharmacokinetic Drug Interactions B. Distribution Mechanism Examples Displacement from Displacement of methotrexate from plasma plasma proteins proteins by NSAIDs may increase risk of methotrexate toxicity Pharmacokinetic Drug Interactions C. Metabolism Enzymes associated with drug metabolism are called cytochrome P450 enzymes ‘’cytochrome’’ is derived from color of liver cells (dark red) attributed to iron content of the enzymes P450 refers to ultraviolet light wavelength absorbed by enzymes Drugs that undergo hepatic biotransformation are frequently substrates for the same enzymes While requiring these enzymes for their own metabolism, they also may induce or inhibit enzyme activity on other drugs taken concurrently Pharmacokinetic Drug Interactions C. Metabolism Mechanism Examples Enzyme Inhibition Inhibitors of CYP2C9 (amiodarone) can increase Resulting in risk of toxicity from phenytoin, warfarin Increasing Risk of Toxicity Enzyme Inhibition Analgesic and toxic effects of codeine result from Resulting in Reduced its conversion to morphine by CYP2D6. Drug Effect Thus, CYP2D6 inhibitors can impair therapeutic effect of codeine. Pharmacokinetic Drug Interactions C. Metabolism Mechanism Examples Enzyme Induction Barbiturates, carbamazepine, phenytoin, rifampin Resulting in Reduced Drug Effect Enzyme Induction Enzyme inducers can increase formation of toxic R e s u l t i n g i n T o x i c metabolite & increase risk of hepatotoxicity Metabolites A small amount of acetaminophen is converted to a cytototoxic metabolite Pharmacokinetic Drug Interactions D. Elimination Altered Renal Elimination For some drugs, active secretion into the renal tubules is an important route of elimination Examples: ▫ Digoxin is eliminated primarily through renal excretion, and drugs such as amiodarone, clarithromycin, itraconazole can inhibit this process; and therefore digoxin toxicity may result.  Stages of Drug Interactions I- Loss of drug action due to interactions in the pharmaceutical phase:  Unwanted interactions between the components in a pharmaceutical preparation are known as pharmaceutical incompatabilities.  In the pharmaceutical phase the active substance is released from the pharmaceutical preparation (e.g.tablets, capsules) and becomes available for absorption.  Drug interactions in this phase may decrease the pharmaceutical availability (the fraction of the dose of the drug available for absorption).  Not only interactions between the components of the pharmac eutical preparation, but a l s o between the pharmaceutical preparation and the package or container may take place. e.g. 1 Packaging nitroglycerine tablets into plastic packages resulted in a loss of action due to migration of the strongly fat-soluble and volatile nitro-compounds from the tablets to the plastic container. e.g. 2 Tetracyclines and the quinolone antibiotics with preparations containing polyvalent metals such as iron, magnesium and aluminium, form poorly soluble complexes which are not absorbed.  II-Loss of Drug Action Due to Interactions in the Pharmacokinetic Phase: 1- Alteration of Gastrointestinal Absorption: A) pH effect: Changing the pH may lead to decrease solubility of some drugs as tetracycline capsules, there is a decrease of about 50% in its absorption by sodium carbonate. (The rate of dissolution and thus the fraction of tetracycline available for absorption seemed to be markedly reduced at higher pH values) B) Adsorption: e.g.1 antidiarrheal mixtures containing kaolin, pectin, charcoal and attapulgite seriously impair the absorption of many drugs. e.g.2:a multiple dose regimen of bismuth-subsalicylate mixture, more typical of usage in traveler's diarrhea, reduced doxycycline absorption by about 50%.  C) Chelation:  Some substances have the ability for chelate formation so reduce the absorption of other drugs. e.g.1 Cholestyramine (More) and colestipol (Less) Are used for the treatment of elevated plasma cholesterol or bile acid levels.  They are not absorbed but exert their effects by binding bile acids in intestine, preventing their reabsorption.  These resins also bind certain anionic and neutral drugs in the intestine and are known to interfere with the absorption of anticoagulants (warfarin), NSAIDs (piroxicam, tenoxicam), thyroxine, digoxin, vit. K.  However, colestipol appears less likely than cholestyramine to interact by this mechanism.  D) Alteration of motility of the gastrointestinal tract:  Since most drugs are largely absorbed in the upper part of the small intestine, drugs which alter the rate at which the stomach empties its contents can affect absorption of other drugs. e.g. 1 :Propantheline (anticholinergic), delays gastric emptying and reduces paracetamol absorption (intestine) whereas, metoclopramide has the opposite effect by increasing the gastric emptying rate. e.g.2:Tricyclic antidepressants (by anticholinergic effect) can increase the absorption of dicoumarol by increasing the time available for dissolution and absorption (stomach)  E) Alteration of bacterial flora:  Bacterial flora predominate in large bowel, less in small bowel and stomach.  The bacterial flora play a role in the metabolism of drugs.  A number of drugs are excreted in the bile, either unchanged or conjugated to make them more water soluble, these conjugates are metabolized to the parent compound by the gut flora which are then reabsorbed.  This recycling process prolongs the stay of the drug within the body ( Biliar y excretion and the entero-hepatic circulation).  If the activity of the gut flora is destroyed by the presence of an antibiotic, the drug is not recycled and is lost more quickly. e.g.1 This may possibly explain the failure of the oral contraceptives which can be brought about by the concurrent use of penicillins (amoxycilllin or flucloxacillin) or tetracyclines. e.g.2:A considerable fraction of the oral dose of digoxin is reduced in the lower intestine to inactive metabolite by the bacterial flora, and that limits the bioavailability of digoxin, especially the slowly dissolving preparations.  Certain oral antibiotics including tetracycline and erythromycin, alter the bacterial flora and decrease the inactivation of digoxin.  Thus, after an antibiotic treatment the digoxin levels were increased and may precipitate digoxin toxicity.  2- Alteration of Drug Distribution (Plasma protein binding):  Acidic (e.g. phenytoin, warfarin, digoxin) and neutral drugs (e.g. digitoxin) will primarily bind to albumin. If albumin becomes saturated, then these drugs will bind to lipoprotein.  Basic drugs (e.g. propranolol) will bind to the acidic alpha-1-acid glycoprotein. Competition on Protein Binding Sites: Displacement from plasma proteins is likely to lead to a sustained change in steady state free plasma concentration only of drugs which are extensively bound to plasma proteins e.g.1:Warfarin is displaced by salicylates and aspirin leading to increased circulating warfarin and a state of haemorrhage. e.g.2:Phenytoin is displaced by salicylates, phenylbutazone, sulfafurazole, and acetazolamide so the drug concentration increased and potency increased than required. e.g. 3 :Tolbutamide is displaced by salicylates, phenylbutazone and sulfonamides leading to hypoglycemia  e.g.4 Prescribing any sulfonamide or salicylate to young infants and newborns cause displacement of bilirubin since these drugs showing higher affinity to albumin binding sites resulting in hyperbilirubinemia and jaundice.  Neurologic complication of jaundice is called kernicterus. K e r m i c t e r u s i s a b i 1 i r u b i m - i m d u c e d b r a i m d y s f u m c t i o m. B i 1 i r u b i m i s a h i g h 1 y m e u r o t o x i c s u b s t a m c e t h a t m a y b e c o m e e 1 e v a t e d im t h e s e r u m , a comditiom kmowmas hyperbi1irubimemia. 3- Alteration in Drug Metabolism A-Induction of drug metabolizing enzymes: The most powerful enzyme inducers in clinical use are the antibiotic rifampicin and antiepileptic agents such as barbiturates, phenytoin and carbamazepine. The drug griseofulvin, cigarette smoking and chronic alcohol use can also induce drug-metabolizing enzymes. e.g.1: Phenobarbital by causing enzyme induction can increase the rate of metabolism of warfarin. The result is a decreased response to the anticoagulant. The benzodiazepines (diazepam (valium)) are not likely to interact with anticoagulants, so might be useful as an alternative to a barbiturate.  B-Inhibition of drug metabolizing enzymes:  Such interactions often result in exaggerated and prolonged responses with an increased risk of toxicity. Allopurinol Isoniazide Amiodarone Itraconazole Azapropazone Ketoconazole Chloramphenicol Metroindazole Cimetidine Omeprazole Ciprofloxacin Oral contraceptives Diltiazem Phenylbutazone Disulfiram Propoxyphene Enoxacin Sulphonamides Erythromycin Valproate Ethanol (acute) Verapamil  Interactions of this type are most likely to affect drugs with a narrow therapeutic range, such as theophylline. e.g.1, the introduction of an enzyme inhibitor such as ciprofloxacin or cimetidine in a patient taking chronic theophylline could result in a doubling of plasma concentrations. e.g.2: Benzodiazepines and cimetidine: inhibit the metabolism of leading to enhanced sedative effect. e.g.3: Chloramphenicol and tolbutamide: Chloramphenicol is a potent inhibitor of the biotransformation of.  In case of tolbutamide this cause hypoglycemia and in case of phenytoin treated patients this cause nystagmus (a condition of involuntary eye movement).  4- Changes in Hepatic Blood Flow:  After absorption in the intestine, the portal circulation takes drugs directly to the liver before they are distributed by the blood flow around the rest of the body.  A number of highly lipid-soluble drugs undergo substantial biotransformation during this "first pass" through the gut wall and liver. e.g. 1 :Cimetidine decreases hepatic flow rate and thereby increases the bioavailability of propranolol. e.g. 2 :Propranolol also induced -blockade, results in a reduction in cardiac output and hepatic blood flow rate, reduces its own clearance and that of other drugs such as lignocaine (lidocaine). 5- Interactions Due to Changes in Excretion A- Change in urinary pH: Change pH of urine can inhibit or enhance the passive tubular re-absorption of drugs. Passive re-absorption of drugs depends upon the extent to which the drug exists in the non-ionized lipid soluble form which in turn depends on its pKa and pH of urine.  Systemically alkalinizing substances e.g. sodium bicarbonate and antacids will enhance excretion of weakly acidic compounds and the reverse is true. e.g.1 :Quinidine, amphetamine, barbiturate and salicylate excretion changes due to alterations in urinary pH caused by antacids.  For treatment of over dosage of drugs as phenobarbitone and salicylates, urinary pH changes (alkalinization of the urine) have been used to increase the loss of these drugs. e.g.2 : Sodium bicarbonate is given in a significant Aspirin overdose, as it enhances elimination of aspirin in the urine. It is given until a urine pH between 7.5 and 8 is achieved. e.g.3 Urine acidification by ammonium chloride increases excretion of basic drugs such as amphetamine.  B- Changes in active tubular excretion:  Drugs which use the same active transport systems in the kidney tubules can compete with one another for excretion e.g.1:Propencid, reduced the excretion of penicillin( plasma level) and other drugs as; cephalosporins, dapsone, and nalidixic acid. e.g.2:Salicylates reduced the excretion of methotrexate and some other NSAIDs. e.g.3:Furosemide interferes with tubular excretion of acetyl-salicylic acid leads to aspirin toxicity. e.g.4:Phenylbutazone slows the excretion of hydroxyhexamide which is the active metabolite of acetohexamide (first-generation sulfonylurea agent), and therefore the hypoglycemic effect of hydroxyhexamide increased and prolonged due to reduced renal excretion.  c- Modify urinary electrolyte excretion: e. g. 1 : Corticosteroids use leads to decrease K concentration (hypokalemia) so on concurrent use of digitalis alkaloids this lead to increased digitalis toxicity. e.g.2: Spironolactone induces hyperkalemia which decreases digitalis activity. Pharmacodynamic Drug Interactions A. Additive Pharmacodynamic Effects When two or more drugs with similar pharmacodynamic effects are given, additive effects may result in excessive response and toxicity. Examples: ▫ Combining ACEI with potassium-sparing diuretics results in augmented hyperkalemia. ▫ Combining a diuretic with a beta blocker provides a greater reduction in blood pressure than either can impart alone. B. Antagonistic Pharmacodynamic Effects Drugs with opposing pharmacodynamic effects may reduce the response to one or both drugs. Examples: ▫ NSAIDs may inhibit the antihypertensive effect of ACEI.  Reduction in the synthesis of the vasodilating renal prostaglandins. III. Interactions in the Pharmacodynamic Phase  Pharmacodynamic drug–drug interactions occur when one drug (A) alters the effects of another drug (B) without affecting its pharmacokinetics.  Pharmacodynamic drug-drug interactions occur when drugs act at the same or interrelated receptor sites, resulting in additive, synergistic, or antagonistic effects of each drug at the target receptor. a) Drugs Having Opposing Pharmacological Actions: e.g.1:Loss of action of the guanethidine-type antihypertensive agents (e.g. guanethidine, bethanidine, debrisoquine) in the presence of:  tricyclic antidepressants (e.g. imipramine, desipramine, amitriptyline)  or chlorpromazine-type neuroleptic agents (antipsychotic drugs)  or CNS stimulant drugs as amphetamine  This interaction can be accommodated by raising the dose of the antihypertensive to balance the effects of the antidepressant.  but this has a great risk of severe hypotension if the antidepressant is withdrawn. b) Drugs Having Similar Pharmacological Actions - If two drugs which have the same pharmacological effect are given together, this results in excessive response attributable to additive or synergistic effects. e.g.1: CNS depressants  An excessive CNS depressant effect resulting from the concurrent use of two or more drugs exhibiting a depressant action, (e.g. barbiturates, benzodiazepines, opioids)  The same with sedative, hypnotics, antipsychotics, anticonvulsants and antihistamines. e.g.2: Alcohol with CNS depressants: e.g.3: Drugs exhibiting hypotensive effects: Certain antihypertensive drugs (prazosin, alpha blocker (α1)) with other classes of medications (tricyclic antidepressants) can cause orthostatic hypotension C) Indirect Pharmacodynamic Interactions MAOIs act by inhibiting the MAO enzymes. These enzymes are involved in the breakdown of catecholamines, serotonin, dopamine, and tyramine. Administration of a sympathomimetic amine, such as phenylpropanolamine, or dietary tyramine, to a patient taking a MAOI will lead to the release of accumulated noradrenaline from storage sites, producing a syndrome of sympathetic over-activity characterized by severe hypertension, headache, excitement, delirium, and cardiac arrhythmias, haemorrhages and death.  Examples of MAOIs: isocarboxazide (Marplan), phenelzine (Nardil), used as antidepressants. Because of potentially lethal dietary and drug interactions, monoamine oxidase inhibitors have historically been reserved as a last line of treatment, used only when other classes of antidepressant drugs (for example selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants) have failed.  Drug Combinations Drug combinations may be incidental or intentional. If intentional, they are based on a rationale (on a reason or a logical basis). Rationale Drug Combinations 1- At the pharmaceutical phase The aim of the combination may be to increase the pharmaceutical availability and thus the bioavailabilityand this improve the therapeutic efficacy. e.g.1:The combination of Ferrous salts with ascorbic acid (antioxidant) to maintain the iron in the well absorbed, less irritant reduced ferrous form. e.g.2:Combination of Anthelmintics with saline laxatives to prevent or reduce the absorption of the relatively toxic anthelmintic.  Rationale Drug Combinations 2- At the pharmacokinetic phase: An increase in the biological availability and improve the therapeutic efficacy are the main goals. e.g.1:Combination of Penicillins with probenecid to delay excretion of penicillins. (MOA)acts as a uricosuric agent by inhibiting the tubular reabsorption of uric acid.  It also inhibits tubular secretion of penicillin and other drugs as cephalosporins, indomethacin, so increases their plasma levels (Indirect synergism). e.g. 2 :The combination of local anaesthetics with vasoconstrictors to localize the action of the anaesthetics.  Rationale Drug Combinations 3- At the pharmacodynamic phase: The objective of the combination is to increase the therapeutic efficacy by potentiation, complementarity or reduction of the side effects without an interference with the therapeutic effect. A- Complementarity: 1. Combinations of Diuretics with Antihypertensive agents. 2. Combinations of Estrogens with Progestogens in oral contraceptives. B- Suppression of side effects: 1. Combination of diuretics causing loss of potassium with diuretics which causing potassium retention. 1. Combination of corticosteroids for local use with antibiotics to counteract the increased risk for infections.  Relevance of Drug Interactions Impossible to memorize all drug interactions (2500 drug pairs) Most potential drug interactions do not lead to actual clinical effect. Determine which drug interactions are most clinically important. Managing Drug Interactions Comprehensive medication review Identify potential drug interactions Assess clinical significance Continue/discontinue/substitute Monitor and follow-up Document Communicate with patient & healthcare professionals  Managing Drug Interactions Recognize factors that alter a patient’s risk for an adverse event when exposed to interacting drugs. Consider the risk of the potential interaction against the benefit of administering the drugs. If the risk to patient appears to be greater than expected benefit, identify a suitable alternative.  Drug Interaction Resources Print & Electronic Resources ▫ Micromedex ▫ Lexicomp ▫ Facts and Comparisons ▫ Hansten and Horn’s The Top 100 Drug Interactions ▫ Websites ▫ Drug Interaction Checker (Medscape) ▫ Drug Interaction Checker (Drugs.com) Role of the Pharmacist in Managing Drug Interactions 1. Take a medication history 2. Remember high risk patients 3. Check pocket reference 4. Check up-to-date computer program 5. Documenting the care 6. Counseling the patients 7. Monitoring and evaluating the patient’s response to therapy 8. Work with health care practitioners to eliminate unnecessary medications 9. Maintaining patient database including: ▫ patient’s gender ▫ age ▫ vital signs ▫ medical diagnosis ▫ drug allergies ▫ diet ▫ laboratory tests soprotection.com ▫ complete listing of medication being taken