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Erin E. Jobst, PT, PhD April 16, 2016

Pharmacology Considerations for Older Adults in the Skilled Nursing Facility

Presented at Infinity Rehab Symposium 2016

Outline for today

�  Key definition �  Drug development �  Drug monitoring �  Reliable, up-to-date resources �  Supplements

¡  Definition, consequences of federal regulation, evidence-based resources

�  Pharmacokinetics ¡  Effect of exercise on pharmacokinetics

�  Pharmacodynamics ¡  Dose-response curves ¡  Therapeutic index

Outline for today

�  Adverse Drug Reactions (ADRs) ¡  Incidence ¡  Types ¡  Organ-specific toxicities

÷  Dermatologic toxicity ÷  Ototoxicity ÷  Gastrointestinal toxicity ÷  Nephrotoxicity ÷  Hepatotoxicity ÷  CNS toxicity ÷  Cardiovascular toxicity

¡  Therapists� role in managing medications

�  Pharmacology & aging ¡  Frequency of ADRs in older

adults ¡  Drugs and falls ¡  Beers Criteria – 2012 and 2015

÷  Top 10 drugs for older adults to avoid

Specific drugs/drug classes we�ll cover

�  Drugs for treatment of pain �  viscosupplementation �  Duragesic (fentanyl) �  NSAIDs �  acetaminophen

�  Drugs for treatment of CV disorders �  Procardia (nifedipine) �  digoxin �  Coumadin (warfarin) �  antihypertensives �  antiarrhythmics

�  Drugs for the treatment of insomnia, anxiety, and Alzheimer�s disease

¡  benzodiazapines (BZDs) ¡  non-BZD receptor agonists ¡  melatonin/melatonin receptor

agonist ¡  suvorexant (Belsomra) ¡  diphenhydramine (Benadryl) ¡  buspirone ¡  selective serotonin reuptake

inhibitors (SSRIs) ¡  serotonin-norepinephrine

reuptake inhibitors (SNRIs) ¡  tricyclic antidepressants (TCAs) ¡  acetylcholinesterase inhibitors

(Aricept) ¡  glutamate NMDA receptor

antagonist (Namenda)

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Why should rehabilitation therapists understand pharmacology?

�  Medication use may alter clinical presentation and/or course of therapy ¡  �Medications are involved in 80% of all treatments and impact every

aspect of a patient�s life.��(Patient-Centered Primary Care Collaborative; www.pcpcc.org)

�  Knowledge of drug classes & mechanism of their actions is key to understanding patients� responses to drugs

�  To identify and potentially avoid or limit common adverse drug reactions (ADRs, ADEs, or AEs) relevant to rehab ¡  Anticipate ADRs in patients/clients with altered pharmacokinetics

and pharmacodynamics ¡  We should always think - are there possible therapy solutions? ¡  ADRs are best recognized by those who spend the most time with

the patient!

Potential areas of involvement for rehabilitation therapists

�  Monitor for compliance with drug regimen �  Identify and differentiate rehabilitation therapy benefits

versus drug therapy benefits �  Monitor for exercise-induced changes in pharmacological

effects �  Educate patient on preventative health care �  Ever-evolving scopes of practice…

Key Definitions

� Drug ¡  Substance intended for use in the diagnosis, cure,

mitigation, treatment, or prevention of disease ¡  Substance (other than food) intended to affect the structure

or function of the body

� Pharmacology ≠ Pharmacy ¡  Pharmacology: study of drugs ¡  Pharmacy: preparation & dispensing of prescription drugs

Key Definitions

�  Polypharmacy ¡  More drugs prescribed than clinically warranted ¡  All prescribed drugs are clinically warranted, but there

are just too many pills to take ¡  Use of ≥ 5 drugs/day ¡  Use of ≥ 10 drugs/day is termed excessive polypharmacy ¡  At any given time, an older patient takes 4-5 prescription

drugs and 2 over-the-counter drugs

(Haider et al., 2009; Beers, 1999)

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Key Definitions

�  Increased risk of ADRs ¡  ~13% chance of having an ADR if

taking 2 medications… ¡  ~82% if taking 7 medications ¡  ~100% if taking 10 medications

�  Low adherence to drug therapy

�  Unnecessary healthcare costs

Why is polypharmacy a problem?

Key Definitions

� Rational use of medicines ¡  Requires that �patients receive medications appropriate to

their clinical needs, in doses that meet their own individual requirements, for an adequate period of time, and at the lowest cost to them and their community�

¡  WHO estimates that > 1/2 of all medications are prescribed, dispensed, or sold inappropriately - and that 1/2 of all patients fail to take them correctly.

(http://www.who.int/medicines/areas/rational_use/en/ )

Key Definitions

�  Pharmacodynamics: effect of the drug on the body ¡  Systemic effects ¡  Cellular effects

�  Pharmacokinetics: effects of the body on the drug ¡  Absorption ¡  Distribution ¡  Metabolism ¡  Excretion

n.b. elimination = metabolism + excretion

Drug nomenclature

�  chemical ¡  (1S)-cis-4-(3,4-

dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine

�  generic

¡  sertraline hydrochloride

�  Brand name ¡  Zoloft

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What government agency monitors and approves drugs?

�  USA: Food & Drug Administration (FDA) �  Canada: Health Products & Food Branch (HPFB) of the

Department of National Health and Welfare

How are new drugs developed & approved?

�  Basic science and testing on animals �  Company applies to FDA for permission to test a specific drug

on patients (may take ≈ 6.5 yr from basic science to this application)

�  If approved, the company can start Clinical Trials:

¡  (Phase 0): few drugs go through this phase; designation since 2006 ¡  Phase I: ≈1 yr; ≈ <100 healthy subjects to determine maximum

tolerated dose and likely ADRs ¡  Phase II: ≈2 yr; ≈ 200-300 subjects with target disease to

determine effects of test drug on disease state ¡  Phase III: ≈3 yr; ≈ 1-3K subjects with target disease; usually drug

is tested against a placebo or a FDA-approved drug

How are new drugs developed & approved?

�  When the 3 phases are completed (≈ 7 yr), FDA reviews the results, consults experts, and decides whether to approve the drug.

�  If approved, the drug is released to the market (for prescription by authorized prescribers) ¡  This is a KEY time for HCPs to pay close attention to

patients� medication lists!

Where can I find reliable & up-to-date information about drugs?

�  Concise, current, easy-to-use & free drug information: www.epocrates.com ¡  Web-based and mobile product that enables point of care

information ¡  Proprietary database developed by pharmacists & physicians ¡  Source of Epocrates data

÷ Package inserts, FDA drug safety alerts, textbooks, specialty society recommendations, clinical guidelines, consensus documents, review articles, primary literature

¡  Database updated at least 1X/wk

FAQs about Epocrates: http://www.epocrates.com/company/content/faqs.html

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Where can I find reliable & up-to-date information about drugs?

�  Drug monitoring (post-marketing surveillance - Phase IV) ¡  www.fda.gov/medwatch/safety.htm ¡  Provides:

÷ Drug-specific consumer/patient information ÷ Market withdrawals and recalls, public health advisories ÷ Safety alerts for drugs, devices, and dietary supplements

What about supplements?

�  Supplements do NOT fall under drug law, but instead under food law (Dietary Supplement Health & Education Act, 1994)

�  A dietary supplement is defined under the DSHEA as a product that meets each of the following criteria:

1)  It is intended to supplement the diet and contains one or more of the following ingredients: a vitamin, a mineral, an herb or other botanical (excluding tobacco), an amino acid, a dietary substance for use to supplement the diet by increasing the total daily intake (e.g., enzymes or tissues from organs or glands), a concentrate, such as a meal replacement or energy bar, or a metabolite, constituent, or extract.

2)  It is intended for ingestion in pill, capsule, tablet, or liquid form.

3)  It is not represented for use as a conventional food or as the sole item of a meal or diet.

4)  It is labeled as a "dietary supplement".

Consequences of current federal regulation of supplements

(1) Supplements are NOT required to be tested or approved before being marketed and sold to the public.

(2) Supplements do NOT need to be shown to be safe, just to give �reasonable assurance� that there is not significant risk of harm.

¡  Burden is on the FDA to show products are not safe; however, FDA generally lacks resources to enforce.

(3) Supplements do NOT need to show evidence of effectiveness.

(4) FDA does not analyze contents of supplements (e.g., concentration of active ingredient, contamination with heavy metals)

(5) If a product has been shown to be unsafe or harmful, the FDA does not have mandatory recall authority.

Does my supplement contain the amount of active ingredient the label claims? Does it contain heavy metals or other harmful contaminants?

1st step – SAFETY of a supplement

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Independent testing of dietary supplements

U.S. Pharmacopeial Convention (USP) http://www.usp.org/about-usp

�  USP Verified Mark on a dietary supplement label indicates the product: ¡  Contains ingredients listed on the label, in declared potency and amounts ¡  Does not contain harmful levels of specified contaminants ¡  Will break down and release into the body within a specified amount of time ¡  Has been made according to FDA current Good Manufacturing Practices using sanitary and well-controlled procedures

Independent testing of dietary supplements

ConsumerLab.com Ø  To learn more about the

potency and purity of a specific supplement

Ø  No financial interest in any companies that make or distribute consumer products

Ø  Subscription $39/year

Use evidence-based tools to find out!

How do I find out if a supplement is EFFECTIVE for what it claims?

2nd step – EFFECTIVENESS of supplement DSHEA allows supplement manufacturers to make 3 types of claims

1) Health claims that refer to prevention and treatment of a specific disease MUST be approved by FDA. •  Example: �Eating 3g of soluble fiber daily from oatmeal, in a diet

low in saturated fat and cholesterol, may reduce the risk of heart disease.� From Quaker Oats

2) Qualified health claims •  Example: Supportive, but not conclusive research shows that

omega-3 fatty acids may reduce the risk of heart disease.

3) Structure and function claims do not need FDA approval. •  These are the most common: vague statements about supporting

functions of body

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Structure and function claim disclaimer

Example of a Structure and Function claim: Label from glucosamine/chondroitin product

Howdoourpa*ents/clientsinterpretthislanguage??

Evidence-based resources for dietary supplements

•  NIH: Office of Dietary Supplements ¡  Dietary Supplement Fact Sheets

÷ http://ods.od.nih.gov/Health_Information/Information_About_Individual_Dietary_Supplements.aspx

�  FDA ¡  Tips for supplement users:

http://www.fda.gov/food/dietarysupplements/usingdietarysupplements/ucm110567.htm

¡  Tips for older supplement users: ¡  http://www.fda.gov/food/dietarysupplements/

usingdietarysupplements/ucm110493.htm ¡  NIH: drug and supplement interactions ¡  http://www.nlm.nih.gov/medlineplus/druginfo/herb_All.html

Be a good skeptic…

How are drugs classified?

� Prescription � Over-the-counter (OTC)

¡  Benefits ÷ Increased access ÷ Less expensive…

¡  Risks ÷ Decreased awareness of importance of recommended

dosages ÷ Increased frequency of drug interactions because of

increased total drug use ÷ Can delay use of more effective medications

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Pharmacokinetics (ADME) “What the body does to the drug�

� Absorption: � Distribution: � Metabolism � Excretion Elimination

Drug routes of administration

�  Parenteral (nonalimentary)

¡  Inhalation* ¡  Injection

÷ Intravenous ÷ Intra-arterial ÷ Intramuscular ÷ Subcutaneous ÷ Intrathecal* ÷ Intra-articular*

¡  Topical* ¡  Transdermal

�  Enteral (alimentary) ¡  Oral ¡  Sublingual or buccal ¡  Rectal

*generally not considered systemic routes of administration

Enteral routes

� Oral cavity (PO) ¡  Advantages

÷ Easy ÷ “Safe”:

¡  Disadvantages ÷ Must not be destroyed by acidic gastric environment ÷ Can cause GI upset ÷ Less predictable timeframe to reach effective plasma levels

¡  First-pass effect (first pass metabolism or inactivation) ÷ Mouth ⇒ absorption from GI tract ⇒ portal vein ⇒ liver

First-pass effect with oral drug administration ¡  Drugs are taken up from capillaries in stomach & intestine and are

transported by hepatic portal vein to liver cells ¡  Dosage of oral drug must be high enough to allow adequate amount of

drug to survive metabolism by enzymes in liver cells ¡  Each oral drug has a distinct first-pass effect - can vary from ~ 0-100%

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Oral route

� Factors affecting rate of GI absorption

¡ Blood flow & intestinal motility ¡ Gastric emptying time ¡ Food

÷ Decreases absorption rate of most drugs ÷ Opportunity for drug-food interactions

¢ e.g., grapefruit juice, fermented cheese and wine

Enteral routes

� Sublingual: under tongue � Buccal: between cheek and gums

� For both sublingual and buccal routes: ¡  Oral mucosa ⇒ veins ⇒ superior vena cava ⇒ heart ¡  Bypasses first-pass effect

÷ e.g., nitroglycerin (NTG)

Enteral routes

� Rectal ¡ Advantages

÷ Unconscious patients ÷ If vomiting prevents oral administration

¡ Disadvantages ÷ Poor absorption ÷ Rectal irritation

Parenteral routes

� Primary advantage ¡  Quantity of drug that reaches target site is more predictable

than with enteral routes � 4 Main Routes

¡  Inhalation ¡  Injection

÷  Intravenous, intra-arterial, intramuscular, subcutaneous, intrathecal, intra-articular ¡  Topical ¡  Transdermal

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Parenteral routes

�  Inhalation: gases or aerosols ¡  Rapid entry into bloodstream ¡  Excellent for pulmonary conditions

÷ e.g., bronchodilators (albuterol and salmeterol)

¡  Irritation of respiratory tract may be limiting ÷ Devices can help:

¢ Nebulizer ¢ Spacer with metered-dose inhalers

Spacer: one-way valved holding chamber

Excellent guide on proper use of metered-dose inhalers (MDI) with & without a spacer: http://my.clevelandclinic.org/devices/inhalers/hic_how_to_use_a_metered_dose_inhaler.aspx

Parenteral routes

�  Injection ¡ Advantages

÷ Can get peak drug level to target tissue very quickly (sometimes almost instantaneously)

¡ Disadvantages ÷ Easier to overdose ÷ Easy to introduce infection

Methods of injection

1)  Intravenous (IV): bolus or indwelling catheter o  e.g., antibiotics, cancer chemotherapeutic drugs

2)  Intra-arterial (IA): targets agent to certain tissues o  e.g., diagnostic imaging

3)  Intramuscular (IM): rapid but stable drug release o  e.g., botulinum toxin, most vaccines, some opioid analgesics

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Methods of injection

4) Subcutaneous: injection directly under skin; can be bolus or implanted

o  e.g., insulin, some opioid analgesics

5) Intrathecal: targets drug next to spinal cord; can bypass blood-brain barrier

o  e.g., baclofen (typically delivered via pump)

6) Intra-articular: injection into intra-articular space, usually to treat joint pain

o  e.g., glucocorticoids, local anesthetics, opiates, viscosupplementation

Viscosupplementation

�  Intra-articular injection of fluid to �supplement� thinning & less elastic synovial fluid in joints with mild to moderate OA

�  Injection contains hyaluronic acid, a glycosaminoglycan

�  Large sugar molecules that tangle with synovial fluid to act as a shock absorber ¡  Hyalgan® (FDA drug) ¡  Synvisc® (FDA medical device)

�  Joints injected: ¡  KNEE, hip, carpometocarpal of the

thumb, shoulder

Effectiveness of viscosupplementation

�  In knee OA, decreased pain & disability usually in ~1 week and lasting ~3-6 months

�  Comparable efficacy to NSAIDs (with fewer GI ADRs) & intra-articular glucocorticoids (with longer-lasting effects)

�  ADRs - generally well tolerated

�  In 76 trials for knee OA, compared to �controls�: beneficial effects on pain, function, patient global assessments, especially at 5 to 13 weeks post-injection period (Bellamy et al., Cochrane Database Syst Rev, 2006)

�  May be more beneficial when given in earlier stages of OA

�  When combined with conventional therapy or other pharmacologic agents, viscosupplementation more effective at managing OA than conventional care alone. (Ray TR, Phys Sportsmed, 2013)

Gigante and Callegari, Rheumatol Int, 2011

Topical administration: applied on skin or mucous membranes

1) Skin: drugs applied to skin for treating skin problems ÷  e.g., antibiotics for skin infection (Neosporin), topical anti-

inflammatory steroid cream (topical hydrocortisone), local anesthetic/analgesic (Lidoderm)

¡  Generally poor systemic absorption from skin

2) Mucous membranes: significant amount of systemic absorption is possible

÷  e.g., nasal decongestants (Neo-Synephrine nasal, Afrin) can increase BP, which may precipitate angina in patients during exercise as result of increased cardiac workload

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Transdermal administration

�  Drugs applied to skin with goal of absorption beyond skin (subcutaneous tissues or peripheral circulation)

¡  Drug must penetrate skin and resist breakdown by enzymes within epidermis and dermis

¡  Iontophoresis or phonophoresis to assist in drug delivery ÷  e.g., anti-inflammatory agents such as dexamethasone

sodium phosphate ¡  �Patches� that achieve slow & prolonged drug plasma levels

÷  e.g., patches that contain NTG, scopolamine, opioids, nicotine, sex hormones

Patches: transdermal drug delivery

Scopolamine for motion sickness

Duragesic® (fentanyl) for chronic pain

CAUTION with patches… Illustration using the Black Box Warning for Duragesic®

Black Box Warning for Duragesic® �  Only for use by opioid tolerant

patients with persistent moderate/severe chronic pain

�  High potential for abuse �  Only for transdermal use and only on

intact skin �  Avoid heat exposure �  CYP450 3A4 inhibitors should not be

taken at the same time

Drug Absorption

�  How much of the drug actually gets to target cells?

�  Bioavailability: percentage of drug that actually reaches the systemic circulation

= ([systemic] / [administered] ) * 100%

Curry, Figure 4-7, 1999

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Drug Distribution

�  Movement of a drug out of systemic circulation and into interstitial spaces to its target site (i.e., its receptor) which may be within or on a cell

�  Depends on:

1)  Blood flow

2)  Binding to plasma proteins, especially albumin

3)  Tissue permeability

4)  Binding within cells

Drug Distribution: Why is drug “storage” in certain tissues a problem?

�  Decreases amount of drug that reaches target tissue

�  �Redistribution� of a drug as it moves out of a �storage depot� ¡  Movement of lipophilic drugs like anesthetics out of adipose

tissue may contribute to prolonged drug effects

�  Damage to cells/tissues in which drugs are stored

Drug Metabolism

�  Chemical alteration of drug to make it inactive (usually) and more suitable for excretion from body ÷  Liver is primary organ for drug metabolism

¢  Relies on liver enzymes (cytochrome P450, or CYP450 enzymes) ÷  Usually occurs in minutes to hours ÷  Affected by health of liver, blood flow to liver, and degree of

protein binding ÷  Occurs to lesser extent in other organs

Factors affecting drug metabolism

�  Age ¡  Very young: possibly deficient in specific drug-metabolizing

enzymes, different membrane properties, blood flow ¡  Elderly have reduced hepatic and renal function

�  Genetics ¡  Abnormal, deficient, or absent drug-metabolizing enzymes ¡  Pharmacogenomics: branch of genetics to tailor drug therapy

more specifically to individuals (due to polymorphisms) �  Disease

¡  Dysfunction or decreased blood flow to liver or kidney decrease metabolism

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Factors affecting drug metabolism Drug-drug interactions

�  CYP450 enzymes metabolize thousands of compounds ¡  Many different families (types) of CYP450 enzymes

break down specific types of drugs ÷ e.g., CYP450 3A4

�  CYP450 enzymes can be induced or inhibited by drugs, supplements, & even some foods.

http://www.psychresidentonline.com/CYP450druginteractions.htm

CYP450 enzyme inducers

�  If a drug increases the number or activity of a family of CYP450 enzymes, subsequent drugs metabolized by the same family of CYP450 enzymes can be broken down FASTER.

�  Result: decreased therapeutic effect of subsequent drug (so, increased dosage would be needed for same effect)

¡  Examples of common CYP450 enzyme inducers ÷  St. Johns Wort (3A4), chronic cigarette smoking (1A2), chronic

ethanol use

Example of the impact of long-term ingestion of St. John�s Wort (a CYP450 inducer) on plasma levels of

indinavir (HIV protease inhibitor)

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CYP450 enzyme inhibitors

�  If a drug inhibits the activity of a family of CYP450 enzymes, subsequent drugs metabolized by the same family of CYP450 enzymes can be broken down SLOWER.

�  Result: increased drug plasma levels & increased frequency of ADRs

¡  Examples of common CYP450 enzyme inhibitors ÷  fluoxetine, ciprofloxacin, grapefruit juice (3A4)

Drug-food interactions Grapefruit juice: CYP450 inhibitor

�  Old news (since 1990s) ¡  > 50 drugs carry a warning that grapefruit juice may turn a

safe dose of medicine to an overdose! ÷ Active constituent in grapefruit: bergamottin

�  �Newer� news (since ≈2006) ¡  Other juices can act as milder CYP450 enzyme inhibitors

÷ Black mulberry, wild grape, pomegranate, black raspberry (Kim et al., 2006)

�  �Newest� news (since 2008) ¡  Grapefruit, apple, and orange juices can also have opposite effect -

that is, they can act as enzyme inducers, too (Bailey DG, unpublished reports) ÷ These juices decreased absorption of certain drugs.

What conclusions CAN we make regarding drug-drug or drug-food interactions?

�  Ask prescriber or pharmacist about known interactions!! �  Check epocrates.com – use Interaction Check �  Check links on next slides �  Be aware of significant concerns about many drug-supplement

interactions

Drug Excretion

�  Physical elimination of the drug from the body �  Kidney is primary organ for drug excretion.

¡  Generally, drugs are excreted as result of glomerular filtration ¡  Many drugs can also be actively secreted into nephron tubules ¡  Affected by health of kidney, blood flow to kidney, pH of urine,

and degree of protein binding �  Lungs: primary role in excreting volatile drugs �  GI: minor role

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Drug Elimination Rates

�  Rate at which a drug is eliminated helps determine the dose and frequency drug is prescribed/recommended ¡  At a certain point, the amount of drug administered during

dosing exactly replaces the amount excreted = steady-state

�  Half Life (t1/2): amount of time required for 50% of the drug remaining in the body to be eliminated

Why is knowledge of the half-life of a drug helpful to a rehabilitation therapist?

1)  To determine whether your patient’s symptoms/signs could be the result of the drug�s effect

¡  For most drugs*, it takes ≈ 5 half-lives for > 95% of drug

to be eliminated from the body.

*For drugs eliminated by 1st-order process - in which a fixed portion of drug is eliminated in a given time period

Why is knowledge of the half-life of a drug helpful to a rehabilitation therapist?

Case example: Your 45-year-old patient was taking nifedipine (Procardia®), a commonly prescribed calcium channel blocker, for stable angina. He has been experiencing severe headaches & dizziness. His doctor suggested he stop taking the drug for a few days. He arrives for his therapy appointment stating that his symptoms have not changed since his last dose 2 days ago. •  Could Procardia® still be the cause of his symptoms? •  It is unlikely…Why? •  t1/2 of Procardia® is 2 hours.

•  Within 10 hrs (5 X 2 = 10 hr) since the last dose, ≈95% of the Procardia® should be eliminated from his body.

Why is knowledge of the half-life of a drug helpful to a rehabilitation therapist?

2)  In patients with decreased clearance and/or increased Vd, you can usually anticipate an increase in t1/2

¡  t1/2 = 0.7 X Vd/ CL ¡  where

÷  Vd is the volume of distribution of the drug ÷ CL is the clearance of the drug from the body

3) To monitor and emphasize compliance with

recommended dosage and frequency of drug administration.

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ED50

TD50

24-hr dosage: 240 mg

8-hr dosage: 60 mg

(Katzung, Basic and Clinical Pharmacology, 10th Ed, Fig 3-6)

Theophylline: t1/2 = 8 hrs Site of drug administration

Effects of Exercise on drug absorption Clinical Effect

Oral

•  Highly variable •  Exercise ⇓ GI motility & splanchnic blood flow

Generally, exercise ⇓ absorption rate, which will lead to delayed drug effect

Transdermal

•  Increase in skin temperature, cutaneous blood flow, tissue hydration

May cause ⇑ in absorption rate due to warming of region under patch

Subcutaneous & Intramuscular (injection)

•  ⇑ blood flow • May cause ⇑ in absorption rate •  e.g., insulin (SC) may be absorbed more quickly if injected into exercising body part, resulting in hypoglycemia

How does exercise affect pharmacokinetics?

Exercise Effects Clinical Effect

Absorption Dependent on site of administration

See previous table

Distribution

•  Highly variable •  Changes blood flow & perfusion •  Can ⇑ serum albumin by 30%

•  Decreased free drug in blood available to bind to target cells •  May lead to ⇓ effect

Metabolism

As exercise intensity ⇑, blood flow to liver ⇓

•  May ⇓ metabolism and ⇑ drug effect (time of dose important) •  Change in drug protein binding may off-set reduced metabolism

Excretion

Decreases renal blood flow and glomerular filtration rate

•  Decreased drug elimination rate •  May lead to prolonged drug effect

Pharmacodynamics

�  �What the drug does to the body� � Mechanisms of action by which drugs produce

their physiological effects

� Relationship between drug concentration (dose) and the magnitude of the drug effect (response) can be shown in dose-response curves

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Drug Receptor Theory

�  To produce a response, a drug must combine with a receptor embedded in the cell membrane or inside a cell.

�  A physiological response is triggered by the drug-receptor interaction.

�  Receptors on cells respond to neurotransmitters, hormones, other endogenous substances, or drugs.

�  Drugs are designed to interact with specific receptors.

Drug Receptors

�  A drug binds to and activates a specific receptor (sub)type and initiates some change in the function of the cell. ¡  Most receptors are protein complexes located on or within a cell.

�  Receptors can affect cell function by: ¡  Acting at an ion channel and directly changing membrane

permeability (very fast!) ¡  Acting enzymatically to directly influence functions within cell (still

fast) ¡  Directly affecting gene function (these responses are much slower)

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Drug-receptor interactions

�  Crude key-lock analogy �  Affinity: amount of attraction between drug & receptor �  Many receptor populations can be divided into various

subtypes ¡  e.g., adrenergic receptors have 2 main classes: alpha & beta

(alpha & beta are further subdivided into subclasses) �  Drug is considered �selective� if it binds to only 1

receptor subtype & produces a single physiologic response… �  No drug is perfectly selective!

Drug-receptor interactions

�  Agonist: drug binds to receptor & produces change in cell function ¡  e.g., albuterol is a selective beta-2 adrenergic receptor

agonist, which binds to and activates beta-2 receptors on smooth muscle of bronchioles, causing bronchodilation

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Drug-receptor interactions

�  Antagonist (�blocker�): drug binds to receptor but produces NO change in cell function ¡  Prevent endogenous agonist from having effect on cell ¡  e.g., metoprolol is a selective beta-1 adrenergic

receptor antagonist, which binds to beta-1 receptors on cardiac muscle cells; this prevents activation by norepinephrine & epinephrine, resulting in ⇓ HR and BP

Cumulative dose response curves

�  Give relationship between dose of a drug and the % of people who exhibit the specific response

�  Information we can get from cumulative DR curves:

1)  Median Effective Dose (ED50) 2)  Toxicity (TD50) 3)  Lethality (LD50) 4)  Therapeutic index (TI) = (TD50)/(ED50)

÷ Estimate of drug safety: the closer to 1, the more toxic the drug 5) Therapeutic window

÷ Dosage range between minimal effective dose & minimal toxic dose

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Therapeutic Index

(Ciccone, 2007, Figure 1-4 )

Min E.D.

Min T.D.

(Or, adverse drug reaction, ADR)

Therapeutic index of this hypothetical drug: 320/10 =32

Therapeutic Index Indicator of a drug�s safety profile

�  TI: assessment of clinical efficacy compared to toxicity �  What�s the clinical relevance for drugs with low

therapeutic indices? 1)  Patients are more likely to have ADRs at therapeutic drug

concentrations 2)  More likely to monitor plasma levels

÷ warfarin (Coumadin) ÷ digoxin (Lanoxin)

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warfarin (Coumadin)

�  Oral anticoagulant used for chronic anticoagulation �  Interferes with Vitamin K-dependent clotting factors

�  Clinical uses ¡  DVT ¡  Pulmonary embolism ¡  Acute MI ¡  Atrial fibrillation

warfarin (Coumadin)

�  Most common ADR is bleeding! ¡  Nosebleeds, rectal bleeding, bruising, tarry stools, joint or muscle aches

�  Patients should have plasma INR checked regularly ¡  Therapeutic levels for patients on warfarin: 2.0-3.0 (3.5) ¡  Greater risk of hemarthrosis during exercise with INR value ≥ 3.0

or 3.5 ÷ Guidelines for when to defer physical therapy are hard to find! ÷ No evidence-based guidelines for physical activity in the

patient/client with elevated INR are currently available ÷ Excellent review: Tuzson A, Acute Care Perspectives, 2009

warfarin (Coumadin)

�  Variations in Vit K alter the anticoagulant effects of warfarin ¡  Increase in dietary Vit K decreases

anticoagulation effect ¡  Decrease in dietary Vit K increases risk

of bleeding

�  There are MANY drug and supplement interactions with warfarin! ¡  www.mayoclinic.com/health/warfarin-

side-effects/HB00101 ¡  http://ods.od.nih.gov/factsheets/cc/

coumadin1.pdf

http://dietary-supplements.info.nih.gov/factsheets/cc/coumadin1.pdf

digoxin (Lanoxin)

�  Increases heart contractility ¡  Used in treatment of congestive heart failure,

atrial fibrillation/flutter �  Low therapeutic index! �  Signs/symptoms of �dig toxicity�

¡  Fatigue, palpitations, syncope, confusion, agitation, nausea/vomiting, SOB, dizziness, vision disturbances ÷  Increased risk in patients with decreased

kidney function ¡  If signs/symptoms, report to PCP

immediately!

Digitalis purpurea (foxglove)

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Adverse Drug Reactions (ADRs)

�  �Harmful, unintended reactions to medicines that occur at doses normally used for treatment are called adverse drug reactions (ADRs)��World Health Organization

�  Typically excludes reactions that result from an overdose or failure of the drug to produce expected pharmacological response ¡  In other words, the effects of an underdose or overdose are not

considered ADRs.

Incidence of ADRs in USA

�  > 2 million serious ADRs (100,000 deaths) annually (IOM, National Academy Press, 2000)

�  Ambulatory patients ADR rate - unknown

�  Prospective analysis of ADRs in 3,695 inpatient hospital episodes (Davies et al., 2009) ¡  14.7% experienced ≥ 1 ADR ¡  ADRs increased LOS in ~27% of patients ¡  Patients experiencing ADRs more likely to be older, female,

have longer LOS, and be taking larger number of medications ÷ Most common drugs associated with ADRs: diuretics, opioids,

anticoagulants

Why so many ADRs?

�  ~ 2/3 of patient visits result in a prescription

�  70-90% of all illnesses are �self-treated� and not brought to attention of a HCP

�  Incidence of ADRs increases exponentially with ≥ 4 medications!!!

� Also…consider that ADRs are often underreported

Schappert SM, Nat. Center Health Statistics 1999;Series 13 #143 National Association of Chain Drug Stores. 2001

Jacubeit T et al., Agents Actions Suppl 1990; 29:117-25

Types of ADRs

�  Intrinsic ¡  Predictable based on

properties of the drug ¡  Typically dose-dependent ¡  70-80% of ADRs

�  Idiosyncratic ¡  Unpredictable ¡  Can be due to genetic

differences in metabolism

�  Hypersensitivity (drug allergy) ¡  Reactions usually occur

after prior exposure ¡  Dose independent

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Organ-specific ADRs

� Dermatologic toxicity � Ototoxicity � Gastrointestinal toxicity � Nephrotoxicity � Hepatotoxicity � CNS toxicity � Cardiovascular toxicity

Dermatologic toxicity

�  Development of cutaneous disease due to combined effects of drug and light

�  Common Drugs ÷  tetracyclines & sulfonamides (e.g.,

antibiotics Bactrim & Septra) ÷ NSAIDs ÷ oral contraceptives ÷ diuretics: furosemide (Lasix) &

hydrochlorothiazide (Microzide) ÷ oral anti-diabetic agents: glipizide

(Glucotrol) & glyburide (Diabeta)

�  Clinical Relevance ¡  Decrease sun exposure

between 10AM - 4PM ¡  Wear sun protective clothing,

sunglasses, sunscreen

Image from: www.sunsmart.com.au

Ototoxicity

�  Damage to organs or nerves in the ear, which can lead to hearing and balance problems

�  Common Drugs

¡  aminoglycosides (class of antibiotics including neomycin, streptomycin)

¡  loop diuretics (e.g., Lasix) ¡  salicylates (e.g., aspirin)

�  Clinical Relevance ¡  Incidence dramatically increases

with renal impairment ¡  If patient reports new ringing in

ears or difficulty hearing - OR, if patient presents with new balance problem… ÷ ASK about initiation of any new

drug, or increase in dosage of a current drug

÷  Inform PCP or prescribing health care provider ASAP!

Gastrointestinal toxicity

�  Damage to mucosal lining of the GI tract (ranging from minor to serious lesions such as bleeding, perforation, or obstruction)

�  Nausea, vomiting �  Common Drugs

¡  NSAIDs ¡  Cancer chemotherapy

�  Clinical Relevance ¡  Know risk factors for GI

complications with NSAIDs ÷  History of ulcers ÷  > 60 years old ÷  Concomitant use of other

NSAIDs, glucocorticoids, antiplatelet or anticoagulant drugs

¡  Report signs/symptoms of ulcer to PCP immediately

¡  New Public Health Initiative ÷  Use lowest effective dose for

the shortest period of time!

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Nephrotoxicity

�  Damage to kidney cells, or causing renal impairment

�  Common Drugs

¡  NSAIDs ¡  aspirin ¡  acetaminophen (Tylenol)

�  Clinical Relevance ¡  Recognize that kidney disease

tends to be asymptomatic until end stages

¡  Identify patients with risk factors for kidney disease ÷ DM ÷ HTN ÷ ≥ 60 years of age ÷ Family history of kidney

disease ¡  Encourage high-risk patients

to decrease chronic NSAID consumption

Hepatotoxicity

�  Damage to liver cells, or causing liver impairment

�  Common Drug ¡  acetaminophen

÷ OTC: Tylenol

÷ Prescription: Vicodin, Percocet

Acetaminophen toxicity is most common cause of liver failure in USA (39% of cases)

�  Clinical Relevance ¡  Patients with liver disease and

individuals who regularly consume ≥ 3 alcoholic drinks/day should avoid taking acetaminophen! ÷ Refer patient to pharmacist or

PCP for different analgesic or fever-reducer.

FDA�s safety alert on acetaminophen

�  FDA asked manufacturers of prescription combination drug products containing acetaminophen to limit amount to no more than 325 mg in each tablet/capsule by Jan 14, 2014 to reduce risk of liver failure, liver transplant, and death

�  Cases of severe liver injury have occurred in patients who ¡  Took more than prescribed dose in a

24-hr period ¡  Took more than 1 acetaminophen-

containing product at same time; or ¡  Drank alcohol while taking

acetaminophen products

�  FDA will address OTC medicines that contain acetaminophen in a separate regulatory action. ¡  Max level allowed for these

products is 500 mg, but a few extended-action pain relievers that are taken less frequently can go up to 650 mg.

CNS toxicity

�  Observable disruption of normal brain function ¡  Sedation, dizziness, confusion,

incoordination, seizures, hallucinations

�  Common Drugs

¡  antidepressants ¡  barbiturates ¡  antihistamines ¡  analgesics, especially opioids

�  Clinical Relevance ¡  Elderly are vulnerable to ADRs

and overdose with analgesics ¡  Generally, reduced dosages and

longer time intervals between doses are used in elderly ÷  Opioid transdermal formulations

tend to have lower toxicity (especially at lower doses)

¡  In patients taking these drugs, recent change in cognition should be reported to PCP asap.

Okon MG, J of Pain & Symptom Management, 2008 Vadivelu & Hines, Clin Interv Aging, 2008 Pergolizzi et al., Pain Practice, 2008

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Cardiovascular toxicity

�  Many heart medications! ¡  Antihypertensives often cause orthostatic hypotension

÷ Perform transfers slowly ÷ Incorporate cool-down period in exercise ÷ Caution when exiting warm aquatherapy area

¡  Antiarrhythmics often cause rate & rhythm disturbances ÷ Monitor vital signs and patients� symptoms!

Pharmacology and aging

�  In the USA, the elderly population will more than double between 2000 and 2030, growing from 35 million to over 70 million.

¡  Between 2000-2010, the population ≥ 65 yrs of age increased 15.1% (while total population growth was 9.7%)

�  Though older adults make up ≈13% of the

population, they consume ≈ 33% of prescription medications.

�  There is a positive association between increasing age & increased incidence of ADRs.

U.S. Census Bureau, �65+ in the United States: 2005�

Common themes in older adults Decline, Disease, Diversity

�  Polypharmacy - many reasons why… �  Altered pharmacokinetics - decreased renal and

liver function; change in body composition ¡  DECREASED RENAL FUNCTION is the MOST

IMPORTANT pharmacokinetic factor resulting in ADRs in older adults

¡  Renal excretion decreased for most drugs (by up to 50% at age 75)

�  Altered pharmacodynamics - increased sensitivity to benzodiazepines, opiates, warfarin, NSAIDs

What does non-compliance with medications actually mean? (and can we help…?)

�  Failure to fill prescriptions �  Failure to follow recommendations for consumption with food or

avoidance of certain foods �  Taking the wrong dose �  Taking meds at the wrong time or only when symptoms occur �  Keeping poor records (retaking or skipping a dose) �  Using wrong techniques with inhalers, suppositories, or nasal sprays �  Premature discontinuation of medications due to

¡  ADRs ¡  Improvement in symptoms ¡  Fear of dependency ¡  Lack of funds Cervantes et al., Caring, (15): 58-63, 1996

Curry et al., J Gerontol Nurs, (31): 33-42, 2005

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Therapists� role in managing medications

1)  Take a complete drug history OR review inpatient medical chart daily

2)  Be aware of changes in patient�s condition 3)  Recognize ADRs

v  Maintain a HIGH degree of suspicion regarding ADRs and drug interactions - consider any new sign or symptom to be drug-related until proven otherwise (Beer MH, Arch Int Med, 1997; Fick DM et al., Arch Int Med, 2003)

4)  Be exceptionally aware of drugs that affect mobility (especially with relationship to fall risk)

5)  Communicate with physician!

Therapists� role in managing medications

�  Document complete list of medications, including prescription, OTC, and herbal products

�  Considerations (often in home health setting): ¡  Are these the original bottles they came in? ¡  When do you take them? ¡  How much do you take? ¡  Do you know what each medication is for?

�  Recommend �brown bag� medication review with PCP or pharmacist, if available/possible

Review and think about patient�s medication list

As a therapist, consider these questions when reviewing the medication list:

�  WHAT HAS CHANGED? ¡  New medications? Change(s) in dosage? ¡  Withdrawal of medication patient has taken previously?

�  Number of medications? �  How many medications in same class of drugs?

¡  Known indications and intrinsic ADRs? �  Timing of medication with respect to therapy session? �  How would my patient/client�s characteristics impact

pharmacokinetics?

Drugs and falls

Drugs that can cause orthostatic hypotension

�  Vasodilators (used for HTN) �  Diuretics (used for CHF) �  Opiate analgesics (used for pain) �  Cathartics (used for constipation) �  Phenothiazine antipsychotics

¡  haloperidol (Haldol) ¡  chlorpromazine (Thorazine)

�  Some antidepressants ¡  trazodone ¡  amitriptyline

Drugs that can cause confusion

�  Alcohol �  Anti-depressants �  Barbiturates �  Benzodiazepines �  Digoxin

Likelihood of falls increases with confusion & orthostatic hypotension!

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Beers Criteria �Potentially inappropriate medications� in older adults

�  List of medications (�PIMs�) generally considered inappropriate to give to elderly secondary to ADRs due to physiological changes accompanying aging ¡  PIMs: risks tend to outweigh the

potential benefits

Beer MH, Arch Int Med, 1997 Fick DM et al., Arch Int Med, 2003 The American Geriatrics Society 2012 Beers Criteria Update Expert Panel, JAGS, 2012

Mark Beers, M.D.

Beers Criteria

�  Most frequently consulted source for information about safety of prescribing medications to older adults ¡  Used in: research; training of HCPs; inform quality measures (CMS

uses to evaluate nursing home adherence to medication-related regulations)

�  Do not prevent or ban the use of certain drugs for older adults ¡  Emphasize that certain drugs should be avoided because they are

ineffective, benefit/risk profile is poor, or that a safer (sometimes nonpharmacological) alternative is available

¡  Do not substitute for professional judgment for treating an individual patient

�  Originally published in 1991; revised: 1997, 2003, 2012, and 2015

The American Geriatrics Society 2012 Beers Criteria Update Expert Panel, JAGS, 2012 Resnick and Pacala, JAGS, 2012

2012 Beers Criteria

�  Includes 53 drugs or drug classes, �  Divided into 3 categories

¡  Potentially inappropriate medications and classes to avoid in older adults

¡  Potentially inappropriate medications and classes to avoid in older adults with certain diseases and syndromes that the drugs listed can exacarbate

¡  Medications to be used with caution in older adults

The American Geriatrics Society 2012 Beers Criteria Update Expert Panel, JAGS, 2012

2012 Beers Criteria 2 documents intended for the public

www.americangeriatrics.org/files/documents/beers/FHATipMEDS.pdf

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1)  Chronic use of traditional NSAIDs; avoid use of long-acting NSAIDs (indomethacin and piroxicam)

2)  Digoxin > 0.125 mg/day 3)  Certain drugs for type 2 diabetes (glyburide and diabinese) 4)  Certain anticholinergic drugs 5)  Certain OTC products containing diphenhydramine or

chlorpheniramine 6)  Certain medications for anxiety and/or insomnia (benzodiazepines

and z-drugs) 7)  Muscle relaxants 8)  Demerol (an opioid analgesic) 9)  Antipsychotics (unless they are being treated for psychosis) 10)  Estrogen pills and patches

www.americangeriatrics.org/files/documents/beers/FHATipMEDS.pdf

Top 10 drugs that older adults should avoid or use with caution (2012 Beers Criteria)

�  Not as extensive as changes made in previous update

�  Updated existing criteria

�  Added 2 major components based on evidence in older adults that they are at risk of serious harm if a drug dose is not adjusted or a drug interaction is overlooked

2015 Beers Criteria

Acetylcholine

�  Central & peripheral neurotransmitter ¡  Decreases with age ¡  Decreased in patients with Alzheimer’s

disease & other dementias

�  > 600 known anticholinergic medications

¡  11% are commonly prescribed to older adults

�  Toxicity often results from cumulative anticholinergic effect of multiple medications

Tollefson et al., J Neuropsychi Clin Neurosci, 1991 Tune, LE J Clin Psychiatry, 2001

in brain Anticholinergic effects

� Dry mouth � Constipation � Urinary retention � Visual impairments � Confusion � Delirium � Memory and attention deficits �  Severe cognitive decline

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Drugs with anticholinergic properties

�  Increase risks of functional and cognitive decline, morbidity and mortality, institutionalization and length of hospital stay in older people

�  Anticholinergic burden should be considered as a component of medication therapy management programs for seniors.

Salahudeen et al., Drugs Aging, 2014 Karimi et al. Consult Pharm, 2012

Management of elderly patients, particularly those suffering from dementia, should aim to reduce the use of medications with anticholinergic effects.

American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate

Medication Use in Older Adults

Select common conditions in older adults

�  Insomnia � Anxiety � Alzheimer�s disease

Common CNS neurotransmitters

�  Glutamate �  Gamma-amino butyric acid (GABA) �  Dopamine (DA) �  Serotonin (5-HT) �  Acetylcholine (Ach) �  Norepinephrine (NE) �  Endorphin/enkephalin �  Anandamide (cannabinoid)

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Insomnia

�  Sleep disturbance characterized by repeated difficulty initiating or maintaining sleep ¡  Sleep onset insomnia ¡  Sleep maintenance insomnia

�  Occurs despite adequate time & opportunity for sleep that results in some form of daytime impairment

�  Occurs independently or, more commonly, with ≥1 medical, psychiatric, or primary sleep disorders (co-morbid insomnia)

�  Types of insomnia: transient, short-term, chronic

Insomnia

�  Prevalence: 10-30% of US population ¡  More common in women in all age cohorts (1.2-2X more common) ¡  Common co-morbidities: anxiety, depression, pain, neurological

diseases ¡  Patients with chronic medical conditions have higher frequency of

insomnia

�  Prevalence in older adults: ≈ 50% ¡  Causes: more co-morbid medical conditions, greater psychosocial

stressors and losses, polypharmacy, changing sleep �architecture�

Ohayon MM, Sleep Med Rev, 2002 Bloom HG et al., J Am Geriatr Soc, 2009

Sleep maintenance insomnia is bigger problem for older adults

�  ~49% of elderly patients experienced sleep maintenance symptoms (compared with ~19% who experienced sleep-onset symptom) ¡  30% complained of waking

during night ¡  19% complained of waking

too early

Webb, J Gerontol, 1982 Foley et al., Sleep, 1995

Insomnia – when is diagnosis made?

�  No guidelines for how much sleep is normal in older adults.

�  Common changes that progress gradually with age ¡  Spending more time in bed,

with no additional time spent asleep

¡  More time in stage 1 (light) sleep & less time in deep sleep

¡  Abnormal breathing events and leg movements

�  Management of insomnia requires careful evaluation and exclusion of an underlying medical or psychiatric condition.

�  Diagnosis usually based on: detailed sleep history; medical, psychiatric, and social history; medications; lab studies?

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McCall WV, Prim Care Companion J Clin Psychiatry, 2004

Insomnia – sample sleep history questionnaire

Schutte-Rodin et al., J of Clinical Sleep Medicine, 2008

Insomnia – Diagnostic Criteria

Chronic insomnia - What�s the impact?

�  Annual financial cost in US ¡  $2 billion for sleep-promoting agents ¡  $100 billion for accidents & poor work

productivity �  Decreased concentration & memory �  Decreased QOL �  Increased risk of depression, anxiety,

alcohol & drug dependence, suicide �  Increased risk of accidents �  Increased risk of falls (even after taking

into account use of benzodiazepines) �  Independent risk factor for CVD mortality

¡  33% ⇑ risk of mortality in prospective study of >9,000 older adults in France Ancoli-Israel et al., Harv Rev Psych, 2008

Stone et al., Sleep Med, 2008 Empana et al., Stroke, 2009

Passaro EA, emedicine, 8/3/09

Insomnia: non-pharmacological treatments

�  GOOD SLEEP HYGIENE! ¡  Regular sleeping habits; limit/

avoid naps ¡  Only use bed for sex and sleeping ¡  Avoid caffeine after lunch ¡  Avoid alcohol within 6 hr of

bedtime ¡  Don�t go to bed hungry or full ¡  Keep bedroom quiet, dark, and

comfortable temperature ¡  Don�t force yourself to sleep ¡  Exercise daily, but no later than

~6 or 7PM

https://www.healthypeople.gov/2020/topics-objectives/topic/sleep-health

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Insomnia: non-pharmacological treatments

�  Development of good sleep hygiene �  Relaxation techniques

¡  Progressive relaxation therapy ¡  Biofeedback

�  Sleep-restriction therapy �  Cognitive behavioral therapy (CBT) �  Music �  Structured physical activity �  Mindfulness: guided imagery & meditation

Effect of structured physical activity on sleep quality in older adults

�  Multi-center RCT with sedentary community-dwelling adults (70 to 89 years old) to assess effect of moderate-intensity physical activity versus health education over 24-30 months

�  Outcome measures: ¡  Insomnia Severity Index (ISI) (≥8 defined insomnia) ¡  Epworth Sleepiness Scale (ESS) (≥10 defined daytime drowsiness) ¡  Pittsburgh Sleep Quality Index (PSQI) (>5 defined poor sleep quality)

�  Structured physical activity resulted in lower likelihood of developing poor sleep quality (PSQI >5) compared to health education, but had no effect on prevalent cases of poor sleep quality.

Vaz Fragoso et al., J Am Geriatr Soc, 2015

Effect of mindfulness on sleep quality in (nonelderly) adults

�  18 adults with chronic insomnia randomized to 8 weeks of ¡  Mindfulness-based stress

reduction (MBSR) group format program, or

¡  Nightly use of prescription sedative

�  Followed for 5 months

Hubbling et al., BMC Complement Altern Med, 2014

�  MSBR participants reported they were not sleeping more, but: ¡  sleeping better ¡  waking more refreshed ¡  feeling less distressed about

insomnia ¡  better able to cope with

insomnia when it occurred �  The “body scan” was identified

as an effective tool to enable falling asleep faster.

How is sleep generated?

�  Sleep and wakefulness are tightly regulated by neural circuits within the hypothalamus and brainstem.

�  These processes are also entrained by light to occur at specific times of 24-hour cycle. ¡  When light decreases, retinal cells

signal the pineal gland to release melatonin, which promotes sleepiness.

Hypothalamus

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Brain circuits that regulate wakefulness and sleep

Ascending arousal system Inhibitory sleep-promoting system

Image from: http://emedicine.medscape.com/article/1187829-overview

Certain neurotransmitters promote arousal OR sleep

�  NTs that promote arousal ¡  Histamine ¡  Norepinephrine ¡  Serotonin ¡  Dopamine ¡  Acetylcholine

�  NTs that promote sleep ¡  GABA ¡  Galanin ¡  Melatonin (hormone)

Drugs that promote sleep work by: Ø  Increasing the action of NTs that promote sleep, or by Ø  Inhibiting the action of NTs that promote arousal

Pharmacological treatments for insomnia

�  Sedative-hypnotics ¡  Benzodiazepines (BZDs) •  Long-acting (flurazepam/Dalmane) •  Intermediate-acting (temazepam/

Restoril) •  Short-acting (triazolam/Halcion)

•  Nonbenzodiazepine benzodiazepine receptor agonists (NBRAs) •  zolpidem (Ambien) •  zaleplon (Sonata) •  eszopiclone (Lunesta)

•  Melatonin & melatonin receptor agonists

•  Orexin receptor antagonist •  suvorexant (Belsomra)

•  H1-receptor antagonists (not indicated for insomnia, but commonly used) •  diphenhydramine (Benadryl)

Benzodiazepines (BZDs)

�  Agonists at the GABAA ion channel receptor complex

�  After BZD binds to receptor, Cl- flow through channel increases ¡  Result: hyperpolarization of

neuron

�  Ultimate result of BZDs: decreased arousal and muscle relaxation

�  Drug indications: insomnia, anxiety, muscle spasms

Receptors for BZDs are present throughout the neuraxis (supraspinal & spinal interneurons, thalamus, limbic structures, cerebral cortex)

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Benzodiazepines

�  Usually given as single dose at bedtime ¡  Should be used infrequently as the only therapy for chronic insomnia

�  Short- or intermediate-acting agents (triazolam, lorazepam) usually prescribed for insomnia for short-term use (1-2 weeks)

�  Long-acting BZDs are rarely used for insomnia : ¡  clonazepam (Klonopin): t1/2 ≈20-50 hr ¡  diazepam (Valium): t1/2≈30-60 hr ¡  flurazepam (Dalmane): t1/2≈ 2-3hr; 40-100h (active metabolite, librium)

�  Half-lives of many BZDs increase 50%-100% in adults 30-70 yrs old – much of this change occurs between 60-70 yrs of age

Benzodiazepines

�  Tolerance: higher dose required for same effect

�  Withdrawal with abrupt discontinuation

÷ Muscle cramps, irritability, insomnia

�  Common ADRs ¡  Muscle weakness, ataxia,

drowsiness, confusion

�  Serious ADRs ¡  Dependency/abuse

�  Drug interactions ¡  Alcohol & other CNS depressants

potentiate sedation ¡  Grapefruit juice may increase

sedation with some BZDs (e.g., Valium, Xanax)

BZDs: Serious concerns in older adults

Beers Criteria Update Expert Panel, JAGS, 2012

�  2012 Beers Criteria: �avoid benzodiazepines for treatment of insomnia, agitation, or delirium� ¡  Strong recommendation based on high quality evidence

BZDs: Serious concerns in older adults

American Geriatrics Society 2015: Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults, JAGS, 2015

�  2015 Beers Criteria: maintained 2012 recommendation to avoid benzodiazepines with the rationale:

�  “Older adults have increased sensitivity to benzodiazepines and decreased metabolism of long-acting agents: in general, all benzodiazepines increase risk of cognitive impairment, delirium, falls, fractures, and motor vehicle crashes in older adults”

�  Long-acting benzodiazepines “may be appropriate for seizure disorders, rapid eye movement sleep disorders, benzodiazepines or alcohol withdrawal, severe generalized anxiety disorder, periprocedural anesthesia”

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Benzodiazepines Documented specific concerns in older adults

�  ADRs in older adults ¡  Dependence/abuse ¡  Increased risk of falls & hip

fractures ¡  Rebound insomnia ¡  Anterograde amnesia ¡  Cognitive impairment ¡  Psychomotor impairment ¡  Impairment of driving skills,

MVAs ¡  Drug poisoning suicide ¡  Complex sleep-related

behaviors ¡  Delirium

Grad RM, J of Family Practice, 1995 Carlsten A, Scandinavian J of Public Health, 2003

Madhusoodanan & Bogunovic, Expert Opinion Drug Safety, 2004

�  Risk Factors for ADRs ¡  Elderly ¡  Female ¡  Comorbid medical and

psychiatric conditions ¡  Multiple medications

Nonbenzodiazepine BZD receptor agonists (NBRAs)

�  Individual subunits of GABAA ion channel complex mediate specific effects ¡ Alpha1 subunit: sedation ¡ Alpha2 and alpha3: antianxiety

�  Alpha1-selective agents ¡  zolpidem (Ambien) ¡  zaleplon (Sonata) ¡  eszopiclone (Lunesta)

http://www.nature.com/nrn/journal/v6/n7/images/nrn1703-i1.gif

Nonbenzodiazepine BZD receptor agonists (NBRAs)

�  Shorter durations of action and may be associated with less risk of tolerance and abuse than BZDs

�  May be helpful in insomnia that is comorbid with depression or anxiety

�  ADRs similar to those of BZDs in older adults, with minimal improvement in sleep latency and duration

�  2012 Beers Criteria: avoid chronic use ( >90 days), strong recommendation based on moderate quality evidence

However, this recommendation was updated in 2015 Beers Criteria…

Beers Criteria Update Expert Panel, JAGS, 2012

2015 noteworthy changes to PIMs

“Nonbenzodiazepine, benzodiazepine receptor agonist hypnotics are to be avoided without consideration of duration of use because of their association with harms balanced with their minimal efficacy in treating insomnia.”

American Geriatrics Society 2015: Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults, JAGS, 2015

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Melatonin & melatonin receptor agonists

�  Melatonin ¡  Supplement: dose??? ¡  No clear evidence of its

effectiveness at decreasing sleep latency or increasing sleep time

Hypothalamus

Melatonin receptor agonist �  Melatonin receptor agonist (ramelteon/Rozerem)

¡  Binds to melatonin receptors in �biological clock��in brain ¡  Review of 12 RCTs with ramelteon (Borja & Daniel, 2006)

÷ Decreased sleep latency (10-19 min) & increased total sleep time (8-22 min) compared to placebo

÷ No evidence of cognitive impairment, abuse potential, rebound insomnia, or withdrawal effects

¡  Most common ADRs: headache, dizziness, fatigue ¡  In 33 older adults, ramelteon did not impair middle-of-the-

night balance, mobility, or memory compared to placebo. ¡  May represent safer alternative for older adults

with sleep-onset insomnia

Borja & Daniel, Clin Ther, 2006 Zammit et al., J Clin Sleep Med, 2009

Neural circuitry of orexin

�  Orexin is a neurotransmitter that is abundant in the lateral hypothalamus that sends projections all over brain (except cerebellum)

�  Orexin plays key role in arousal, wakefulness, and appetite

�  suvorexant is an antagonist at orexin receptors, thus it reduces arousal and improves sleep consolidation

Sakurai, Nature Reviews Neurosci, 2007

suvorexant (Belsomra) �  Of 3 major RCTs, only one

included adults > 65 yr of age

�  Results ¡  Total sleep time and time-to-

sleep onset improved compared to placebo

¡  Subjects that continued therapy beyond 1 year reported continued benefit.

¡  No significant safety or withdrawal/rebound effects.

Michelson et al., Lancet Neurol, 2014

�  Approved in 2014 by FDA for sleep onset and sleep maintenance insomnia

�  ADRs: dizziness, somnolence, headache, impaired mental alertness on next-day ¡  FDA cautions prescribers on use of

higher doses in females, obese patients, and patients taking competing CYP3A4 inhibitors

�  Cost and availability may be barrier ¡  ~$200-$300/month compared to

generic benzodiazepines that can cost as low as $5–$10/month.

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Pharmacological treatments for insomnia

�  Sedative-hypnotics ¡  Benzodiazepines (BZDs) •  Long-acting (flurazepam/Dalmane) •  Intermediate-acting (temazepam/

Restoril) •  Short-acting (triazolam/Halcion)

•  Nonbenzodiazepine benzodiazepine receptor agonists (NBRAs) •  zolpidem (Ambien) •  zaleplon (Sonata) •  eszopiclone (Lunesta)

•  Melatonin & melatonin receptor agonists

•  Orexin receptor antagonist •  suvorexant (Belsomra)

•  H1-receptor antagonists (not indicated for insomnia, but commonly used) •  diphenhydramine (Benadryl)

�off-label��use

diphenhydramine (Benadryl)

�  Pharmacodynamics ¡  Antagonist at central & peripheral H1

receptors �  Effective for relief of short-term

insomnia (taken ~30-60 min before bedtime) ¡  Not as effective as temazepam, but resulted

in fewer falls in elderly ¡  Tolerance to sedative effect within few days

(15 healthy men; 18-50 years of age) �  ADRs

¡  Drowsiness, incoordination, dry mucous membranes, thickened pulmonary secretions, arrhythmias

Ascending arousal system

Richardson GS et al., J Clin Psychopharm, 2002 Glass et al., J Clin Psychopharm, 2008

Clinical Bottom Line for insomnia treatment in older adults

� Nonpharmacological treatments are recommended before (and continued in conjunction with) any pharmacological treatment

� Pharmacological interventions either have poor benefit/risk ratio (BZDs, NBRAs, and diphenhydramine – all on Beer’s Criteria), are effective for sleep-onset vs. sleep maintenance insomnia (ramelteon), or currently have limited evidence for safety and effectiveness in older adults (suvorexant – approved 2014).

Anxiety disorders

�  Psychiatric condition characterized by fearfulness & uncertainty that lasts at least 6 months

�  Often associated with physiological symptoms

¡  Headache, muscle spasms, palpitations, sweating, HTN

�  Commonly occur with other mental or physical disorders, especially depression

Image from: http://living-with-ms.blogspot.com/2009/01/ms-copaxone-anxiety.html

http://www.nimh.nih.gov/health/publications/anxiety-disorders/ Kessler et al., Archives of General Psychiatry, 2005

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Anxiety disorders

�  Affect ≈ 40 million adults in USA annually �  Prevalence in elderly

¡  ≈10% of older adults ¡  May affect 2X as many older adults as

depression �  Often unrecognized & inadequately treated

in elderly ¡  Comorbid medical conditions and

depression ¡  Overlap with cognitive disorders ¡  Ageism ¡  Older adults more likely to emphasize

physical complaints

Small GW, J Clin Psychiatry, 1997 Beaudreau & O�Hara, Am J of Geriatr Psychiatry, 2008

http://www.adaa.org

Anxiety disorders

�  Generalized anxiety disorder �  Panic disorder �  Social anxiety disorder �  Obsessive-compulsive disorder �  Post-traumatic stress syndrome �  Specific phobias

Anxiety disorders: nonpharmacological treatment

�  Diet assessment & modification ¡  Discontinue or decrease consumption of caffeine-containing

products �  Psychotherapy

¡  Cognitive behavioral therapy ¡  Exposure therapy ¡  Relaxation training

�  Aerobic exercise ¡  Daily, at mild-moderate intensity

�  Discontinuation of supplements with ephedrine �  Improving sleep hygiene

http://www.adaa.org

Antianxiety (anxiolytic) agents

�  Precise medication (or combination) depends on type of anxiety disorder

�  Challenge is to decrease anxiety without producing sedation �  Major classes of anxiolytics

¡  Benzodiazepines (BZDs) ¡  Buspirone ¡  Selective serotonin reuptake inhibitors (SSRIs) ¡  Serotonin-norepinephrine reuptake inhibitors (SNRIs)

÷  venlafaxine (Effexor) ÷  duloxetine (Cymbalta)

¡  Tricyclic antidepressants (TCAs) ÷  imipramine (Tofranil)

Usually 1st line agents

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Anxiolytics: benzodiazepines

�  Short-term anxiety treatment (≈6 wk) �  Decreases anxiety, promotes relaxation, & decreases physical

symptoms of anxiety �  Pharmaceutics

¡  lorazepam (Ativan); t1/2 ≈ 14 hr ¡  alprazolam (Xanax); t1/2 ≈16 hr in elderly ¡  clonazepam (Klonopin); t1/2 ≈20-50 hr ¡  diazepam (Valium); t1/2≈30-60 hr

Anxiolytics: buspirone (BuSpar)

�  Exact mechanism of action unknown ¡  Binds to serotonin & dopamine

receptors

�  Better ADR profile than BZDs ¡  ⇓ sedation & motor impairment ¡  ⇓ tolerance & dependence ¡  t1/2 ≈ 2-3 hr

�  Common ADRs ¡  Drowsiness, dizziness,

nausea

�  Serious (rare) ADRs ¡  Involuntary movements

�  Other considerations ¡  Alcohol potentiates sedation ¡  Avoid grapefruit juice

Selective serotonin reuptake inhibitors (SSRIs)

�  Pharmacodynamics ¡  Inhibit presynaptic reuptake of

serotonin, leading to increased serotonin in synapse

�  Pharmaceutics ¡  fluoxetine (Prozac) ¡  paroxitine (Paxil) ¡  sertraline (Zoloft) ¡  citalopram (Celexa) ¡  escitalopram (Lexapro) http://www.nature.com/jp/journal/v25/n9/

fig_tab/7211352f1.html

Selective serotonin reuptake inhibitors (SSRIs)

�  1st line agents for anxiety and drug class of choice for late-onset depression

�  ADRs: GI disturbances, insomnia, sexual dysfunction, hyponatremia ¡  Nausea usually short-lived ¡  Hyponatremia may occur in 25% of older adults taking SSRIs

�  Serotonin syndrome: rare, but can be severe �  Common drug interactions: warfarin and some antibiotics

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Case study �  Brief history

¡  Patient is an 81 y/o female with osteoporosis. Although her cognition was intact, her mobility & independence level declined after the recent death of her husband. She moved into her daughter�s home.

�  Current medical status & drug therapy ¡  Shortly after moving to her daughter�s home, the patient complained of

difficulty sleeping & she became increasingly anxious. She was prescribed an intermediate-acting benzodiazepine (Ativan; t1/2≈14 hr) by her PCP. Three weeks later, she fell in the middle of the night on the way to the bathroom & fractured her hip. She recalls that when she was walking to the bathroom, she felt dizzy & sluggish. She immediately stopped taking her Ativan, because she felt it was the drug that caused her to fall. Her hip was surgically repaired the next day.

�  Rehabilitation setting ¡  The patient began physical therapy one day after surgery. She is drowsy &

confused, though the PT is able to assist her to the EOB with MIN A. Her alertness improves with sitting upright and the PT interviews the patient more completely. She complains of muscle cramps and feeling slightly �foggy-headed�. She is motivated to walk, though upon standing in a FWW with MOD A, she becomes increasing agitated & irritable. She attempts to take a couple steps, though her coordination is too poor to continue gait training.

Case study

�  Problem & clinical options (1) (2) (3)

Most common cause of dementia ~5.3 million Americans in 2015 Alzheimer�s Disease (AD)

�  Irreversible, progressive neurodegeneration resulting in cognitive & behavioral impairment

�  No single cause �  5 hallmarks of brains in AD

¡  Amyloid plaques: clumps of beta-amyloid protein

¡  Neurofibrillary tangles: twisted strands of tau protein

¡  Loss of connections (synapses) between neurons

¡  Loss of neurons ¡  Inflammation

http://www.ahaf.org/alzheimers/about/understanding/plaques-and-tangles.html

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Alzheimer�s Disease - Risk Factors

�  NON-MODIFIABLE ¡  AGE ¡  Family history ¡  Genetics

÷ Risk genes ¢  Apolipoprotein E-e4 (APOE4)

increases risk ¢  Implicated in ~20% of cases

÷ Deterministic genes ¢  Directly cause the disease

(“familial”, or early-onset AD) ¢  Account for <5% of cases

Buschert et al., Nature Reviews Neurology, 2010 https://www.nia.nih.gov/alzheimers/publication/preventing-alzheimers-disease/risk-factors-alzheimers-disease

Age IS the greatest risk factor

After age 65, risk doubles every 5 years…

Alzheimer�s Disease - Risk Factors �  MODIFIABLE

¡  Prior (repetitive) head injury, depression, CVD risk factors (Type 2 diabetes mellitus, hyperlipidemia, HTN, low activity level)

¡  Take home point:�What is good for the heart is good for the head!�

¡  However…NIH Consensus statement concluded that evidence is insufficient to support association of any modifiable factor, pharmacologic agent, or dietary supplement with a reduced risk of AD

Daviglus et al., NIH Consens State Sci Statements, 2010 https://www.nia.nih.gov/alzheimers/publication/alzheimers-disease-fact-sheet

Alzheimer�s Disease - Diagnosis

�  History of progressive memory loss, cognitive impairment, language disorders, executive functions, impaired visuospatial skills ¡  Metabolic conditions, brain

neoplasms, & other potential dementia causes must be ruled out

�  Clinical accuracy in differentiating AD from other dementia types estimated at 23%-88% (Ballard C, Lancet, 2011)

http://www.ahaf.org/alzheimers/about/understanding/brain-with-alzheimers.html

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2011 diagnostic guidelines from NIA and Alzheimer�s Association

�  1st guidelines to incorporate biomarker & imaging techniques ¡  CSF analysis - decreased levels of Aβ42; increased levels of tau ¡  MRI - atrophy in temporal and parietal lobes ¡  PET scanning - decreased glucose metabolism in particular brain

areas; radioactive tracers that bind to Aβ

�  Not yet recommended for routine diagnostic purposes ¡  Used in research and in specialized neurological practice when

clinical diagnosis is unclear

�  Goals: enable treatment before development of cognitive impairment and advanced pathology, track disease progression, assess effectiveness of treatments

Fraller, DB, J of Neuroscience Nursing, 2013

http://www.alz.org/research/diagnostic_criteria/#overview

Alzheimer�s Disease - Treatment

�  There is no cure.

�  Currently, no drugs stop, decelerate, or reverse disease progression.

�  Drugs provide symptomatic treatment that may help patients remain independent for longer and assist caregivers.

Alzheimer�s Association et al., Alzheimer�s and Dementia, 2011

FDA-approved medications

�  All five medications are from two drug classes ¡  Acetylcholinesterase inhibitors (Aricept, Razadyne, Exelon) ¡  Glutamate NMDA receptor antagonist (Namenda) ¡  Combination drug (Namzaric)

How is the effectiveness of drugs for AD determined?

�  Most common tools to measure cognitive impairment ¡  Alzheimer�s Disease

Assessment Scale for Cognition (ADAS-cog; 70-point scale)

¡  Alzheimer�s Disease Cooperative Study Activities of Daily Living inventory (ADCS-ADL; 54-point scale)

¡  Severe Impairment Battery (SIB; 100-point scale)

�  A change of at least 10% of the scale length is considered the minimal clinically important difference (MCID) defined as a noticeable improvement by patient or caregiver

�  MCIDs ¡  ADAS-cog = 7 points ¡  ADCS-ADL = 5 points ¡  SIB = 10 points

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Acetylcholinesterase inhibitors (ChEIs)

�  Neurons in the hippocampus & neocortex that release acetylcholine (Ach) are impaired early in AD

�  ChEIs inhibit the breakdown of Ach in the CNS, which makes it more available in synapses

�  1st-line agents for treatment of mild to moderate AD �  3 drugs available

¡  donepezil (Aricept): oral ¡  galantamine (Razadyne): oral ¡  rivastigmine (Exelon): oral or transdermal patch

Effectiveness of CHEIs

�  No notable differences in effectiveness among the three CHEIs

�  Systematic review of 13 RCTs found that treatment for 6-12 months resulted in 2.7-pt improvement on ADAS-cog (MCID= 7 pts) (Birks J. Cochrane Database Syst Rev, 2006)

�  Systematic review of 59 studies found statistically significant improvement (0.1 to 5.3 pts on ADAS-cog), but none met marker of clinical improvement (MCID= 7 pts) (Raina et al., Ann Intern Med, 2008)

Treatment with CHEIs

Mimica et al., Psychiatr Danub, 2009 Lockhart et al., Dementia Geriatr Cogn Disord., 2009

Winslow et al., American Family Physician, 2011

�  Likelihood of any ADR: 15% to 78%

�  Discontinuation because of ADRs: 2.4%-40%

�  Common ADRs ¡  Nausea/vomiting/diarrhea ¡  Loss of appetite & weight loss ¡  Headache ¡  Dizziness

�  Serious ADRs ¡  Cardiac arrhythmia, seizures

�  Recommended to discontinue treatment if no improvement in 6-8 weeks

�  Anticholinergic drugs should be avoided, because they counteract these AD drugs! ¡  diphenhydramine (Benadryl) ¡  tricyclic antidepressants

Glutamate NMDA receptor antagonist: memantine (Namenda)

�  One theory of AD etiology is that neurons are damaged by excessive activation called neuronal excitotoxicity

�  Pharmacodynamics of

memantine ¡  Noncompetitive antagonist at

glutamatergic NMDA receptors ¡  Inhibits prolonged influx of

calcium ions that are involved in neuronal excitotoxicity

http://homepage.psy.utexas.edu/homepage/students/Rojas-Martinez/estrategias/estrategias.html

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Effectiveness of memantine

McShane et al., Cochrane Database Syst Rev, 2006 Grossberg et al., Dement Geriatr Cogn Disord, 2009

Schneider et al., Arch Neurol, 2011

�  In patients with moderate ⇒ severe AD ¡  2 out of 3 six-month RCTs showed small beneficial effect on

cognition (3-pt improvement on SIB; MCID = 10), mood, behavior, and ADL performance (1.3-pt improvement on ADCS-ADL; MCID = 5)

¡  Slightly less likely to develop agitation

�  Meta-analysis including 431 patients with mild AD and 697 patients with moderate AD, no significant differences between memantine and placebo on any outcome measure

Treatment with memantine

�  Often used in combination with CHEIs �  Generally well tolerated, though typically taken

twice/day (decreased adherence) �  ADRs: dizziness, headache, diarrhea, vomiting

Winslow et al., American Family Physician, 2011

Recent reviews of the effectiveness of CHEIs and memantine

Buckley and Salpeter, Drugs Aging, 2015

�  Systematic review of 257 studies (through 2014)

�  ChEIs ¡  Produced small improvements in cognitive, functional, and global

benefits in mild to moderate AD, but clinical significance unclear ¡  Efficacy decreases over time (minimal benefit seen after 1 year) ¡  No benefit for those with advanced disease or those > 85 years old ¡  ADRs increased in dose-dependent manner; those >85 years old had

double the risk of ADRs �  Memantine

¡  May provide some cognitive benefit for patients with moderate to severe AD, but benefit is small and may wane over several months

¡  No benefit in mild dementia or as add-on treatment with ChEIs, but may have minimal benefits in moderate to severe dementia

Matsunaga et al., Int J Neuropsychopharmacol, 2014

�  Meta-analysis of 7 identified RCTs (included 2182 patients) of combination therapy with CHEIs and memantine

�  Combination therapy: ¡  significantly affected behavioral disturbance, ADL, and

global assessment scores ¡  showed a trend toward improved cognitive function scores ¡  was more significant in moderate-to-severe AD subgroup in

all efficacy outcomes ¡  was well tolerated

Recent reviews of the effectiveness of CHEIs and memantine

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Effect of donepezil, memantine, or combination on nursing home placement

�  DOMINO-AD trial: RCT with 295 community-living elderly with moderate to severe AD that investigated effect of Donepezil, Memantine, or combination on nursing home placement in following 3 years

�  4 groups ¡  25% continued on donepezil alone ¡  25% discontinued donepezil ¡  26% discontinued donepezil and started memantine ¡  25% continued donepezil and started memantine

Howard et al., Lancet Neurol, 2015

Effect of donepezil, memantine, or combination on nursing home placement

RESULTS �  1st year: more nursing home placements in the combined

donepezil discontinuation groups than in combined donepezil continuation groups ¡  Next 3 years: no difference

�  No effect of patients starting memantine compared with not starting memantine during 1st year or next 3 years

�  Bottom Line: Withdrawal of donepezil in patients with moderate-to-severe AD increased risk of nursing home placement during 12 months of treatment, but made no difference during next 3 years of follow-up.

Howard et al., Lancet Neurol, 2015

Bottom Line for current AD medications

�  There are 2 current FDA-approved medication classes (CHEIs and memantine).

�  No treatment halts or reverses the course of the disease. �  CHEIs – may produce small (though perhaps clinically

insignificant) cognitive and functional improvements in mild to moderate AD with ADRs predictable based on mechanism of action that may be significant enough to discontinue treatment

�  Memantine – may provide small cognitive benefit for moderate to severe AD, but benefit may wane over several months; fairly well tolerated with safer ADR profile than CHEIs

What drugs are in the research pipeline?

1)  Solanezumab: monoclonal antibody designed to lower amount of beta-amyloid in the brain to prevent plaque formation

2)  Beta-secretase (BACE) inhibitor: drug that inhibits one of the enzymes that clips amyloid precursor protein (APP) to form beta-amyloid §  MK-8931 is being tested in two Phase 3 clinical trials

3)  AADvac1 vaccine: stimulates the immune system to attack an abnormal form of tau protein (the primary component of tangles) §  AADvac1 was safe & well tolerated in a Phase 1 clinical trial

4)  CSP-1103: microglial modulator that aims to reduce inflammation in the brain

5)  Intranasal insulin: may help increase insulin signaling in brain

http://www.alz.org/research/science/alzheimers_treatment_horizon.asp

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Case study �  Brief history

¡  Patient is an 84 y/o female living with her son. She was diagnosed with Alzheimer�s disease ~8 yr ago. She has atrial fibrillation and bilateral knee osteoarthritis. She is a limited independent community ambulator with a FWW.

�  Current medical status & drug therapy ¡  Patient was started on donepezil (Aricept) 7 years ago when her disease

was diagnosed as mild. Her cognitive status has remained relatively stable over the past several years. She has taken Coumadin daily for anticoagulation for 12 years. During the past 2 weeks, she has had difficulty sleeping, so her son has given her Benadryl in the evenings, which has helped her get to sleep.

�  Rehabilitation setting ¡  The patient has been actively participating in physical therapy for

increasingly limiting LE weakness for the past 2 months. When the patient arrives at her outpatient PT appointment today, she is very confused and does not even recall her last visit with the PT 3 days ago. The PT questions the son about his mother�s recent dramatic change in cognition.

Case study �  Problem & clinical options

Questions???

Thank you for your interest!!! Erin E. Jobst: jobste@pacificu.edu