PK/PD in Elderly Flashcards
Why is geriatric PK important?
- People 65 y.o. and older are prescribed the highest percentage of mediations
- Currently, 13% of population buy 33% of Rx
- By 2040, 25% of the population will buy 50% of Rx
Adverse Drug Events
- ADE - 5-28% of acute geriatric hospital admissions
- ADE occur in 35% of community-dwelling elderly
- ADE incidence: 26/1000 hospital beds
- In nursing homes, they spend $1.33 on ADE for every $1 they spend on medications
Risk of ADE in Elderly
- Multiple medications: >20% of elderly use 3+ medications (increases frequency of drug-drug interactions, and decreases likelihood of adherence)
- Multiple comorbidities
- Age-related changes in PK
- Age-related changes in PD
* *All increase risk of ADE**
ADE General Risk Factors
- 6+ concurrent chronic conditions
- 12+ doses of drugs per day
- 9+ medications
- Decreased body weight/BMI
- Age: 85+ y.o.
- Estimated CrCl < 50 mL/min
Prescribing Basics for Elderly
- Start with low dose
- Titrate up slowly as tolerated by the patient
- Avoid starting 2 drugs simultaneously
- Consider deprescribing
ADE Cascade
- Prescribed one drug, have ADE
- Prescribed second drug for last drug’s ADE, experience new ADE
- Prescribed third drug…… and so on
Questions to Ask Before Starting New Medication
- Is this medication necessary?
- What are the therapeutic endpoints?
- Do the benefits outweigh the risks?
- Is it used to treat effects of another drug?
- Could one drug be used to treat 2 conditions?
- Could it interact with disease states or other drugs?
- Does patient know what it’s for, how to take it , what ADEs to look for?
Aging + Absorption
- Clinical significance is not well characterizes
- Most drugs are passively absorbed through proximal small bowel
- Exception: Levodopa, 3x increase in bioavailability due to decreased dopa-decarboxylase activity in stomach wall
GI Absorption Alterations
- Alterations in GI from decreases parietal cell function - decrease in HCl secretion (increases pH) which can effect drug absorption of drugs like iron and ketoconazole
- Decrease in gastric emptying - antichol. Fe, anticonvulsants
- DDI - Divalent cations (iron, magnesium) + Fluoroquinolones (ciprofloxacin)
Topical Absorption Alterations
- Patches, creams, ointments, etc.
- Thinning and reduction of absorptive surgaces
- Skin atrophy and reduction in fat
- Reduction in vascular network and increased risk of contact dermatitis
Aging + Vd
-Depends on physiochemical properties of individual medications mainly
t1/2 = 0.693 * Vd / Cl
Physiologic Changes + Vd
- Decreased in body water (10-15%) - decreased in Vd for hydrophilic drugs like warfarin, digoxin, lithium, APAP
- Decrease in lean body mass - decrease in Vd for muscle binding drugs
- Increase in fat store - increase in Vd for lipophilic drugs like diazepam, lidocaine, TCA, propranolol
Distribution
- Decreases Serum Albumin
2. Increases in alpha-1-acid-glycoprotein
Decreases in Serum Albumin
- 10-20% in hospitalized/poorly nourished
- Increase in fraction unbound of highly protein bound, acidic drugs
- Monitor drug levels - warfarin, phenytoin, naproxen (levels of free phenytoin with decreased albumin)
Increased Alpha-1-acid-glycoprotien
- Decrease in unbound fraction of highly protein bound basic drugs
- Includes lidocaine, propranolol, imipramine
Aging + Metabolism Changes
- Decrease in hepatic blood flow
- Decrease in liver size
* *Liver is most common site of metabolism**
Decrease in Hepatic Blood Flow
- 40-45% with aging (connected to cardiac function)
- Increase in bioavailability
- Decrease in first pass metabolism - more parent drug which means you can lower initial dose and titrate up
Decrease in Liver Size
- 25-50% decline in absolute weight up to age 80%
- Decrease in total amount of metabolizing enzymes
- Decrease in Cl and increase in half life
- Start with lower dosages
- CAUTION WITH TOXIC METABOLITES (Ex: Meperidine)
Elimination
- Most exit via kidney
- Decrease elimination leading to drug accumulation and toxicity
- Aging and common disorders can impair kidney function
Aging + Kidneys
- Decrease in kidney size
- Decrease in renal tubular secretion
- Decrease in renal blood flow (~1%/year after age 50)
- Decrease in number of functioning nephrons
RESULT: Decreased GFR, ~35% in healthy individuals ages 20-90; leads to drug accumulation and increased toxicity risk. EX: Lithium, NSAIDs, captopril
SCr Doesn’t Equate to CrCl
- Decrease in lean body mass leads to decreased SCr production
- Therefore leads to decreased GFR
- Result: elderly can have normal SCr levels that masks changes in CrCl
CrCl Measurement Methods
- Time-consuming in order to be accurate
- 24-h urine collection
- 8-h collection may be accurate, not widely accepted
CrCl Estimate Methods
- Cockroft & Gault
- MDRD
PD
- Time course and intensity of pharmacological effect of a drug
- Impairment varies considerably person to person
- All organs are affected: Kidney, liver, GI, CNS, CV, GU
Altered PD Mechanisms
- Changes in receptor numbers
- Changes in receptor affinity
- Postreceptor alterations
- Age-related impairment of homeostatic mechanisms
CNS PD Alterations
- Changes are significant but idiosyncratic - decrease in weight/volume of brain, alterations in cognition
- Increase in sensitivity to meds - Benzos, opioids, antichol. NSAIDs
- Chol. Blockade - sedation, confusion, decreased ability to recall (EX: TCAs, diphenhydramine, antispas, antipsy.)
- Benzos - cause severe CNS depression which can lead to falls and hip fractures, use with caution and in small doses
CV PD Changes
- Decrease in baroreceptor responsiveness
- Result: orthostatic hypertension ==> antihypertensives
GU PD Changes
- Urinary incontinence
- Affect 15-30% of community dwellers
- 50% of nursing home residents
- Increase in prostate and urinary retention
Beers List
- List of meds/classes to avoid in elderly
- Also lists disease/conditions and medications to avoid when having those diseases/conditions
- Other resources that provide similar information
- Independent of diagnosis
Beers List - Analgesics
- Meperidine - long half life metabolite, CNS effects, avoid
- Non-COX selective NSAIDs, oral - Indomethacin (CNS) & Ketorolac (GI Bleeds), AVOID, only use if patient isn’t responding to other therapies and takes a GI protective agent
- Skeletal Muscle relaxants - questionable effectiveness, antichol. SE, AVOID
Beers List - CNS
- Antidepressants
- Hypnotics/Anxiolytics
- Antipsychotics
Beers List - Antidepressants
-Amitriptyline
-Doxepin, >6 mg/day
-Clomipramine
-Nortriptyline
-Paroxetine
-Trimipramine
Lead to antichol. and orthostasis
Beers List - Hypnotics/Anxiolytics
- Benzos (CNS/falls) - long acting may be appropriate for seizures and REMS
- Nonbenzo Hypnotics - Ezopiclone, zolpidem, zalpeon - CNS, falls, minimal improvement of sleep
Beers List - Antipsychotics
- All 1st/2nd generation antipsychotics
- Except in SCZ, bipolar, and short term use with chemo
Beers List - CV
- Alpha blockers - orthostasis; doxazosin, prazosin, terazosin
- Alpha agonist, central - orthostasis; clonidine, methyldopa, guanfacine
- Amiodarone - avoid 1st line a. fib unless has heart failure
- Dromdarone - avoid, permanenet a.fib/severe heart failure
- Digoxin - avoid 1st line a.fib/heart failure
Beers List - Endocrine/GI
- Insulin, sliding scale
- Sulfonylureas - long duration (hypoglycemia, SIADH) - chlorpropraniamide, glyburide, glimepiride
- Megestrol
- Growth hormone
- Estrogen - patch or oral
- Androgens: Testosterone
- Dessicated thyroids (cardiac effects)
- Metoclopramide (EPS) - don’t exceed 12 weeks of use
- Mineral oil, oral (aspiration)
- PPIs - C. Difficile, bone loss, fractures; don’t exceed 8 weeks of use unless patient is high risk
Beers List - Antichol/Anti-infective
- Antihistamines - Diphenhydramine (confusion, sedation), meclizine, promethazine, hydroxyzine
- Antiparkinsons - Benztropine, Trihexyphenidyl
- Antispasmodics - avoid except in palliative care - Belladonna, dicyclomine, hyoscyamine, scopolamine
- Nitrofuratoin - avoid; long term suppression and CrCl < 30 mL/min
Beers List - Heart Failure
-NSAIDs
-Cox-2 Inhibitors
-TZDs
EX: Diltiazem, verapamil (avoid, decrease effectiveness)
Beers List - Syncope
- AChEIs - Non-selective
- Alpha blockers
- TCAs
Beers List - Delirium
- TCAs
- Antichol.
- Benzos
- H2RA
- Nonbenzos
Beers List - Dementia
- Antichol.
- Benzos
- Antipsychotics
Beers List - Falls/Fractures
- Anticonvulsant
- Antipsychotics
- Benzos
- Nonbenzo hypnotics
- Opioids
- TCAs
- SSRIs
- SNRIs
Beers List - Parkinsons
- All antipsychotics (except quetiapine, clozapine)
- Antiemetics - promethazine, metaclopramide
Beers List - Gastric/Duodenal Ulcers
- NSAIDs
- Aspirin > 325 mg
Beers List - CKD Stages 4-5
-NSAIDs
Beers List - Urinary Incontinence (women)
- All estrogens (all causes)
- Alpha blockers (stress and mixed causes)
Beers List - BPH
-Strong, oral antichol. (except for UI)
Drugs to Use With Caution
- Aspirin for primary prevention in ages 70+
- Dabigatron in ages 75+ and CrCl < 30 mL/min
- Rivaroxaban - increased risk of serious bleeds compared to other anticoagulants
- Anything that may cause SIADH/hyponatremia - Antipsychotics, diuretics, SSRIs, SNRIs, TCAs, Mirtazapine, Tramadol
- Dextromethorphan/Quidine (Nuedexta) - questionable effectiveness in dementia
- Trimethoprim/Sulfamethoxazole (Bactrim) - increase hyperkalemia when used with ACEIs/ARBs in those with CKD
DDIs - Opioids + Benzos
-Increase overdose risk
DDIs - Opioids + Gabapentin/Pregabalin
-Increased overdose risk
DDIs - Phenytoin + Bactrim
-Increased phenytoin toxicity risk
DDIs - Theophylline + Ciprofloxacin
-Increased risk of theophylline toxicity
DDIs - Warfarin
- Increased bleeding risk
- Interacts with ciprofloxacin, Macrolides (minus zithromax), Bactrim
DDIs - Increased fall risk
- Benzos
- Antidepressants (SSRIs, TCA)
- Antipsychotics
- Opioids
DDIs - Peripheral Alpha Blockers/Loop diuretics
-Increased UI in women
Misc. DDIs
- Multiple antichol.
- Corticosteroids/NSAIDs
- Warfarin/NSAIDs
Dose Reductions + Kidney Function
- Colchicine (CrCl <30) reduce dose
- Gabapentin (CrCl <60) reduce dose
- Enoxaparin (CrCl <30) reduce dose
- Rivaroxaban (CrCl 30) reduce dose
- Spironolactone (CrCl <30) Avoid
- Triamterene (CrCl <30) Avoid
- Ciprofloxacin (CrCl<30)-Increased risk CNS effects
- Bactrim (CrCl<30)-Worsening renal function and
hyperkalemia
