Drug Interactions M. E. Blair Holbein, Ph.D. Clinical Pharmacologist Presbyterian Hospital of Dallas

Drug InteractionsDrug Interactions

M. E. Blair Holbein, Ph.D.

Clinical Pharmacologist

Presbyterian Hospital of Dallas

Drug Interactions

Introduction Concepts Case examples Questions

Why study drug interactions?

er

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

Clinical Significance of Drug Interactions

Over 2 MILLION serious ADRs and 100,000 deaths yearly ADRs 4th 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

Preventable drug interactions are 1/3 of adverse drug events and 1/2 cost.

Wright JM. 2000. Drug Interactions. In: Carruthers SG, Hoffman BB, et al. , ed. Melmon and Morrelli’s Clinical Pharmacology: Basic Principles in Therapeutics, 4th ed. New York:McGraw-Hill.

Definition

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)

May be harmful: toxicity, reduced efficacy May be beneficial: synergistic combinations, pharmacokinetic boosting,

increased convenience, reduced toxicity, cost reduction .

Characterizing Drug Interactions

MechanismPharmacodynamic

Receptor inhibitionAdditive effects

PharmacokineticAltered absorption,

distribution, metabolism, or elimination

Interacting agentsDrug-drug

PrescriptionNon-prescriptionIllicit, recreational

Food, supplements, herbal products

Clinical SignificanceMajor

Substantial morbidity and mortalityTherapy altering

ManageableLittle or no change in therapyOptimize therapy

IntentionalAdditive or synergistic effectsEnhanced pharmacokinetics

Mechanisms of Interactions

Pharmacodynamic

Receptor

Non-receptor

Pharmacokinetic

Absorption

Distribution

Metabolism

Excretion

Pharmacodynamic: Pharmacological

Interaction at the drug receptor Activity is function of intrinsic activity and affinity for

receptor Agonist and antagonists

• Effect also function of concentration at receptor Effect can be additive

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

Agents that can act in concert or in opposition via different cellular mechanisms.

Both theophylline and -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

Altered cellular environment Agents that change the state of the host

• Hypokalemia caused by diuretics increases toxicity of digoxin.

Pharmacodynamic: Neutralization

Neutralization systemically in the host (as opposed to prior to absorption)

Protamine used to neutralize heparin Purified antidigoxin Fab fragments used to treat digoxin toxicity

Mechanisms of Interactions

Pharmacodynamic

Receptor

Non-receptor

Pharmacokinetic

Absorption

Distribution

Metabolism

Excretion

Pharmacokinetic: Absorption

Alters rate that drug enters the system with altered level or time to peak

Mechanisms: Physical interaction, chelation, binding. e.g. tetracyclines and

cations Altered GI function: changes in pH (ketoconazole), motility,

mucosal function, metabolism, absorption sites, perfusion

Absorption: in the gut

Sucralfate, some milk products, antacids, and oral iron preparations

Omeprazole, lansoprazole,H2-antagonists

Didanosine (givenas a buffered tablet)

Cholestyramine

Block absorption of quinolones, tetracycline, and azithromycin

Reduce absorption of ketoconazole, delavirdine

Reduces ketoconazole absorption

Binds raloxifene,thyroid hormone, and digoxin

Interactions: Presystemic Elimination

Gut transit and metabolism Intestinal wall CYP3A4 metabolizes a number of drugs Inhibition/induction results in altered bioavailability Ex: grapefruit juice inhibits intestinal CYP3A4

• 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

Inhibition results in increased bioavailabilty. Propranolol, metoprolol, labetalol, verapamil, hydralazine,

felodipine, clhlorpromazine, imipramine, amitriptyline, morphine

Fig: First pass metabolism

Wilkinson, G. R. N Engl J Med 2005;352:2211-2221

First-Pass Metabolism after Oral Administration of a Drug, as Exemplified by Felodipine and Its Interaction with Grapefruit Juice


Consequences of the Inhibition of First-Pass Metabolism, as Exemplified by the Interaction between Felodipine and Grapefruit Juice


Some Common Drugs with Low Oral Bioavailability and Susceptibility to

First-Pass Drug Interactions

Monoamine Oxidase Inhibitors

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 Relative to :

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)• .1-acid glycoprotein (basic drugs) • acute phase reactants


Protein-binding displacement Effect is rapid and transient and usually compensated

by increased elimination May result in transient pharmacologic effect Overall result is unpredictable New steady-state attained


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. Cyclosporin A, quinidine, verapamil, itraconazole and

clarithromycin inhibit PGP Some correlation with CYP3A4 affinities

May be significant for some anticancer drugs

Phases of Drug Metabolism

Phase IOxidation/Reduction/Hydrolysis

Phase IIConjugation

Drug Interactions Due to Hepatic MetabolismNearly always due to interaction at Phase I enzymes, rather than Phase II

i.e. commonly due to interaction at cytochrome P450 enzymes…some of which are genetically variable in population

Relative Contribution to Drug Metabolism - Phase I

Evans & Relling Science 1999

http://www.sciencemag.org/cgi/content/full/286/5439/487?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=relling&searchid=1114544535046_9445&stored_search=&FIRSTINDEX=0



Hepatic Metabolism

Cytochrome P450 system responsible for the majority of oxidative reactions

Significant polymorphism in many. CYP2C9, CYP2C19, and CYP2D6—can be even be

genetically absent! Drugs may be metabolized by a single isoenzyme

Desipramine/CYP2D6; indinavir/CYP3A4; midazolam/CYP3A; caffeine/CYP1A2; omeprazole/CYP2C19

Drugs may be metabolized by multiple isoenzymes Most drugs metabolized by more than one isozyme

• Imipramine: CYP2D6, CYP1A2, CYP3A4, CYP2C19 If co-administered with CYP450 inhibitor, some isozymes may

“pick up slack” for inhibited isozyme.

Pharmacokinetic: Metabolism 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.

Host factors include age, genetic makeup (acetylation, CYP2D6), nutritional state, disease state, hormonal milieu, environmental and exogenous chemical exposure.

P450 isoenzymes are variously affected. Isoenzymes characterized

• Substrates• Inhibiting agents• Inducing agents

No consistent correlation of substrate versus inhibitor or inducer Good reference: http://medicine.iupui.edu/flockhart/

Cytochrome P450 Nomenclature

e.g. for CYP2D6

CYP = cytochrome P4502 = genetic familyD = genetic sub-family 6 = specific gene

NOTE that this nomenclature is genetically based: it has NO functional implication

Proportion of Drugs Metabolized by CYP450 Enzymes

CYP2C198%

CYP1A211%

CYP2A63%

CYP2C916%

CYP2E14%

CYP3A438%

CYP2D620%

Cytochrome P450 3A4,5,7 Largest number of drugs metabolized Present in the largest amount in the liver.

Present in GI tract Not polymorphic

Inherent activity varies widely Activity has been shown to predominate in the gut.

Responsible for metabolism of: Most calcium channel blockers Most benzodiazepines Most HIV protease inhibitors Most HMG-CoA-reductase inhibitors Cyclosporine Most non-sedating antihistamines Cisapride

Cytochrome P450 3A4,5,7 -continued

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 CYP3A, According to Drug

Class

Cytochrome P450 2D6

Second largest number of substrates. Polymorphic distribution

Majority of the population is characterized as an extensive or even ultra-extensive metabolizer.

Approximately 7% of the U.S. Caucasian population and 1-2% of African or Asian inheritance have a genetic defect in CYP2D6 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

Common Drug Substrates and Clinically Important Inhibitors of CYP2D6


Cytochrome P450 2C9

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 P450 1A2

Substrates include: theophylline, imipramine, clozapine

Inhibited by: many fluoroquinolone antibiotics, fluvoxamine, cimetidine

Induced by: smoking tobacco

Copyright restrictions may apply.

Cornelis, M. C. et al. JAMA 2006;295:1135-1141.

Coffee Intake and Relative Risk of Myocardial Infarction by CYP1A2 Genotype

Cytochrome P450 2C19

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 P450 2B6

Substrates include: bupropion, cyclophosphamide, efavirenz, methadone

Inhibited by: thiotepa Induced by: phenobarbital, rifampin

Cytochrome P450 2E1

Substrates include: acetaminophen

Cytochrome P450 2C8

Substrates; paclitaxel, torsemide, amodiaquine, cerivastatin, repaglinide

Inhibited by: trimethoprim, quercetin, glitazones, gemfibrozil, montelukast

Induced by: rifampin

Monoamine Oxidase

Many interactions 112 listed for Selegiline!

May be very significant Used less frequently due to safer agents

Pharmacokinetic: Metabolism

Characteristics of interactions due to INCREASED metabolism Induction of metabolizing enzymes

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: Phenobarbital, phenytoin, carbamazepine Rifampin > rifabutin Cigarettes and charred or smoked foods Prolonged and substantial ethyl alcohol ingestion Isoniazid


Mechanism of Induction of CYP3A4-Mediated Metabolism of Drug Substrates (Panel A) and the Resulting Reduced Plasma Drug

Concentration (Panel B)

Pharmacokinetic: Metabolism

Characteristics of interactions with DECREASED metabolism Inhibition of metabolizing enzymes

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 P450 system)

• Other systems affected; less well characterized• Conjugation, acetylation, etc.

• P450 isoenzymes are variously affected. Most important with drugs with narrow TI, brittle hosts, agents with few

alternate metabolic pathways Examples: theophylline, antihypertensive agents, hypoglycemic agents,

chemotherapeutic agents, some hormonal agents, HAART agents

The “Usual Suspects” - Inhibitors

Amiodarone

Ketoconazole

Cimetidine

Ciprofloxacin (1A2)

Diltiazem

Erythromycin (3A4)

Ethanol (acute)

Fluconazole (3A4)

Fluoxetine (2C9, 2C19, 2D6)

Fluvoxamine (1A2, 2C19, 3A4)

Grapefruit (3A4)

Isoniazid (2E1)

Itraconazole (3A4)

Ketaconazole (3A4)

Metronidazole

Miconazole (3A4)

Nefazodone (3A4)

Oral contraceptives

Paroxetine (2D6)

Phenylbutazone

Quinidine (2D6)

Sulfinpyrazone

Valproate

Verapamil

The “Usual Suspects” - Inducers

Barbiturates (2B)

Carbamazepine (2C19, 3A4/5/7)

Charcoal-broiled food (1A2)

Dexamethasone

Ethanol (chronic) (2E1)

Griseofulvin

Isoniazid (2E1)

Primidone (2B)

Rifabutin (3A4)

Rifampin (2B6, 2CB, 2C19, 2C9, 2D6, 3A4/5/7)

Tobacco smoke (1A2)

Relative Contribution to Drug Metabolism - Phase II

Evans & Relling Science 1999




Pharmacokinetic: Excretion Filtration

Renally cleared drugs affected notably digoxin and aminoglycoside antibiotics

Metabolic products of parent drug Highly dependent upon GFR of host, elderly of great concern

Active secretion Two non-specific active transport systems (pars recta)

• Organic acids• Organic bases

Also digoxin in distal tubule Reabsorption

Distal tubule and collecting duct Dependent on flow, pH Useful for enhancing excretion of selected agents with inhibition

• Probenecid, drug ingestions

Drug-Disease Interactions

Liver disease Renal disease Cardiac disease (hepatic blood flow) Acute myocardial infarction? Acute viral infection? Hypothyroidism or hyperthyroidism? SIRS ?

Drug-Food Interactions

Tetracycline and milk products Warfarin and vitamin K-containing foods Grapefruit juice

Effects of grapefruit juice on felodipine pharmacokinetics and pharmacodynamics.

Dresser GK et al Clin Pharmacol Ther 2000;68(1):28–34

Effects of grapefruit juice on felodipine pharmacokinetics and pharmacodynamics

Drug-Herbal Interactions

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 A stepwise approach: Use mnemonic “THOUGHT”

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 “low-problem”

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. What is the toxic potential and therapeutic index of the parent compound? (Converse may be true – see #3)

2. What are the other pathways involved in the metabolism of the substrate.

3. What is the role of an active metabolite?4. What is the result of inhibition?5. Is the inhibitor selective (one CYP) or broad in effect?6. Does the subject have an isoform of the enzyme that

makes them a poor or rapid metabolizer? 7. Do the metabolites have inhibitory effects of their own?8. How harmful (or helpful) is the inhibition?

Conclusions Drug-drug interactions are part of drug therapy

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%

Managing drug interactions is often more important than avoiding 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

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.


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.


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.


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

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: Ciprofloxacin, Erythromycin, Fluconazole, Fluoxetine,

Grapefruit juice, Itraconazole Prototypic inducing agents include:

Carbamazepine (2C19, 3A4/5/7) Rifampin (2B6, 2CB, 2C19, 2C9, 2D6, 3A4/5/7)

Questions? Blair Holbein, Ph.D.

• Presbyterian Hospital of Dallas Email: [email protected] Website: http://phdres.caregate.net Annotated bibliography Slides

April 29 : • Age and Pharmacokinetics: Pediatric and Geriatric

Considerations May 2:

• Drug Interactions

References

Wright JM.. Drug Interactions. In: Carruthers SG, Hoffman BB, et al. , ed. Melmon and Morrelli’s

Clinical Pharmacology: Basic Principles in Therapeutics, 4th ed. New York 2000 :McGraw-Hill.

Centers for Education & Research on Therapeutics Agency for Healthcare Research and Quality Dept. Health Human Service

Case Studies

Illustrate general principles Patients at risk Management versus avoidance Varied presentations

• Patient demographics• Interacting agents: drugs, foods, etc.• Therapeutic decision making

Case 1

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

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

What accounts for his failure to respond to his inhaler What alterations would you make to his drug therapy?

Case 1, Discussion

The failure of the -agonist to produce bronchodilatation is due to a direct pharmacodynamic antagonism by the -blocker at the level of the adrenergic receptor.

Case 1, Discussion continued

Non- -1 selective -blocker can be hazardous for asthmatic patients.

The non-selective agents are more problematic than the -1 selective agents.

• Patients can take the -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: DiPiro JT et al. Pharmacotherapy: A Pathophysiologic Approach 4th edition.

Case 2

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 the therapy reasonably well after titration.

Case 2, continued

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

Pharmacokinetic interaction Itraconazole inhibits the metabolism of carbamazepine.

J. K.’s symptoms are from carbamazepine toxicity. Therapeutic alternatives available.

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

If the cosmetic value of treating her onychomycosis is important

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.


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: McNamara JO. Drugs Effective in the Therapy of the epilepsies. In: Hardman JG and Limbird LE. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. Verrotti A. Discontinuation of anticonvulsant therapy in children with partial epilepsy. Neurology 2000;55:1393-5.

Case 3

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 non-benzodiazepine 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

Medications 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

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.


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.

Drug metabolism via conjugation better preserved than P450. Renal clearance proportional to GFR.


Discontinue the Diphenhydramine and Donepezil. Evaluate the need for the Amitriptylline and discontinue

if possible. Reevaluate the need for the Ipratropium and

Oxybutynin.

Additional reading: 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, 3rd Ed.

Case 4

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. Lab reports the INR = 6.

Case 4, continued

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.

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

This is both a pharmacodynamic and a pharmacokinetic interaction.

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 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

His medications include: 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

Pharmacokinetic interaction 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 CYP3A4 enzymes which results in higher blood levels of the drugs.


The drop in blood pressure in Mr. D.N.is attributable to the elevated peak in felodipine levels.

Terazosin is a selective -1- adrenergic blocker that can cause orthostatic hypotension.

Pharmacodynamic interaction• May also account for the symptomatic

hypotension.


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

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

His other medications include:Lovastatin 40 mg dailyDigoxin 0.125 mg dailyRanitidine 300 mg a.m. and at bedtime for reflux Aspirin 81 mg dailyFurosemide 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

Your response: Continue with the therapy prescribed.

• The U. S. Carvedilol Heart Failure Study included patients receiving digoxin with carvedilol and demonstrated improved survival.


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

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.

What is your response?

What additional information do you need?

Case 7 Discussion

Inactive codeine is metabolized to an active intermediate by CYP2D6.

Patients with multiple CYP2D6 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 CYP2D6 genes do not metabolize codeine to morphine and do not experience analgesic effects.

CYP2D6 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

Your patient may have an altered drug metabolism. Dextromethorphan is a competitive inhibitor of 2D6

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. Other therapeutic concerns include inadequate dosing.

Patient information should include sufficient information (weight, height, BMI) for adjusted dosing.

Documents

Drug Interactions M. E. Blair Holbein, Ph.D. Clinical Pharmacologist Presbyterian Hospital of Dallas