Polypharmacy—the Pearls, the Perils,
and the Pitfalls of Pharmaceuticals in
the Aging Population
Barb Bancroft, RN, MSN
www.barbbancroft.com
August 3, 2010
Chicago IL
1
Definitions of “age”…
• Stratification of the older patient group into 3
groups:
• “young old” – 65-75
• “old”—75 to 85
• “old-old”– over 85
• By 2020 there will be ~1,000,000 centanarians
in the U.S.
2
So, do you want to live to be 100?
• “If you live to be 100, you have it made. Very
few people die past that age.”
--George Burns, who died at age 100 in 1996
SO, IF YOU ARE 100 TODAY…
3
Your life expectancy as a…
Black Male – 2.9 years
Black Female – 3.0 year
White Male – 2.3 years
White Female – 2.5 years
If you are 60 today—
WM – 20.3
WF – 23.6
BM – 17.6
BF – 21.6
4
As an FYI: Life expectancy
If you are 40 today:
WM—37.4 years
WF—41.6 years
BM—32.8
BF—38.1
If you are 50 today:
WM—28.5
WF—32.4
BM—21.0
BF—25.4
5
Women have the age advantage at every
age, except conception and over 100 for
black males…
• Why is conception the exception?
6
The sperm carrying the Y chromosome
is the faster swimmer…
• The early sperm gets the worm, so to speak…
• Why?
7
Because…
• The sperm carrying the Y chromosome is 23%
lighter than the sperm carrying the X
chromosome
• Hence, the Y-carrying sperm weighs less and
therefore is a faster swimmer
• And, ladies…
Polypharmacy
• Most info on pharmacokinetics and
pharmacodynamics has been developed for
the “young-old” (65 to 75) and “old” (75 to
85)—very little info for the “old-old”(older
than 85)
• The effectiveness of drug therapy for many
disease processes in the older patient is as
great as it is for the younger patient
population
9
The biggest problem… “poly”conditions = “poly”-pharmacy
• The average older adult has 6.5 chronic
conditions, and multidrug therapy is the rule
rather than the exception to the rule
(Zurakowski)
• Usually an average of 1 to 3 drugs given per
condition—YOU DO THE MATH…
10
For example…
• 72-year –old male with diabetes, hypertension,
hypercholesterolemia, erectile dysfunction, benign
prostatic hypertrophy, glaucoma, osteoarthritis,
peripheral artery disease, and depression
• Let’s do the math…how many drugs for diabetes? 1 to
4; Hypertension? 2 to 3; hypercholesterolemia? 1 to 2;
erectile dysfunction? 1 drug; BPH? 1; glaucoma? 1 to 2;
osteoarthritis? 1 to 2; peripheral artery disease? 1 to 2;
depression? 1 to 2
• Anywhere from 10 to 19 drugs
• And that doesn’t include…OPRAH and Suzanne
Sommers
11
“alternative” and “complementary
therapies…”
…St. John’s wort for depression
…cinnamon for diabetes
…red yeast rice for high cholesterol
…mistletoe (Iscador) for breast cancer
…saw palmetto or for BPH
…glucosamine for osteoarthritis
…yohimbine for ED
…gingko for PAD (AHA News Release, 12/02/08)
…ginseng for “whatever ails ya’”
…soy for hot flashes
12
Soy for menopausal symptoms
• I hate to be the bearer of bad news, but after
years of study, nearly 20 clinical trials have
failed to show a statistically significant
improvement in menopausal symptoms
(Sitiri)
13
As an FYI…
• Approximately one in four persons taking a
prescription medication also takes a dietary
supplement. Asthma, insomnia, depression,
chronic GI disorders, pain, memory problems,
and menopausal symptoms are the medical
conditions for which supplements are most
commonly used. Patients at high risk for
interactions, such as those with seizure
disorders, cardiac arrhythmia, or CHF, often
report supplement use. (Gardiner)
Plus, over-the-counter drugs for aches and
pain, sinus problems, allergies, colds,
“indigestion”
•
•
•
•
•
•
•
•
•
Aspirin—drills a hole in the stomach and decreases renal blood flow
Acetaminophen—liver and kidney damage with long-term use
Excedrin—aspirin + acetaminophen…a double whammy
Ibuprofen—can negate aspirin’s cardioprotective effect, not to
mention drill another hole in the stomach and decrease renal blood
flow (and damage the kidney over time)
Prilosec OTC can negate the effects of clopidogrel and interact with
“3,456” other drugs
TUMS, Citracal, Oscal – calcium supplements can interfere with
thyroid replacement therapy
Cimetidine (Tagamet), ranitidine (Zantac)
Antihistamines (anticholinergic and wreak havoc with the elderly)—
of the two, SAY NO TO TAGAMET
YIKES
15
So, is there an established definition of
polypharmacy?
• Old definition? Greater than 5 drugs…hahahaha
• New definition? Nine or more drugs
• One study found an average of 3.8 different
therapeutic categories per patient with CV drugs,
CNS drugs, and hormone (thyroid, ET) as the
most common
• Individual patients were prescribed an average of
6.1 medications across those categories with
women averaging more and also having more
therapeutic categories (Linton)
16
So, are there some absolute NO-NOs?
• And if they’re not “absolute” NO-NO’s should
you think twice about using certain
combinations?
• Anything potentially life-threatening?
• YES…the combination of erectile dysfunction
drugs and…
• Nitroglycerine
17
And, the combination of ED drugs + certain
BPH drugs can also be dangerous
• The alpha one antagonists (no longer chosen for primary BP
control due to their “extreme” hypotensive effects)
• …especially with the first dose
• Prazosin (Minipress), doxazosin (Cardura), and terazosin
(Hytrin) – block the alpha-one receptors on the smooth
muscle of the prostate, subsequently reducing the size;
however, they also block the same receptors on the
arteriole smooth muscle and BP drops significantly…
• Combo with ED drugs? Severe hypotension
• Use tamsulosin (Flomax) or sildodosin (Rapaflo) or the
“sterides”—dutasteride (Avodart) or finasteride (Proscar)
18
Another potentially deadly
combination…
• ACE inhibitors (any drug with the last name “pril”) with
either of the K+ sparing diuretics, the aldosterone
antagonists—spironolactone (Aldactone) and eplerenone
(Inspra)
• Combined with the reduced GFR in the older population,
throw in NSAIDs (which decrease blood flow to the kidney
and cause sodium, potassium, and water retention) and
you could have a deadly rise in potassium and a fatal
cardiac arrhythmia
• Did you know that TMP-SFX (Bactrim/Septra) can also
cause hyperkalemia and is especially dangerous w/ an ACE• Is thACE/Aldactone combo used all of the time?
Yes…CAREFULLY in HF patients…more later…
19
Tamoxifen, paroxetine (Paxil),
fluoxetine (Prozac)
• 30% of patients on tamoxifen also take an SSRI
for either depression or hot flashes
• Use of paroxetine (Paxil), fluoxetine (Prozac), and
sertraline (Zoloft) with tamoxifen—
• The P’s are strong inhibitors of CYP 2D6
• Tamoxifen is converted to an active metabolite via
CYP 2D6 (endoxifen—100x more potent than
tamoxifen)
• Use of either of the above antidepressants can
almost double the risk of recurrence (13.9% vs. 7.5%
w/placebo)
• (Prescriber’s Letter July 2009)
What to do?
• Switch antidepressants or switch to an
aromatase inhibitor (for example:
anastrozole/Arimidex) if the postmenopausal
female
• Use citalopram (Celexa)* for hot flashes if you
pick an SSRI
• *the only antidepressant that has shown
some effectiveness for hot flash reduction
• Or try gabapentin (Neurontin)
21
Dig and clarithromycin (Biaxin)
• A 7-year study of Ontario residents over age 66 treated
with digoxin showed that those admitted to the
hospital with dig toxicity were about 12 times more
likely to have been treated with clarithromycin than
those who have not (Juurlink)
• Clarithromycin Rx is commonly chosen for communityacquired pneumonia and H. pylori infections
• Digoxin with clarithromycin--elimination of digoxin is
primarily renal; however, about one-fourth of dig is
eliminated through the intestinal lumen, excreted in
bile, or secreted directly into the lumen by Pglycoprotein (P-gp).
22
Why? Dig--clarithromycin
• Clarithromycin inhibits intestinal P-gp and dig
cannot be eliminated—resulting in dig-toxcity
• Elevated dig levels* to potentially fatal
arrhythmia levels have been reported with the
clarithromycin.
• *Therapeutic dig levels are between 0.8-2.0
ng/mL; patients with AF may require higher
dig levels; patients with HF may do better at
lower levels
23
Speaking of dig…fun facts for nursing students…
• Digitalis is over 200 years old—from the foxglove
plant
• Dr. William Withering gets the credit but it was
actually a witch from the village of Shropshire that
first discovered its clinical usefulness for “dropsy”
• Leeches and other forms of “blood-letting” were
used by the medical establishment at the time
One more potentially deadly interaction—
high-dose simvastatin and amiodarone
• Amiodarone inhibits the metabolism of
simvastatin—the higher the dose of simvastatin
the greater the build up of the drug
• Very high risk of rhabdomyolysis and subsequent
acute renal failure
• Variation on the theme…amiodarone and
grapefruit juice…grapefruit juice inhibits the
enzyme in the small intestine that metabolizes
amiodarone—increased bioavailability and
increased toxic side effects (fatal ventricular
dysrhythmias)
25
Before the prescription pad is pulled
out…
• What is the problem being treated?
• What is the drug of choice for the diagnosis?
• Is the drug necessary and is it effective for
this problem?
• Is the safest drug being used for this age
group?
26
Consider my Aunt Betty Jo…
• Dx: Mild Alzheimer’s disease
• Dx: Osteoporosis
• Her M.D. prescribed alendronate (Fosamax) for her
osteoporosis…I said to my mother…
• “I don’t think that was a wise move, based on her memory
impairment…”
• OK, I’ll talk to her on Saturday (it was Monday when my
concern was voiced)
• On Saturday, my Aunt Betty Jo said…”well, I don’t know
why the pharmacist won’t give me any more of the pills, I
ran out of them in LESS than a week…”
• One shot of RECLAST once or twice a year would have been
the better choice…
27
• Are there nonpharmacologic alternatives?
• Back brace for vertebral fractures
• Cognitive behavioral therapy for mild to
moderate depression
28
NON-pharmacologic alternatives?
• How about for the osteoporosis? Weightbearing exercise, calcium citrate and vitamin
D; however, neither of these do the job totally,
so drugs are much better at building bone +
non-pharmacologic alternatives
29
Questions…continued…
• Is the lowest effective dose being used?
• For most indications in the elderly, “start slow
and go slow” is the rule…one major exception
to the rule is the group of drugs called the
statins to lower the LDL cholesterol…start with
a dose that reduces LDL cholesterol by 30-40%
30
Questions…
• Does the patient have symptoms potentially
attributable to the drug?
• Erectile dysfunction drugs and GERD—ED
drugs induce the production of the potent
vasodilator nitric oxide; nitric oxide also opens
the lower esophageal sphincter and can
contribute to GERD
• Muscle aches and pains—also on a statin
perhaps
31
Digression on ED drugs and the elderly
• The fastest rising group for STDs in U.S. is the
over 60 crowd—an increase of over 300%
since sildenafil (Viagra, the Pfizer riser) hit the
market in 1998 (November 1, to be exact)
• HPV, HSV, HIV, GC, Syphilis
• Why?
32
because…more sex
•
•
•
•
•
•
•
Many are swingin’ singles
No pregnancy risks
No frontal lobe…who cares what the neighbors think??
Sex on the beach, in swimming pools, on golf courses
Also an increase in UTIs
Increased marital bliss in some;
marital nightmares in others due infidelity issues and
wanting sex all of the time after not having it for 30
years…
33
More questions…
• Is the patient capable of following directions?
Amiodarone* and grapefruit juice?
Alendronate and directions…
• Is specific monitoring necessary (e.g., liver
enzymes or drug levels)? INRs for warfarin,
LFTs and TSH for amiodarone, serum
creatinine befor metformin, dig levels,
potassium levels for ACE inhibitors
34
Is there a more cost-effective
alternative? Example: beta blockers for HF
• Cost? Carvedilol (generic) and bisoprolol
(generic) can be purchased at WalMart,
Target, etc. for $4.00 for a 30-day supply,
$10.00 for a 90-day supply
• Carvedilol/Coreg CR is $145.80 for 30 days;
nebivolol/Bystolic is $55.80 for 30 days
35
How old is the patient and how long will it
take the patient to benefit from the drug?
• It takes 8 years to see benefits for the
treatment of diabetes to reduce the
microvascular complications
• It takes 3 years to see the macrovascular
benefits of treatment in diabetes
36
What is the half-life of the drug?
• If the half life is longer than the patient’s life, it’s NOT a
good choice
• Half-life should be less than 24 hours with no active
metabolites
• …and that’s usually a drug like amitryptyline to
NORtriptyline (choose nortryptyline to treat depression
or the pain of peripheral neuropathy); meperidine to
NORmeperidine (don’t choose meperidine OR NOR
meperidine), don’t choose fluoxetine (Prozac) as it is
metabolized to NORfluoxetine with an elimination halflife of 7 to 9 days in the elderly
37
Last question…is there a drug that might “kill
two birds with one stone” so to speak?
• Losartan (Cozaar) for managing chronic gout…has a
modest uricosuric effect that plateaus at 50 mg/d; may
be useful in patients with hypertension or heart failure
or diabetes (Reuben)
• Doxazosin (Cardura) for BPH and HTN (normally one
would avoid doxazocin as a first-line therapy for HTN,
however, it’s a good choice for the combination of a big
ol’ “prostrate” and hypertension
• HCTZ for hypertension in women over 60 as first-line
therapy—competes with calcium excretion; the drug is
excreted , the calcium is retained and bones are strong
like bull.
38
And, last but not least, is this one of the
medications on the Beers List? (Fick)
39
BEERS List – USE THIS, NOT THAT
• Medications are classified as inappropriate when
the risk of adverse effects outweighs the benefits.
In 1991, Beers and colleagues published the first
article to examine which medications are
inappropriate to prescribe in the elderly.
• List updated in 2003—medications are deemed
inappropriate because there are safer, equally
efficacious alternative medications.
• Whenever possible, the use of medications on
the Beer’s List should be avoided. (Fick)
40
The proverbial caveat…
• Prescribing medications on the Beer’s List of
increases the risk of drug-related morbidity and
mortality; however, not all of these medications
are inappropriate in all older patients
• Some healthy 80-year-olds can tolerate
medications on this list while a 60-year-old with
many comorbid conditions may not tolerate the
same medication
• Don’t JUST look at age…consider the whole
patient—warts, comorbidities and all….
41
Beers Criteria—the most frequently seen harmful
interactions involve the following BEERS drugs:
1) cardiovascular drugs (Digoxin, amiodarone/Cordarone)
2) pain medications (long-acting NSAIDS such as
piroxicam/Feldene, oxaprozin/Daypro,
meperidine/Demerol, propoxyphene/Darvon and it’s
combination products
3) anti-depressants/antipsychotic drugs/anti-anxiety drugs
(fluoxetine/Prozac; haloperidol/Haldol,
diazepam/Valium; oxazepam/Serax;
flurazepam/Dalmane; triazolam/Halcion;
amitriptyline/Elavil)
4) OTC drugs—cimetidine/Tagamet;
diphenhydramine/Benadryl)
Lots of drugs on the BEERS list have anticholinergic
effects—amitriptyline and cimetidine, for example
42
Normal functions of acetylcholine
•
•
•
•
•
•
Mentation (CNS)
Pupillary constriction (PNS)
Decreases heart rate (PNS)
Increases salivation (PNS)
Increases peristalsis (PNS)
Loosens urinary sphincter (PNS)
43
Anti-cholinergic drugs—side effects
•
•
•
•
•
•
Confusion
Pupillary dilation (blurred vision, glaucoma)
Tachycardia (angina, possible MI)
Decreased salivation (dry mouth)
Decreased peristalsis in GI tract (constipation)
Tighten urinary sphincter (urinary retention)
44
Drugs for OAB (overactive bladder)—
anticholinergic effects
 oxybutynin (Ditropan)(Gelnique—topical
gel)(Oxytrol patch)
 Toterodine (Detrol LA); fesoterodine (Toviaz)
 Darifenacin (Enablex); solifenacin (Vesicare)
 Trospium (Sanctura)
 (Prescriber’s Letter, June 2009;16(6):36
45
Anti-cholinergic drugs—the usual suspects and some
surprises…
• Amitryptyline (Elavil)—the higher the dose, the higher the risk of
anti-cholinergic effects; Rx for neuropathic pain vs. Rx for
depression
• Hyoscyamine (Anaspaz, Atropine)
• Doxepin (Sinequan)
• Meclizine (Antivert)
• Captopril (Capoten), nifedipine (Procardia)
• Prednisolone
• dig, dipyridamole (Persantine)
• warfarin
• Furosemide (Lasix)
• isosorbide dinitrate (Isordil)
46
And then some…
•
•
•
•
•
•
•
•
•
•
Paroxetine (Paxil)
Codeine
Oxycodone
Diphenhydramine
Fexofenadine (Allegra)
Hydroxyzine (Atarax)
Loratadine (Claritin)
dicyclomine (Bentyl)
Cimetidine (Tagamet), ranitidine (Zantac)
Haloperidol (Haldol)
47
What is aging?
• “Aging seems to be the only available way to
live a long life.” –Daniel Auber, French
composer (1782-1871)
• Aging is just getting older…by the time you
leave here today…
48
More importantly…what is
senescence??
• The rate of deterioration of the structure and
function of body parts
• Functional reserve capacity of tissues is 4-10 times
greater than baseline (the amount needed just to
function)
• Peak functional capacity is reached at age 24
• 6 good years
49
Senescence and normal aging...
the 1% rule
Peak at 24, 6 good years, gradual decline to baseline of
~ 1% per year;
FC%
Baseline function
1yr
30
75 yrs
50
But between 24 and 30…
• We’re cookin’ on the all burners…
• Our brain, our kidneys, our hearts, our
lungs…
51
Variation on the theme: senescence accelerates
with chronic disease (DM, COPD)...
FC%
Baseline function
1yr
30
75 yrs
52
Senescence and gender
differences...the demise of the ovary
•
Gender differences—the ovary (51.3 +/- 2.7)
FC%
Baseline function
1yr
30
75 yrs
53
Do men’s testicles die at 51.3 +/- 2.7
years? NOOOOOOOOOOOOO
54
The 1% rule and the kidney…
• Glomerular filtration rate (GFR)—120-125
ml/min at age 25; decreases by ~1% per year; as
an estimate:
– 75-year-old = 1.2 mL/min x 45 years = 53
mL/min; 120-53=67 mL/min in a HEALTHY
75-year-old (not taking into account weight,
ethnicity, or gender)
– BUT, a GFR of 60-89 mL/min=mild renal
insufficiency
– a GFR of less than 60 mL/min/1.73 m2
represents a loss of more than half of normal
kidney function
55
1% rule…renal function and aging…
• Diminished renal blood flow
• Increased retention of water soluble drugs
such as dig—increased toxicity
• Many doses of drugs need to be adjusted
based on the GFR
The Geriatric Kidney—the scope of the
problem
• Chronic kidney disease is caused by irreversible
age-related and disease-related damage to the
kidney and affects nearly 30% of all elders
• Among older adults, the incidence of druginduced nephrotoxicity may be as high as 66
percent
• Compared with 30 years ago, today’s patients are
older, have a higher incidence of CV disease and
diabetes, take multiple medications, and are
exposed to more diagnostic and therapeutic tests
with a predisposition to harm renal function
57
Assessing renal function in the elderly
• Serum creatinine is misleading in older patient
• Why? Serum creatinine is based on the breakdown of creatine
from muscle mass; older patients have reduced muscle mass
and therefore make LESS creatine
• Combine that with a reduced GFR and the serum creatinine
provides a false normal reading
• Best measurement is the creatinine clearance which equates
to the GFR via the Cockcroft-Gault equation (MDRD equation
as it tends to overestimate kidney function in the older adult
(Gill )
• IBW (140-age)(0.85 if female)
72(stable serum creatinine
For example…
• Radiocontrast dyes for diagnostic purposes
• Renal staghorn calculus as demonstrated by
an IVP
Drugs and the kidney
• Don’t forget to stop the metformin (Glucophage)
for 48 hours after a radiocontrast dye
• Increased risk of lactic acidosis (albeit a low risk,
but the risk is highest in the elderly)
• Metformin competes with the contrast dye for
excretion; the contrast dye wins and dives into
the toilet; metformin is retained and can
accumulate
• You won’t be using Metformin anyway if the
kidneys are not working well (serum creatinine
should be drawn before prescribing Metformin)
60
Gross anatomy
Drugs and the kidney
• Tubular cell toxicity—especially the proximal tubule—
extremely vulnerable to toxic effects of drugs and the
lack of oxygen since the proximal tubule does the lion’s
share of reabsorbing the glomerular filtrate
• (Acute Tubular Necrosis/ATN—what’s the good news?
epithelial cells line the renal tubules)
• What drugs? Aminoglycosides (gentamicin and
friends), amphotericin B, cisplatin (Platinol),
antiretrovirals (adefovir/Hepsera, cidofovir/Vistide,
tenofovir/Viread), contrast dye, zoledronate
(Zometa)—just to name a few
62
Various mechanisms of damage
• Inflammation: Drugs can cause inflammatory
changes in the glomerulus (glomerulonephritis)
and the medullary interstitium (interstitial
nephritis)
• Drug-induced glomerulonephritis is associated
with 3-4+ proteinuria (in the nephrotic syndrome
range)--Gold therapy, hydralazine, interferon-alfa
(Intron A), lithium, NSAIDS, PTU, pamidronate
(Aredia in high doses or prolonged courses)
63
Various mechanisms of damage
• Inflammation with acute medullary interstitial
nephritis: Usually results from an allergic
response and develops in an idiosyncratic nondose-dependent fashion
• Thought to bind to antigens in the kidney or act
as an antigen eliciting an immune response
• Allopurinol (Zyloprim), antibiotics (beta-lactams,
quinolones, rifampin (Rifadin), sulfonamides, and
vancomycin (Vancocin)
64
Nephrotoxic drugs and the elderly
• Drugs that inhibit angiotensin 2 (ACE inhibitors or
the “prils” and the ARBs—angiotensin receptor
blockers) are especially dangerous if renal blood
flow is compromised—renal artery atherosclerosis
(stenosis) (Baciewicz) or with NSAIDs
• NSAIDs and vasoconstriction of the renal artery and
afferent arteriole
• Renal blood flow relies more on prostaglandin
synthesis to maintain a vasodilated state in the
elderly patient
• NSAIDs combined with ACE inhibitors or ARBs in the
elderly may precipitate acute renal failure—HOW?
65
The healthy kidney
• Afferent arteriole
(normally vasodilated
(via prostaglandins)
• Blood entering
glomerulus
• Glomerulus→filter
• Efferent arteriole
(normally vasoconstricted
(via angiotensin II)
Prostaglandins –
blocked by NSAIDs
filter
Angiotensin
II—blocked
by ACE --
Toilet
66
The combination of ACE inhibitors and NSAIDs can
precipitate acute renal failure
• EXPLANATION OF PREVIOUS SLIDE
• NSAIDs block prostaglandins and vasoconstrict the afferent
arteriole decreasing blood flow to the glomerulus ( since
prostaglandins are more important in the aging kidney than in
the younger kidney the risk is much higher in an 80-year-old
compared to a 20-year-old)
• ACE inhibitors block ACE and the production of angiotensin
II—blocking angiotensin II vasodilates the efferent arteriole of
the kidney
• Decreased blood IN and increased blood OUT = decreased
filtration and acute renal failure
67
Drugs that can wreak havoc with RENAL
FUNCTION in the elderly…
• Aminoglycoside antibiotics (Amikacin/Amikin;
gentamicin/Garamycin; tobramycin/Nebcin),
diabetes, and concomitant use of ACE inhibitors
increase the risk of nephrotoxicity
• Adjust dose with GFR less than 60
• Ears and kidneys
Drugs that are excreted by the kidneys
and potentially retained in the elderly
•
•
•
•
•
•
•
•
•
•
•
Allopurinol
Aminoglycosides
Amoxicillin
Ampicillin
Atenolol
Captopril
Chlopropamide
Cimetidine
Clarithromycin
Colchicine
digoxin
•
•
•
•
•
•
•
•
•
•
•
•
Disopyramide
Enalapril
Famotidine
Fluconazole
Furosemide
Gabapentin
Gancyclovir
HCTZS
Levofloxacin
Lisinopril
Lithium
metformin
69
Drugs that are excreted by the kidneys
and potentially retained in the elderly
•
•
•
•
•
•
•
•
•
•
Methotrexate
Penicillin
Phenobarbital
Procainamide
Ramipril
Ranitidine
Spironolactone
Sulfamethoxazole
Tetracycline
Trimethoprim
70
General changes--water loss and aging
• Decrease in total body water stores
• Decreased osmoreceptors and diminished
thirst
• Decreased volume of distribution
• Increased drug toxicity with water-soluble
drugs—examples include dig, oxycodone,
atenolol (Tenormin), captopril (Capoten),
venlafaxine (Effexor), cimetidine (Tagamet),
ethanol, lithium
71
General changes…body fat changes—
distribution and amount
• Loss of subcutaneous fat (actually you don’t LOSE the fat, you
just move it to the internal visceral organs) with age--difficulty
maintaining internal temperatures with extremes of ambient
temperature
• Hypothermia/hyperthermia
• “You’re not dead until you’re warm and dead.”
• Always check the thyroid gland—myxedema coma + cold
ambient temperature
• Another implication of visceral fat? Increased insulin
resistance—T2DM
72
Body fat changes—distribution and
amount
• Somewhat variable in non-obese individuals, total body
fat is 10% to 20% of total body weight in younger men
and 20% to 30% in younger women. In older
individuals this increases to 20% to 30% total body fat
in men and 30% to 40% total body fat in women.
• Fat-soluble drugs such as diazepam/Valium and
anesthetics have much greater distribution in older and
obese individuals
• Results in retention of fat/lipid soluble drugs—can
result in toxicity if dosing interval is not increased or if
dose is not decreased
73
Benzodiazepines for example
• Half-life (T1/2) of diazepam (Valium) is the
patient’s “age, in hours”
25-year old = 25 hours
75-year old = 75 hours
• Use of a long-acting BZ in the geriatric patient is a
NO-NO (see Beers List)
• Shorter-acting benzodiazepines should be used in
the elderly (temazepam/Restoril,
oxazepam/Serax, lorazepam/Ativan (Beers List)
74
Amidarone
vs. dronedarone
• Dronedarone/Multaq will shortly over take
amiodarone for atrial fibrillation, if it hasn’t
already
• Dronedarone—elimination half-life of less
than 24-hours versus several weeks for
amiodarone; less lipophillic; much smaller
volume of distribution, and the iodine
moieties have been removed to reduce the
toxic effects to the thyroid
General changes—decreased albumin
levels, therefore less drug- binding sites
• Adult/elderly levels are 3.5-5 g/dl or 35-50 g/L
• In addition to maintaining osmotic pressure,
albumin binds drugs (protein-bound (inactive)
vs. “free” or active drug)
• Drugs will be “competing” for binding sites
• Hypoalbuminemia (less than 3.0 g/dL or 30
g/L)—what are the causes?
76
Hypoalbuminemia
• Three major causes of hypoalbuminemia
1) liver disease—not making enough
2) kidney disease –excreting too much
(nephrotic syndrome)
3) the very old geriatric patient due to the
aging liver and malnutrition
Low albumin and competition for
binding sites
• As a result of hypoalbuminemia, medications that are
highly albumin-bound may have elevated free drug
concentrations, leading to a higher incidence of drug
toxicity
• Plus, drugs are competing for a decreased number of
binding sites so someone is “bound” (no pun intended)
to be knocked off the binding sites, especially if they
are “weak” binders
• Warfarin is a weak binder and numerous drugs knock
“her” off “her” binding sites—two unexpected drugs
also knock warfarin off of the albumin binding sites
78
Who are they?
• Acetaminophen (yep, and how many elderly patients
are on Tylenol for muscle aches and pains)?
• Miconazole (Monistat)—yep, even topical miconazole
can knock warfarin off of her binding sites
• Sulfa-based drugs are also big bullies and can knock
warfarin off albumin’s binding sites
• Trimethoprim-sulfamethoxazole (Bactrim/Septra)
• And, metronidazole (Flagyl), erythromycin, cipro and
other FQs (floxacins)
• ASA competes with warfarin for binding sites
79
So when should the INR levels be
checked in patients on warfarin?
• Any time you add or subtract a drug from the
regimen of a patient on warfarin, you should
check the INR levels within 72 hours
• Warfarin (Coumadin) is the most common drug
that brings the elderly patient to the emergency
room (17.3%)
• WARF (Wisconsin Alumni Research Foundation)
• Can anyone guess what the second most
common drug that brings the elderly patient to
the ER
80
Other examples of drugs being
knocked off their binding sites
• Digoxin – quinidine and verapamil displace dig
and can increase dig levels by 50%--T O X I C I
T Y…
• Digoxin toxicity—the 3rd most common drug
that brings the elderly to the ER
• Dig is on the BEERS LIST
Drugs that are highly bound to albumin require
close monitoring for adverse effects…
•
•
•
•
•
•
•
•
•
•
•
Amiodarone
Amlodipine
Antipsychotics
Bupropion
Buspirone
Carbamazepine
Cefazolin
Ceftotetan
Ceftriaxone
Cilostazol
citalopram
•
•
•
•
•
•
•
•
•
•
•
•
Ditiazem
Dipyridamole
Felodipine
Lansoprazole
Midazolam
Nifedipine
NSAIDs
Omeprazole
Pantoprazole
Phenytoin
Rabeprazole
raloxifene
82
Drugs that are highly bound to
albumin
•
•
•
•
•
•
•
•
Rifabutin
Sertraline
Sulfonylureas
Tamsulosin
Terazosin
Valproic acid
Verapamil
warfarin
83
THE LIVER and DRUG METABOLISM
• Hepatic blood flow may be reduced due to atherosclerosis
• IS THERE ANY ARTERY THAT DOESN’T FILL WITH FAT????
• Decreased metabolism of drugs resulting in increased
bioavailability and toxicity
• Tagamet (cimetidine) also hepatic artery vasoconstriction
resulting in the decreased metabolism of drugs and a higher
bioavailability
• Can cause beta blockers to decrease the HR to dangerously
low levels; morphine and derivatives may decrease
respirations to dangerously low levels
• TAGAMET—BEERS List
NEUROPHARMACOLOGY OF
AGING
85
Neurology of aging…
• 5% loss of cerebral weight in females by 70
• 10% loss in men – don’t get too smug, ladies…(men
start out with a bigger brain)
• By 80, 17-20% loss
• Selected areas are the frontal lobes and the medial
temporal lobes
86
Medial temporal lobe and the loss of
hippocampal cell function
• Loss of recent memory
• This is the first neurologic function to go with
the process of senescence
• Benign forgetfulness
• Mild cognitive impairment
• Full-blown dementia
87
Which brings us, of course, to the
dementias…Alzheimer (s) disease or DAT
•
•
•
•
•
•
•
The hallmark of all dementia is memory loss
Alzheimer’s dementia
Cortical atrophy
Sulcal widening
“feathering”
Decreased brain weight
90% decline in acetylcholine, the neurotransmitter of
cognition
88
Pathology—it takes 5 to 20+ years before
the 1st symptom of memory loss
• Beta-amyloid plaques (BAP)—sticky globs outside the
cells; abnormal processing and cleaving of amyloid
precursor protein—earliest indication of the
development of dementia
• Less AD in people from India and Pakistan
• Turmeric the spice? Curcumin is the active
ingredient
•
89
It takes “tau” to tangle…1 to 5 years
before first symptom
• Neurofibrillary tangles—tangled microtubules inside
the cells; tau protein helps to stabilize the
microtubules and thus, maintain the integrity of the
neuron
• Neuronal degeneration
• Tau is predominant in FTD (frontal temporal
dementia)
• BAPtists vs TAUists
90
Cholinergic dysfunction in the AD brain
• What do all of these plaques and tangles do? Reduce the
function of acetylcholine—the transmitter of cognition
• Cholinergic impairment has been implicated in memory and
cognitive dysfunction in the elderly
• Accentuated in patients with Alzheimer’s disease and other
dementias
• Decreased acetylcholine receptors in the forebrain and other
regions as well as altered acetylcholinesterase enzyme
function
91
One of two available treatments for AD
today…boost remaining acetylcholine …
• Acetylcholinesterase inhibitors such as donepezil (Aricept)—
inhibit the breakdown of ACH in the brain; helps about 50-70
percent of the patients, but effects are modest; think back to
what the patient was doing 7-8 months ago; reprieve only
lasts a few months
• Others—galantamine (Razadyne, Razadyne ER), rivastigmine
(Exelon)(patch is well-tolerated)
• Reminyl was renamed Razadyne to avoid errors with the
diabetes drug, Amaryl (glimepiride)…mistakes led to
hospitalizations and deaths
• Donepezil and rivastigmine have also been approved for other
types of dementia—vascular/Parkinson’s, Lewy Body
Dementia; galantamine w/ vascular dementia
92
Benefits of cholinesterase inhibitors?
• Many clinicians doubt the practical significance of response to
ChEIs; however, other reports show that ChEIs have significant
efficacy in the treatment of neuropsychiatric symptoms in AD
patients.
• BOTTOM LINE? the numbers needed to treat (NNT) for 1
additional patient to experience benefit in the area of
cognition were 7 for stabilization or better, 12 for minimal
improvement or better, and 42 for marked improvement.
93
Benefits of cholinesterase inhibitors?
• Other tangible clinical outcomes:
Delayed nursing home admission by as much as 21 months
with donepezil (Aricept); Donepezil (Aricept) also slows the
progression of atrophy of the hippocampus in the brains of
patients with AD—suggesting a neuroprotective effect of this
particular cholinesterase inhibitor.
• Galantamine (Razadyne) and donepezil (Aricept) have also
been shown to be neuroprotective by preventing neuronal
apoptosis (programmed cell suicide).
94
Drug interactions with the
cholinesterase inhibitors
• Drugs with anti-cholinergic properties can
potentially decrease the effectiveness of the
acetylcholinesterase inhibitors
• Paroxetine (Paxil) is an excellent example—the
anticholinergic effects of Paxil can negate the
acetylcholine boosting effects of Aricept and
friends
• Paroxetine (Paxil) has the MOST
anticholinergic effects of all SSRIs…do not use.
95
Memantine (Namenda/US;Ebixa/Canada)
2nd drug used for AD
• Namenda, {Ebixa }(memantine)—decreases excessive
activation of NMDA receptor by glutamate; offers modest
functional improvements in patients with Alzheimer’s disease
• Who is glutamate? Excitatory transmitter that plays a major
role in memory and learning; continuous stimulation of the
NMDA receptor leads to increased calcium influx and ultimate
damage to the neuron; Memantine allows normal glutamate
fx; blocks excessive excitation
• Mild to moderate to severe AD as an add-on or has been used
alone
96
On the horizon…
• AAC-001 –vaccination against beta amyloid
• Alzhemed (tramiprosate)—prevents neurofibrillary
tangles and build up of beta amyloid
• Bapineuzumab—monoclonal antibody to beta
amyloid
• LY2042430—may inhibit beta amyloid
• LY450139—gamma secretase inhibitor
• PBT-2—decreased levels of beta amyloid
• TTP488—reduces amyloid burden
97
Delirium in the elderly
• 1-2% of community dwelling; 10-22% of
hospitalized inpatients, 58% of nursing home
patients
• 15-26% of elderly with delirium die
• Cause of death is the underlying cause of
delirium
• Treating delirium improves cognitive
dysfunction
98
“Assume that the onset of delirium in the old
person is due to infection.”—Clifton Meador, M.D.
• It’s either a UTI or pneumonia
• Listen to the lungs and do a urinalysis
99
If it’s a female, consider a urinary tract infection
as the cause of acute delirium…
• Check the urinary tract
• WBCs in urine, WBC casts in the urine (pyelo)
• Only 8% of the women in nursing homes today
receive estrogen in one form or another
• Estrogen and the urinary tract maintains the health
of the urinary tract; lowers pH of urine, keeps it
acidic
• Topical estrogen and a reduction in urinary tract
infections
100
If it’s a male…either go with pneumonia or
a UTI due to a “prostrate” the size of Texas
101
The second major cause of delirium is
polypharmacy…
• The blood brain barrier in the elderly is more permeable to
drugs—everything that is lipid-soluble gets in
• Narcotics and NSAIDS
• Benzodiazepines
• Any drugs with “anti” as their first name…Anticholinergics,
antiarrhythmics, anti-histamines, antihypertensives,
antipsychoticcs, antiparkinsonism, antianxiety,
antidepressants, antimicrobials
• Cimetidine (Tagamet), digoxin, steroids, acetaminophen,
diuretics, meperidine, amantidine
• Sudden withdrawal of drugs
102
The third major cause of delirium is electrolyte
imbalance…many of the electrolyte imbalances
are caused by medications
• Low sodium—consider thiazide and loop diuretics, but a
lesser known cause is the SIADH induced by SSRIs;
acetaminophen; hyperglycemia lowers sodium (for every
100 mg/dL increase in plasma glucose, sodium decreases
by 1.6 mEq/L
• Low or high potassium—consider diuretics again for low
potassium; for high potassium go straight for the ACE
inhibitors especially combined with spironolactone or
eplerenone
• ACE inhibitors combined with TMP-SFX has also been
shown to cause hyperkalemia
• Hypercalcemia--#1 cause in the elderly??? Not drugs, not
hyperparathyroidism, but…..
103
Depression…
• More common than dementia
• Often co-exists with dementia
• May appear withdrawn, uncooperative or
intermittently agitated
• Functionally or cognitively impaired
• May prolong recovery from illness due to lack
of cooperation, negativism, and poor selfesteem
104
The usual neurovegetative signs of depression are
unreliable in the elderly…(The SALSA signs)
• Sleep disturbances, appetite changes, low, self esteem, and
anhedonia (lack of interest in day-to-day activities)
• There is NO significant illness or medical condition in late life
that does NOT impinge upon sleep, appetite or energy or
sense of vitality
• Usual aging also brings changes in sleep patterns and energy
expenditure…
• If within 10 minutes…
• Geriatric Depression Scale
• Sertraline (Zoloft) and escitalopram (Lexapro; Cipralex) are
excellent choices—few side effects, few drug interactions,
short half-lives
105
Cardiovascular system and
drugs in the elderly
106
The Cardiovascular system and aging
• Increased prevalence of cardiovascular disease
with aging
• People over 65 account for 65% of all
cardiovascular hospitalizations and 80% of all
heart failure admissions
107
The aging heart and vascular system…
• 1% rule--maximal O2 consumption and cardiac
output decrease by 1% per year starting at age
30;
• Interestingly and fortunately, the heart rate
does not decrease by 1% per year with age
• However, elderly patients have a decreased
heart rate reserve and maximum attainable
heart rate
108
The aging heart and vascular system
• Endothelial dysfunction—increased risk for
atherosclerosis which in turn increases the risk
of coronary artery disease, cerebrovascular
disease, PAD, etc.
• Use of the “statins”—lova, prava, simva,
atorva, rosuva, pitava…
109
The “Statin Sisters”…
Who are they?
• lovastatin (Mevacor)
• simvastatin (Zocor)
• atorvastatin (Lipitor)
• fluvastatin (Lescol)
• pravastatin (Pravachol)
• rosuvastatin (Crestor)
• pitavastatin (Livalo)
Other manifestations of
atherosclerosis in the elderly
•
•
•
•
•
Renal artery stenosis
Hypertension
Chronic kidney disease
Abdominal aortic aneurysm
Abdominal bruit
111
“You’re not getting enough blood flow to
your ‘private parts’”--ED
• The little blue pill that changed the lives of millions-November of 1998
• The “Pfizer riser” and friends
(sildenafil, vardenafil, tadalafil)
Viagra, Levitra, Cialis (the weekend warrior)
• Boost nitric oxide and increase blood flow to the “privates”
• Before 1998; After 1998
• Pilots
• Tetanus shots
112
Chronic Heart Failure
• Approximately 2% of adults suffer from heart
failure, but in those over the age of 65, this
percent increases to 6–10%
• 6% of diabetic men develop heart failure, 10%
of diabetic women
• HF costs more than $35 billion/year in the US.
Although some patients survive many years,
progressive disease is associated with an
overall annual mortality rate of 10%.
113
Chronic Heart Failure-- CHF
• Decreased contractile reserve along with multiple risk factors
(atherosclerosis, hypertension, diabetes, valvular heart
disease) results in an increased risk of CHF
• Nomenclature has changed—just a tweak…congestive to
chronic; we can still keep the acronym
• Left-sided vs. right-sided (old classification and useful for
teaching purposes)
• Current classification: Systolic vs. diastolic (is it pump failure
or filling failure?)
• An ejection fraction of less than 40% indicates systolic
dysfunction; an ejection fraction of ≥ 40% indicates heart
failure with preserved systolic function (diastolic dysfunction)
BB’s causes of heart failure
• The broken heart—primary cardiac muscle failure
(myocarditis, alcohol and thiamine deficiency—why
don’t we just add thiamine to booze, darn-it? )—90%
is dilated cardiomyopathy
• The betrayed heart—the heart that is let down by its
friends—decreased O2 with COPD, atherosclerosis,
diabetes
• The befuddled heart—the heart that beats funny
• The defeated heart—working too hard against a
resistance (HTN, stenotic or leaking valves)
Heart failure caveats
• The leading cause of hospitalization due to
deteriorating heart failure is “excessive sodium
intake.” (Archives of Internal Medicine, 2001, Vol.
161(19), pp. 2337-42)
• The second cause of hospitalization and deteriorating
heart function is respiratory infection. Archives of
Internal Medicine 2001; 161 (19): 2337-42)
• The third leading cause of deteriorating heart failure
and hospitalization is not taking prescribed
medications. Archives of Internal Medicine, 2001;
161 (19): 2337-42)
The pathophysiology of heart failure…
• Regardless of the cause, if the heart is unable to pump
adequately; the ventricular myocardium, the kidneys,
and the adrenal glands are going to compensate
• A first mechanism of compensation results as a response
to ventricular dysfunction and increased wall stretching;
the ventricular myocardium releases B-type natriuretic
peptide (BNP). BNP stimulates diuresis and vasodilation
as part of a counter-regulatory system to oppose the RAA
system and sympathetic response
• Synthetic BNP is nesiritide (Natrecor)—for hospitalized
decompensated HF patients with dyspnea at rest
Pathophysiology of Heart Failure
• The sympathetic nervous system (SNS) response-the adrenal gland pumps out epinephrine/adrenalin
to increase the heart rate and the contractile state
(chronotropic and inotropic functions)
• The epinephrine/adrenalin also causes remodeling of
the heart muscle and increases the risk of ventricular
dysrhythmias
Enter the beta blockers for heart
failure
• Bisoprolol (Zebeta or generic) – QD*
• Carvedilol (Coreg, Coreg CR or generic) BID (also an
vasodilator via alpha 1 blockade)
• Metoprolol succinate (not tartrate) Toprol XL or
generic)—QD
• Nebivolol (Bystolic)*—QD (also a vasodilator via
nitric oxide production)
• *bisoprolol and nebivolol have not been FDA
approved for heart failure but they work; nebivolol is
the least effective…
119
Beta blockers
• Start with low-dose
• Fatigue (non-selective beta blockers cross the
BBB and block norepinephrine in the brain—
makes you tired and listless); hypotension,
worsening heart failure in the first 2 to 4
weeks of treatment; increase dose gradually;
full clinical benefits may not occur for 3 to 6
months
120
The kidney compensates… “I can
help!”
• The third compensatory mechanism with
heart failure—the KIDNEY “senses” low
volume and/or low pressure
121
The kidney and the renin-angiotensinaldosterone system
• Think of HF as a “hyper-reninemic” state
• Not enough blood flowing to the kidney (low
volume, low pressure), results in the release
of renin, which in turn triggers the release of
angiotensin I from the liver. Angiotensin I
stimulates the production of Angiotensin II
• Angiotensin II triggers the release of
aldosterone
• Too much of a good thing…
122
In other words, Angie is a bad girl in
heart failure
• Angie ‘tenses’ your angios and vasoconstricts)
and “al”dosterone (conserves sodium and
water and secretes potassium)—resulting in
increased afterload and preload
• Now the heart has to work even harder
• Angie also remodels the myocardium and
increases the risk for ventricular dysrhythmias
123
•
•
•
•
•
•
To the rescue…ACE inhibitors-- “the
PRILS”—block the conversion of
angiotensin I to II
Captopril (Capoten and generic)—TID (compliance problems)
Enalapril (Vasotec and generic)--BID
Lisinopril (Prinivil, Zestril and generic)--QD
Perindopril (Aceon)--QD
Trandolapril (Mavik and generic)--QD
Ramipril (Altace and generic)--QD
124
“PRILS”—The ACE inhibitors
• Who is “ACE” and why do
we want to inhibit him?
• Angiotensin Converting
Enzyme (ACE) inhibits the
conversion of ATI to ATII
RENIN
ANGIOTENSIN 1
ACE--
ANGIOTENSIN 2
125
A few notes on ACE inhibitors
• Use cautiously in patients with SBP < 90
mmHg
• Draw serum creatinine and potassium levels
prior to starting ACE inhibitors
• Use cautiously in patients with creatinine
levels > 3 mg/dL, or potassium levels greater
than 5.5 mEq/L (> 5.0 mEq/L in diabetics)
• Do not use in patients with hx of angioedema
or bilateral renal artery stenosis
126
Adverse effects are due to 3
mechanisms
1) inhibiting breakdown of endogenous kinins
(cough—females more than males),
angioedema—smokers, AA, asthmatics)
2) suppression of angiotensin II (hyperkalemia,
hypotension and renal insufficiency)
3) Reduction of aldosterone production
(hyperkalemia)
FYI: ARBs do not increase concentrations of kinins
to the same degree, hence less cough and
decreased risk of angioedema (8% crossreactivity)
127
BOTTOM LINE: ACE inhibitors
• Improve symptoms in patients with heart
failure (sometimes within the first 48 hours,
but more commonly over 4 to 12 weeks)
• Decrease the incidence of hospitalization and
myocardial infarction
• Prolong survival
• (Medical Letter, July 2009)
128
“Sartans”--ARBs
• Angiotensin receptor blockers (bypass ACE) and work by
blocking the tissue receptors
• Who are they? The “Sartan Sisters”…
• losartan—Cozaar
• valsartan—Diovan
• candesartan—Atacand
• irbesartan—Avapro
• telmisartan—Micardis
• olmesartan—Benicar
• eprosartan--Tevetan
If additional aldosterone blockade is
necessary…aldosterone antagonists
• Eplerenone (generic or Inspra) QD @ $106.20
for 30 days or Inspra for $135.30 x 30 days
• OUCH.
• Spironolactone (generic or Aldactone) QD
@$94.00 for 30 days generic or $28.20 for 30
days for Aldactone
130
Please note:
• RALES (1999) (Random Aldactone Evaluation
Study)—adding spironolactone/Aldactone
postpones or prevents 200 deaths/1000
people w/CHF
• BUT…For every 1000 new spironolactone RX
in heart failure patients, there are 50 more
hospitalizations for hyperkalemia
• Dose 12.5-25 mg per day of spironolactone
Other drugs for heart failure??
• Digoxin, of course—especially if the myocardium
needs a little extra boost
• When should dig be used? Persistent symptoms,
despite optimum therapy with ACE inhibitors,
diuretics, and beta blockers to reduce
hospitalization in patients with a Class IIa
indication…(Stage C with a reduced left
ventricular ejection fraction
• Diuretics—HCTZ or loop diuretics depending on
GFR
132
NSAIDs and heart failure…
• NSAIDs and fluid retention (due to vasoconstriction of the
afferent arteriole)—especially the long-acting nonselective
NSAIDs -- (piroxicam/Feldane), meloxicam (Mobic,
Mobicox), nabumetone (Relafen), oxaprozin (Daypro)
• NSAIDs can counteract the positive effects of thiazide
diuretics for blood pressure control
• Why? Opposing actions
• NSAIDs can exacerbate HF symptoms due to sodium and
water retention (+peripheral edema) and renal dysfunction; can
also increase K+ levels
133
Hypertension
• Increased vascular stiffness—increased systolic
BP with widened pulse pressure; increased
afterload
• One-third of the adult population in the US has
HTN; somewhere in the vicinity of 65 million give
or take a few
• Only 31% of patients on hypertensive therapy
reached target blood pressure goals of less than
140/90 mm Hg; and control rates were lowest
among those age 60 and older
134
Isolated Systolic Hypertension (ISH)
• Two thirds of hypertensive patients over 60 have ISH
• Systolic rises with age due to arterial stiffness,
diastolic tends to plateau or even decrease during 6th
decade
• Isolated systolic (ISH) is defined as (S > 140; D< 90)
pulse pressure increases in the same manner; high S,
normal or low D; elevated pulse pressure is
increasingly recognized as an important predictor of
CAD/CVD (p.s. another cause of widened pulse
pressure is aortic regurgitation)
135
Blood pressure—Ideal? 120/80, BUT…
• Depending on co-morbidities it may be kept
slightly higher in the frail elderly to avoid
hypotension, falls, and a broken hip
• But not TOO high as it is the MAJOR risk factor
for strokes (besides AGE)—66% of all strokes
are due to hypertension
• Keeping the blood pressure BELOW 140/90
prevents strokes, ACS, CHF, dementia, and
renal failure
136
So, is it worth treating patients who
are over 80 for hypertension?
• Yes, indeedy. In the HYVET, double-blind, randomized,
placebo-controlled trial involving 3845 patients 80
years and older with hypertension the authors found
that active treatment with indapamide to start and
adding perindopril as needed was associated with a
21% reduction in the relative risk of death from any
cause, a 64% reduction in the relative risk of heart
failure, and a 30% reduction in the relative risk of
stroke
• It only takes 2 years to see the benefit of
antihypertensive therapy (Becket, et al. and Kostis)
137
How many drugs?
• Most older hypertensive patients may require
at least two drugs to achieve goal BP,
especially those at high risk for CV events
(Nash)
138
When choosing…
Would this drug have a favorable effect on co-morbidities?
• Angina—beta blocker, calcium channel blocker
• Atrial fibrillation—beta blocker, calcium channel
blocker
• Benign prostatic hypertrophy—alpha one blocker
• Congestive Heart Failure—beta blocker, ACE
inhibitor
• Hyperthyroidism—beta blocker
• MI—beta blocker, ACE inhibitor
• Diabetes Mellitus—ACE inhibitors, Angiotensin
receptor blockers
139
How about aspirin for one and for all? What
are the risks of aspirin for cardioprotection?
• First of all, let’s calculate the risks of having a
heart attack or dying of heart disease
• Go to…www.health.harvard.edu/116
• Let’s say, just for the sake of saying it…that
you are a 59- year- old- nursing instructor with
a TC of 220, HDL of 68, non-smoker with a
systolic BP of 130 mg/dL…anyone in this room
fit the bill?
140
• Risk is 2%...
Means 2 of 100 people with this level of risk
will have a heart attack in the next 10 years
141
Heart disease risk over 10 years? If
your risk is…
• 1%--aspirin will avoid 2 to 8 heart attacks and heartrelated events, cause 0 to 2 hemorrhagic strokes, ~12
gastrointestinal bleeds—GREATER HARM THAN GOOD
• 6%--aspirin will avoid 8 to 24 heart attacks and heartrelated deaths, cause 0 to 2 hemorrhagic strokes, and
cause ~12 gastrointestinal bleeds—GOOD and HARM
balanced
• 10%--aspirin will avoid 12 to 40 heart attacks and
heart-related deaths, cause 0-2 hemorrhagic strokes,
and cause ~12 GI bleeds—Greater GOOD than harm
(Harvard Health Letter, August 2007)
142
An easier way to look at it?
• Daily aspirin use by 1000 people for 10 years is
estimated to cause up to 2 hemorrhagic strokes and 12
episodes of GI bleeding; HOWEVER,
• The chances of dying from an aspirin-related
complication are the same as dying in an automobile
accident—about 1 per 1000 people over a 10-year
period
• Let’s compare aspirin to a class of drugs that has
received a terrible “reputation” over the years due to
the media…the statin drugs.
• Aspirin is 100 x more likely to cause a fatal side effect
than the statin drugs
143
So, who benefits?
• Diabetics over 40, or between 30 and 40 with
other risk factors such as smoking, HTN, FH, high
cholesterol
• Patients with chronic kidney disease (CKD),
especially patients on dialysis
• Patients at risk for heart disease—parent or sibling
with heart attack under 55 for a man and 65 for a
female, HTN, substantially overweight, no exercise
• One or more of these plus older than 65 for female
and older than 55 for male tips balance in favor of
aspirin
144
ASA and ibuprofen (Advil, Motrin)
• How many older patients take ASA and a
NSAID??? OTC ibuprofen is a NO-NO at the same
time…
• Ibuprofen blocks aspirin’s entry into the COX-1
pocket. If your patients take the two for various
conditions, take the aspirin 1st and wait at least
30 minutes before taking ibuprofen
• If that isn’t possible, hold off on the aspirin for 8
hours or so after taking ibuprofen
(Harvard Heart Letter, August 2007)
145
Switching gears…back to the 1% rule…An exception
to the 1% rule--an INCREASE in clotting factors by 1%
per year
146
Triple antithrombotic therapy
• Scenario—72 y.o. patient who needs
clopidogrel and aspirin after a coronary stent;
plus warfarin for atrial fibrillation, DVT, and a
mechanical heart valve
• YIKES…what to do? What to do?
147
To do…
• Aim for the lower end of the INR target of 2.0 to 3.0
• Try to stop clopidogrel as soon as it’s safe—often after
4 weeks after a bare-metal stent or one year for a drugeluting stent—this can vary
• Use the low-dose 81 mg of aspirin
• Prescribe GI prophylaxis for patients with risk factors of
GI bleeding
• PPIs (omeprazole and esomeprazole) and clopidogrel
(Prescriber’s Letter, September 2009)
148
Atrial fibrillation
• Approximately 2 million; risk increases with age
• Increased risk of TIAs/stroke
• AF can occur as a part of normal aging via minor, patchy scarring
that occurs in the atria that disrupt the normal circuitry
• Lots of other causes—hyperthyroidism, hypertension, CHD, valvular
heart disease, congenital abnormalities, diabetes, rheumatic heart
disease, ETOH
• Fibrillation potentiates mural thrombus formation in the left atrium
and results in 2-5 fold greater risk for embolic stroke*--Middle
cerebral artery
• Warfarin is the drug of choice to reduce the risk of a mural
thrombosis and stroke
• AF reduces CO by 10-15 %
Respiratory system
150
Respiratory
• Fever and tachypnea in the older adult—consider an acute
pulmonary syndrome—
• Pulmonary embolism (over 85? 700 PE/100,000)—WHY DO
YOU THINK EVERYONE IS ON COUMADIN?
• Pneumonia—confusion, tachypnea, fever and shoulder pain—
referred pain due to a big “wet” lung*
• Pneumococcus (strep pneumoniae) is the most prevalent
pathogen; Strep pneumoniae and Legionella are the most
serious;
• Antibiotics are common in the geriatric population
151
Other anti-inflammatory measures
• Give those flu shots!
Reduces the risk of an
acute coronary
syndrome by 66%
• Pneumococcal vaccine
Geriatric changes in the GI tract
• Decreased intestinal motility and blood flow
• Decreased gastric acid secretion (may not be a
universal phenomenon with aging and may only
be observed with atrophic gastritis; however,
implications of decreased acid from ANY cause
are important)
• Some drugs require a gastric pH of less than 5 for
absorption—the “conazoles” for example—
ketoconazole (Nizoral) and itraconazole
(Sporanox)
153
Gastric pH and calcium supplements
• Calcium carbonate supplements can be taken
with or without food, but they are tolerated
better when take with food and with an acid pH
• Calcium citrate is absorbed in low acid states and
should be used in older women with osteopenia,
osteoporosis or in women who are on proton
pump inhibitors for GERD (the prazoles—
omeprazole (Losec or Prilosec), esomeprazole
(Nexium), pantoprazole (Protonix), lansoprazole
(Prevacid), rabeprazole (Aciphex)
154
NSAIDs and the GI Tract
• The older the patient, the higher the risk of a GI
bleed, especially with the non-selective NSAIDS
• GI complications are 3-10x more common in users of
nonselective NSAIDs than in nonusers
• Use celecoxib (selective COX-2) if possible (also
decreases risk of lower GI bleeding as well as
perforations, obstructions and bleeds in upper GI)
• Use PPI with nonselective NSAIDS and celecoxib if
over age 75
• Celecoxib does NOT affect platelets so can be used
up to and following surgical procedures (Stillman MJ)
155
An increased risk of constipation in the
elderly…why?
156
Constipation is one of the major complaints in the
older population…drugs are a major cause
• Drugs—drugs with anticholinergic side effects,
opiods; verapamil (Isoptin, Calan); diltiazem
(Cardizem)
• Combined with decreased fluid and fiber intake
combined with laxative abuse—prune abuse
combined with dementia-- “the neglect of the call to
stool”, not to mention cancer of the colon, and
decreased activity
157
Bibliography
• Andersen K, et al. Do nonsteroidal anti-inflammatory
drugs decrease the risk for Alzheimer’s disease? The
Rotterdam Study. Neurology 1995;45:1441-1443.
• Baciewicz AM, Sokos DR, Cowan RI. Ann
Pharmacotherapy 2003;37
• Beckett NS, et al. Treatment of hypertension in patients
80 years of age or older. N Engl J Med
2008;358(18):1887-97.
• Fick DM, Cooper JW, et al. Updating the Beers criteria
for potentially inappropriate medication use in older
adults: results of a US consensus of a panel of experts.
Arch Intern Med. 2003;163:2716-2724.
158
Bibliography
• Gardiner P, Phillips R, Shaughnessy AF. Herbal and dietary
supplement-drug interactions in patients with chronic illnesses. Am
Fam Phys 2008 Jan 1; 77(1):73-78.
• Gardiner P, Phillips R, Shaughnessy AF. Herbal and dietary
supplement-drug interactions in patients with chronic illnesses. Am
Fam Phys 2008 Jan 1; 77(1):73-78.
• Gill J et al. Use of GFR equations to adjust drug doses in an elderly
multi-ethnic group: a cautionary tale. Nephrol Dial Tranplant
2007:22:2894-99.
• Juurlink DN, et al. Drug-drug interactions among elderly patients
hospitalized for drug toxicity. JAMA 2003;289:1652-58.
• Kostis JB. (editorial) Treating hypertension in the very old. N Engl J
Med 2008;358(18):1958-59.
159
Bibliography
• Linton A, Garbor M, Fagan NK, Peterson MR.
Examination of multiple medication use among
TRICARE beneficiaries aged 65 years and older. J
Manage Care Pharm. 2007;13(2):155-162.
• Myllykangas-Luosujarvi R, Isomaki H. Alzheimer’s
disease and rheumatoid arthritis. Br J Rheumatol
1994;33:501-502.
• McGeer PL, Rogers J. Anti-inflammatory agents as a
therapeutic approach to Alzheimer’s disease.
Neurology 1992:42:447-449.
• Nash DT. Systolic hypertension. Geriatrics
2006;61(12):22-28
160
Bibliography
• Reuben DB, et al. Geriatrics At Your Fingertips. 20082009. 10th ed. The American Geriatrics Society, NY.
• Sirtori CR et al. Risks and benefits of soy
phytoestrogens in cardiovascular diseases, cancer,
climacteric symptoms and osteoporosis. Drug Saf.
2001;24:665-82.
• Stillman MJ, Stillman MT. Choosing nonselective
NSAIDs and selective COX-2 inhibitors in the elderly: A
clinical use pathway. Geriatrics 2007;62(2):26-34.
• Zurakowski T. The practicalities and pitfalls of
polypharmacy. The Nurse Pract 2009; 34(4):36-41.
161
More slides…
• The following slides contain many more blurbs
for your reading and classroom pleasure.
162
Bowel preps
• Preps containing sodium phosphate (Fleet
Phosphosoda and Fleet ACCU-PREP, have led to
kidney calcification and resulting kidney damage
• Existing renal insufficiency can exacerbate this
problem as can any drugs (NSAIDS) that reduce
renal blood flow
• Use other preps such as magnesium citrate and
polyethylene glycol to avoid kidney problems
163
Levothyroxine (LT4) and tachycardia
• Caution when using with elderly—in older
adults who might have clinically silent cardiac
disease, experts recommend an initial starting
dose of 25-50mcg per day; in patients with
cardiac risk factors or a hx of cardiac disease,
LT4 replacement may begin at doses of 12.525 mcg per day
164
Interactions with LT4
• Levothyroxine decreases digoxin’s effect; starting
LT4 in a patient taking dig may reduce the
therapeutic effect of dig; digoxin dose may need
to be increased when LT4 is initiated (Med Letter
2009 (August)
• Estrogens—increase LT4 requirements; increased
thyroxine-binding globulin concentrations,
leading to decreased FT4; LT4 doses may need to
be adjusted when starting or stopping HT
165
Historical Highlight
• In the 1930s physicians would sometimes
deliberately induce hypothyroidism in patients
with severe coronary artery disease to reduce
the severity of angina. Unfortunately, the
severely hypothyroid patient was quite
debilitated by the symptoms of NO
metabolism
166
Drugs and weight in the elderly
• Drugs and weight loss (dig, metformin, chemo,
cholinesterase inhibitors for dementia)
• Drugs and weight gain-- insulin, sulfonylureas,
SSRIs (paroxetine/Paxil; fluoxetine/Prozac),
corticosteroids, atypical antipsychotics—
clozapine/Clozaril and olanzepine/Zyprexa,
mirtazepine/Remeron
167
Will pills that contain salt increase blood
pressure?
•
•
•
•
Antacids
Effervescent formulations
Zegerid (omeprazole) has 304 mg of sodium per cap
Alka-Seltzer Original has over 500 mg per tab
• Most oral meds that come as a sodium salt, such as
leveothyroxine sodium or pravastatin sodium, won’t
increase BP
168
Combos
• Beta blockers and diuretics
– atenolol/chlorthalidone—Tenoretic (50/25, 100/25 mg)
– bisoprolol/HCTZ—Ziac (2.5/6.25, 5/6.25, 10/6.25 mg)
– metoprolol/HCTZ—Lopressor HCT (50/25, 100/25, 100/50
mg)
– nadolol/bendroflumethiazide—Corzide (40/5, 80/5)
– propranolol/HCTZ—Inderide (40/25, 80/25 mg)
– propranolol LA/HCTZ—Inderide LA (80/50, 120/50, 160/50
mg)
– timolol/HCTZ—Timolide (10/25 mg)
169
Combos
• ACE inhibitors and diuretics
– benazepril/HCTZ—Lotensin HCT (5/6.25, 10/12.5, 20/12.5,
20/25 mg)
– enalapril/HCTZ—Vaseretic (5/12.5, 10/12.5 mg)
– lisinopril/HCTZ—Zestoretic (10/12.5, 20/12.5, 20/25 mg)
• Angiotensin II receptor antagonist and diuretics
-losartan/HCTZ—Hyzaar (50/2.5 mg)
170
Combos
• Other combinations
–
–
–
–
–
–
triamterene/HCTZ—Dyazide (37.5/25 mg)
triamterene/HCTZ—Maxide (37.5/25, 70/50 mg)
spironolactone/HTCZ—Aldactazide (25/25, 50/50 mg)
amiloride/HCTZ—Moduretic (5/50 mg)
hydralazine/HCTZ—Apresazide (25/25, 50/50, 100/50 mg)
methyldopa/HCTZ—Aldoril (250/15, 250/25, 500/30,
500/50 mg)
– reserpine/hydralazine/HCTZ—Ser-Ap-As (0.10/25/15 mg)
171
Coumadin (warfarin sodium)…
• Interacts with everyone and everything…
• Usual maintenance dose is 2-10 mg/day
• Inhibits vitamin K-dependent activation of II, VII, IX, X
which are formed in the liver
• Has no direct effect on established thrombi and can’t
reverse ischemic tissue damage
• However, it may prevent additional clot formation,
extension of formed clots, and secondary
complications of thrombosis
Stats on depression and heart disease
• Major depressive disorder (MDD) is as serious a risk
factor for CHD as HBP, ↑Cholesterol, obesity, smoking,
diabetes, +FH
• Precedes a heart attack in up to 50% of cases
• 20% of patients with ACS have MDD
• Depressed patients are 3-5x more likely to die in the first
year after MI
• Symptoms of depression are associated with impaired
endothelial function; depression increases arterial plaque
2 fold
• Treating depression significantly reduces the risk
of dying from heart disease
• (Feb 2003 Archives of General Psychiatry; July 2005 Archives of General
Psychiatry)
3 most common drugs for ER visits for the
elderly
•
•
•
•
Warfarin (Coumadin)(17.3%)
Insulin (13%)
Digoxin (3.2%)
The above 3 accounted for 33.3% ER of all ER visits
for Geriatric patients
• Excessive bleeding, hypoglycemia,
arrhythmias/nausea
• (Annals of Internal Medicine, December 4, 2007)
174
Pathophysiology of Delirium
• Widespread reduction in oxidative metabolism leading to
neurotransmitter deficiency and/or dysfunction
• Pharmacologic reduction of neurotransmitters involved in
cognition
• Increased levels of cytokines (acute inflammatory mediators
released by the immune system—IL-1, IL-2, IL-6, TNF-alpha)
caused by illness, physical stresses or both—leading to
impaired neurotransmitter dysfunction
175
Drugs/conditions and heart rate
changes
• Bradycardia—hypothyroidism, dig, beta
blockers (even topical beta blocker eyedrops
{Timoptic, Betoptic, etc.) can cause
bradycardia), calcium channel blockers such as
verapamil and diltiazem, and cholinergic drugs
for AD--galantamine (Razadyne), rivastigmine
(Exelon), donepezil (Aricept)
176
Tachycardia
• Tachycardia in the diabetic (loss of vagus
nerve due to autonomic neuropathy) leads to
silent ischemia in diabetics with
atherosclerosis of the coronary arteries
• Unexplained tachycardia (60 to 80 is the
normal resting heart rate)—consider
hyperthyroidism, atrial fibrillation (which can
also be caused by hyperthyroidism),
anticholinergic drugs
177
Combos of a calcium channel blocker
and a “pril” in one pill…compliance!
• Calcium channel blockers and ACE inhibitors
• amlodipine/benazepril—Lotrel (2.5/10, 5/10,
5.20 mg)
• diltiazem/enalapril—Teczem ((180/5 mg)
• verapamil/trandolapril—Tarka (180/2, 240/1,
240/2, 240/4 mg)
• felodipine/enalapril-5/5 mg
178
Quality of Life issues
• CCBs “dipines” and ACE inhibitors “prils” have an overall +
effect on quality of life; no class is clearly superior in quality of
life issues
• HCTZ and beta blockers increase the risk of DM (Diabetes Care
2006; 29(5):1065-70)—use of ACE inhibitors and CCBs is not
associated with DM; IN FACT…
• Prelim evidence—Combo ACE inhibitor “pril” + CCB “dipine”
may lower the risk of DM (ASCOT, Lancet 2006;366(9489):895906)
• HTN increases risk of cognitive dysfunction— “dipine” + “pril”
+/- HTCZ decreases incidence of dementia compared with
placebo in patients over 60 w/ISH (Arch Int Med
2001;161(2):152-6)
179
Did you know?
• Observational studies have suggested a
protective effect of NSAIDs on the prevalence
of Alzheimer’s Disease. (Anderson)
• Epidemiologic studies also showed lower
prevalence of AD in patients using NSAIDS
regularly (Myllykangas)
• Patients with RA have been found to die from
AD 5 times less often than the general
population (McGeer)
180