Drug Interactions M E Blair Holbein Ph D
Drug Interactions M. E. Blair Holbein, Ph. D. Clinical Pharmacologist Presbyterian Hospital of Dallas
Drug Interactions v v Introduction Concepts Case examples Questions
Why study drug interactions?
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Clinical Significance of Drug Interactions v Over 2 MILLION serious ADRs and 100, 000 deaths yearly n n v v v ADRs 4 th leading cause of death ahead of pulmonary disease, diabetes, AIDS, pneumonia, accidents and automobile deaths Greater than total costs of cardiovascular or diabetic care ADRs cause 1 out of 5 injuries or deaths per year to hospitalized patients Mean length of stay, cost and mortality for ADR patients are DOUBLE that for control patients Account for 6. 5% hospital admissions Nursing home patients ADR rate— 50, 000 yearly Ambulatory patients ADR rate—unknown Ref: Institute of Medicine, National Academy Press, 2000, Lazarou J et al. JAMA 1998; 279(15): 1200– 1205, Gurwitz JH et al. Am J Med 2000; 109(2): 87– 94. Johnson JA et al. Arch Intern Med 1995; 155(18): 1949– 1956, Leape LL et al. N Engl J Med 1991; 324(6): 377– 384, Classen DC et al. JAMA 1997; 277(4): 301– 306
Preventable drug interactions are 1/3 of adverse drug events and 1/2 cost.
Definition v A drug interaction is defined as a measurable modification (in magnitude or duration) of the action of one drug by prior or concomitant administration of another substance (including prescription and nonprescription drugs, food, or alcohol) n n May be harmful: toxicity, reduced efficacy May be beneficial: synergistic combinations, pharmacokinetic boosting, increased convenience, reduced toxicity, cost reduction. Wright JM. 2000. Drug Interactions. In: Carruthers SG, Hoffman BB, et al. , ed. Melmon and Morrelli’s Clinical Pharmacology: Basic Principles in Therapeutics, 4 th ed. New York: Mc. Graw-Hill.
Characterizing Drug Interactions Mechanism Pharmacodynamic Receptor inhibition Additive effects Pharmacokinetic Altered absorption, distribution, metabolism, or elimination Interacting agents Drug-drug Prescription Non-prescription Illicit, recreational Food, supplements, herbal products Clinical Significance Major Substantial morbidity and mortality Therapy altering Manageable Little or no change in therapy Optimize therapy Intentional Additive or synergistic effects Enhanced pharmacokinetics
Mechanisms of Interactions Pharmacodynamic Pharmacokinetic Receptor Absorption Non-receptor Distribution Metabolism Excretion
Pharmacodynamic: Pharmacological v v Interaction at the drug receptor Activity is function of intrinsic activity and affinity for receptor n v Agonist and antagonists • Effect also function of concentration at receptor Effect can be additive n Several agents that act via the same receptor • Example, several agents with anticholinergic activity or side effects can result in serious anticholinergic toxicity especially in elderly patients.
Pharmacodynamic: Physiological v Agents that can act in concert or in opposition via different cellular mechanisms. n n n Both theophylline and b-receptor agonists can cause bronchiolar muscle relaxation Sensitization of myocardium to arrhythmogenic action of catecholamines by general anesthetics. Combinations of antihypertensive (can be intentional)
Pharmacodynamic: Altered physiology v Altered cellular environment n Agents that change the state of the host • Hypokalemia caused by diuretics increases toxicity of digoxin.
Pharmacodynamic: Neutralization v Neutralization systemically in the host (as opposed to prior to absorption) n n Protamine used to neutralize heparin Purified antidigoxin Fab fragments used to treat digoxin toxicity
Mechanisms of Interactions Pharmacodynamic Pharmacokinetic Receptor Absorption Non-receptor Distribution Metabolism Excretion
Pharmacokinetic: Absorption v v Alters rate that drug enters the system with altered level or time to peak Mechanisms: n n Physical interaction, chelation, binding. e. g. tetracyclines and cations Altered GI function: changes in p. H (ketoconazole), motility, mucosal function, metabolism, absorption sites, perfusion
Absorption: in the gut v v Sucralfate, some milk products, antacids, and oral iron preparations Block absorption of quinolones, tetracycline, and azithromycin Omeprazole, lansoprazole, H 2 -antagonists Reduce absorption of ketoconazole, delavirdine Didanosine (given as a buffered tablet) Reduces ketoconazole absorption Cholestyramine Binds raloxifene, thyroid hormone, and digoxin
Interactions: Presystemic Elimination v Gut transit and metabolism n n n v Intestinal wall CYP 3 A 4 metabolizes a number of drugs Inhibition/induction results in altered bioavailability Ex: grapefruit juice inhibits intestinal CYP 3 A 4 • Results in increased bioavailability of calcium channel blockers (dihydropyridine), cyclosporin, saquinavir (HIV-1 protease inhibitors), carbamazepine, lovastatin, terazosin, triazolam and midazolam. High intrinsic hepatic clearance dependent upon hepatic blood flow n n Inhibition results in increased bioavailabilty. Propranolol, metoprolol, labetalol, verapamil, hydralazine, felodipine, clhlorpromazine, imipramine, amitriptyline, morphine
First-Pass Metabolism after Oral Administration of a Drug, as Exemplified by Felodipine and Its Interaction with Grapefruit Juice Fig: First pass metabolism Wilkinson, G. R. N Engl J Med 2005; 352: 2211 -2221
Consequences of the Inhibition of First-Pass Metabolism, as Exemplified by the Interaction between Felodipine and Grapefruit Juice Wilkinson, G. R. N Engl J Med 2005; 352: 2211 -2221
Some Common Drugs with Low Oral Bioavailability and Susceptibility to First-Pass Drug Interactions Wilkinson, G. R. N Engl J Med 2005; 352: 2211 -2221
Monoamine Oxidase Inhibitors v v Intestinal MAO inhibited by nonselective irreversible agents and inhibit metabolism of dietary tyramine resulting in increased release of norepi from sympathetic postganglionic neurons Less problematic for selective MAO B inhibitor selegiline and reversible agent moclobemide
Pharmacokinetic: Distribution Protein-binding displacement v Relative to : n n n Concentration - a high concentration of one drug relative to another will shift the binding equilibrium Relative binding affinity - only relatively highly bound drugs will be effected Volume of distribution - small Vd allows for greater proportional effect Therapeutic index - mostly drugs with a narrow TI are clinically significant Alterations in protein-binding capacity • hypoalbuminemia (acidic drugs) • . a 1 -acid glycoprotein (basic drugs) • acute phase reactants
Pharmacokinetic: Distribution Protein-binding displacement v Effect is rapid and transient and usually compensated by increased elimination v May result in transient pharmacologic effect v Overall result is unpredictable v New steady-state attained
Pharmacokinetic: Distribution v v Cellular distribution interactions Cellular transport systems “Promiscuous” and affect several agents requiring active transport Best studied example is P-glycoprotein (PGP) an organic anion transporter system. n n v Cyclosporin A, quinidine, verapamil, itraconazole and clarithromycin inhibit PGP Some correlation with CYP 3 A 4 affinities May be significant for some anticancer drugs
Phases of Drug Metabolism v v Phase I Oxidation/Reduction/Hydrolysis Phase II Conjugation Drug Interactions Due to Hepatic Metabolism Nearly always due to interaction at Phase I enzymes, rather than Phase II i. e. commonly due to interaction at cytochrome P 450 enzymes…some of which are genetically variable in population
Relative Contribution to Drug Metabolism - Phase I Evans & Relling Science 1999
Hepatic Metabolism v v Cytochrome P 450 system responsible for the majority of oxidative reactions Significant polymorphism in many. n v Drugs may be metabolized by a single isoenzyme n v CYP 2 C 9, CYP 2 C 19, and CYP 2 D 6—can be even be genetically absent! Desipramine/CYP 2 D 6; indinavir/CYP 3 A 4; midazolam/CYP 3 A; caffeine/CYP 1 A 2; omeprazole/CYP 2 C 19 Drugs may be metabolized by multiple isoenzymes n n Most drugs metabolized by more than one isozyme • Imipramine: CYP 2 D 6, CYP 1 A 2, CYP 3 A 4, CYP 2 C 19 If co-administered with CYP 450 inhibitor, some isozymes may “pick up slack” for inhibited isozyme.
Pharmacokinetic: Metabolism v v Interactions can result from increased as well as decreased metabolism Clinical relevance is dependent upon timing of interaction, therapeutic index of affected drug, duration of therapy, metabolic fate of affected drug, metabolic capacity of host. n v Host factors include age, genetic makeup (acetylation, CYP 2 D 6), nutritional state, disease state, hormonal milieu, environmental and exogenous chemical exposure. P 450 isoenzymes are variously affected. n n n Isoenzymes characterized • Substrates • Inhibiting agents • Inducing agents No consistent correlation of substrate versus inhibitor or inducer Good reference: http: //medicine. iupui. edu/flockhart/
Cytochrome P 450 Nomenclature e. g. for CYP 2 D 6 CYP 2 D 6 = = cytochrome P 450 genetic family genetic sub-family specific gene NOTE that this nomenclature is genetically based: it has NO functional implication
Proportion of Drugs Metabolized by CYP 450 Enzymes
Cytochrome P 450 3 A 4, 5, 7 v v Largest number of drugs metabolized Present in the largest amount in the liver. n v Not polymorphic n n v Present in GI tract Inherent activity varies widely Activity has been shown to predominate in the gut. Responsible for metabolism of: n n n n Most calcium channel blockers Most benzodiazepines Most HIV protease inhibitors Most HMG-Co. A-reductase inhibitors Cyclosporine Most non-sedating antihistamines Cisapride
Cytochrome P 450 3 A 4, 5, 7 -continued v v v Substrates: macrolide antibiotics – clarithromycin, erythromycin; benzodiazeines- diazepam, midazolam; cyclosporine, tacrolimus, ; HIV Protease Inhibitors – indinavir, ritonavir; chlorpheniramine; Calcium Channel Blockers – nifedipine, amlodipine; HMG Co A Reductase Inhibitors – atorvastatin, lovastatin; haloperidol, buspirone; sildenafil, tamoxifen, trazodone, vincristine Inhibited by: HIV Protease Inhibitors, cimetidine, clarithromycin, fluoxetine, fluvoxamine, grapefruit juice, itraconazole, ketoconazole, verapamil Induced by: carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s wort, troglitazone
Common Drug Substrates, Inhibitors, and Inducers of CYP 3 A, According to Drug Class Wilkinson, G. R. N Engl J Med 2005; 352: 2211 -2221
Cytochrome P 450 2 D 6 v v Second largest number of substrates. Polymorphic distribution Majority of the population is characterized as an extensive or even ultra-extensive metabolizer. n Approximately 7% of the U. S. Caucasian population and 1 -2% of African or Asian inheritance have a genetic defect in CYP 2 D 6 that results in a poor metabolizer phenotype. Substrates include: many beta-blockers – metoprolol, timolol, amitriptylline, imipramine, paroxetine, haloperidol, risperidone, thioridazine, codeine, dextromethorphan, ondansetron, tamoxifen, tramadol Inhibited by: amiodarone, chlorpheniramine, cimetidine, fluoxetine, ritonavir n v v
Common Drug Substrates and Clinically Important Inhibitors of CYP 2 D 6 Wilkinson, G. R. N Engl J Med 2005; 352: 2211 -2221
Cytochrome P 450 2 C 9 v v Note: Absent in 1% of Caucasian and African. Americans. Substrates include: many NSAIDs – ibuprofen, tolbutamide, glipizide, irbesartan, losartan, celecoxib, fluvastatin, phenytoin, sulfamethoxazole, tamoxifen, tolbutamide, warfarin Inhibited by: fluconazole, isoniazid, ticlopidine Induced by: rifampin
Cytochrome P 450 1 A 2 v v v Substrates include: theophylline, imipramine, clozapine Inhibited by: many fluoroquinolone antibiotics, fluvoxamine, cimetidine Induced by: smoking tobacco
Coffee Intake and Relative Risk of Myocardial Infarction by CYP 1 A 2 Genotype Cornelis, M. C. et al. JAMA 2006; 295: 1135 -1141. Copyright restrictions may apply.
Cytochrome P 450 2 C 19 v v v Note: Absent in 20 -30% of Asians, 3 -5% of Caucasians Substrates include: omeprazole, diazepam, phenytoin, phenobarbitone, amitriptylline, clomipramine, cyclophosphamide, progesterone Inhibited by: fluoxetine, fluvoxamine, ketoconazole, lansoprazole, omeprazole, ticlopidine
Cytochrome P 450 2 B 6 v v v Substrates include: bupropion, cyclophosphamide, efavirenz, methadone Inhibited by: thiotepa Induced by: phenobarbital, rifampin
Cytochrome P 450 2 E 1 v Substrates include: acetaminophen
Cytochrome P 450 2 C 8 v v v Substrates; paclitaxel, torsemide, amodiaquine, cerivastatin, repaglinide Inhibited by: trimethoprim, quercetin, glitazones, gemfibrozil, montelukast Induced by: rifampin
Monoamine Oxidase v Many interactions n v v 112 listed for Selegiline! May be very significant Used less frequently due to safer agents
Pharmacokinetic: Metabolism Characteristics of interactions due to INCREASED metabolism v Induction of metabolizing enzymes n n n v v Timeframe is slow “Recovery” to basal state is also slow Mostly in hepatic microsomal enzymes but also in other tissues Clinical relevance is dependent upon timing of interaction, therapeutic index of affected drug, duration of therapy. Most frequently encountered inducing agents: n n n Phenobarbital, phenytoin, carbamazepine Rifampin > rifabutin Cigarettes and charred or smoked foods Prolonged and substantial ethyl alcohol ingestion Isoniazid
Mechanism of Induction of CYP 3 A 4 -Mediated Metabolism of Drug Substrates (Panel A) and the Resulting Reduced Plasma Drug Concentration (Panel B) Wilkinson, G. R. N Engl J Med 2005; 352: 2211 -2221
Pharmacokinetic: Metabolism Characteristics of interactions with DECREASED metabolism v Inhibition of metabolizing enzymes n n n v Timeframe is rapid Duration and extent of effect is dependent upon concentration of agents and enzyme affinities. • Maximum effect seen in 4 -5 half-lifes Mostly in hepatic microsomal enzymes (mixed-function oxidases of cytochrome P 450 system) • Other systems affected; less well characterized • Conjugation, acetylation, etc. • P 450 isoenzymes are variously affected. Most important with drugs with narrow TI, brittle hosts, agents with few alternate metabolic pathways n Examples: theophylline, antihypertensive agents, hypoglycemic agents, chemotherapeutic agents, some hormonal agents, HAART agents
The “Usual Suspects” - Inhibitors Amiodarone Ketoconazole Cimetidine Ciprofloxacin (1 A 2) Diltiazem Erythromycin (3 A 4) Ethanol (acute) Fluconazole (3 A 4) Fluoxetine (2 C 9, 2 C 19, 2 D 6) Fluvoxamine (1 A 2, 2 C 19, 3 A 4) Grapefruit (3 A 4) Isoniazid (2 E 1) Itraconazole (3 A 4) Ketaconazole (3 A 4) Metronidazole Miconazole (3 A 4) Nefazodone (3 A 4) Oral contraceptives Paroxetine (2 D 6) Phenylbutazone Quinidine (2 D 6) Sulfinpyrazone Valproate Verapamil
The “Usual Suspects” - Inducers Barbiturates (2 B) Carbamazepine (2 C 19, 3 A 4/5/7) Charcoal-broiled food (1 A 2) Dexamethasone Ethanol (chronic) (2 E 1) Griseofulvin Isoniazid (2 E 1) Primidone (2 B) Rifabutin (3 A 4) Rifampin (2 B 6, 2 CB, 2 C 19, 2 C 9, 2 D 6, 3 A 4/5/7) Tobacco smoke (1 A 2)
Relative Contribution to Drug Metabolism - Phase II Evans & Relling Science 1999
Pharmacokinetic: Excretion v Filtration n v Active secretion n n v Renally cleared drugs affected notably digoxin and aminoglycoside antibiotics Metabolic products of parent drug Highly dependent upon GFR of host, elderly of great concern Two non-specific active transport systems (pars recta) • Organic acids • Organic bases Also digoxin in distal tubule Reabsorption n Distal tubule and collecting duct Dependent on flow, p. H Useful for enhancing excretion of selected agents with inhibition • Probenecid, drug ingestions
Drug-Disease Interactions v v v v Liver disease Renal disease Cardiac disease (hepatic blood flow) Acute myocardial infarction? Acute viral infection? Hypothyroidism or hyperthyroidism? SIRS ?
Drug-Food Interactions v v v Tetracycline and milk products Warfarin and vitamin K-containing foods Grapefruit juice n Effects of grapefruit juice on felodipine pharmacokinetics and pharmacodynamics.
Effects of grapefruit juice on felodipine pharmacokinetics and pharmacodynamics Dresser GK et al Clin Pharmacol Ther 2000; 68(1): 28– 34
Drug-Herbal Interactions v v St. John’s wort with indinavir St. John’s wort with cyclosporin St. John’s wort with digoxin? Many others
After St. John’s wort
Drug Interactions in a Clinical Setting v A stepwise approach: Use mnemonic “THOUGHT” n n n n Take a good medications history: • “AVOID Mistakes” [Allergies, Vitamins and herbs, Old drugs/OTC, Interactions, Dependence, Mendel (polymorphisms)] High risk patients (multiple meds, old, frail, ill) Optimize therapy by decreasing number of drugs, use “lowproblem” agents Use interactions guides (pocket reference, computerized data banks, experts) Give counsel about OTC and “herbals” Have a monitoring plan to look for potential problems Time, remember some interactions will take time to occur; some are rapid
Assessing Impact of Inhibition of Metabolizing Enzymes 1. 2. 3. 4. 5. 6. 7. 8. What is the toxic potential and therapeutic index of the parent compound? (Converse may be true – see #3) What are the other pathways involved in the metabolism of the substrate. What is the role of an active metabolite? What is the result of inhibition? Is the inhibitor selective (one CYP) or broad in effect? Does the subject have an isoform of the enzyme that makes them a poor or rapid metabolizer? Do the metabolites have inhibitory effects of their own? How harmful (or helpful) is the inhibition?
Conclusions v Drug-drug interactions are part of drug therapy n n v Managing drug interactions is often more important than avoiding n n n v v v May be beneficial or hazardous Polypharmacy (therapy with many agents) is often unavoidable • Estimated that for 5 or more agents the probability of interaction approaches 100% Be most cautious with narrow TI agents Make use of resources Some interactions are absolutely contraindicated Drug interactions are significant cause of adverse drug events and cost billions in additional health care costs. At-risk patients are most affected, e. g. the elderly, the very young, the critically ill Presentation posted on Presbyterian Hospital Internal Medicine Residency website http: //phdres. caregate. net
Summary: Drug Interactions v v Pharmacokinetic drug interactions are defined as those that alter drug absorption, distribution, metabolism, or excretion. Pharmacodynamic drug interactions result in an alteration of the biochemical or physiological effects of a drug. Interactions of this type are more difficult to characterize than pharmacokinetic interactions.
Summary: Drug Interactions v v Drug interactions that alter the rate of absorption are usually of lesser concern that those that affect the extent. Overall outcomes of interactions of agonists and antagonists at the drug receptor are dependent on the varying affinities and activities of the different agents involved.
Summary: Drug Interactions v v v Alteration of metabolism of drugs in the liver, gut and other sites is an important but not singular source of significant drug interactions. In general, those drugs that are susceptible to the effects of induction of metabolism are also subject to inhibition. Drug interactions involving induction of metabolism develop more slowly than those involving inhibition.
Summary: Drug Interactions v A full profile of the interaction potential of any given drug generally takes an extended amount of time in the marketplace to be characterized. Many, but not all, important drug interactions are described in the official labeling.
Summary Drug Metabolism v v Polymorphism of CYP gene(s) can result in a “poor metabolizer” phenotype, but occurs in less than 20% of the U. S. general population. Prototypic inhibiting agents include: n v Ciprofloxacin, Erythromycin, Fluconazole, Fluoxetine, Grapefruit juice, Itraconazole Prototypic inducing agents include: n n Carbamazepine (2 C 19, 3 A 4/5/7) Rifampin (2 B 6, 2 CB, 2 C 19, 2 C 9, 2 D 6, 3 A 4/5/7)
Questions? v Blair Holbein, Ph. D. • Presbyterian Hospital of Dallas v v Email: bholbein@hcin. net Website: http: //phdres. caregate. net Annotated bibliography Slides n n April 29 : • Age and Pharmacokinetics: Pediatric and Geriatric Considerations May 2: • Drug Interactions
References v Wright JM. . Drug Interactions. n v In: Carruthers SG, Hoffman BB, et al. , ed. Melmon and Morrelli’s Clinical Pharmacology: Basic Principles in Therapeutics, 4 th ed. New York 2000 : Mc. Graw-Hill. Centers for Education & Research on Therapeutics n n Agency for Healthcare Research and Quality Dept. Health Human Service
Case Studies v Illustrate general principles n n n Patients at risk Management versus avoidance Varied presentations • Patient demographics • Interacting agents: drugs, foods, etc. • Therapeutic decision making
Case 1 v v v Mr. L. P. is a 47 year-old man who presents to the E. R with rapidly progressive worsening of his asthma. He states that he had been at a friend’s home for about 1 hour when he began to wheeze. He states that the friend has 3 cats and he is “very” allergic to cats. He repeatedly used his albuterol inhaler which usually provides relief. This time he perceived no benefit and quickly became very short of breath and came to the hospital.
Case 1, continued v His PMH is significant for his asthma and recently diagnosed mild hypertension. His medications include: • Budesonide 400 mcg twice daily by inhalation • Albuterol 180 mcg two puffs by inhalation as needed may repeat in 4 – 6 hours if needed • Nadolol 40 mg daily v v What accounts for his failure to respond to his inhaler What alterations would you make to his drug therapy?
Case 1, Discussion v The failure of the b-agonist to produce bronchodilatation is due to a direct pharmacodynamic antagonism by the b-blocker at the level of the adrenergic b receptor.
Case 1, Discussion continued v Non- b-1 selective b-blocker can be hazardous for asthmatic patients. n v v The non-selective agents are more problematic than the b-1 selective agents. • Patients can take the b -blocker for some time without incident until provoked. Fatal asthma attacks have been reported with this interaction. Note too that ophthalmic Timolol maleate is sufficiently absorbed to be included in this class. Ophthalmic solutions of betaxolol may be an alternative. Additional reading: Marshik PL and Kelly HW. Drug-induced pulmonary diseases. In: Di. Piro JT et al. Pharmacotherapy: A Pathophysiologic Approach 4 th edition.
Case 2 v v Miss J. K. is a 19 -year old black female. She calls your office complaining of drowsiness and says that she feels dizzy and unsteady on her feet. Her PMH includes partial seizures treated with 200 mg sustained release carbamazepine twice daily. She has been seizure-free for over 5 years and has tolerated therapy reasonably well after titration.
Case 2, continued v v v After questioning her mother you find out that J. K. had been seen by a dermatologist three days earlier who had prescribed itraconazole 200 mg daily for treatment of onychomycosis of J. K. ’s toenails. What has caused the symptoms in J. K. ? What therapeutic options are appropriate
Case 2, Discussion v Pharmacokinetic interaction n v v Itraconazole inhibits the metabolism of carbamazepine. J. K. ’s symptoms are from carbamazepine toxicity. Therapeutic alternatives available. n n Newer anti-epileptic medications • Better tolerability and fewer potential interactions. . The patient has had no seizures for 5 years. • Consider cautiously discontinuing seizure medication.
Case 2 Discussion, continued v If the cosmetic value of treating her onychomycosis is important n n Closely monitored adjustment of the carbamazepine dose can be made Pulse therapy is equally efficacious with decreased cost. However, this will not eliminate the need to adjust the carbamazepine dose.
Case 2 Discussion, continued v v v Constantly review medications for indications and adjusting accordingly. In patients receiving drugs with narrow therapeutic windows, it is imperative that they are aware of the need to discuss any therapeutic alterations with the primary physician. Additional reading: Mc. Namara JO. Drugs Effective in the Therapy of the epilepsies. In: Hardman JG and Limbird LE. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 10 th ed. Verrotti A. Discontinuation of anticonvulsant therapy in children with partial epilepsy. Neurology 2000; 55: 1393 -5.
Case 3 v v v Mrs. S. V. is an 87 -year old Hispanic woman who resides in a nursing home. The nurse calls you to report worsening mental status. Ten days ago your colleague added Diphenhydramine 50 mg at bedtime as a nonbenzodiazepine sleep aid. He also added Donepezil 5 mg daily two days ago after the nurse called reporting a change in mental status.
Case 3, continued v Medications n n n v v Amitriptylline 75 mg at bedtime for post-herpetic neuralgia Oxybutynin 5 mg three times daily for urinary incontinence Ipratropium bromide inhaler 2 puffs (36 mg) twice daily for her COPD Diphenhydramine 50 mg at bedtime Donepezil 5 mg daily Can Mrs. . S. V. ’s change in mental status be drug-induced? If so, why? What should be done in this case?
Case 3 Discussion v v v Pharmacodynamic interactions acting in concert. The addition of Diphenhydramine resulted in a delirium due to additive anticholinergic side effects of her other medications. Donepezil, which is a cholinesterase inhibitor, is indicated for dementia and was erroneously added to try to reverse the side effects.
Case 3 Discussion, continued v v v Drug therapy in the elderly requires careful attention to the alterations in pharmacokinetics of many medications. Every medication in a therapeutic regimen requires careful consideration. Minimizing the number of medications and using lower doses is a good strategy in geriatric pharmacotherapy. n n Drug metabolism via conjugation better preserved than P 450. Renal clearance proportional to GFR.
Case 3 Discussion, continued v Discontinue the Diphenhydramine and Donepezil. Evaluate the need for the Amitriptylline and discontinue if possible. Reevaluate the need for the Ipratropium and Oxybutynin. v Additional reading: v v n n Montamont SC and Vestal RE. Management of drug therapy in the elderly. N Engl J Med 1989; 321: 303 -9 Avorn J and Gurwitz JH. Principles of Pharmacology. In Cassel CK et al. Geriatric Medicine, 3 rd Ed.
Case 4 v v v Mr. J. H. is a 59 -year old male with a mechanical aortic valve. He takes anticoagulant medication, Warfarin 10 mg daily, and his INR has been stable at 3. 0 for over a year. He calls and reports that his gums are bleeding following routine oral hygiene. You ask him to come to the clinic. n Lab reports the INR = 6.
Case 4, continued v You question him about any changes in his diet and medications. He states that nothing has changed except the brand of daily vitamins that he usually takes. n n He changed from One-a-Day Maximum to Centrum Silver. • He further states that he changed his “heartburn medicine” from Ranitidine to Cimetidine because of cost. • Upon further questioning he also admits to starting Ginko supplements because he is worried about getting Alzheimer’s Disease. Is the change in anticoagulation attributable to his change in vitamins, non-prescription medicines and/or supplements? What do you need to do to prevent similar problems in the future
Case 4 Discussion v This is both a pharmacodynamic and a pharmacokinetic interaction. n n Non-prescription medications can cause adverse drug events. Vitamin K antagonizes the pharmacodynamic effect of Warfarin • One-a-Day Maximum (with K) versus Centrum Silver (without K) • Many vitamin preparations contain varying amounts of vitamin K. • Cimetidine inhibits the metabolism of Warfarin; Ranitidine does not. • Ginko has been reported to have an anticoagulant effect that is either additive or synergistic with Warfarin.
Case 5 v v v Mr. D. N. is a black 64 -year old male. He was brought into the E. R. by his wife. She said that he had become weak and unable to stand unassisted. His blood pressure was 78/45 supine. He has a positive tilt. His wife reports that he had followed his routine of taking his medications followed by breakfast. About 2 hours later he said that he began to feel “bad. ” His PMH includes moderate hypertension, hypercholesterolemia, and benign prostatic hypertrophy. His breakfast this morning was 8 oz. grapefruit juice and low-fat cereal with skim milk.
Case 5, continued v His medications include: n n n v v Felodipine 5 mg daily for his hypertension Atorvastatin 10 mg daily for his hypercholesterolemia Terazosin 5 mg daily for his BPH. What caused his drop in blood pressure. What changes in his medications do you need to make?
Case 5 Discussion v Pharmacokinetic interaction n v v Enhanced absorption of the felodipine The intestinal metabolism of a number of medications, including felodipine and atorvastatin, is a substantial proportion of the overall metabolism. Grapefruit juice inhibits intestinal CYP 3 A 4 enzymes which results in higher blood levels of the drugs.
Case 5 Discussion, continued v v The drop in blood pressure in Mr. D. N. is attributable to the elevated peak in felodipine levels. Terazosin is a selective a-1 - adrenergic blocker that can cause orthostatic hypotension. n Pharmacodynamic interaction • May also account for the symptomatic hypotension.
Case 5 Discussion, continued v v Patients should be warned to avoid grapefruit juice if they are taking any of the medications known to have interactions. Consider using an antihypertensive with less orthostatic side effects and better cardiovascular profile in this patient with hypercholesterolemia and potential atherosclerosis. His BPH can be treated with Finasteride as an alternative. Additional reading: Kane GC; Lipsky JJ. Drug-grapefruit juice interactions. Mayo Clin Proc 2000; 75: 933 -42.
Case 6 v v v Mr. J. H. is a 64 -year old white male. He has mild chronic heart failure. In accordance to the U. S. Carvedilol Heart Failure Study that showed improved survival in heart failure patients receiving carvedilol, you decide to start him on carvedilol. You initiate therapy with carvedilol 3. 125 mg twice daily and expect to titrate upwards to a goal of 50 mg twice daily.
Case 6 continued v v v His other medications include: Lovastatin 40 mg daily Digoxin 0. 125 mg daily Ranitidine 300 mg a. m. and at bedtime for reflux Aspirin 81 mg daily Furosemide 20 mg in the morning Lisinopril 5 mg daily The pharmacist calls and says that the computerized drug interaction program “DRUG-REAX® Interactive Drug Interactions” indicated an class warning of an interaction between digoxin and beta-blockers with the possibility of inducing heart block and suggests that you choose an ACE inhibitor instead. What is your response?
Case 6 Discussion v Your response: n Continue with therapy prescribed. • The U. S. Carvedilol Heart Failure Study included patients receiving digoxin with carvedilol and demonstrated improved survival.
Case 6 Discussion, continued v v v Many of the computerized drug-interaction programs will flag interactions with a complete range of severity and degree of documentation. Many will flag a class of drugs without regard to individual agents within the class. In managing drug therapy it is impossible to provide optimum drug therapy without occasionally incurring known drug interactions. It requires clinical judgment to manage drug interactions while optimizing therapy. In the case of carvedilol and digoxin, the class warning is not sufficient reason to change a therapy with a likelihood of providing significant survival benefit. Nonetheless, careful attention to the tolerance of a new therapy is necessary. Additional reading: Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U. S. Carvedilol Heart Failure Study Group. N Engl J Med 1996; 334: 1349 -55.
Case 7 v v Mr. R. D. is a 15 -year old white male whose mother calls your office asking for an additional pain medication for her son. He had major orthodonic surgery the day before. The dental surgeon prescribed Tylenol#3 (Acetaminophen - 300 mg + Codeine Phosphate - 30 mg) to be taken two (2) tablets every 6 hours, as needed. The mother says that her son is in substantial pain that is unrelieved by the prescription. When she contacted the oral surgeon he was concerned about “drug-seeking” by the boy. v What is your response? v What additional information do you need?
Case 7 Discussion v v v Inactive codeine is metabolized to an active intermediate by CYP 2 D 6. Patients with multiple CYP 2 D 6 gene copies metabolize codeine more rapidly (ultra-rapid metabolism). 4 to 5% of the United States population and up to 29% of the population of Ethiopia and Saudi Arabia. Patients that lack functional CYP 2 D 6 genes do not metabolize codeine to morphine and do not experience analgesic effects. n v v CYP 2 D 6 is absent in 5 to 10% of the Caucasian population. Your patient may have an altered drug metabolism. Inquiries about family history for evidence of polymorphism or OTC medications may be useful.
Case 7 Discussion continued v v v Your patient may have an altered drug metabolism. Dextromethorphan is a competitive inhibitor of 2 D 6 activity. It is also a common ingredient in OTC cough medications. Inquiries about OTC medications may be useful. To avoid these problems, agents with hydrocodone are a better choice. Otherapeutic concerns include inadequate dosing. Patient information should include sufficient information (weight, height, BMI) for adjusted dosing.
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