Pharmacokinetic and Pharmacodynamic Drug Interactions in Palliative Care

Pharmacokinetic and Pharmacodynamic Drug Interactions in Palliative Care Kathryn Walker, Pharm.D., BCPS, CPE Assistant Professor University of Maryland School of Pharmacy

Disclosure • Nothing to disclose

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Learning Objectives • Differentiate between pharmacokinetic and pharmacodynamic drug properties • Define a drug interaction • List 3 drug-drug interactions that are common in long term care facilities

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Are Palliative Care Patients at Risk for Drug Interactions (DI)?

• General population: 3-20% depending on severity of illness and number of medications • Risk Factors: – Live alone – 3 or more medications – Elderly and/or memory problems – Many doctors and pharmacies involved – Adherence Bruera E, Bernard SA. JCO. 2000; 18:1780-1799.

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Illustrating the Challenge • Average 5.6 (1-16) medications per patient (n=106) • 60% noncompliant (n=111 terminally ill palliative care patients) • 33% took less medications than prescribed (commonly analgesics) • 16% took additional medication (e.g., OTC vitamins/analgesics) • 11% both

• 90% had two or more prescribers Zeppetella G. Palliat Med. 1999; 13:469-475.

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Illustrating the Challenge • Survey of 405 cancer patients • 25% at risk for potential drug interactions • 87% noncancer medications (e.g., warfarin, HTN corticosteroids, anticonvulsants) • Severity – 9% considered major interactions – 77% considered moderate interactions

Riechelmann RP, et al. J Natl Cancer Inst. 2007; 99: 592-600.

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Challenges in Palliative Care • Difficult to distinguish between “True” drug interactions vs. disease progression or adverse effect

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Pharmaco-Stuff • Pharmacokinetic – Absorption, distribution, metabolism, excretion

• Pharmacodynamic – The action of the drug once it reaches its target (receptor) in the body

• Pharmaceutical – Relating to the preparation of the drug, including its inactive components, form, solvent, etc.

Defining a Drug Interaction • “A measurable modification (in magnitude or duration) of the action of one drug by prior or concomitant administration of another substance.”

– Drug-drug (Rx, OTC, herbal) – Drug-food, drug-alcohol – Drug-lab, drug-disease, drug-chemical

Wright 1992. Drug Interactions. In: Melmon and Morrelli’s Clinical Pharmacology 1992

Drug metabolism in the liver • Metabolism is characterized by two phases of enzymatic reactions which make the drug more water soluble to facilitate elimination from the body – Phase I (biotransformation) • Oxidation, hydroxylation, reduction, hydrolysis • Chemical modification to add a functional group

– Phase II (conjugation) • Functional group used to attach a conjugate • Acetylation, glucuronidation, sulfation, methylation

Phase I Drug Oxidation

www.fda.gov/cder/drug/drugReactions/

Cytochrome P450 System • A very large and diverse superfamily of hemecontaining proteins – Founds in mammals, birds, fish, insects, worms, sea squirts, sea urchins, plants, fungi, slime molds, bacteria and archaea

• The cytochrome P450 system – Drug-metabolizing enzymes – Enzymes that are used to make cholesterol, steroids, and other lipids (prostacyclins, thromboxane A2)

Cytochrome P450 Oxidase (CYP2C9)

http://en.wikipedia.org/wiki/Image:CytP450Oxidase-1OG2.png

Cytochrome P450 Nomenclature (e.g. CYP2D6) CYP = cytochrome P450 (root) 2 = genetic family D = genetic sub-family 6 = specific gene – All CYP isoenzymes in the same family have at least 40% structural similarity – All member in the same subfamily have at least 60% structural similarity • NOTE that this nomenclature is genetically based: it has NO functional implication • • • •

www.fda.gov/cder/drug/drugReactions/

Major CYP450 Enzymes • More than 90% of human drug metabolism is due to six CYP isoenzymes • 1A2 • 2C9 • 2C19 • 2D6 • 2E1 • 3A4

Importance of CYP450s Relative Importance of P450s in Drug Metabolism CYP2E1

Relative Quantities of P450s in Liver

CYP1A2

?

CYP1A2

CYP2C CYP2C CYP3A CYP2D6

CYP2E1 CYP3A

Shimada T et al. J Pharmacol Exp Ther 1994;270(1):414. www.fda.gov/cder/drug/drugReactions/

CYP2D6

Consequences of drug metabolism • • • • • •

Inactive products Active metabolites Similar to parent drug More active than parent New action Toxic metabolites

www.fda.gov/cder/drug/drugReactions/

Alteration in drug metabolism • May alter consequences of drug metabolism • Altered activity may be due to – Interacting drugs that increase or decrease inherent enzyme activity – Inter-individual capability of metabolic enzymes – Other patient factors

What is a substrate?

• Substrate – a compound that is metabolized by a given enzyme – Fluoxetine (substrate) is metabolized by CYP2D6 and CYP3A4 • More than one enzyme can metabolite a single agent • If one enzyme system is shut down (or otherwise altered) the other can still metabolize fluoxetine

What is an inhibitor?

• Inhibitor – a compound that “slows down” the metabolism of a substrate by a given enzyme – Fluoxetine (inhibitor) slows down the metabolism of desipramine (substrate) by CYP2D6 – Causes desipramine levels to rise – Can have adverse clinical consequences • Arrhythmias • Possibly fatal

http://apotential.wordpress.com/2011/08/22/how-to-memorize-cyp450/

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What is an inducer?

• Inducer – a compound that “speeds up” the metabolism of a substrate by a given enzyme – Carbamazepine (inducer) speeds up the metabolism of clozapine (substrate) by both CYP1A2 and CYP3A4.

– Clozapine plasma levels will fall – If carbamazepine is discontinued, clozapine levels will rise

• Potent inducers of multiple CYP450 enzymes: – Rifampin, barbiturates, carbamazepine, griseofulvin, primidone, phenytoin – Roy’s Black Car Goes Putt Putt

http://apotential.wordpress.com/2011/08/22/how-to-memorize-cyp450/

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Effects of inducers and inhibitors Toxic

Concentration of Drug X

Therapeutic

A

B

Subtherapeutic

Drug Y

Drug Z

A – an inducer (Drug Y) was added to drug regimen (Drug X) B – an inhibitor (Drug Z) was added to drug regimen (Drug X)

www.drug-interactions.com

Methadone: bad kitty • Primarily metabolized by N-demethylation to an inactive metabolite: – 2-ethylidene-1,5-dimethyl-3,3diphenylpyrrolidene (EDDP)

• Metabolized by – CYP3A4, CYP2B6, and CYP2C19 – To a lesser extent CYP2C9 and CYP2D6 Weschules, et al. Pain Medicine. 2008;9:315-44.

Methadone Inhibitors • • • • • • • • • •

Amiodarone (Cordarone) Cimetidine (Tagamet) Ciprofloxacin (Cipro) Erythromycin (EES) Clarithromycin (Biaxin) Fluconazole (Diflucan) Fluoxetine (Prozac) Paroxetine (Paxil) Ketoconazole (Nizoral) Ritonavir (Norvir)

• Results in INCREASED methadone serum concentrations • Reduce calculated methadone dose by approximately 25%

Methadone Inducers • Carbamazepine (Tegretol) • Phenobarbital (Luminal) • Phenytoin (Dilantin) • Primidone (Mysoline) • Rifampin (Rifadin) • METHADONE (autoinduces)

• Results in REDUCED methadone serum concentrations • Encourage use of breakthrough opioid as needed

Polymorphic distribution for CYP2D6

Number of Subjects

• Polymorphic = a trait that has differential expression in >1% of the population

PM

EM Increasing Metabolic Capacity

www.fda.gov/cder/drug/drugReactions/

URM

Metabolizer status in racial/ethnic groups Enzyme

Phenotype

Frequencies

CYP1A2

PM

Caucasians 12%

CYP2C9

PM

Caucasians 2-6%

CYP2C19

PM

Caucasians 2-6% Chinese 15-17% Japanese 18-23%

CYP2D6

PM

Caucasians 3-10% Chinese/Japanese/ AA < 2%

UR

Ethiopians 20% Hispanics 7% Scandinavians 1.5%

Pain Medicine 2004;5(1):81-93

PM â&#x20AC;&#x201C; poor metabolizer UR â&#x20AC;&#x201C; ultra-rapid metabolizer

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Top Ten DI in LTC Drug Interaction

Description

Warfarin ↔ NSAIDs

Bleeding risk

Warfarin ↔ Sulfa drugs

Bleeding risk

Warfarin ↔ Macrolides

Bleeding risk

Warfarin ↔ Quinolones

Bleeding risk

Warfarin ↔ Phenytoin

Bleeding risk

ACE Inhibitors ↔ Potassium Supplements Increased K levels ACE Inhibitors ↔ Spironolactone

Increased K levels

Digoxin↔ Amiodarone

Digoxin toxicity

Digoxin↔ Verapamil

Digoxin toxicity

Theophylline↔ Quinolones

Theophylline toxicity

http://www.amda.com/tools/clinical/m3/topten.cfm

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Drug interactions in palliative care • Mostly involve warfarin and anticonvulsants • Higher risk groups – Older – More comorbidity – Increasing number of meds – CNS tumors

Riechelmann, et al. J Pain Symptom Manage. 2008;35:535-43.

Examples in palliative care • Codeine (CYP2D6) – Poor metabolizers are unable to convert codeine to morphine (no pain relief)

• Hydrocodone, oxycodone (CYP2D6) – Structurally similar to codeine and as such their metabolism could be under genetic control leading to variability of clinical response (side effects, efficacy, and dependence) Bernard. Hematol Oncol Clin N Am 2002;16:641-55.

Examples in palliative care • Phenytoin (CYP1A2, CYP2C9, CYP2C19) – Phenytoin toxicity for poor metabolizers; low levels of drug for ultra-rapid metabolizers at therapeutic doses

• Diazepam (CYP2C19, CYP3A4) – Unacceptable prolonged sedation in poor metabolizers, unconsciousness noted more in Asian populations Bernard. Hematol Oncol Clin N Am 2002;16:641-55.

Examples in palliative care • Venlafaxine (CYP2D6) – Metabolism slower in those lacking a functional CYP2D6 gene

• Nortriptyline (CYP2D6, CYP1A2) – Ultra-rapid metabolizers require up to 500 mg/day to reach therapeutic dose

Bernard. Hematol Oncol Clin N Am 2002;16:641-55.

Warfarin • Several hundred interacting drugs, foods, herbs, and supplements, and the list continues to expand • Potentiation (high INR): acetaminophen, amiodarone, ciprofloxacin, fenofibrate, fish oil, sertraline, metronidazole, fluconazole, traimethoprim/sulfamethoxazole • Induce (low INR): vitamin K foods, avocado, sucralfate, all inducers Holbrook et al. Arch Intern Med 2005;165:1095-1106.

Mnemonic and mechanisms of Interaction for the FAB-4 Significant Warfarin Drug Interactions Medication F

A B

Mechanism of Drug Interaction

Clinical Outcome

Patient Education

Elevated INR

Inform patient of drug interaction and management approach.

Fluconazole (Diflucan)

• Inhibition of CYP2C9 • Decreased vitamin K production

Amiodarone (Cordarone)

• Inhibition of CYP2C9

Increased risk of bleeding

Bactrim (TMP/SMX)

• Inhibition of CYP2C9 • Decreased vitamin K production

Consider alternative agents when appropriate

Four Flagyl (metronidazole)

• Inhibition of warfarin metabolism • Decreased vitamin K production

The Consultant Pharmacist March 2009; Vol 24, No 3

Stress importance of follow-up and frequent INR monitoring.

Review sxs bleeding and actions to take 41

Food-drug interactions • Grapefruit juice – a selective inhibitor of intestinal metabolism – Inhibits CYP3A enzymes in intestinal cells (minimal effect on hepatic CYP3A enzymes) – Felodipine increased from 14.2% with water to 25.3% after grapefruit juice – One glass of juice / day x 3 days doubled serum concentrations of lovastatin – Three glasses / day: 15-fold increase in lovastatin and simvastatin serum concentrations Kiani J, Imam SZ. Nutr J. 2007;6:33.

Drug Interactions • Pharmacodynamics – The study of the action and effects of medications on physiologic function

• Pharmacodynamic drug interactions can be: – Additive (two or more analgesics) – Synergistic – Antagonistic (dexamethasone and glyburide)

Pharmacodynamic Drug Interactions in Palliative Care • • • • • •

Anticholinergic effects Constipation Lowered seizure threshold Serotonin syndrome CNS depression QTc prolongation

Antimuscarinic Pharmacologic Effects: Peripheral • • • •

Dry eyes Urinary retention Dry mouth Constipation

• Heat intolerance • Tachycardia • Decreased sweating

Carnahan et al. J Clin Pharmacol 2006;46:1481-1486

Antimuscarinic Pharmacologic Effects: Central • • • •

Forgetfulness • Dizziness Agitation / confusion • Drowsiness Delirium • Falls Paranoia

Carnahan et al. J Clin Pharmacol 2006;46:1481-1486

Evoking Antimuscarinic Effects Overactive bladder • Oxybutynin (Ditropan) • Toleradine (Detrol) • Trospium (Sanctura) • Solifenacin (Vesicare) • Darifenacin (Enablex) Anticholinergic / • Trihexyphenidyl (Artane) Antiparkinson’s • Benztropine (Cogentin) • Amantadine (Symmetrel) Antivertigo / • Meclizine (Antivert) antiemetic • Scopolamine (TransDerm Scop)

Evoking Antimuscarinic Effects Gastrointestinal / Antispasmodics Antisecretory / Drying Agents Bronchospasm

• Diphenoxylate (Lomotil) • Dicyclomine (Bentyl) • Hyoscyamine (Levsin) • Atropine (ophthalmic given PO) • Ipratroptium (Atrovent) • Tiotroptium (Spiriva)

Antimuscarinic Adverse Effects Sedating Antihistamines

• Diphenhydramine (Benadryl) • Hydroxyzine (Vistaril)

Tricyclic Antidepressants

• Amitriptyline (Elavil) • Nortriptyline (Pamelor) • Desipramine (Norpramin) • Doxepin (Sinequan) • Chlorpromazine (Thorazine) • Olanzapine (Zyprexa) • Clozapine (Clozaril) • Thioridazine (Mellaril)

Antipsychotic Agents

Antimuscarinic Adverse Effects Phenothiazines

• Prochlorperazine (Compazine) • Promethazine (Phenergan)

Antiarrhythmic Agents

• Disopyramide (Norpace)

Muscle relaxants

• Cyclobenzaprine (Flexeril) • Orphenadrine (Norflex)

Constipation • 40% of all ADR affect the GI tract • Drug-induced constipation occurs at therapeutics doses of drugs and is dose-related • Medications most likely to cause constipation include: – – – – – –

Antispasmodics (11.6%) Antihistamines (9.2%) Antidepressants (8.2%) Diuretics (5.6%) Aluminum antacids (3.0%) Opioids (2.6%) Talley NJ et al. Amer J Gastroenterology 2003;98:1107-1111.

Drug-Induced Constipation Therapeutic Category

Examples

Analgesics

Opioids (morphine), NSAIDs (ibuprofen)

Anticholinergics

TCA, antipsychotics (haloperidol), antiparkinsonian agents (benztropine), antihistamines (H1; diphenhydramine), antispasmodics (dicyclomine)

Cation-containing agents

Aluminum (antacids, sucralfate), calcium (antacids, supplements), bismuth, iron supplements, lithium

Chemotherapy

Vinca alkaloids (vincristine), alkylating agents (cyclophosphamide)

Antihypertensives

CCB (verapamil, nifedipine), diuretics (furosemide), centrally-acting (clonidine), antiarrhythmics (amiodarone), beta blockers (atenolol)

Bile acid sequestrants

Colestyramine, colestipol

5HT3-receptor antagonists

Ondansetron

Laxatives

Chronic abuse Branch RL, Butt TF. Drug-induced constipation. Adverse Drug Reaction Bulletin 2009;257.

Drug-Induced Constipation Therapeutic Category

Examples

Excess fiber

Dietary or prescribed

Other antidepressants

Monoamine amine oxidase inhibitors

Other antiparkinsonian agents

Dopamine agonists

Other antispasmodics

Peppermint oil

Anticonvulsants

Carbamazepine

Miscellaneous

Barium sulphate, octreotide, polystyrene resins, oral contraceptives Vitamin C tablets, 131I thyroid ablation, erythropoietin, baclofen Pamidronate, alendronic acid, PPI and H2 antagonists

Branch RL, Butt TF. Drug-induced constipation. Adverse Drug Reaction Bulletin 2009;257.

DDIs in Palliative Care • Retrospective chart review of 200 consecutive PC unit inpatient • 631 potential DI in 151 patients (75%) • Median number of meds: 14 (2-25) • Common DI meds: scopolamine, neuroleptics, metoclopramide, antihistamines, non-steroidal anti-inflammatory drugs, (levo-) methadone, amitriptyline, carbamazepine and diuretics

• No documentation of clinical relevance in high risk for severe DI patients (n=8) Gaertner J, et al. Palliat Med. 2011; July 7.

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Top Offenders 300

Red Flag Score

250 200 150 100 50 0

Red Flag Score: # DDIs class 1-4 per pt. exposed55

Risky Business • Check Interactions in advance: – Micromedex – Lexi-Comp

• Look at the data • Assess your patient • Make a good decision

Assessing DI • Consider potential risk • Assess clinical signs/symptoms • Compare onset to timeframe of new meds or medication changes

I Found A DI… now what?!

• drug interaction does not automatically negate the usefulness of the drug combination • dose may be changed • timing of administration may be altered

• And you may have beneficial results for required drug regimen

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Questions?

Weschules DJ, Bain KT, Richeimer S. Actual and potential drug interactions associated with methadone. Pain Medicine 2008;9(3):315-344.

Bernard SA and Bruera E. Drug interactions in palliative care. Journal of Clinical Oncology 2000;18(8):1780-99.

Kapur BM, Hutson JR, Chibber T, Luk A, Selby P. Methadone: A review of drug-drug and pathophysiological interactions. Critical Reviews in Clinical Laboratory Sciences 2011;48(4):171-195.