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CHAMP: Bedside Teaching
Drugs and the Aging Hospitalized Patient
Paula M. Podrazik, MD
Adverse Drug Reactions and the Aging Hospitalized Patient
Teaching Trigger:
An elderly patient is admitted with delirium secondary to a suspected adverse drug
reaction to a medication or medications in combination.
Clinical Question:
Why is the aging patient at risk for adverse drug reactions (ADRs)?
How can ADRs be minimized in the aging hospitalized patient?
Teaching Points:
1. Backgound information:
a. Adverse drug reactions (ADRs) represent any undesirable drug effect at
standard drug treatment doses. These reactions include amplified drug
effects, side-effects, drug-drug interactions, drug-disease interactions,
drug-nutrient interactions. ADRs do not include adverse drug withdrawal
events or therapeutic failures.
b. Adverse drug events (ADE) include ADRs and errors of drug
administration. Errors in drug administration represent an error that can
occur at any step in the process from writing a medication order—to the
drug being dispensed to the patient.
2. Older patients are at greater risk of ADRs because they are on greater #s of
medications, have more co-morbid conditions and take certain medications that
put them at higher risk of ADRs (high risk/low benefit medications).
3. Summary of risk factors for ADRs in the elderly are:
a. increased #s of medications
b. increased #s of medical problems
c. high risk medications (high risk/low benefit drugs, e.g., Demerol,
benadryl)
d. aspects of aging pharmacology, history of prior ADRs, and fragmented
medical care probably play a role but the evidence from the literature is
mixed.
4. Although ADRs may seem to be inevitable in hospitalized patients, there is
evidence that some of this error is preventable.
5. Strategies for reducing ADRs by drug review:
a. reduce #s of unnecessary medications
b. avoid high risk-low benefit drugs—find a lower risk alternative
c. certain aspects of aging pharmacology, e.g., the aging kidney, the aging
liver, aspects of aging pharmacodynamics such as the blunting of the
baroreceptor reflex in the aging patient.
d. review for hazardous drug interactions (drug-drug, drug-disease, drugnutrient)
6. Drug review should be ongoing from the point of admission until discharge,
especially in the older patient on greater than 5 medications.
7. Discarding, adding or changing medications in the older hospitalized patient must
be done in concert with the patient’s primary care physician.
Polypharmacy in the Aging Hospitalized Patient
Teaching Trigger :
During presentation of an admitting H&P, > than 5 medications noted.
Reviewing the MAR at bedside, > than 5 medications noted.
At the point of discharge, > than 5 medications are identified on the discharge instruction
sheet.
Clinical Question:
What is the importance of reducing polypharmacy in the aging hospitalized patient?
Teaching Points:
1. Polypharmacy is defined as the administration of more drugs than clinically
indicated.
2. The risk of a drug interaction greatly increases to approximately
50-60% when greater than 5 medications are taken. For patients taking 10
medications, there is approximately a 90% risk of drug interactions.
3. Approximately 50% of the elderly in the community setting take one or more
unnecessary meds. So ….the point of entry into the hospital is an important
opportunity for medication review and discussion with the primary care
physician re: eliminating unnecessary medications.
4. At hospital discharge, the elderly are taking the greatest number of
medications, making medication review and communication with the primary
care physician likewise crucial in reducing the number of unnecessary
medications.
5. The lower the # of medications the less risk for an ADR—so review for
medications that have no indication or have lost an indication.
6. Corollary: If you see a new symptom complaint and the patient is on an
increased # of medications—think ADR in the differential diagnosis and
review the medication list.
Drugs and Aging Pharmacokinetics
Teaching Trigger:
An elderly patient is admitted with digoxin toxicity.
Clinical Question:
What are the pharmacokinetic changes that occur with aging?
Which of these changes contibute to digoxin toxicity?
Teaching Points:
Overview:
1. Pharmacokinetics deals with the drug properties from the point of drug
absorption to its distribution, transformation (usually in the liver), and
drug elimination (most commonly via the liver and kidney).
2. Pharmacodynamics measures the intensity of a drug response at its
receptor site.
3. Most of drug research looks at the pharmacokinetic properties of drugs
because these properties are easier to quantify than pharmacodynamic
properties of drugs.
4. In general, older patients are excluded from drug trials, esp., the older old
(>75) and the oldest old (>85 years of age).
a. In general, the exclusion of the old from drug trials is seen
in investigational trials and also in most Phase III trials due
to small sample sizes.
b. Drug trials have exclusion criteria that often encompass the
co-morbid conditions or medications that are common in an
aging person.
c. Much of the drug prescribing information for the oldest old
group is extrapolated from the younger elderly population.
d. Little is known from formal research about the combining
of drugs in “vivo”, commonly seen in the aging population.
e. The deficiencies in knowledge regarding drug disposition
and efficacy in the geriatric population, particularly with
regard to cardiovascular drugs, need to be bridged to enable
the development of clinical guidelines for use and use in
combination in the aging population.
5. Pharmacokinetic changes with aging:
a. Drug absorption: no clinically significant change with
normal aging. However, may see slower absorption with
increased time to effect due to decrease in gastric pH,
motility and absorptive surface. Slower absorption may be
seen due to increased gastric emptying time in the older
patient.
b. Drug Distribution:
i. Volume of distribution (Vd)—represents an estimate of
the fluid volume required to distribute a drug evenly
throughout the body.
ii.Vd of a drug is determined by its plasma protein
binding, tissue binding characteristics and polarity.
iii.Changes in protein binding can affect the Vd of a drug.
Warfarin (99%) protein bound is one such example. A
common drug interaction with warfarin is displacement
from its protein binding sites. Amiodarone, rifampin,
phentoin, keto/iatraconazole antifungals, and
sulfonamides are drugs known to cause displacement of
warfarin.
With aging:
i. With increase in body fat from ages 20 to approximately
60-70 years, the Vd for lipophilic (nonpolar) drugs can
increase with aging, e.g., TCAs, antipsychotic agents.
After age 70, both body fat and lean body mass
decrease and so does Vd.
ii.The decrease in serum albumin seen with aging is
usually secondary to disease. Acute phase reactant
decreases in albumin are also partially
counterbalanced by -1 acid glycoprotein; so total
protein binding is not usually effected in the elderly.
Aging and digoxin:
i. Digoxin has a narrow toxic-therapeutic window,
avidly muscle bound and renally excreted.
Digoxin toxicity can be anticipated in the aging patient
due to a loss of muscle mass resulting in more
unbound digoxin, loss of renal function with decreased
clearance of the drug and the effects of other commonly
drugs taken in combination such as diuretics to
decrease renal drug clearance.
c. Hepatic drug biotransformation and clearance
See Drugs and the Aging Liver
d. Renal drug clearance
See Drugs and the Aging Kidney
Drugs and the Aging Liver
Teaching Trigger:
Reviewing the MAR a potent Cytochrome P450 inhibitor or inducer is identified.
Clinical Question:
What happens to the aging liver?
Why is the aging patient at particular risk for drug interactions with regard to liver
biotransformed drugs?
Teaching Points:
1. Background:
a. Liver metabolism occurs in the Cytochrome P450 system—a multigene
family of approximately 100 variations of enzymes responsible for
metabolizing drugs, food, chemicals, toxins, hormones. Most metabolism
occurs in CYP 1,2,3. Phase I reactions are oxidative. Phase II reactions are
acetylation and conjugation reactions.
b. With aging:
i. Decrease in liver blood flow by 35% or greater—so there is a decrease in
high clearance liver metabolized drugs including amitriptyline, labetolol,
lidocaine, propranolol, verapamil.
ii. CYP450 Phase I oxidative processes decrease.
2. CYP450 and pharmaceuticals:
a. CYP3A metabolizes > 60% of prescribed drugs including: calcium
channel blockers, certain beta-blockers, most “statins”, warfarin,
amiodarone.
b. CYP3A Inhibitors include: amiodarone, cimetadine, cyclosporin,
erythromycin, azole antifungals, grapefruit juice.
c. CYP2D6 metabolizes: metoprolol, propranolol, tramadol, codeine,
oxycodone, TCAs, SSRIs.
d. CYP2D6 Inhibitors include: cimetadine, SSRIs, quinidine
e. CYP 450 Inducers include: rifampin, primidone, tegretol, phenytoin
f. With aging:
The aging patient takes many prescribed drugs, often in great #
and/or in combination. For example, if a CYP3A inhibitor such as
amiodarone is prescribed, anticipate increased drug levels of digoxin,
warfarin.
Drugs and the Aging Kidney
Teaching Trigger:
At admission or during review of the MAR at bedside, a 90 year old with CHF is
noted to have a normal Cr of 1.1 and on multiple drugs cleared by the kidney.
Clinical Question:
What happens to the kidney with aging?
What is the most accurate way to estimate renal function at bedside in the aging
adult?
.
Teaching Points:
1. Renal function declines with aging starting at age 30-40— at a rate of about 1%
per year.
2. NHANES III REFERENCE POPULATION MEAN GFR
Age /Average GFR (mL/min/1.73m2)
20-29/116
30-39/107
40-49/99
50-59/93
60-69/85
>69/75
3. Serum creatinine measures in the aging patient are inaccurate. Creatinine is a
product of muscle breakdown, but with aging there is decrease in muscle mass
and its breakdown and muscle mass between the genders is different, hence the
serum creatinine does not accurately reflect GFR.
4. Cr Clearance measured by 24-hour collections generally provides a poor
estimate of true GFR due to a variety of factors in collection, analysis,
pharmacology and physiology.
5. At bedside, one can estimate Cr Clearance as a measure of GFR using the
Cockcroft-Gault equation:
Cr Clearance=
( (140-age)*wt(kg)/72 *serum Cr ) (x 0.85 in women)
6. The recommended best estimation of GFR by the National Kidney Disease
Education Program (NKDEP) of the NIH, the Kidney Disease Outcome Quality
Initiative (K/DOQI) of the National Kidney Foundation, and the American Society
for Nephrology is the use of a prediction equation based on serum creatinine to
estimate GFR. This method of estimating GFR in adults is a modified version of
the Modification of Diet in Renal disease (MDRD) equation, based on Cr, age,
sex, race, but not weight. Results are normalized to average adult body surface
area of 1.73 m2 and uniformly reported in mL/min/1.73m2:
GFR estimate=
186x(Cr)-1.154x (Age)-0.203x (0.742, if female) x (1.21, if African American)
Drugs and Aging Pharmacodynamics
Teaching Trigger #1: An 80 year old admitted for chest pain has a near syncopal
episode in-hospital after being started on cardiac meds including: nitrates and a betablocker.
Clinical Question: What are the changes in drug pharmacology and aging physiology
that effect doing and contribute to the near syncope in this patient.
Note: See the discussion below of the blunting of the baroreceptor reflex with aging and
decrease in beta-blockade with aging. With beta-blockers still start low and go slow, but
dose to effect because:
1. Increase in conduction system disease with age.
2. Beta-blocker side effects
3. Beta-blockers and other disease entities, e.g., asthma, COPD
4. Beta-blockers are often used with other HR slowing meds.
Teaching Trigger #2: An 83 year old is admitted to the hospital with delirium. PMH
includes dementia, lumbar spinal stenosis, and depression. The medication list includes:
Elavil, Paxil, Aricept, Ativan--prn agitation. The daughter recently had added Tylenol
PM for sleep to her mother’s medications.
Note: See discussion below of drugs with anticholinergic properties. Note the
cummulative effects of the anticholinergic properties in Paxil, Elavil, tylenol PM
(acetaminophen + benadryl)
Clinical Question: What are some pharmacodynamic age-related changes that could be
contributing to the potentially delirium causing medication combination in this case?
Teaching Points:
Overview:
1. Pharmacodynamics attempts to quantify the intensity of drug effect at its receptor site
with a given drug dose or concentration.
2. In pharmacodynamic study, the drug-receptor model is most commonly used.
3. In clinical practice, the relationship of drug dose or concentration versus response
approximates a sigmoidal shape. A threshold concentration is required to see initial
effect, with an essentially linear relationship through 20%-80% of the dosing range
and a plateau that represents a drug dose or concentration at which maximal drug
effect is seen. Most of therapeutic drug dosing is done in the linear portion of the
curve and maximal drug effect is avoided because of potential drug toxicity.
With Aging:
1. Decline in beta-adrenergic responsiveness due to both decrease in receptor numbers
and altered G-protein coupling to the beta-adrenergic receptor occurs with aging.
Clinically, a decline in maximal heart rate to exercise and stress is seen. Pharmacologic
response to beta-agonists and antagonists declines with aging.
2. Although the cardiovascular system shows a decrease in response to parasympathetic
blockade, more pronounced central nervous system side effects occur with use of
anticholinergic drugs, including urinary retention and delirium. Age-related changes in
other parts of the autonomic nervous system are less clearly defined.
3. Reflex responses to drug effects are also affected by aging. The baroreceptor reflex,
important in modulating changes in blood pressure, is blunted with aging.
.