Anticholinergic and Sedative Burden & Pharmacogenomics...without dementia, in men, the use of drugs with definite anticholinergic activity was associated with greater risk of subsequent

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Anticholinergic and Sedative Burden& Pharmacogenomics

Kevin T. Bain, PharmD, MPH, BCPS, BCGP, CPH, FASCP

SVP, Research & Development

CareKinesis Clinical Advisory Panel

September 21, 2018

• At the completion of this training activity, the participant should be able to:

• Explain the risks associated with anticholinergic and sedative medication use in older adults

• Compare and contrast methods for quantifying anticholinergic and sedative burden

• Describe how genetic variants may affect drug pharmacokinetics and pharmacodynamics for a series of drugs

Objectives

Anticholinergic and Sedative Pathophysiology

Anticholinergic PathophysiologyCholinergic Hypothesis

A loss of cholinergic function in the CNS contributes significantly to the cognitive decline associated with advanced age and Alzheimer’s disease (AD)

Terry AV Jr, et al. J Pharmacol Exp Ther. 2003;306:821-7.

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PathophysiologyCholinergic Hypothesis

• Alterations in high-affinity choline uptake / transport

• Impaired acetylcholine release

• Deficits in the expression of nicotinic and muscarinic receptors

• Dysfunctional neurotrophin support

• Deficits in axonal transport

Net Result- Low level of the neurotransmitter acetylcholine (ACh)- Leads to both cognitive and non-cognitive (e.g., behavioral) symptoms

Terry AV Jr, et al. J Pharmacol Exp Ther. 2003;306:821-7.DeKosky ST. J Am Geriatr Soc. 2003;51:S314-20.

Sedative PathophysiologyAlterations in the BBB

Age-related alterations in the blood brain barrier (BBB) contribute significantly to the exaggerated response associated with medications affecting the CNS

Wong AD, et al. Front Neuroeng. 2013;6:1-22.Cabezas R, et al. Front Cell Neurosci. 2014;8:1-11.

Sedative PathophysiologyAlterations in the BBB

P-glycoprotein activity of lymphocytes in young & elderly subjects as a function of age

Vd of (R)-verapamil in brain in young & elderly subjects as a function of age

Toornvliet R, et al. Clin Pharmacol Ther. 2006;79:540-8.

Anticholinergic Pharmacology

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Anticholinergic PharmacologyAnticholinergic Hypothesis

Block acetylcholine receptors in neurons through

competitive inhibition

Antagonistic effects are reversible

Pasqualetti G, et al. Clin Interv Aging. 2015;10:1457-66.

Anticholinergic PharmacologyAnticholinergic Hypothesis

• Most anticholinergics interact with muscarinic ACh receptors• A few can also affect the nicotinic ACh receptors (e.g., glycopyrrolate)

• The anticholinergic activity expressed by a drug is directly related to its potential to bind to muscarinic ACh receptors

• Presuming the cholinergic hypothesis is correct then one would expectthe elderly & those with AD to be especially sensitive to the cognitive impairing effects of anticholinergic drugs• Indeed, substantial data to support this premise have been published

Terry AV Jr, et al. J Pharmacol Exp Ther. 2003;306:821-7.Rudd KM, et al. Pharmacotherapy. 2005;25:1592-601.

Anticholinergic PharmacologyAnticholinergic Drug Interactions

• Clinically-important drug-drug interactions• Cholinergic / muscarinic agonists – Pharmacodynamic

Direct: BethanecholIndirect: Acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine)

• CYP450-mediated drug interactions (competitive inhibition) – Pharmacokinetic• Drug specific

• Clinically-important drug-disease interactions• Benign prostatic hyperplasia• Constipation• Dementia• Glaucoma (narrow-angle)

Sedative PharmacologyMultiple CNS Mechanisms

• Agonism of the benzodiazepine receptor (GABA-A complex)• Benzodiazepines & barbiturates

• Antagonism of histamine H1 receptors• Antihistamines, antipsychotics, & TCAs

• Binding to the μ-opioid receptor• Opioids

• Antagonism of α1-adrenergic receptors• Antipsychotics

• Blockage of muscarinic receptors• Smooth muscle relaxants (urinary antispasmodics)

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Anticholinergic PharmacologySedative Drug Interactions

• Clinically-important drug-drug interactions• CNS effects – Pharmacodynamic

Concomitant administration with other drugs that cause CNS depression e.g., Opioid + Benzodiazepine + Antidepressant

• Respiratory effects – Pharmacodynamic Concomitant administration with other drugs that cause respiratory depression e.g., Opioid + Benzodiazepine

• CYP450-mediated drug interactions (competitive inhibition) – PharmacokineticDrug specific (e.g., opioids are weak substrates for the CYP2D6 isoenzyme)

• Clinically-important drug-disease interactions• Use of opioids in patients with conditions accompanied by hypoxia, hypercapnia, or

decreased respiratory reserveCOPD, cor pulmonale, morbid obesity

• Use of sedative drugs in patients at high-risk for fallsHistory of falls, orthostatic hypotension, syncope

Adverse Effects of Anticholinergic and Sedative Medications

Including Morbidity & Mortality

THIS IS YOUR BRAIN

THIS IS YOUR BRAIN ON DRUGS

Anticholinergic & Sedative

YES, we have questions

Adverse EffectsOlder Adults’ Susceptibility

• Older adults are particularly vulnerable to anticholinergic and sedative-related adverse effects for several reasons:• They have a high probability of being exposed

• High medical comorbidity & polypharmacy

• They are more sensitive to experience serious effects• Especially cognitive adverse effects (e.g., gait instability & falls)

• Age-related physiological changes• Increase in blood-brain barrier permeability• Decline in hepatic drug metabolism and renal drug clearance• Reduction in central cholinergic activities (i.e., decreased neurons & receptors, decreased

acetylcholine-mediated transmission)• Increase in % of adipose tissue (increased distribution of lipophilic drugs, e.g., diazepam)

Taipale HT, et al. Clin Psychopharmacol. 2012;32:218-24.Boustani M, et al. Aging Health. 2008;4:311-20.Tune LE. J Clin Psychiatry. 2001;62:11-4.

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Anticholinergic Adverse Effects

http://lookfordiagnosis.com/mesh_info.php?term=anticholinergic+syndrome&lang=1

Anticholinergic Risks

• Agitation / delirium• Onset or worsening BPSD• Loss of independence• Institutionalization

• Cardiac dysrhythmias• Arrhythmias

• Constipation• Fecal impaction• Paralytic ileus• Pain

• Urinary retention• Increased UTI• Loss of independence• Acute kidney injury (AKI)

• Dry mouth• Dysphagia• Dental caries• Impaired communication

• Blurred vision (ACB) + Dizziness (SB)• Gait disturbances / falls

Boustani M, et al. Aging Health. 2008;4:311-20.Tune LE. J Clin Psychiatry. 2001;62:11-4.

Sedative Risks

• Daytime sleepiness• Sedentary

• Social isolation

• Memory impairment• Anterograde amnesia

• Depression

• Blurred vision (ACB) + Dizziness (SB)• Gait disturbances / falls

• Dependence• Physical

• Psychological

• Tolerance• Abuse

• Withdrawal

Taipale HT, et al. Int Clin Psychopharmacol. 2012;32:218-24.Taipale HT, et al. Drugs Aging. 2009;26:871-81.

Taipale HT, et al. Clin Psychopharmacol. 2012;32:218-24.Taipale HT, et al. J Gerontol A Biol Sci Med Sci. 2011;66:1384-92.

Anticholinergic MorbidityCognitive Function

• Cause or worsen cognitive impairment & delirium• Myriad studies have found a significant association between

anticholinergic burden and either cognitive impairment or delirium

• Increase the risk of dementia & Alzheimer’s Disease• A recently published study (2015) demonstrated that higher cumulative

anticholinergic drug use is associated with incident dementia• The risk was statistically significant among patients with the highest exposure

(dementia: adjusted HR, 1.54 [95% CI, 1.21-1.96]; Alzheimer’s disease: adjusted HR, 1.63 [95% CI, 1.24-2.14]) compared with those with no use

Boustani M, et al. Aging Health. 2008;4:311-20.Campbell N, et al. Clin Interv Aging. 2009;4:225-33.

Carrière I, et al. Ann Intern Med. 2009;169:1317-24.Gray SL, et al. JAMA Intern Med. 2015;175:401-7.

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Anticholinergic MorbidityCognitive Function

• Increased brain atrophy• A study published in 2016 found the use of drugs with moderate to strong

anticholinergic activity was associated with brain atrophy • Whole brain & temporal lobe atrophy

• In cognitively normal older adults

• As well as poorer cognition (e.g., immediate memory recall & executive function) and reduced glucose metabolism

• The effect appeared additive• An increased anticholinergic burden was associated with worsening executive

function & increased brain atrophy

Risacher SL, et al. JAMA Neurol. 2016;73:721-32.

Anticholinergic MorbidityPhysical Function

• Higher anticholinergic burden is significantly associated with falls• In a longitudinal study of community-dwelling older adults >65 years

without dementia, in men, the use of drugs with definite anticholinergic activity was associated with greater risk of subsequent injurious falls (aRR, 2.55 [95% CI, 1.33-4.88])

• Recent study (2015) reveals 16% greater risk of injury in older adults currently using anticholinergic drugs compared with non-users• Included falls (with injury) but not exclusively injuries as a result of falls

Aizenberg D, et al. Int Psychogeriatr. 2002;14:307-10.Dauphinot V, et al. J Clin Psychopharmacol. 2014;34:565-70.

Richardson K, et al. J Am Geriatr Soc. 2015;63:1561-9.Spence MM, et al. J Am Geriatr Soc. 2015;63:1197-202.

Anticholinergic MorbidityPneumonia & Hospitalization

• Possibly cause pneumonia• New study reveals link between anticholinergic drug use and CAP

• Acute & chronic use

• Low- & high-potency drugs

• Possible mechanism involves:• Sedation & altered mental status

• May contribute to poor pulmonary hygiene, atelectasis & aspiration

• Increase risk of hospitalization• When using >2 anticholinergic drugs

Paul KJ, et al. J Am Geriatr Soc. 2015;63:476-85.Kalisch Ellett LM, et al. J Am Geriatr Soc. 2014;62:1916-22.

• Association with increased risk of death has been reported• In a longitudinal study of community-dwelling and institutionalized

participants, two-year mortality was greater for those taking definite & possible anticholinergics• Definite anticholinergics: OR, 1.68 (95% CI, 1.30-2.16), P<.001

• Possible anticholinergics: OR, 1.56 (95% CI, 1.36-1.79), P<.001

• For every additional point (above 5) scored on the ACB tool, the odds of dying increased by 26%

Anticholinergic Mortality

Fox C, et al. J Am Geriatr Soc. 2011;59:1477-83.

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• Increase risk of cognitive decline / impairment• Complex relationship with other risk factors• In the Health, Aging and Body Composition Study, researchers found that

combined use of CNS medications was associated with cognitive decline (adjusted HR, 1.37 [95% CI, 1.11-1.70]) over 5 years

• Further, longer duration (adjusted HR, 1.39 [95% CI, 1.08-1.79]) & higher doses (adjusted HR, 1.87 [95% CI, 1.25-2.79]) of CNS medications conferred greater risk

• Increase risk of delirium• Paradoxical aggressive or hyperactive behavior

Sedative MorbidityCognitive Function

Evidence strongest with sedative-hypnoticsGray SL, et al. BMJ. 2016;352:i90.Airagnes G, et al. Curr Psychiatry Rep. 2016;18:89.

AGS. J Am Geriatr Soc. 2012;60:616-31.Wright RM, et al. J Am Geriatr Soc. 2009;57:243-50.

Sedative MorbidityPhysical Function

• Cause or worsen physical inactivity

• Decline in muscle strength

• Reduced balance & mobility

• Impaired performance in ADLs/IADLs

• Increased risk of falling & fractures

A threat to independent living among older adults

Large-scale studies indicate that sedative-hypnotics increase the risk of postural instability, falls and fractures in the elderly

Non-benzodiazepine sedative-hypnotics

do not appear to be safer

Gray SL, et al. J Am Geriatr Soc. 2003;51:1563-70.Gray SL, et al. J Am Geriatr Soc. 2006;54:224-30.Hanlon JT, et al. J Gerontol A Biol Sci Med Sci. 2009;64:492-8.Finkle WD, et al. J Am Geriatr Soc. 2011;59:1883-90.Allain H, et al. Drugs Aging. 2005;22:749-65.

Sedative MorbidityAccidents & Overdoses

• Cause or contribute to motor vehicle accidents• In a study of 72,685 drivers involved in injury-related road traffic accidents, the risk

of being responsible for a traffic accident was higher in users of benzodiazepine hypnotics (OR, 1.39 [1.08-1.79]; P<0.01)

• Plausibly related to impaired physical function (e.g., poorer performance in coordination, grip strength and/or mobility)

• Risk of respiratory failure, particularly in susceptible patients• Chronic obstructive pulmonary disease (COPD)

• In a matched case-control study, the use of benzodiazepine receptor agonists was associated with an increased risk of respiratory failure (adjusted OR, 1.56 [95% CI, 1.14-2.13])

Yang YH, et al. J Epidemiol. 2011;21:37-43.Chen SJ, et al. Sleep. 2015;38:1045-50.

Sigona N, et al. J Pharm Pract. 2015;28:119-23.Orriols L, et al. Clin Pharmacol Ther. 2011;89:595-601.

Sedative MorbidityAccidents & Overdoses

• Increase risk of ED visits and hospitalizations• ADEs from the therapeutic use of psychiatric medications are responsible

for nearly 90,000 ED visits annually in the United States, and almost 1 in 5 of those ED visits (19.3%, 95% CI, 16.3%-22.2%) results in hospitalization

• Among psychiatric medications, antidepressants, antipsychotics, and anxiolytics and sedatives are the most implicated

• The majority of ADE-related ED visits caused by psychiatric medications are from ADRs and unintentional overdoses or supratherapeutic dosages

Hampton LM, et al. JAMA Psychiatry. 2014;71:1006-14.

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Sedative Mortality

• No association overall• Between sedative drug use and mortality

• Certain drug classes • Antipsychotics have been linked to an increased risk of death (in dementia)

• Plethora of good-quality evidence

• A meta-analysis of 15 placebo-controlled trials, 10 to 12 weeks in duration and enrolling 5,110 patients, revealed a risk of death in antipsychotic users of approximately 1.6 times the risk of death in patients using placebo

• Risk is greatest in the first 30 days

• Nevertheless, risk appears to be unrelated to sedative effects (i.e., sudden death)

• Results of studies with other sedative drugs in comparison are inconsistentSchneider LS, et al. JAMA. 2005;2945:1934-43.

Wilson NM, et al. Drugs Aging. 2012;29:157-65.Lowry E, et al. J Clin Pharmacol. 2012;52:1584-91.

Sedative Mortality

• Overdose deaths• In 2010, the latest year for which these data are available, there were 38,329 drug

ODs in the United States; most (57.7%; 22,134) involved pharmaceuticals

• Of the pharmaceutical-related overdose deaths, the majority (74.3%; 16,451) were unintentional

• Opioids (75.2%; 16,651), benzodiazepines (29.4%; 6,497), and antidepressants (17.6%; 3,889) were the pharmaceuticals most commonly involved in these overdose deaths

• Further, among overdose deaths involving opioids, the pharmaceuticals most often also involved in these deaths were benzodiazepines (30.1%; 5,017), antidepressants (13.4%; 2,239), and antipsychotics and neuroleptics (4.7%; 783)

Jones CM, et al. JAMA. 2013;309:657-9.

Quantifying Drug Burden

Basis of Drug Burden

• Different drugs, even within similar drug classes, have varying degrees of anticholinergic and sedative activity• Affinity for muscarinic (anticholinergic) & other receptors (sedative)

• Some drugs have well-recognized activity • First-generation antihistamines (e.g., diphenhydramine)• Urinary antispasmodics (e.g., oxybutynin)• Anticholinergics (e.g., hyoscyamine)

• Opioids (e.g., morphine)• Anesthetics• Benzodiazepines & sedative hypnotics

Therapeutic Anticholinergics

Therapeutic Sedatives

Boustani M, et al. Aging Health. 2008;4:311-20.

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Basis of Drug BurdenAnticholinergics Further Explored

• However, clinicians may not be aware that some commonly used drugs also have anticholinergic activity• Anticoagulants (e.g., warfarin)

• Antidepressants (e.g., paroxetine)

• Diuretics (e.g., furosemide)

• They also may not realize that using multiple drugs with weaker activity can be additive and/or synergistic• Also there may be a cumulative effect (i.e., exposure [dose & duration])

Unintentional (secondary) Effects

Keep in mind that drug interactions may further increase serum anticholinergic activity (i.e., plasma concentrations)

Often go unnoticed

Boustani M, et al. Aging Health. 2008;4:311-20.

Methods for Quantifying

• Serum anticholinergic activity (SAA) assay

• In vitro measurements• Anticholinergic activity• Muscarinic receptor affinity

• Expert-based tools• Anticholinergic Cognitive Burden

(ACB)• Anticholinergic Risk Scale (ARS)• Anticholinergic Drug Scale (ADS)

• Expert-based tools• Sedative Load Model

• Sloane Model

• Drug Burden Index

• CNS Drug Model

Anticholinergic Burden Sedative Burden

Methods for QuantifyingExpert-Based Tools

• Based on experts’ experiences & opinions combined with available drug information (e.g., adverse effects, pharmacology)

• Simple list of drugs with known & different degrees of anticholinergic & sedative activity• Help clinicians decide the degree of risk a drug & combination of drugs

may pose for individual patients

• May be the only method clinically useful for assessing the central or cognitive effects of drugs

Rudd KM, et al. Pharmacotherapy. 2005;25:1592-601.Boustani M, et al. Aging Health. 2008;4:311-20.

Methods for QuantifyingExpert-Based Tools – Focus on ACB

• Prioritizes ranking criteria• Drugs with cognitive adverse effects and those that permeate the BBB

• Drugs with peripheral anticholinergic activity also are included

• Excludes topical, ophthalmic, otologic & inhaled drug preparations

• Uses categorical scoring • Possible anticholinergics = score of 1 (mild)

• Score of 1 – in vitro data (i.e., • SAA or affinity for muscarinic receptors but little to no clinically relevant effects

• Definite anticholinergics = score of 2 or 3• Score of 2 – clinical anticholinergic effect (moderate)

• Score of 3 – drug may cause delirium (severe)

www.agingbraincare.orgBoustani M, et al. Aging Health. 2008;4:311-20.West T, et al. J Am Pharm Assoc. 2013;53:496-504.

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Methods for QuantifyingExpert-Based Tools – Focus on ACB

• Cumulates on numerical scoring• Sum (∑) drug scores for a cumulative ACB

• Clinically meaningful scores• ACB score >3

• Examples • Amitriptyline

• Diphenhydramine

• Paroxetine

www.agingbraincare.org

Score 1 Score 2 Score 3

Alprazolam Carbamazepine Atropine

Bupropion Cyproheptadine Oxybutynin

Ranitidine Meperidine Olanzapine & Quetiapine

Risperidone Oxcarbazepine Tolterodine

Anticholinergic Cognitive Burden Scoring of Drugs

ACB score = 3

Methods for QuantifyingExpert-Based Tools – Sedative Burden

• Expert-based tools• Sedative Load Model (SLM)

• Sloane Model

• CNS Drug Model

• Drug Burden Index (DBI)

Let us take a closer look

Taipale H, et al. Kuopio (Finland). 2012.

Methods for QuantifyingExpert-Based Tools – Focus on SLM

• Assigns sedative ratings categorically

• Bases ratings on drug characteristics• Primary sedatives = rating of 2• Prominent side effect = rating of 1

• Cumulates on numerical scoring• Sum (∑) drug scores for a sedative load

• Clinically meaningful scores• SLM score >3• >2 CNS-active drugs (e.g., Beers criteria)

Primary sedatives = 3Prominent side effect = 2Potential side effect = 1

Taipale H, et al. Kuopio (Finland). 2012.Linjakumpu T, et al. Int J Geriatr Psychiatry. 2003;18:542-44.

Methods for QuantifyingExpert-Based Tools – Focus on SLM

• Examples (sedative rating = 2)• Amitriptyline

• Diazepam

• Zolpidem

• Examples (sedative rating = 1)• Morphine

• Paroxetine

• Quetiapine

REVISED Sedative Load Model Scoring of Drugs

Score 1 Score 2 Score 3

Glipizide Baclofen Amitriptyline

Metoprolol Morphine Chlorpromazine

Omeprazole Paroxetine Diazepam

Ranitidine Quetiapine Zolpidem

Taipale H, et al. Kuopio (Finland). 2012.Linjakumpu T, et al. Int J Geriatr Psychiatry. 2003;18:542-44.

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Limitations of MethodologiesOverall

• Hundreds of drugs are thought to have anticholinergic and/or sedative activity and, thus, these methods may not be all inclusive• Non-prescription drugs, namely herbals & supplements, may are not captured in

these methods

• There are individual differences in pharmacodynamics, pharmacokinetics, especially drug interactions, and blood-brain barrier permeability that are not accounted for in these methods• Similarly, drug dosages can affect receptor potency yet may not be accounted for

in these methods

• Endogenous factors affect physiologic activity

Limitations of MethodologiesExpert-Based Tools

• Most clinically relevant but least standardized method (subjective)• Depends on the expert’s perspective, knowledge & experience

• Not routinely updated

• The combination of drug lists & clinical tools, such as the MMSE, is not sensitive enough to detect mild drug-induced cognitive changes

• Intra-class variation in regard to drug activity is not accounted for (e.g., some antidepressants / antipsychotics are more sedating than others within the drug class)• Should we be rating individual drugs on their anticholinergic/sedative potential?

Limitations of MethodologiesExpert-Based Tools

• Do not include doses of drugs• The presence of dose-response relationship is commonly regarded as

evidence for causality of an ADR (i.e., Naranjo)

• May or may not take into account PRN usage• Commonly, sedative drugs are used PRN

by older adults

Utility of MethodologiesFocus on Expert-Based Tools

• Expert-based tools are simple lists of medications with individual anticholinergic & sedative activity scores• Can be incorporated into clinical decision support (CDS) systems to

determine cumulative drug burden

• These tools could be used as a component of MTM services to identify older adults who are at higher risk for potential anticholinergic and sedative effects• Pharmacists are ideally positioned to address or prevent unintended

sequelae of drug burden & preserve the QoL and overall health status of older patients

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• Drugs with anticholinergic and sedative properties can negatively affect cognitive & physical function in older adults considerably • Associated with poor outcomes

• Threat to independent living

• Knowing a patient’s medication risk aids in personalizing a medication care plan• A tailored, systemic approach can reduce anticholinergic and sedative

burden

Take-Away Points Reference• Terry AV Jr, Buccafusco JJ. The cholinergic hypothesis of age and Alzheimer's disease-related cognitive deficits: recent

challenges and their implications for novel drug development. J Pharmacol Exp Ther. 2003;306:821-7.

• DeKosky ST. Pathology and pathways of Alzheimer's disease with an update on new developments in treatment. J Am Geriatr Soc. 2003;51(5 Suppl Dementia):S314-20.

• Wong AD, Ye M, Levy AF, et al. The blood-brain barrier: an engineering perspective. Front Neuroeng. 2013;6:1-22.

• Cabezas R, Avila M, Gonzalez J, et al. Astrocytic modulation of blood brain barrier: perspectives on Parkinson’s disease. Front Cell Neurosci. 2014;8:1-11.

• Toornvliet R, van Berckel BN, Luurtsema G, et al. Effect of age on functional P-glycoprotein in the blood-brain barrier measured by use of (R)-[(11)C]verapamil and positron emission tomography. Clin Pharmacol Ther. 2006;79:540-8.

• Pasqualetti G, Tognini S, Calsolaro V, et al. Potential drug-drug interactions in Alzheimer patients with behavioral symptoms. Clin Interv Aging. 2015;10:1457-66.

• Rudd KM, Raehl CL, Bond CA, et al. Methods for assessing drug-related anticholinergic activity. Pharmacotherapy. 2005;25:1592-601.

• Boustani M, Campbell N, Munger S, et al. Impact of anticholinergics on the aging brain: a review and practical application. Aging Health. 2008;4:311-20.

Reference• Tune LE. Anticholinergic effects of medication in elderly patients. J Clin Psychiatry. 2001;62 Suppl 21:11-4.

• Taipale HT, Bell JS, Gnjidic D, et al. Sedative load among community-dwelling people aged 75 years and older: association with balance and mobility. J Clin Psychopharmacol. 2012;32:218-24.

• Taipale HT, Bell JS, Gnjidic D, et al. Muscle strength and sedative load in community-dwelling people aged 75 years and older: a population-based study. J Gerontol A Biol Sci Med Sci. 2011;66:1384–92.

• Taipale HT, Bell JS, Hartikainen S. Sedative load among community-dwelling older individuals: change over time and association with mortality. Int Clin Psychopharmacol. 2012;27:224-30.

• Taipale HT, Bell JS, Soini H, et al. Sedative load and mortality among residents of long-term care facilities: a prospective cohort study. Drugs Aging. 2009;26:871-81.

• Campbell N, Boustani M, Limbil T, et al. The cognitive impact of anticholinergics: a clinical review. Clin Interv Aging. 2009;4:225-33.

• Carrière I, Fourrier-Reglat A, Dartigues JF, et al. Drugs with anticholinergic properties, cognitive decline, and dementia in an elderly general population: the 3-city study. Ann Intern Med. 2009;169:1317-24.

• Gray SL, Anderson ML, Dublin S, et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015;175:401-7.

Reference• Risacher SL, McDonald BC, Tallman EF, et al. Association between anticholinergic medication use and cognition, brain

metabolism, and brain atrophy in cognitively normal older adults. JAMA Neurol. 2016;73:721-32.

• Aizenberg D, Sigler M, Weizman A, et al. Anticholinergic burden and the risk of falls among elderly psychiatric inpatients: a 4-year case-control study. Int Psychogheriatr. 2002;14:307-10.

• Dauphinot V, Faure R, Omrani S, et al. Exposure to anticholinergic and sedative drugs, risk of falls, and mortality: an elderly inpatient, multicenter cohort. J Clin Psychopharmacol. 2014;34:565-70.

• Richardson K, Bennett K, Maidment ID, et al. Use of medications with anticholinergic activity and self-reported injurious falls in older community-dwelling adults. J Am Geriatr Soc. 2015;63:1561-9.

• Spence MM, Karim FA, Lee EA, et al. Risk of injury in older adults using gastrointestinal antispasmodic and anticholinergic medications. J Am Geriatr Soc. 2015;63:1197-202.

• Paul KJ, Walker RL, Dublin S. Anticholinergic medications and risk of community-acquired pneumonia in elderly adults: a population-based case-control study. J Am Geriatr Soc. 2015;63:476-85.

• Kalisch Ellett LM, Pratt NL, Ramsay EN, et al. Multiple anticholinergic medication use and risk of hospital admission for confusion or dementia. J Am Geriatr Soc. 2014;62:1916-22.

• Fox C, Richardson K, Maidment ID, et al. Anticholinergic medication use and cognitive impairment in the older population: the medical research council cognitive function and ageing study. J Am Geriatr Soc. 2011;59:1477-83.

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Reference• American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society updated Beers

Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2012;60:616-31.

• Wright RM, Roumani YF, Boudreau R, et al. Effect of central nervous system medication use on decline in cognition in community-dwelling older adults: findings from the Health, Aging and Body Composition Study. J Am Geriatr Soc. 2009;57:243-50.

• Gray SL, Dublin S, Yu O, et al. Benzodiazepine use and risk of incident dementia or cognitive decline: prospective population based study. BMJ. 2016;352:i90.

• Airagnes G, Pelissolo A, Lavallee M, et al. Benzodiazepine misuse in the elderly: risk factors, consequences, and management. Curr Psychiatry Rep. 2016;18:89.

• Gray SL, Penninx BW, Blough DK, et al. Benzodiazepine use and physical performance in community-dwelling older women. J Am Geriatr Soc. 2003;51:1563-70.

• Gray SL, LaCroix AZ, Hanlon JT, et al. Benzodiazepine use and physical disability in community-dwelling older adults. J Am Geriatr Soc. 2006;54:224-30.

• Hanlon JT, Boudreau RM, Roumani YF, et al. Number and dosage of central nervous system medications on recurrent falls in community elders: the Health, Aging and Body Composition study. J Gerontol A Biol Sci Med Sci. 2009;64:492-8.

• Finkle WD, Der JS, Greenland S, et al. Risk of fractures requiring hospitalization after an initial prescription for zolpidem, alprazolam, lorazepam, or diazepam in older adults. J Am Geriatr Soc. 2011;59:1883-90.

Reference• Allain H, Bentue-Ferrer D, Polard E, et al. Postural instability and consequent falls and hip fractures associated with use

of hypnotics in the elderly: a comparative review. Drugs Aging. 2005;22:749-65.

• Sigona N, Williams KG. Driving under the influence, public policy, and pharmacy practice. J Pharm Pract. 2015;28:119-23.

• Orriols L, Philip P, Moore N, et al. Benzodiazepine-like hypnotics and the associated risk of road traffic accidents. ClinPharmacol Ther. 2011;89:595-601.

• Yang YH, Lai JN, Lee CH, et al. Increased risk of hospitalization related to motor vehicle accidents among people taking zolpidem: a case-crossover study. J Epidemiol. 2011;21:37-43.

• Chen SJ, Yeh CM, Chao TF, et al. The use of benzodiazepine receptor agonists and risk of respiratory failure in patients with chronic obstructive pulmonary disease: a nationwide population-based case-control study. Sleep. 2015;38:1045-50.

• Hampton LM, Daubresse M, Chang HY, et al. Emergency department visits by adults for psychiatric medication adverse events. JAMA Psychiatry. 2014;71:1006-14.

• Wilson NM, Hilmer SN, March LM, et al. Associations between drug burden index and mortality in older people in residential aged care facilities. Drugs Aging. 2012;29:157−65.

• Lowry E, Woodman RJ, Soiza RL, et al. Drug burden index, physical function, and adverse outcomes in older hospitalized patients. J Clin Pharmacol. 2012;52:1584-91.

Reference• Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-

analysis of randomized placebo-controlled trials. JAMA. 2005;2945:1934-43.

• Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United States, 2010. JAMA. 2013;309:657-9.

• West T, Pruchnicki MC, Porter K, et al. Evaluation of anticholinergic burden of medications in older adults. J Am Pharm Assoc (2003). 2013;53:496-504.

• Taipale H. Sedative load and adverse events among community-dwelling older people [dissertation]. Kuopio (Finland): University of Eastern Finland;2012.

• Linjakumpu T, Hartikainen S, Klaukka T, et al. A model to classify the sedative load of drugs. Int J Geriatr Psychiatry. 2003;18:542−44.

Pharmacogenomics

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PGx Preface

DNA & Genes

• DNA…library or book

• Chromosome…cookbook or chapter

• Gene…recipe or sentence• Nucleotides…ingredients or alphabet

• Protein (Enzyme)…meal or paragraph

Pharmacogenomics

• Genetic variability is a key component of life• Changes protein expression and function

• Pharmacogenomics (PGx)• How a person’s genes affect the way he or she responds to drugs

• Relationship between variations in a large collection of genes (not just a single gene)

• Change gene change protein’s effect change drug’s response

• Links genetic variations to clinically important events• Drug response or lack of response• Adverse drug reactions (ADRs) or adverse drug events (ADEs)• Dose requirements

Interindividual VariabilityDrug Response

Same Diagnosis & Same Drug

Non-toxic and effective

Toxic and ineffective

Toxic and effective

Non-toxic and ineffectiveOne drug does NOT

fit all

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PGx PrinciplesFocus on Drug Metabolism

Drug Metabolizing Enzymes (DMEs)Cytochrome P450• Genetic variants can affect the function and/or expression of drug metabolizing

enzymes (DMEs)• Can differ between substrates

• The most well-studied DMEs are the cytochrome P450 (CYP) enzymes• Approximately 225 genes encode for DMEs

• A superfamily of enzymes responsible for the metabolism (chemical alteration) of substrates so they can be eliminated (excreted) from the body

[HUMAN] CYP2C19*1

Species

Family

Subfamily

Isoform

Allele

Cytochrome P450 DMEsProportion of Drug Metabolism

CYP1A10%

CYP2C20%

CYP2D25%

CYP2E3%

CYP3A42%

Cytochrome P450 DMEsStandardizing Terms

Caudle KE, et al. Genet Med. 2017;19:215-23.

“Extensive Metabolizer” is now called “Normal Metabolizer”

Added “Rapid Metabolizer”

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Cytochrome P450 DMEsExample – CYP2C19

• Highly polymorphic• Over 30 allelic variants

• The wild-type (normal function) allele is classified as *1

• The most common loss-of-function alleles are *2 and *3• Associated with reduced enzyme activity

• Another common allele, *17, is a gain-of-function allele• Associated with increased enzymatic activity

http://www.cypalleles.ki.se/cyp2c19.htm

https://www.pharmgkb.org/page/cyp2c19RefMaterials

Caudle KE, et al. Genet Med. 2017;19:215-23.

Definition (Diplotype) Phenotype

Two increased function alleles, or more than 2 normal function alleles(e.g., CYP2C19*17|*17)

Ultra-Rapid Metabolizer (UM)

Combinations of normal function and increased function alleles(e.g., CYP2C19*1|*17)

Rapid Metabolizer (RM)

Combinations of normal function & decreased function alleles(e.g., CYP2C19*1|*1)

Normal Metabolizer (NM)

Combinations of normal function, decreased function, and/or no function alleles

(e.g., CYP2C19*1| *2)

Intermediate Metabolizer (IM)

Combination of no function alleles and/or decreased function alleles(e.g., CYP2C19*2|*2)

Poor Metabolizer (PM)

Terpening C. Clin Med Insights Cardiol. 2010;4:117-28.Hicks JK, et al. Clin Pharmacol Ther. 2015;98:127-34.

Cytochrome P450 DMEsExample – CYP2D6

• One of the most polymorphic CYP450 DMEs• At least 100 gene variants & 120 alleles identified

• Multiple wild-type (normal function) alleles • *1, *2, *27, *33, *35, *39, *45, *46, *48, *53

• Reduced function alleles include the following• *9, *10, *14B, *17, *29, *41, *49, *50, *54, *55, *59, *72

• Non-functional alleles include the following• *3, *4-*8, *11-*14A, *15, *18, *20, *21, *31, *36, *38, *40, *42, *44, *47, *51, *56, *57, *62

• Increased function alleles include the following• *1xN, *2xN, *35xN

http://www.cypalleles.ki.se/cyp2d6.htmhttps://www.pharmgkb.org/page/cyp2d6RefMaterials

Functional StatusActivity Score

Alleles

Functional/wild-typeNormal

1*1, *2, *27, *33, *35, *39, *45, *46,

*48, *53

Reduced Function 0.5*9, *10, *17, *29, *41, *49, *50, *54,

*55, *59, *72

Non-functional 0*3, *4-*8, *11-21, *31, *36, *38, *40,

*42, *44, *47, *51, *56, *57, *62Adapted & modified from: Crews KR. Clin Pharmacol Ther 2012;91:321-6.

Activity Score Phenotype

>2 Ultra-Rapid Metabolizer (UM)

1.5-2.0 Normal Metabolizer (NM)

0.5-1.0 Intermediate Metabolizer (IM)

0 Poor Metabolizer (PM)Hicks JK, et al. Clin Pharmacol Ther 2013;93:402-8.

PGx ApplicationsDrug-Gene Interactions

How genetic variations affect drug disposition & response

Cytochrome P450 DMEsDrug-Gene Interactions (DGIs)

Verbeurgt P, et al. Pharmacogenomics. 2014;15:655-65. Pulley JM, et al. Clin Pharmacol Ther. 2012;92:87-95. Grice GR, et al. Pharmacogenomics. 2006;7:61-5.

• A DGI occurs when a patients genetic CYP450 type (e.g., CYP2D6 poor metabolizer) affects that patient’s ability to metabolize a drug

• Drug-gene relationships can help identify patients at risk for undesired drug response (e.g., adverse drug reactions [ADRs], ineffectiveness)

It is estimated that 1 in 4 patients (25%) take >1 drug that commonly causes ADRs due to genetic variation in drug metabolism

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Cytochrome P450 DMEsGenotype to Phenotype

Citation: U.S. Food and Drug Administration. Paving the Way for Personalized Medicine. October 2013.Source: Xie H, Frueh FW. Pharmacogenomics steps toward personalized medicine. Personalized Medicine. 2005;2:333.

Cytochrome P450 DMEsPhenotype Expression

Caudle KE. Genet Med. 2017;19:215-23.

Respond as expected to drugs when dosed

at standard dosing

• Poor Metabolizer (PM)• Drug A (e.g., *3|*3)

• Intermediate Metabolizer (IM)• Drug B (e.g., *1|*3)

• Normal Metabolizer (NM)• Drug C (i.e., *1|*1)

• Ultra-Rapid Metabolizer (UM)• Drug D (e.g., *17|*17)

Time

Co

ncen

tration

TOXIC

EFFECTIVE

Cytochrome P450 DMEsPhenotype Expression

Exception: Prodrugs DGIs Principles

ActiveDrug A

InactiveDrug B

Inactive Metabolite

Active Metabolite

CYP

CYP

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PGx ApplicationsDrug-Gene Interaction Examples

Clopidogrel Metabolic Pathway

Clopidogrel(inactive)

Inactive metabolite

CES1

2-oxo-clopidogrel(inactive)

1A2

2C19

2C9

Active metabolite

2B6

2B63A4

3A5

2C19

Platelet inhibitionUM 2C19

(too much)Increased Bleeds

PM 2C19(too little)

Increased Clots

Increased Effects?

Elimination P2RY12

85%

15%

Hepatocyte

Clopidogrel Response | Guidelines

CPIC Recommendations for Clopidogrel Based on CYP2C19 Phenotype

Phenotype Interpretation Recommendation

UMIncreased platelet inhibition & decreased residualplatelet aggregation.

Label-recommended dosage and administration

EMNormal platelet inhibition & normal residual platelet aggregation.

Label-recommended dosage and administration

IMReduced platelet inhibition, increased residual platelet aggregation, & increased risk for adverse CV events.

Alternative antiplatelet therapy (if no contraindication) such as prasugrel or ticagrelor.

PMSignificantly reduced platelet inhibition, increased residual platelet aggregation, & increased risk for adverse CV events.

Alternative antiplatelet therapy (if no contraindication) such as prasugrel or ticagrelor.

Scott SA, et al. Clin Pharmacol Ther 2013;94:317-23.

For ACS/PCI

Monitor for bleed

Prasugrel Contraindications: History of stroke or TIA or active bleeding

Prasugrel Cautions: Increased bleeding risk in patients age > 75 years or body weight < 60 kg, or with certain drugs

Ticagrelor Contraindications: History of intracranial hemorrhage, active bleeding, or severe hepatic impairmentTicagrelor Cautions: Avoid aspirin doses >100 mg/day due to reduced Ticagrelor effectiveness

Alternative Metabolic Pathways

Ticagrelor* AR-C124910XX*CYP3A4/5

Ferri N, et al. Drugs 2013;73:1681-1709.

*Active

Prasugrel (inactive) Thiolactone (inactive)

CYP2B6CYP3A4

CYP2C9CYP2C19

R-138727*Esterases

NOT a prodrug

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OpioidsOpioid CYP2D6 CYP3A4 CYP2B6

Codeine 5* 10

Morphine NON P450

Tramadol 50

Oxycodone 15* 30

Oxymorphone NON P450

Hydrocodone 10* 55

Hydromorphone NON P450

Fentanyl 90

Methadone 10 50

Tapentadol 25

Dihydrocodeine 25

https://www.intermedrx.com/* = Pro-drug or drug that is converted to a more active metabolite

Oxycodone Metabolic Pathway

Oxycodone

CYP2D6

Glucuronidation

Hepatocyte

Smith HS. Mayo Clinic Proceedings. 2009;84:613-24.

CYP3A4 Noroxycodone

NoroxymorphoneOxymorphone

CYP2D6

CYP3A4

Oxycodone ResponseNormal Response

Oxycodone OxymorphoneCYP2D6

CYP2D6 *1/*1Normal Metabolizer (NM)

Oxycodone ResponseReduced Response


CYP2D6 *4/*4Poor Metabolizer (PM)

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Oxycodone ResponseEnhanced Response

Oxycodone Oxymorphone

CYP2D6 *1/*1x2Ultra-rapid Metabolizer (UM)

CYP2D6CYP2D6

CYP2D6CYP2D6

CYP2D6

CYP2D6

Oxycodone ResponseAltered Response – Phenoconversion


Bupropion


CYP2D6 behaves like an Intermediate Metabolizer (IM) or

Poor Metabolizer (PM)

This can be mitigated by giving Oxycodone 2-4 hours prior to

Bupropion

Oxycodone ResponseAltered Response – Phenoconversion


Amiodarone


CYP2D6 behaves likePoor Metabolizer (PM)

This can NOT be mitigated by changing time of administration

Oxycodone Response | Guidelines• DPWG (Dutch Pharmacogenetics Working Group)

NM IM PM UM

N/A

Select ALTERNATIVE or be ALERT to symptoms of

insufficient pain relief

Select ALTERNATIVE or be ALERT to symptoms of

insufficient pain relief

Select ALTERNATIVE or be ALERT to ADEs

Alternatives: Acetaminophen, NSAID, morphine (not tramadol or codeine)

!oror

!or

!

Swen JJ, et al. Clin Pharmacol Ther. 2011;89:662-73.

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• PGx is a rapidly developing field that has important clinical applications for personalizing drug therapy to maximize effectiveness (benefits) and/or minimize toxicity (risks)

• It will become increasingly difficult to practice medicine & to provide high quality health care in the future without a fundamental knowledge of PGx

• With their knowledge of the principles discussed herein, PACE clinicians should consider the utility of PGx in their practices

Take-Away Points PGx References

• Caudle KE, Dunnenberger HM, Freimuth RR, et al. Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC). Genet Med. 2017;19:215-23.

• Terpening C. Clopidogrel: a pharmacogenomic perspective on its use in coronary artery disease. Clin Med Insights Cardiol. 2010;4:117-28.

• Hicks JK, Bishop JR, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin Pharmacol Ther. 2015;98:127-34.

• Hicks JK, Swen JJ, Thorn CF, et al. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. ClinPharmacol Ther. 2013;93:402-8.

• Verbeurgt P, Mamiya T, Oesterheld J. How common are drug and gene interactions? Prevalence in a sample of 1143 patients with CYP2C9, CYP2C19 and CYP2D6 genotyping. Pharmacogenomics. 2014;15:655-65.

• Pulley JM, Denny JC, Peterson JF, et al. Operational implementation of prospective genotyping for personalized medicine: the design of the Vanderbilt PREDICT Project. ClinPharmacol Ther. 2012;92:87-95.

PGx References

• Grice GR, Seaton TL, Woodland AM, et al. Defining the opportunity for pharmacogenetic intervention in primary care. Pharmacogenomics. 2006;7:61-5.

• Scott SA, Sangkuhl K, Stein CM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013;94:317-23.

• Ferri N, Corsini A, Bellosta S. Pharmacology of the new P2Y12 receptor inhibitors: insights on pharmacokinetic and pharmacodynamic properties. Drugs. 2013;73:1681-1709.

• Smith HS. Opioid metabolism. Mayo Clin Proc. 2009;84:613-24.

• Swen JJ, Nijenhuis M, de Boer A, et al. Pharmacogenetics: from bench to byte – an update of guidelines. Clin Pharmacol Ther. 2011;89:662-73.

Questions?

Documents

Anticholinergic and Sedative Burden & Pharmacogenomics...without dementia, in men, the use of drugs with definite anticholinergic activity was associated with greater risk of subsequent