drug interactions m. e. blair holbein, ph.d. clinical pharmacologist presbyterian hospital of dallas
TRANSCRIPT
Drug InteractionsDrug Interactions
M. E. Blair Holbein, Ph.D.
Clinical Pharmacologist
Presbyterian Hospital of Dallas
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
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
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
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
Pharmacokinetic: Distribution
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
Pharmacokinetic: Distribution
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
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
Wilkinson, G. R. N Engl J Med 2005;352:2211-2221
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
Wilkinson, G. R. N Engl J Med 2005;352:2211-2221
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 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
Wilkinson, G. R. N Engl J Med 2005;352:2211-2221
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
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.
Summary: Drug 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.
Summary: Drug Interactions
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
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.
Case 2 Discussion, continued
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.
Case 3 Discussion, continued
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.
Case 3 Discussion, continued
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.
Case 5 Discussion, continued
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.
Case 5 Discussion, continued
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.
Case 6 Discussion, continued
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.