11/4- Pharmacology for the Elderly Flashcards
What percentage of the US population is over 65?
How does this compare to the percentage of medication they consume?
Elderly (>65) make up:
- 15% of the US population
- 30% of the consumers of prescribed drugs
- 50% of the consumers of over-the-counter drugs
- Don’t forget “health food meds/nutritional supplements” and over the counter meds
- Injudicious use of meds can be dangerous and expensive
- BUT don’t withhold an indicated drug b/c pt is on a lot of other meds
What population has the most adverse drug events (ADEs)
- Responsible for __% of hospital admissions
- Examples of ADEs
Elderly
- 5-15% of all hospital admission of older people are due to ADEs (28% of admissions from nursing homes)
- Nursing homes spend $1.33 on ADEs for every $1 spent on medications
- Typical ADEs include: falls, anorexia, fatigue, delirium, urinary incontinence
- Any new symptom or sign, think about the drugs
What are risk factors for ADEs?
- 6+ concurrent chronic conditions
- 12+ doses of drugs/day
- 9+ medications
- Prior adverse drug reaction
- Low body weight or BMI
- Age 85+
- Estimated CrCl under 50 mL/min
Why are ADEs so common in the elderly?
- Inadequate pre-clinical information
- Old people are not in drug studies
- Pharmocokinetics
- Pharmacodynamics
- Homeostenosis
Why are old people not in drug studies?
- Concomitant drug use is frequently an exclusion in trials of new agents
- Physically or cognitively frail persons are excluded from almost all randomized drug trials
Problem, because much of pharmacology practice is based on extrapolation from study of younger/healthier persons
What is pharmacokinetics?
- What does it include?
“What the body does to the drug”
- Absorption
- Distribution
- Metabolism
- Excretion
What are the age effects on absorption from the GIT?
- Decreased rate of gut transport
- May increase absorption of sustained release drugs (theophylline)
- Increased metabolism in gut (sometimes by flora; e.g. levodopa, digoxin)
- Increased gastric pH (decreased acid)
- Decreased absorptive surface
- Peak serum concentration may be lower and delayed
- Overall aging changes in the GIT seem to be of minor clinical significance because motility and absorptive area changes cancel out
What are factors that affect absorption from the GIT?
- Divalent cations (Ca, Mg, Fe) can affect absorption of fluoroquinolones (e.g. ciprofloxacin; Fe + thyroxine)
- Enteral (tube) feedings interfere with absorption of some drugs (e.g. phenytoin)
- Drugs that affect GI motility can affect absorption
- Increased gastric pH may increase or decrease absorption of some drugs
How does drug absorption from the skin compare to other methods of administration
- What factors affect absorption
- What meds can be given this way
- Unpredictable rate of absorption of topical agents
- Thin skin favors absorption (seen in elderly)
- Decreased perfusion of skin delays absorption
- Nitroglycerin, estrogens, pain meds, BP meds, Alzheimer’s meds…
What are changes in distribution of mass/composition in the elderly?
- Decrease in lean body mass and total body water; higher concentrations of water soluble or muscle protein bound drugs
- Increased fat increases volume distribution for lipophilic drugs, such as sedatives that penetrate CNS (remember your brain is just a hunk of fat)
How does age change protein binding?
- How does this affect pharmacokinetics
- Increased free fraction of some highly bound acidic drugs
- Albumin may drop rapidly with illness (increasing free concentration of highly bound drugs)
- Alpha-1-acid glycoprotein increases with age and will go up further with illness (binds antidepressent drugs)
- Protein binding changes are of modest significance for must drugs, especially at steady-state because clearance also increases
- Only free proportion is active, blood levels usually give total (free + bound)
Albumin decreases in response to ___, but not ___
Albumin decreases in response to illness, but not aging!
T/F: Albumin has multiple drug binding sites
True
What protein increases with healthy aging?
How does it change with illness?
Alpha-1-glycoprotein increases with healthy aging
- Greatly increases in illness
How do Dilantin (Phenytoin) concentrations change in the elderly?
- In young people, Dilantin (Phenytoin) is 99% bound to have 0.1-0.2 free and a total of 10-20
- In elderly, 98% is bound so 0.1-0.2 is free with a total of only 5-10 THUS, it is OKAY to have lower concentrations in the elderly
- So if older person is seizure-free with total phenytoin of 7, that is satisfactory. Do NOT increase their dose unless they are seizing
- You can always check a free phenytoin level (but expensive, and a hassle)
Since many drugs compete for albumin binding sites, what is the effect of adding a new drug?
- Addition of a new drug will modify the dynamic situation such that some bound drug may be released increasing its free concentration (and effect)
- The more drugs, the harder to anticipate the dynamics
Describe drug metabolism in aging
- First pass metabolism
- Phase I
- Phase II
- Enzyme effect
- Overall decline in metabolic capacity due to decreased liver mass and hepatic blood flow
- Metabolic capcity is highly variable; no good estimation algorithm exists
- Decreased first pass metabolism in old
- Phase I (P450 system -> oxidation, reduction, hydrolysis) is more likely to decrease with advancing age
- Phase II (conjugation) usually unchanged
- Induction decreased for some enzymes
What are the effects of aging on Cytochrome P450 and drug interactions?
- Effects of aging and clinical implications are still being reserached
- CYP3A(4) is involve din > 50% of drugs on the market
- Induced by: rifampin, phenyotin, carbamazepine
- Inhibited by: macrolide Abx, nefazodone, itraconazole, ketoconazole, and grapefruit juice
What is Isosorbide Dinitrate?
- How does its metabolism change with aging
Long acting nitrate preparation for angina BP and heart fialure
- Extensively metabolized in 1st pass through the liver
- Young liver can metabolize 12-15 mg oral dose; old liver does less
- So 10 mg Isosoribde is placebo dose in young and reasonable first dose in old
- Do NOT expect LINEAR effect on BP as you may be tripling the dose by increasing from 10-20 mg
What is Valium (Diazepam)
- How does its metabolism change with aging
Benzodiazepine; it lasts longer in old people
- Elimination half life is 24 hrs in young but 90 hrs in old
- Highly metabolized by P450 enzymes including active metabolites (and highly fat soluble)
- Pharmacokinetic effects add to pharmacodynamic effects
- Other benzodiazepines have shorter, predictable half life
- We use lorazepam (Ativan) but do not like Benzo’s in general
How does drug elimination change in elderly?
- Serum creatinine levels
- EGFR levels
- Decreased renal blood flow, GFR, tubular secretion, and renal mass; all contribute to decreased elimination
- Serum creatinine may appear normal even when significant renal impairment exists
- The “EGFR” calculated by the computer at most of the hospitals is TOTALLY WRONG for old people
How does creatinine clearance change with age?
- Decreased by CrCl by 35% in healthy older men (no HTN, no DM, no drugs)
- Decreased concentrating and diluting capacity
- Increased number sclerotic glomeruli to 30% of total
- Dependence on prostaglandins to maintain filtration
- Decreased renal blood flow and renal mass
- Serum creatinine does not change with age
What are equations that can be used to estimate renal function?
- Cockroft-Gault equation
- The “EGFR” calculated by the computer at most hospitals is TOTALLY WRONG for old people
What are the implications of decreased renal excretion in the elderly?
- Elimination half life is prolonged
- Serum levels of drugs are increased as are changes of toxicity
- Evidence from Gentamicin or Digoxin or Vancomycin, all highly water-soluble drugs
- As old people get sicker or improve, their handling of the drug will change
What are pharmacodynamics?
“What the drug does to the body”
- Generally, the lower drug doses are required to achieve the same effect with advancing age
- Receptor numbers, affinity, or post-receptor cellular effects may change
- Changes in homeostatic mechanisms can increase or decrease drug sensitivity
- Learn a few drugs well and stick to those as much as you can
Are older people more or less sensitive to effects of benzodiazepines?
Older people are MORE sensitive to effects of benzodiazepine
- True for both its sedative and respiratory suppression effects
- Young require increasing doses of IV midolazam to where they don’t startle to a loud noise and show EEG evidence of sedation
Is more or less Coumadin needed to treat older people?
Less Coumadin is needed for older people
Do people need more or less Clopidogrel for treament?
MORE Clopidogrel is needed for older people
- Less old people have adequate anti-platelet effects from Clopidogrel
- Old people have higher tendency to clot
- Fewer older folks are fully anti-coagulated with standard dose of Clopidogrel
Is atropine response increased or decreased with age? Why?
Atropine response is reduced with age.
- Getting to resting heart rate; PS (Vagal) tone is diminished with age
- (Not that much PS tone to remove if giving atropine, for example)
How does parasympathetic (Vagal) tone change with age?
Getting to resting heart rate; PS (Vagal) tone is diminished with age
- (Not that much PS tone to remove if giving atropine, for example)
Summary: is the effect of these drugs felt stronger or weaker in elderly:
- Benzodiazepines
- Coumadin
- Clopidogrel
- Atropine
- Isoproterenol
- Paclitaxel (Taxol)
- Benzodiazepines: stronger effect in elderly
- Coumadin: stronger effect in elderly
- Clopidogrel: weaker effect in elderly
- Atropine: weaker effect in elderly
- Isoproterenol: weaker effect in elderly
- Paclitaxel (Taxol): greater toxicity in elderly
Is Isoproterenol effect increased or decreased with age?
The chronotropic effects of sympathomimetic agents (like Isoproterenol) is greatly decreased in the elderly
- Inotropic and lusitropic responses also decrease with age
How do the effects of Paclitaxel (Taxol) change in the elderly?
- It has greater toxicity in the old
- Paclitaxel is a mitotic inhibitor used in cancer chemotherapy for many tumors and leukemia
- Otherwise funcitonal pts were recruited for this study
- Lower nadir white cell counts and more severe side effects were seen in the old
Pharmacodynamics are modified via multiple mechanisms. Describe how.
- Which drugs result in increased responsiveness
Changes in organ sensitivity or receptor binding or receptor subtypes
- Less responsive to b-agonists or antagonsists
Impaired homeostatic mechanisms
- Antihypertensive induced orhostasis
Results in increased responsiveness to many drugs
- Benzodiazepines
- Digoxin
- Neurleptics
- Opiods
- Some anticoagulants
- Anticholinergics
What are the effects of drug-drug interactions
- What increases the risk
- Most common
- May lead to ADEs
- Likelihood increases as number of meds increase
- Most common: cardiovascular and psychotropic drugs
What are some key facts about drug-drug interactions?
- Absorption can be increased/decreased by other meds
- Drugs with similar or opposite effects can result in exaggerated or diminished effects
- Drug metabolism may be inhibited or induced
- Herbal preparations may also interact
What are the most common adverse effects of drug-drug interactions?
- Hypotension/orthostatic hypotension
- Acute renal failure
- Urinary retention
- Confusion
- Cognitive impairment
What are some common drug-disease interactions?
- Dementia
- Obesity
- Ascites
- Renal/hepatic impairment
- Dementia may increase sensitivity, induce paradoxical reactions to drugs with CNS or anticholinergic activity
- Obesity alters volume of distribution of lipophilic drugs
- Ascites alters VD of hydrophilic drugs
- Renal or hepatic impairment may impair detoxification and excretion of drugs
What is Beers’ Criteria?
- Originally proposed in 1990s to prevent ADEs in elderly
- Last revision published in 2012
- Consensus of experts reached
- One size fits all approach
What drugs have high potential for severe ADEs?
- Amitriptyline
- Chlorpropamide
- Digoxin (>0.125 mg/day)
- Disopyramide
- GI antispasmodics
- Meperidine
- Methyldopa
- Pentazocine
- Ticlopidine
What drugs have high potential for less severe ADEs?
- Antihistamines
- Diphenyhydramine
- Dipyridamole
- Ergot mesylates
- Indomethacin
- Meperidine, oral
- Muscle relaxants
What drug causes the most hospitalizations after ADE?
Warfarin?
Do older people take their drugs?
- Old people are more likely to be non-adherent to their medicine regimen because they take so many drugs
- 20% of prescriptions are not filled
- Almost 50% of meds not taken as directed
- 90% of non-adherence is under-utilization of meds
- Demented people may “forget”
What are some strategies to improve adherence?
- Explain what medicine is for
- Minimize the number of total medications
- Don’t exaggerate potential side effects
- Keep schedule as simple as possible and write it down for the patient
- If no kids then get rid of child proof tops, especially for arthritis meds
- Try less expensive meds if possible
What are the basics for prescribing for older patients?
- Start with a low dose
- Titrate upward slowly, as tolerated by the patient
- Avoid starting 2 drugs at the same time if possible
Before prescribing a new drug, what should you ask yourself?
- Is this medication necessary
- What are the therapeutic end points
- Do the benefits outweigh the risks
- Is it used to treat effects of another drug
- Could 1 drug be used to treat 2 conditions
- Could it interact with disease, other drugs
- Does patient know what it’s for, how to take it, and what ADEs to look for
