bulloch drug adjustments in older adults - almda · 2018-07-24 · 7/23/2018 1 drug adjustments in...

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Drug Adjustments in Older Adults

Marilyn N. Bulloch PharmD, BCPS, FCCMAssociate Clinical Professor

Harrison School of Pharmacy

Auburn University

Disclosures

• Alabama Medicaid Drug Utilization Board

• Pharmacy Times Contributor

Objectives

• Discuss age-related physiologic changes and their subsequent impact on medication use in older adults

• Describe methods for determining need for dose-adjustments based on physiologic changes in older patients

• Recognize dosage forms that cannot be altered and identify potential alternative drug delivery methods

• Explain scales and formulas that have been developed to guide medication dose-adjustments

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Drug Related Complications

Medication Issue

Polypharmacy

Socioeconomic

Physiologic changesComorbidities

Cognition

Suboptimal Prescribing

Overuse Underuse

Inappropriate use Suboptimal use

Suboptimal Prescribing

Lack of Data In Older Adults

• Few medications have specific dose recommendations for geriatrics

• Only 32% of phase II and III study patients are > 65 years old– Up to 35% published studies specifically excluded geriatrics

• Reasons for exclusions– Comorbidities, ageism, economics, communication barriers

• FDA guidance document recommends, but does not require inclusion of geriatrics

Shenoy et al. Perspect Clin Res.2015;6:184-9Watts G. BMJ 2012;344:e3445Herrera et al. Am J Pub Health. 2010;100:s105-112

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Industry Guidance on Organ Impairment Studies

http://www.appliedclinicaltrialsonline.com/early-phase-clinical-trials-patients-hepatic-or-renal-impairment

Age-Related Physiologic Changes

Turnheim. Drugs and Aging.1998;13:357-79Image credit: https://nursekey.com/8-safe-medication-use/

Receptor down regulationChanges in receptor sensitivity

Altered homeostasis mechanisms

“Synergistic” drug-body effects

Roberts et al. Clin Ger Med.1988;4:127-145

Age-Related Physiologic Changes

Turnheim. Drugs and Aging.1998;13:357-79Image credit: https://nursekey.com/8-safe-medication-use/

Receptor down regulationChanges in receptor sensitivity

Altered homeostasis mechanisms

“Synergistic” drug-body effects

Roberts et al. Clin Ger Med.1988;4:127-145

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Drugs Affected By Absorption Changes

Thomas et al. Drugs & Aging.1998;13:199-209Myers et al. Clin Pharmacokin.1989;17:385-95

Others• Pravastatin – H+-coupled monocarboxylic acid-specific transporter• Folate – pH dependent carrier-mediated transporter• Penicillin - ↑ bioavailability due to higher pH; ↓ absorption of IM agent

Obesity

Barras et al. Australian Prescriber.2017:40:189-193

Obesity

Others• Erythromycin – IBW

• Rifampin – IBW

• Theophylline – IBW

• Carvedilol – max 100 mg dose in ≥ 100 kg

Barras et al. Australian Prescriber.2017:40:189-193

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Protein Binding

Shargel L, Yu AC. Applied Biopharmaceutics & Pharmacokinetics, 7e; 2016 Available at: https://accesspharmacy.mhmedical.com/content.aspx?sectionid=100671709&bookid=1592&Resultclick=2 Accessed: April 02, 2018

Highly Protein Bound Medications

• Indomethacin

• Sulindac

• Ibuprofen

• Naproxen

• Piroxicam

• Phenytoin

• Valproic acid

• Glipizide

• Glyburide

• Digoxin

• Diphenhydramine

• Doxycycline

• Clindamycin

• Dicloxacillin

• Cisplatin

• Vincristine

• Acetazolamide

• Furosemide

• Bumetanide

• Chlorthalidone

• Metolozone

Creatinine Clearance

Image credit: https://www.hepatitisc.uw.edu/go/special-populations-situations/treament-renal-impairment/core-concept/allImage credit: http://www.patientcareonline.com/depression/early-renal-disease

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Adjusting Dose: Decreased Kidney Function

• 2nd generation antihistamines

• H1RAs

• Amantadine

• Gout medications

• Gabapentin

• Pregabalin

• Most antimicrobials

• Fesoterodine

• Hydrophillic beta-blockers- atenolol, bisoprolol, nadolol

• Opioids: morphine, codeine

• ACE-inhibitors

• Statins – rosuvastatin, simvastatin, lovastatin

American Geriatrics Society 2015 Beers Criteria Update Expert Panel. J Am Geriatr Soc. 2015;63:2227-47

Hepatic

• 20% of all medications in patients with chronic hepatic dysfunction are dosed incorrectly.– 30% experience ADRs → 80% ADRs are preventable

• Liver Flashback– Enzymes that metabolize drugs located in most body

tissue BUT are in highest levels and most diverse in liver

Weersink. BMJ Open. 2016;6:e012991

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Liver and Drug Metabolism

Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review, 11e; 2015 Available at: https://accesspharmacy.mhmedical.com/ViewLarge.aspx?figid=95701060 Accessed: April 11, 2018

Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e; 2017 Available at: https://accesspharmacy.mhmedical.com/ViewLarge.aspx?figid=172473542 Accessed: April 11, 2018

Hepatic

• Liver – primary organ for drug metabolism occurring in hepatocytes– Phase I – oxidation, reduction, hdyrolosis

– Phase II – glucuronidation, sulfation, acetylation, methylation

• First Pass Metabolism – pre-systemic metabolism after oral intake but before entry into systemic circulation. – May be impacted by ↓ intrinsic clearance → increase in absolute oral

bioavailability• Increased blood concentrations – morphine, meperidine, verapamil, metoprolol,

labetalol, carvedilol, midazolam

• Prodrugs – may see decreased conversion to active form– E.g. clopidogrel, enalapril

Weersink. BMJ Open. 2016;6:e012991Pena et al. Exp Rev Clin Pharmacol.2016;9:441-458

Child-Pugh Classification

Pena et al. Exp Rev Clin Pharmacol.2016;9:441-458

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Hepatic Adjustments: EBM Recommendations

• Unsafe in all hepatic dysfunction – avoid– NSAIDs

– Nebivolol

– Isradipine

– Oral Nicardipine

– Triamterene

– Cimetidine

– Lansoprazole

– Pantoprazole

– Budesonide

– Atorvastatin

– DuloxetineWeersink et al. Drug Saf.2018:httos://doi.org/10.1007/s40264-0635-xPena et al. Exp Rev Clin Pharmacol.2016;9:441-458

Hepatic Adjustments: EBM Recommendations

Unsafe

Child-Pugh C Only• ACE inhibitors

• Domperidone

• Clopidogrel

• Rabeprazole

• Omeprazole

• Verapamil

• Felodipine

• Metoprolol

• Carvedilol

• Diazepam (oral)

• COX2 inhibitors

• Tapentadol

• Morphine

• Hydromorphone

• Tramadol

• Fentanyl

Child-Pugh B and C

• Codeine

• Ezetimibe

• Lomitapide

• Oxycodone

Weersink et al. Drug Saf.2018:httos://doi.org/10.1007/s40264-0635-xPena et al. Exp Rev Clin Pharmacol.2016;9:441-458Image: https://edrugsearch.com/worst-medications-for-liver/

Hepatic Adjustments: EBM Recommendations

Reduce Dose • Simvastatin

• Rosuvastatin

• Pravastatin

• Fluvastatin

• Omeprazole (CP A/B)

• Rabeprazole(CP A/B)

• Verapamil (CP A/B)

• Felodipine (CP A/B)

• Metoprolol (CP A/B)

• Repaglinide

• Most opioids (CP A/B)

• Most antiarrhythmics

• Escitalopram

• Venalfaxine

• Bupropion

• Fluoxetine

• Lamotrigine

Varies by severity– avoid if possible or reduce dose• Prasugrel

• Ticagrelor

• Dipyridamole

• Gemfibrozil

• Sitagliptin

• Canagliflozin

• Alogliptin

• Fentanyl

• Tigecycline

• Qunidine

• Mexiletine

• LithiumWeersink et al. Drug Saf.2018:httos://doi.org/10.1007/s40264-0635-xPena et al. Exp Rev Clin Pharmacol.2016;9:441-458

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Hepatic Adjustments: EBM Recommendations

SAFE!!

• Acetaminophen

• Ciprofloxacin

• Norfloxacin

• Ofloxacin

• Moxifloxacin

• Amoxicillin

• Amoxicillin/clav• Piperacillin/tazobactam

• SMX/TMP

• Azithromycin

• Erythromycin

• Fosfomycin

• Rifaximin

• Acarbose

• Insulin

• Metformin

• Atenolol

• Labetalol (IV)

• Sotalol

• HCTZ

• Amiloride

• Furosemide

• Bumetanide

• Spironolactone

• Eplerenone

• Prednisolone

• Prednisone

• Lactulose

• Cholestyramine

• Colesevalam

• Bisacodyl

• Ranitidine

• Famotidine

• Empagliflozin

• Saxagliptin

• Acebutolol

Weersink et al. Drug Saf.2018:httos://doi.org/10.1007/s40264-0635-xPena et al. Exp Rev Clin Pharmacol.2016;9:441-458

Hepatic Adjustments: EBM Recommendations

SAFE with Dose Adjustment

• Tolbutamide

• Propranolol

• Carvedilol

• Labetalol (oral)

• Amlodipine

• Nifedipine

• Nimodipine

• Metoclopramide

• Aspirin

• Esomeprazole

Weersink et al. Drug Saf.2018:httos://doi.org/10.1007/s40264-0635-xPena et al. Exp Rev Clin Pharmacol.2016;9:441-458

Dose Adjustments

Pena et al. Exp Rev Clin Pharmacol.2016;9:441-458

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Hepatic Adjustments: When EBM Does Not Exist

Verbeeck. Eur J Clin Pharmacol.2008;64:1147-1161

Characteristic Rationale Dose Adjustment

High EH Oral BA significantly ↑Plasma Cl may be ↓

↓ dose

Low EH and > 90% protein binding

Intrinsic clearance ↓↓ protein binding

Adjust even if dose within normal blood concentrations

Low EH and < 90% protein binding

Intrinsic clearance ↓↓ protein binding

Maintain normal total blood concentrations

Partly excreted unchanged in kidneys

Elimination ↓ ↓ dose

Hydrophilic Vd increased with edema,ascites

↑ loading doses

Narrow Therapeutic Index Avoid as much as possible

EH - hepatic extraction ratio

Special PK Considerations

• HCTZ– ↑ plasma concentrations (related to ↑ half-life and ↓CL)

– More electrolyte issues, but less response with doses > 50 mg

• Triamterene– ↑ Cmax (related to ↓CL)

• Diltiazem– ↓ absorption rate (unknown impact on bioavailability)

– ↓ CL and ↑ half-life

– Start with lower doses

• Verapamil– ↓ CL and ↑ half-life

– Start with lower doses

Facts and ComparisonsPiepho et al. Drugs & Aging.1991;1:194-211

Special PK Considerations

• Nifedipine– ↓ absorption rate but ↑ bioavailability

– ↓ Cmax and ↑AUC

– ↑ half-life ↓ CL

• Amlodipine– ↓ CL : start with lower doses

Facts and ComparisonsPiepho et al. Drugs & Aging.1991;1:194-211

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Pharmacogenomics

• Identification of phenotypes for certain genes

• Data required in labeling by FDA

• May help guide need to: Adjust dose, use with caution, or use an alternative agent

• Some identify patients at risk for hypersensitivity reaction

• Phenotypes– Poor Metabolizers

– Intermediate Metabolizers

– Extensive Metabolizers

– Ultra-Rapid Metabolizers

https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=35332&ver=11&CntrctrSelected=228*2&Cntrctr=228&s=22&DocType=All&LCntrctr=140*2&bc=AggAAAIBAAAA&Finkelstein et al. Pharmacogenomics and Personalized Medicine.2016;9:31-45Image: Mayo Clinic

Pharmacogenomics Testing Availability

• Allopurinol

• Aspirin

• TCAs

• Antipsychotics

• Carisoprodol

• Carbamazepine

• Oxcarbazepine

• Clopidogrel

• Donepezil

• Opioids

• SSRIs

• SNRIs

• Ivacaftor

• PPIs

• NSAIDs

• Brivaracetam

• Glimepiride

• Glipizide

• Fluoroquinolones

• Nitrofurantoin

• Bactrim

• Aminoglycosides

• Ondansetron

• Phenytoin

• Tacrolimus

• Tamoxifen

• Tramadol

• Voriconazole

• Valproic acid

• Warfarin

• Carvedilol

• Clozapine

• Diazepam

• Dolasetron

• Flecanide

• Haloperidol

• Metoprolol

• Propafenone

• Propranolol

• Tamsulosin

• Tiotropium

• Tolterodine

• Digoxin

• Salmeterol

• ACE-Is

• Statins

• Bisphosphonates

• Budesonide

• Furosemidde

• Galantamine

• HCTZ

• Lamotrigine

• Latanoprost

• Metformin

• Metoclopramide

• Spironolactone

• Hydralazine

• Isosorbide dinitrate

https://cpicpgx.org/genes-drugs/

Pharmacogenomics Medicare Coverage

• CYP2C19 – metabolizes 15% of medications

• Covered– Clopidogrel – for patients with ACS undergoing PCI

• Not covered– PPIs

– SSRIs

– Amitriptyline

– Warfarin

– Clopidogrel for other indications (including ACS without PCI)

https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=35332&ver=11&CntrctrSelected=228*2&Cntrctr=228&s=22&DocType=All&LCntrctr=140*2&bc=AggAAAIBAAAA&

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Pharmacogenomics Medicare Coverage

• CYP2D6 – metabolizes 20-25% of all drugs

• Covered– Amitriptyline and nortriptyline for depression

– Tetrabenazine doses > 50 mg/day

• Not covered– Tamoxifen

– Antidepressants (except above)

– Codeine

– Antipsychotics

– Donepezil

– Galantamine

https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=35332&ver=11&CntrctrSelected=228*2&Cntrctr=228&s=22&DocType=All&LCntrctr=140*2&bc=AggAAAIBAAAA&

Pharmacogenomics Medicare Coverage

• CYP2C9 – metabolized 10% of medications

• Covered– Warfarin (with strict restrictions)

• Not covered– NSAIDs

– Flovoxamine

https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=35332&ver=11&CntrctrSelected=228*2&Cntrctr=228&s=22&DocType=All&LCntrctr=140*2&bc=AggAAAIBAAAA&

OTHER DRUG DELIVERY CONSIDERATIONS

When Patients Cannot Swallow Pills

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Dysphagia in LTC

• > 60% of all active pharmaceutical ingredients are developed and intended for oral administration– Rationale: ease of administration, increased product

stability, cheaper to manufacturer

• 40-80% of patients in nursing homes may have difficulty swallowing

• 33-60% non-dysphagic ambulatory patients have some difficulty swallowing oral dosage forms

Logrippo et al. Clin Int Age.2017;12:241-51Schiele et al. Dysphagia.2015;30”571-82Carvajal et al. Farm Hosp.2016;40:514-28Manrique et al J Pharm Pharm Sci 2014;17:207-19

Pill Manipulation

• Tablet crushing or capsule opening

• Dispersion/dissolution of material in water, beverages, gels, or food– May allow better deglutition

– Administered orally or via PEG tube

• Any manipulation of approved product is considered an “off-label use” unless outlined in labeling– Technically – prescribers, nurses, and pharmacists can be legally

liable for ADRs resulting from medication administration and use

• Frequent occurrence in LTC

• Up to 42% of medications crushed in LTC should not be

Logrippo et al. Clin Int Age.2017;12:241-51Carvajal et al. Farm Hosp.2016;40:514-28Manrique et al. J Pharm Pharm Sci.2014;17:207-19

Pill Manipulation: Stroke Study

• German study of stroke patients in acute care ward or rehab

• 42.3% of solid oral dosage forms (154/364) prescribed for 25 patients were crushed

• 1/5 inadequately crushed– 47% could have been put into suspension

– 53% had pharmaceutical equivalents or therapeutically equivalent dosage forms suitable for crushing or suspending

• 1/3 required crushing just before administration due to stability concerns

• 38 drugs with unjustified crushing: Pantoprazole, metoprolol SR, probiotics, others

Schiele et al. Dysphagia.2015;30”571-82

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Avoid Crushing: Narrow Therapeutic Window Drugs

Problems

• Imprecise dose

• ↓stability in solution

• Impacted stability when mixed with food, drinks, or vicious gels

Examples

• Warfarin

• Carbamazepine

• Digoxin

• Lithium

• Theophylline

• Phenytoin

Logrippo et al. Clin Int Age.2017;12:241-51

Avoid Crushing: Modified –Release Dosage Forms

Problems

• Altered amount of API released over time– Dose dumping

• Altered API release site –impact absorption

Examples

• Pantoprazole

• Rabeprazole

• Quetiapine

• Tamsulosin

• Levodopa/carbidopa

• Pentoxifylline

Logrippo et al. Clin Int Age.2017;12:241-51

Avoid Crushing: Prolonged/Slow Release

• Nifedipine

• Aggrenox

• Allegra-D

• Lovastatin

• Lubiprostone

• Dutasteride

• Brivaracetam

• Duloxetine

• Divalproex

• Topiramate

• Rivaroxaban

• Isosorbide

• Guanfacine

• Paliperidone

• Hyoscyamine

• Guaifenesin

• Mirabegron

• Felodipine

• Ranolazine

• Benzonate

• Extended release

ISMP: Oral Dosage Forms That Should Not be Crushed 2016

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Avoid Crushing: Enteric Coated Formulations

Problems

• APIs are often acid-labile – designed to be absorbed in intestines

• Drug inactivated by gastric acid

Examples

• Prolonged-release drugs

• Brivaracetam

• Diltiazem

• Pancrelipase

• Bisacodyl

• Erythromycin

• Tamsulosin

• Exceptions– Microencapsulated

oxycodone

Logrippo et al. Clin Int Age.2017;12:241-51

Avoid Crushing: Enteric Coated GI Irritants

Problems

• Safety– Diarrhea

– Mucosal damage

– Perforation

– Hemorrhage

• Efficacy– Delayed absorption/onset

– Inactivated

Examples

• Ferrous sulfate

• Bisphosphonates

• KCL

• NSAIDs

• Tetracyclines

• Clindamycin

• Valganciclovir

Logrippo et al. Clin Int Age.2017;12:241-51

Alternatives in Dysphagia

• Orally disintegrating tablets

• Transdermal patches

• Pulmonary delivery– Under development – levodopa

• Intranasal– Under development - donepezil

• Compounds

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DRUG INTERACTIONS

American Geriatrics Society 2015 Beers Criteria Update Expert Panel. J Am Geriatr Soc. 2015;63:2227-47

Hines et al. Am J Geriatr Pharmacother. 2011;9:364-377

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Hines et al. Am J Geriatr Pharmacother. 2011;9:364-377

Hines et al. Am J Geriatr Pharmacother. 2011;9:364-377

Hines et al. Am J Geriatr Pharmacother. 2011;9:364-377

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MATH AND SCALES

Anticholinergic Burden Calculator

http://www.anticholinergicscales.es/calculate

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Scales• Anticholinergic Risk Scale (ARS)

– Rudolph JL, Salow MJ, Angelini MC, McGlinchey RE. The anticholinergic risk scale and anticholinergic adverse effects in older persons. Arch Intern Med. 2008; 168(5):508-13.

• Chew’s scale (Chew)

– Chew ML, Mulsant BH, Pollock BG, Lehman ME, Greenspan A, Mahmoud RA, et al. Anticholinergic activity of 107 medications commonly used by older adults. J Am Geriatr Soc. 2008; 56(7):1333-41.

• Anticholinergic Drug Scale (ADS)

– Carnahan RM, Lund BC, Perry PJ, Pollock BG, Culp KR. The Anticholinergic Drug Scale as a measure of drug-related anticholinergic burden: associations with serum anticholinergic activity. J Clin Pharmacol. 2006; 46:1481-6.- Update ADS score 2013

• Anticholinergic Activity Scale (AAS)

– Ehrt U, Broich K, Larsen JP, Ballard C, Aarsland D. Use of drugs with anticholinergic effect and impact on cognition in Parkinson's disease: a cohort study. J Neurol Neurosurg Psychiatry. 2010; 81(2):160-5.

• Anticholinergic Load Scale (ALS)

– Sittironnarit G, Ames D, Bush A, Faux N, Flicker L, Foster J, et al. Effects of anticholinergic drugs on cognitive function in older Australians: results from the AIBL study. Dement Geriatr CognDisord. 2011; 31(3):173-8.

http://www.anticholinergicscales.es/calculate

Scales

• Clinician-Rated Anticholinergic Scale (CrAS) – Han L, Agostini JV, Allore HG, Abrahamowicz M, Primeau F, Élie M. Cumulative anticholinergic exposure is associated with

poor memory and executive function in older men. J Am Geriatr Soc. 2008; 56:2203-10.

• Duran’s scale (Duran) – Durán CE, Azermai M, Vander Stichele RH. Systematic review of anticholinergic risk scales in older adults. Eur J Clin

Pharmacol. 2013; 69(7):1485-96.

• Anticholinergic Burden Classification (ABC) – Ancelin ML, Artero S, Portet F, Dupuy AM, Touchon J, Ritchie K. Non-degenerative mild cognitive impairment in elderly

people and use of anticholinergic drugs: longitudinal cohort study. BMJ. 2006; 332:455-9.

• Drug Burden Index (DBI) – Hilmer SN, Mager DE, Simonsick EM, Cao Y, Ling SM, Windham BG, et al. A drug burden index to define the functional

burden of medications in older people. Arch Intern Med. 2007; 167 (8): 781-7.- Dispennette R, Elliott D, Nguyen L, Richmond R. Drug Burden Index score and anticholinergic risk scale as predictors of readmission to the hospital. Consult Pharm. 2014; 29(3):158-68.- Spanish Agency of Medicines and Medical Devices – AEMPS

– A.M. Villalba-Moreno, et al., Systematic review on the use of anticholinergic scales in poly pathological patients, Arch. Gerontol. Geriatr. (2015), http://dx.doi.org/10.1016/j.archger.2015.10.002d

http://www.anticholinergicscales.es/calculate

Ultimate Rules for Drug Dosing

• Start Low and Go Slow

• Trust Nothing

• Look up everything!

• Look up everything often.

• Treat each new symptom as an ADR until proven otherwise.

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QUESTIONS?