Anticholinergic and Sedative Pathophysiology

9/27/2018

Objectives

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

Anticholinergic and Sedative Burden • Explain the risks associated with anticholinergic and sedative & Pharmacogenomics medication use in older adults • Compare and contrast methods for quantifying anticholinergic Kevin T. Bain, PharmD, MPH, BCPS, BCGP, CPH, FASCP and sedative burden SVP, Research & Development • Describe how genetic variants may affect drug pharmacokinetics and pharmacodynamics for a series of drugs CareKinesis Clinical Advisory Panel September 21, 2018

Anticholinergic Pathophysiology Cholinergic Hypothesis

Anticholinergic and Sedative Pathophysiology

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.

Sedative Pathophysiology Pathophysiology Alterations in the BBB Cholinergic 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 Age-related alterations in the blood brain barrier (BBB) contribute significantly to the exaggerated response associated with medications affecting the CNS Terry AV Jr, et al. J Pharmacol Exp Ther. 2003;306:821-7. Wong AD, et al. Front Neuroeng. 2013;6:1-22. DeKosky ST. J Am Geriatr Soc. 2003;51:S314-20. Cabezas R, et al. Front Cell Neurosci. 2014;8:1-11.

Sedative Pathophysiology Alterations in the BBB

Anticholinergic Pharmacology

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

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

Anticholinergic Pharmacology Anticholinergic Pharmacology Anticholinergic Hypothesis Anticholinergic Hypothesis Block acetylcholine receptors in neurons through • Most anticholinergics interact with muscarinic ACh receptors competitive inhibition • A few can also affect the nicotinic ACh receptors (e.g., glycopyrrolate)

Antagonistic effects are reversible • 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 expect the 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. Pasqualetti G, et al. Clin Interv Aging. 2015;10:1457-66. Rudd KM, et al. Pharmacotherapy. 2005;25:1592-601.

Anticholinergic Pharmacology Sedative Pharmacology Anticholinergic Drug Interactions Multiple CNS Mechanisms

• Clinically-important drug-drug interactions • Agonism of the benzodiazepine receptor (GABA-A complex) • Cholinergic / muscarinic agonists – Pharmacodynamic • Benzodiazepines & barbiturates Direct: Bethanechol Indirect: Acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine) • Antagonism of histamine H1 receptors • CYP450-mediated drug interactions (competitive inhibition) – Pharmacokinetic • Antihistamines, antipsychotics, & TCAs • Drug specific • Binding to the μ-opioid receptor • Opioids • Clinically-important drug-disease interactions • Antagonism of α1-adrenergic receptors • Benign prostatic hyperplasia • Antipsychotics • Constipation • Dementia • Blockage of muscarinic receptors • Glaucoma (narrow-angle) • Smooth muscle relaxants (urinary antispasmodics)

Anticholinergic Pharmacology Sedative 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 Adverse Effects of Anticholinergic  Concomitant administration with other drugs that cause respiratory depression  e.g., Opioid + Benzodiazepine • CYP450-mediated drug interactions (competitive inhibition) – Pharmacokinetic and Sedative Medications  Drug 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 Including Morbidity & Mortality decreased respiratory reserve  COPD, cor pulmonale, morbid obesity • Use of sedative drugs in patients at high-risk for falls  History of falls, orthostatic hypotension, syncope

THIS IS YOUR BRAIN Adverse Effects Older Adults’ Susceptibility

Anticholinergic & Sedative • Older adults are particularly vulnerable to anticholinergic and sedative- related adverse effects for several reasons: THIS IS YOUR BRAIN ON DRUGS • 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 YES, we have questions • 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) Boustani M, et al. Aging Health. 2008;4:311-20. Taipale HT, et al. Clin Psychopharmacol. 2012;32:218-24. Tune LE. J Clin Psychiatry. 2001;62:11-4.

Anticholinergic Adverse Effects Anticholinergic Risks

• Agitation / delirium • Urinary retention • Onset or worsening BPSD • Increased UTI • Loss of independence • Loss of independence • Institutionalization • Acute kidney injury (AKI)

• Cardiac dysrhythmias • Dry mouth • Arrhythmias • Dysphagia • Dental caries • Impaired communication • Constipation • Fecal impaction • Blurred vision (ACB) + Dizziness (SB) • Paralytic ileus • Gait disturbances / falls • Pain Boustani M, et al. Aging Health. 2008;4:311-20. http://lookfordiagnosis.com/mesh_info.php?term=anticholinergic+syndrome&lang=1 Tune LE. J Clin Psychiatry. 2001;62:11-4.

Sedative Risks Anticholinergic Morbidity Cognitive Function • Daytime sleepiness • Blurred vision (ACB) + Dizziness (SB) • Sedentary • Gait disturbances / falls • Cause or worsen cognitive impairment & delirium • Social isolation • Myriad studies have found a significant association between anticholinergic burden and either cognitive impairment or delirium • Dependence • Memory impairment • Physical • Anterograde amnesia • Psychological • 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 • Depression • Tolerance • The risk was statistically significant among patients with the highest exposure • Abuse (dementia: adjusted HR, 1.54 [95% CI, 1.21-1.96]; Alzheimer’s disease: adjusted HR, 1.63 • Withdrawal [95% CI, 1.24-2.14]) compared with those with no use

Taipale HT, et al. Clin Psychopharmacol. 2012;32:218-24. Taipale HT, et al. Int Clin Psychopharmacol. 2012;32:218-24. Boustani M, et al. Aging Health. 2008;4:311-20. Carrière I, et al. Ann Intern Med. 2009;169:1317-24. Taipale HT, et al. J Gerontol A Biol Sci Med Sci. 2011;66:1384-92. Taipale HT, et al. Drugs Aging. 2009;26:871-81. Campbell N, et al. Clin Interv Aging. 2009;4:225-33. Gray SL, et al. JAMA Intern Med. 2015;175:401-7.

Anticholinergic Morbidity Anticholinergic Morbidity Cognitive Function Physical Function

• Increased brain atrophy • Higher anticholinergic burden is significantly associated with falls • A study published in 2016 found the use of drugs with moderate to strong • In a longitudinal study of community-dwelling older adults >65 years anticholinergic activity was associated with brain atrophy without dementia, in men, the use of drugs with definite anticholinergic • Whole brain & temporal lobe atrophy activity was associated with greater risk of subsequent injurious falls (aRR, • In cognitively normal older adults 2.55 [95% CI, 1.33-4.88])

• As well as poorer cognition (e.g., immediate memory recall & executive • Recent study (2015) reveals 16% greater risk of injury in older adults currently function) and reduced glucose metabolism using anticholinergic drugs compared with non-users • Included falls (with injury) but not exclusively injuries as a result of falls • The effect appeared additive • An increased anticholinergic burden was associated with worsening executive function & increased brain atrophy Aizenberg D, et al. Int Psychogeriatr. 2002;14:307-10. Richardson K, et al. J Am Geriatr Soc. 2015;63:1561-9. Dauphinot V, et al. J Clin Psychopharmacol. 2014;34:565-70. Spence MM, et al. J Am Geriatr Soc. 2015;63:1197-202. Risacher SL, et al. JAMA Neurol. 2016;73:721-32.

Anticholinergic Morbidity Anticholinergic Mortality Pneumonia & Hospitalization • Association with increased risk of death has been reported • Possibly cause pneumonia • In a longitudinal study of community-dwelling and institutionalized participants, two-year mortality was greater for those taking definite & • New study reveals link between anticholinergic drug use and CAP possible anticholinergics • Acute & chronic use • Definite anticholinergics: OR, 1.68 (95% CI, 1.30-2.16), P<.001 • Low- & high-potency drugs • Possible anticholinergics: OR, 1.56 (95% CI, 1.36-1.79), P<.001 • Possible mechanism involves: • For every additional point (above 5) scored on the ACB tool, the odds of dying • Sedation & altered mental status increased by 26% • 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. Fox C, et al. J Am Geriatr Soc. 2011;59:1477-83.

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. Sedative Morbidity Sedative Morbidity Allain H, et al. Drugs Aging. 2005;22:749-65. Cognitive Function Physical Function

• Increase risk of cognitive decline / impairment • Cause or worsen physical inactivity • Complex relationship with other risk factors • In the Health, Aging and Body Composition Study, researchers found that • Decline in muscle strength combined use of CNS medications was associated with cognitive decline • (adjusted HR, 1.37 [95% CI, 1.11-1.70]) over 5 years Reduced balance & mobility • Further, longer duration (adjusted HR, 1.39 [95% CI, 1.08-1.79]) & higher • Impaired performance in ADLs/IADLs doses (adjusted HR, 1.87 [95% CI, 1.25-2.79]) of CNS medications conferred greater risk • Increased risk of falling & fractures Non-benzodiazepine sedative-hypnotics • A threat to independent living do not appear to be Increase risk of delirium safer • Paradoxical aggressive or hyperactive behavior among older adults Evidence strongest with sedative-hypnotics Large-scale studies indicate that sedative-hypnotics increase the risk AGS. J Am Geriatr Soc. 2012;60:616-31. Gray SL, et al. BMJ. 2016;352:i90. Wright RM, et al. J Am Geriatr Soc. 2009;57:243-50. Airagnes G, et al. Curr Psychiatry Rep. 2016;18:89. of postural instability, falls and fractures in the elderly

Sedative Morbidity Sedative Morbidity Accidents & Overdoses Accidents & Overdoses

• Cause or contribute to motor vehicle accidents • Increase risk of ED visits and hospitalizations • 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 • ADEs from the therapeutic use of psychiatric medications are responsible hypnotics (OR, 1.39 [1.08-1.79]; P<0.01) for nearly 90,000 ED visits annually in the United States, and almost 1 in 5 • Plausibly related to impaired physical function (e.g., poorer performance in of those ED visits (19.3%, 95% CI, 16.3%-22.2%) results in hospitalization coordination, grip strength and/or mobility) • Among psychiatric medications, antidepressants, antipsychotics, and anxiolytics and sedatives are the most implicated • Risk of respiratory failure, particularly in susceptible patients • Chronic obstructive pulmonary disease (COPD) • The majority of ADE-related ED visits caused by psychiatric medications are • In a matched case-control study, the use of benzodiazepine receptor agonists was from ADRs and unintentional overdoses or supratherapeutic dosages associated with an increased risk of respiratory failure (adjusted OR, 1.56 [95% CI, 1.14- 2.13]) Sigona N, et al. J Pharm Pract. 2015;28:119-23. Yang YH, et al. J Epidemiol. 2011;21:37-43. Orriols L, et al. Clin Pharmacol Ther. 2011;89:595-601. Chen SJ, et al. Sleep. 2015;38:1045-50. Hampton LM, et al. JAMA Psychiatry. 2014;71:1006-14.

Sedative Mortality Sedative Mortality

• No association overall • Overdose deaths • Between sedative drug use and mortality • 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

• Certain drug classes • Of the pharmaceutical-related overdose deaths, the majority (74.3%; 16,451) were • Antipsychotics have been linked to an increased risk of death (in dementia) unintentional • Plethora of good-quality evidence • A meta-analysis of 15 placebo-controlled trials, 10 to 12 weeks in duration and • Opioids (75.2%; 16,651), benzodiazepines (29.4%; 6,497), and antidepressants enrolling 5,110 patients, revealed a risk of death in antipsychotic users of (17.6%; 3,889) were the pharmaceuticals most commonly involved in these approximately 1.6 times the risk of death in patients using placebo overdose deaths • Risk is greatest in the first 30 days • Nevertheless, risk appears to be unrelated to sedative effects (i.e., sudden death) • Further, among overdose deaths involving opioids, the pharmaceuticals most often also involved in these deaths were benzodiazepines (30.1%; 5,017), • Results of studies with other sedative drugs in comparison are inconsistent antidepressants (13.4%; 2,239), and antipsychotics and neuroleptics (4.7%; 783) Wilson NM, et al. Drugs Aging. 2012;29:157-65. Schneider LS, et al. JAMA. 2005;2945:1934-43. Lowry E, et al. J Clin Pharmacol. 2012;52:1584-91. Jones CM, et al. JAMA. 2013;309:657-9.

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)

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

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

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

Basis of Drug Burden Methods for Quantifying Anticholinergics Further Explored Anticholinergic Burden Sedative Burden • However, clinicians may not be aware that some commonly used drugs also have anticholinergic activity • Serum anticholinergic activity • Expert-based tools Often go (SAA) assay • Anticoagulants (e.g., warfarin) Unintentional unnoticed • Sedative Load Model • Antidepressants (e.g., paroxetine) (secondary) Effects • In vitro measurements • Sloane Model • Diuretics (e.g., furosemide) • Anticholinergic activity • Drug Burden Index • Muscarinic receptor affinity • CNS Drug Model

• They also may not realize that using multiple drugs with weaker • Expert-based tools activity can be additive and/or synergistic • Anticholinergic Cognitive Burden (ACB) • Also there may be a cumulative effect (i.e., exposure [dose & duration]) • Anticholinergic Risk Scale (ARS) • Anticholinergic Drug Scale (ADS) Keep in mind that drug interactions may further increase serum anticholinergic activity (i.e., plasma concentrations)

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

Methods for Quantifying Methods for Quantifying Expert-Based Tools Expert-Based Tools – Focus on ACB

• Based on experts’ experiences & opinions combined with available • Prioritizes ranking criteria drug information (e.g., adverse effects, pharmacology) • Drugs with cognitive adverse effects and those that permeate the BBB • Drugs with peripheral anticholinergic activity also are included • Simple list of drugs with known & different degrees of • Excludes topical, ophthalmic, otologic & inhaled drug preparations anticholinergic & sedative activity • Uses categorical scoring • Help clinicians decide the degree of risk a drug & combination of drugs may pose for individual patients • 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 • May be the only method clinically useful for assessing the central or • Definite anticholinergics = score of 2 or 3 cognitive effects of drugs • Score of 2 – clinical anticholinergic effect (moderate) • Score of 3 – drug may cause delirium (severe) Rudd KM, et al. Pharmacotherapy. 2005;25:1592-601. Boustani M, et al. Aging Health. 2008;4:311-20. Boustani M, et al. Aging Health. 2008;4:311-20. www.agingbraincare.org West T, et al. J Am Pharm Assoc. 2013;53:496-504.

Methods for Quantifying Methods for Quantifying Expert-Based Tools – Focus on ACB Expert-Based Tools – Sedative Burden

• Cumulates on numerical scoring • Expert-based tools • Sum (∑) drug scores for a cumulative ACB • Sedative Load Model (SLM) Let us take a closer look • Clinically meaningful scores • ACB score >3 • Sloane Model • Examples • CNS Drug Model • AmitriptylineAnticholinergic Cognitive Burden Scoring of Drugs • DiphenhydramineScore 1 Score 2 Score 3 ACB score = 3 • Drug Burden Index (DBI) • ParoxetineAlprazolam Carbamazepine Atropine Bupropion Cyproheptadine Oxybutynin Ranitidine Meperidine Olanzapine & Quetiapine Risperidone Oxcarbazepine Tolterodine www.agingbraincare.org Taipale H, et al. Kuopio (Finland). 2012.

Methods for Quantifying Methods for Quantifying Expert-Based Tools – Focus on SLM Expert-Based Tools – Focus on SLM

• Assigns sedative ratings categorically • Examples (sedativeREVISED Sedative rating Load Model = 2) Scoring of Drugs • Amitriptyline • Score 1 Score 2 Score 3 Bases ratings on drug characteristics • • Primary sedatives = rating of 2 Diazepam • Prominent side effect = rating of 1 • ZolpidemGlipizide Baclofen Amitriptyline

• Cumulates on numerical scoring Metoprolol Morphine Chlorpromazine • Sum (∑) drug scores for a sedative load • Examples (sedative rating = 1) • MorphineOmeprazole Paroxetine Diazepam • Paroxetine • Clinically meaningful scores Ranitidine Quetiapine Zolpidem • SLM score >3 Primary sedatives = 3 • Quetiapine • >2 CNS-active drugs (e.g., Beers criteria) Prominent side effect = 2 Potential side effect = 1 Taipale H, et al. Kuopio (Finland). 2012. Taipale H, et al. Kuopio (Finland). 2012. Linjakumpu T, et al. Int J Geriatr Psychiatry. 2003;18:542-44. Linjakumpu T, et al. Int J Geriatr Psychiatry. 2003;18:542-44.

Limitations of Methodologies Limitations of Methodologies Overall Expert-Based Tools

• Hundreds of drugs are thought to have anticholinergic and/or sedative • Most clinically relevant but least standardized method (subjective) activity and, thus, these methods may not be all inclusive • Depends on the expert’s perspective, knowledge & experience • Non-prescription drugs, namely herbals & supplements, may are not captured in these methods • Not routinely updated

• There are individual differences in pharmacodynamics, • The combination of drug lists & clinical tools, such as the MMSE, is not pharmacokinetics, especially drug interactions, and blood-brain barrier sensitive enough to detect mild drug-induced cognitive changes permeability that are not accounted for in these methods • Similarly, drug dosages can affect receptor potency yet may not be accounted for • Intra-class variation in regard to drug activity is not accounted for (e.g., in these methods some antidepressants / antipsychotics are more sedating than others within the drug class) • Endogenous factors affect physiologic activity • Should we be rating individual drugs on their anticholinergic/sedative potential?

Limitations of Methodologies Utility of Methodologies Expert-Based Tools Focus on Expert-Based Tools

• Do not include doses of drugs • Expert-based tools are simple lists of medications with individual • The presence of dose-response relationship is commonly regarded as anticholinergic & sedative activity scores evidence for causality of an ADR (i.e., Naranjo) • Can be incorporated into clinical decision support (CDS) systems to determine cumulative drug burden • May or may not take into account PRN usage • Commonly, sedative drugs are used PRN • These tools could be used as a component of MTM services to by older adults 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

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. • Drugs with anticholinergic and sedative properties can negatively • 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. affect cognitive & physical function in older adults considerably • Wong AD, Ye M, Levy AF, et al. The blood-brain barrier: an engineering perspective. Front Neuroeng. 2013;6:1-22. • Associated with poor outcomes • Cabezas R, Avila M, Gonzalez J, et al. Astrocytic modulation of blood brain barrier: perspectives on Parkinson’s • Threat to independent living 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 • Knowing a patient’s medication risk aids in personalizing a symptoms. Clin Interv Aging. 2015;10:1457-66. medication care plan • Rudd KM, Raehl CL, Bond CA, et al. Methods for assessing drug-related anticholinergic activity. Pharmacotherapy. • A tailored, systemic approach can reduce anticholinergic and sedative 2005;25:1592-601. • Boustani M, Campbell N, Munger S, et al. Impact of anticholinergics on the aging brain: a review and practical burden application. Aging Health. 2008;4:311-20.

Reference Reference

• Tune LE. Anticholinergic effects of medication in elderly patients. J Clin Psychiatry. 2001;62 Suppl 21:11-4. • 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. • 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. • 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. • 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. • 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. • 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. • 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. • 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. • 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. • Campbell N, Boustani M, Limbil T, et al. The cognitive impact of anticholinergics: a clinical review. Clin Interv Aging. 2009;4:225-33. • 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. • 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. • 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. • 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. • 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.

Reference Reference

• American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society updated Beers • Allain H, Bentue-Ferrer D, Polard E, et al. Postural instability and consequent falls and hip fractures associated with use Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2012;60:616-31. of hypnotics in the elderly: a comparative review. Drugs Aging. 2005;22:749-65. • Wright RM, Roumani YF, Boudreau R, et al. Effect of central nervous system medication use on decline in cognition in • Sigona N, Williams KG. Driving under the influence, public policy, and pharmacy practice. J Pharm Pract. 2015;28:119-23. community-dwelling older adults: findings from the Health, Aging and Body Composition Study. J Am Geriatr Soc. • 2009;57:243-50. Orriols L, Philip P, Moore N, et al. Benzodiazepine-like hypnotics and the associated risk of road traffic accidents. Clin Pharmacol Ther. 2011;89:595-601. • 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. 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. • Airagnes G, Pelissolo A, Lavallee M, et al. Benzodiazepine misuse in the elderly: risk factors, consequences, and • management. Curr Psychiatry Rep. 2016;18:89. 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- • Gray SL, Penninx BW, Blough DK, et al. Benzodiazepine use and physical performance in community-dwelling older 50. women. J Am Geriatr Soc. 2003;51:1563-70. • Hampton LM, Daubresse M, Chang HY, et al. Emergency department visits by adults for psychiatric medication • Gray SL, LaCroix AZ, Hanlon JT, et al. Benzodiazepine use and physical disability in community-dwelling older adults. J adverse events. JAMA Psychiatry. 2014;71:1006-14. Am Geriatr Soc. 2006;54:224-30. • Wilson NM, Hilmer SN, March LM, et al. Associations between drug burden index and mortality in older people in • Hanlon JT, Boudreau RM, Roumani YF, et al. Number and dosage of central nervous system medications on recurrent residential aged care facilities. Drugs Aging. 2012;29:157−65. falls in community elders: the Health, Aging and Body Composition study. J Gerontol A Biol Sci Med Sci. 2009;64:492-8. • Lowry E, Woodman RJ, Soiza RL, et al. Drug burden index, physical function, and adverse outcomes in older • Finkle WD, Der JS, Greenland S, et al. Risk of fractures requiring hospitalization after an initial prescription for hospitalized patients. J Clin Pharmacol. 2012;52:1584-91. zolpidem, alprazolam, lorazepam, or diazepam in older adults. J Am Geriatr Soc. 2011;59:1883-90.

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

DNA & Genes

• DNA…library or book

• Chromosome…cookbook or chapter PGx Preface • Gene…recipe or sentence • Nucleotides…ingredients or alphabet

• Protein (Enzyme)…meal or paragraph

Pharmacogenomics Interindividual Variability Drug Response

• Genetic variability is a key component of life One drug does NOT • Changes protein expression and function fit all Non-toxic and ineffective

• 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) Toxic and ineffective • 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 Toxic and effective Same Diagnosis & Non-toxic and effective Same Drug

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 PGx Principles • Approximately 225 genes encode for DMEs Focus on Drug Metabolism • A superfamily of enzymes responsible for the metabolism (chemical alteration) of substrates so they can be eliminated (excreted) from the body Isoform Family Allele

[HUMAN] CYP2C19*1

Species Subfamily

“Extensive Metabolizer” is now Cytochrome P450 DMEs Cytochrome P450 DMEs called “Normal Metabolizer” Proportion of Drug Metabolism Standardizing Terms Added “Rapid Metabolizer” CYP1A 10%

CYP2C CYP3A 20% 42%

CYP2E CYP2D 3% 25% Caudle KE, et al. Genet Med. 2017;19:215-23.

Cytochrome P450 DMEs Cytochrome P450 DMEs Example – CYP2C19 Example – CYP2D6

• Highly polymorphicDefinition (Diplotype) Phenotype • One of the most polymorphicActivity CYP450 DMEs Functional• At least 100 Status gene variants & 120 alleles identified Alleles Two• increasedOver 30 function allelic alleles, variants or more than 2 normal function alleles Activity Score Phenotype Ultra-Rapid Metabolizer (UM) Score (e.g., CYP2C19*17|*17) • Multiple wild-type (normal function) alleles Combinations of normal function and increased function alleles Rapid Metabolizer (RM) Functional/wild• *1, *2, *27, *33,>2- type*35, *39, *45, *46, *48, *53 *1, *2,Ultra *27,-Rapid *33,Metabolizer *35, *39, *45, (UM) *46, • The wild-type(e.g., CYP2C19*1|*17(normal) function) allele is classified as *1 1 Normal *48, *53 Combinations of normal function & decreased function alleles Normal Metabolizer (NM) • Reduced function alleles include the following • The most common(e.g., CYP2C19*1|*1 loss) -of-function alleles are *2 and *3 • *9, *10, *14B,1.5 *17,-2.0 *29, *41, *49, *50, *54, *55, *59, *72 Normal Metabolizer (NM) Combinations• Associated of normal function, with decreasedreducedfunction,enzyme and/or noactivity function *9, *10, *17, *29, *41, *49, *50, *54, alleles Intermediate Metabolizer (IM) •ReducedNon-functional Functionalleles include0.5 the following (e.g., CYP2C19*1| *2) *55, *59, *72 • *3, *4-*8, *110.5-*14A,-1.0 *15, *18, *20, *21, *31, *36, *38, *40,Intermediate *42, *44, *47, *51, Metabolizer *56, *57, *62 (IM) Combination of no function alleles and/or decreased function alleles • Another common allele, *17, is a gain-ofPoor- functionMetabolizer (PM) allele • Associated with(e.g., CYP2C19*2|*2 increased) enzymatic activity • Increased function alleles include the*3, following *4-*8, *11-21, *31, *36, *38, *40, Non• *1xN,-functional *2xN, *35xN 0 http://www.cypalleles.ki.se/cyp2c19.htm Terpening C. Clin Med Insights Cardiol. 2010;4:117-28. 0 *42, *44,Poor http://www.cypalleles.ki.se/cyp2d6.htm*47,Metabolizer *51, *56, (PM) *57, *62 https://www.pharmgkb.org/page/cyp2c19RefMaterials Hicks JK, et al. Clin Pharmacol Ther. 2015;98:127-34. AdaptedHicks JK, et& modifiedal. Clin Pharmacol from: CrewsTher KR.2013;93:402 Clin Pharmacol-8. Ther 2012;91:321-6. https://www.pharmgkb.org/page/cyp2d6RefMaterials Caudle KE, et al. Genet Med. 2017;19:215-23.

Cytochrome P450 DMEs Drug-Gene Interactions (DGIs)

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

PGx Applications • Drug-gene relationships can help identify patients at risk for Drug-Gene Interactions 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

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.

Cytochrome P450 DMEs Cytochrome P450 DMEs Genotype to Phenotype Phenotype Expression

Respond as expected to drugs when dosed at standard dosing 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. Caudle KE. Genet Med. 2017;19:215-23.

Cytochrome P450 DMEs Exception: Phenotype Expression Prodrugs DGIs Principles • Poor Metabolizer (PM) • Drug A (e.g., *3|*3) Inactive Active CYP Metabolite • Intermediate Metabolizer (IM) TOXIC Drug A • Drug B (e.g., *1|*3) Concentration

• Normal Metabolizer (NM) • Drug C (i.e., *1|*1) EFFECTIVE Inactive Active • Ultra-Rapid Metabolizer (UM) CYP • Drug D (e.g., *17|*17) Drug B Metabolite Time

Clopidogrel Metabolic Pathway

15% 2C19 Clopidogrel (inactive) 1A2 2B6 3A4 2-oxo-clopidogrel PGx Applications (inactive) Hepatocyte Drug-Gene Interaction Examples CES1 2C9 3A5 2B6 2C19 Inactive metabolite PM 2C19 Active metabolite 85% (too little)

Elimination P2RY12 Increased Clots UM 2C19 Increased Bleeds Platelet inhibition (too much) Increased Effects?

Clopidogrel Response | Guidelines Alternative Metabolic Pathways For ACS/PCI CYP2B6 CPIC Recommendations for Clopidogrel Based on CYP2C19 Phenotype Esterases CYP3A4 Prasugrel (inactive) Thiolactone (inactive) R-138727* Phenotype Interpretation Recommendation CYP2C9 Increased platelet inhibition & decreased residual Label-recommended dosage and Monitor for CYP2C19 UM platelet aggregation. administration bleed Normal platelet inhibition & normal residual platelet Label-recommended dosage and EM aggregation. administration *Active Reduced platelet inhibition, increased residual Alternative antiplatelet therapy (if no IM platelet aggregation, & increased risk for adverse CV contraindication) such as prasugrel or events. ticagrelor. Significantly reduced platelet inhibition, increased Alternative antiplatelet therapy (if no PM residual platelet aggregation, & increased risk for contraindication) such as prasugrel or CYP3A4/5 adverse CV events. ticagrelor. Ticagrelor* AR-C124910XX*

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 NOT a prodrug Ticagrelor Contraindications: History of intracranial hemorrhage, active bleeding, or severe hepatic impairment Ticagrelor Cautions: Avoid aspirin doses >100 mg/day due to reduced Ticagrelor effectiveness Scott SA, et al. Clin Pharmacol Ther 2013;94:317-23. Ferri N, et al. Drugs 2013;73:1681-1709.

Opioids Oxycodone Metabolic Pathway Opioid CYP2D6 CYP3A4 CYP2B6

Codeine 5* 10 Oxycodone CYP3A4 Noroxycodone Morphine NON P450 Tramadol 50 Oxycodone 15* 30 CYP2D6 CYP2D6 Oxymorphone NON P450 Hepatocyte Hydrocodone 10* 55 Hydromorphone NON P450 CYP3A4 Noroxymorphone Fentanyl 90 Oxymorphone Methadone 10 50 Glucuronidation Tapentadol 25 Dihydrocodeine 25

* = Pro-drug or drug that is converted to a more active metabolite https://www.intermedrx.com/ Smith HS. Mayo Clinic Proceedings. 2009;84:613-24.

Oxycodone Response Oxycodone Response Normal Response Reduced Response

Oxycodone CYP2D6 Oxymorphone Oxycodone CYP2D6 Oxymorphone

CYP2D6 *1/*1 CYP2D6 *4/*4 Normal Metabolizer (NM) Poor Metabolizer (PM)

Oxycodone Response Oxycodone Response Enhanced Response Altered Response – Phenoconversion

CYP2D6 *1/*1 CYP2D6CYP2D6 Normal Metabolizer (NM) Oxycodone CYP2D6CYP2D6 Oxymorphone CYP2D6 Oxycodone CYP2D6 Oxymorphone CYP2D6

CYP2D6 *1/*1x2 Bupropion This can be mitigated by giving Ultra-rapid Metabolizer (UM) Oxycodone 2-4 hours prior to CYP2D6 behaves like an Bupropion Intermediate Metabolizer (IM) or Poor Metabolizer (PM)

Oxycodone Response Oxycodone Response | Guidelines Altered Response – Phenoconversion • DPWG (Dutch Pharmacogenetics Working Group) NM IM PM UM CYP2D6 *1/*1 Select ALTERNATIVE Normal Metabolizer (NM) Select ALTERNATIVE or be ALERT to or be ALERT to Select ALTERNATIVE N/A symptoms of CYP2D6 symptoms of or be ALERT to ADEs Oxycodone Oxymorphone insufficient pain relief insufficient pain relief

Amiodarone  or or This can NOT be mitigated by or changing time of administration ! ! ! CYP2D6 behaves like Poor Metabolizer (PM) Alternatives: Acetaminophen, NSAID, morphine (not tramadol or codeine)

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

Take-Away Points PGx References

• PGx is a rapidly developing field that has important clinical • Caudle KE, Dunnenberger HM, Freimuth RR, et al. Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics applications for personalizing drug therapy to maximize Implementation Consortium (CPIC). Genet Med. 2017;19:215-23. effectiveness (benefits) and/or minimize toxicity (risks) • 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 • It will become increasingly difficult to practice medicine & to reuptake inhibitors. Clin Pharmacol Ther. 2015;98:127-34. • Hicks JK, Swen JJ, Thorn CF, et al. Clinical Pharmacogenetics Implementation Consortium provide high quality health care in the future without a guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin fundamental knowledge of PGx Pharmacol 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. • With their knowledge of the principles discussed herein, PACE • Pulley JM, Denny JC, Peterson JF, et al. Operational implementation of prospective genotyping for personalized medicine: the design of the Vanderbilt PREDICT Project. Clin clinicians should consider the utility of PGx in their practices Pharmacol Ther. 2012;92:87-95.

PGx References Questions?

• 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.