Download PHARMACOLOGY – Simplified, not Mystified

PHARMACOLOGY – Simplified, not
Mystified
• “The arrival of a good clown exercises a more
beneficial influence on the health of a town
than 20 asses laden with drugs.”
•
Dr. Thomas Sydenham (1624-1689)
The Numbers…
• 30 years ago there were 900 drugs to choose
from in the PDR
• Today there are over 12,000…
• Plus….
The numbers….
• Over 600 herbals products —many of which
interact with prescribed drugs including cardiac
drugs and antidepressants
• St. John’s Wort is the number one herbal product
that interacts with over 60 percent of all
prescription drugs. The interaction is to make the
drugs LESS effective: Cyclosporine, tamoxifen, HIV
Rx, and Combined Oral Contraceptives
• Side effect?
I’m PREGNANT!!!
• CONFUCIUS say:
• “It take many nail to build crib; only one screw
to fill it.”
Vitamins and herbal supplements….
• Vitamin supplements—excess A (liver toxicity), B6
(peripheral neuropathy), C (doesn’t work to prevent
colds but is an excellent way to help absorb iron
when iron supplements are necessary), D for bones,
balance, boosting immune system, E (no extra
benefit on hearts, and in the very old may actually
exacerbate heart failure)…but vitamin E reduces fat
in the liver in patients with fatty liver disease (800
IU/ day)
• Calcium supplements, iron supplements, soy
supplements, and multivitamins interfere with
levothyroxine (Synthroid)—4 hour separation
Speaking of levothyroxine…
• Nighttime dosing may be more efficacious than
daytime dosing (better absorption)(Bolk)
• Most important—take at the same time of day on
empty stomach
• Adjust doses as the patient ages—why?
• Levothyroxine RX can also cause atrial fib if the
dose is too high; levothyroxine doses DECREASE
with aging; some patients only need 0.5
mcg/kg/day vs. younger adults with 1.7
mcg/kg/day (Prescriber’s Letter July 2011)
The Gs and platelet aggregation
• Decrease platelet aggregation; increased risk of platelet
bleeding the more you take…”stacking effect”
• Garlic vs. garlic supplements (interfere with all sorts of
drugs)
• Gingko—not beneficial for dementia, but is beneficial for
PAD
• grapeseed extract—EAT GRAPES
• ginseng –whatever ails ya’; side effects?
• Glucosamine—worth a try
• green tea** (a potentially harmful interaction is with green
tea and simvastatin—the higher the dose of simvastatin the
greater the risk of rhabdomyolysis)
Another G—Grapefruit juice
• When grapefruit juice or grapefruit inhibits
an enzyme in the small intestine--CYP3A4.
• This enzyme normally initiates the metabolism
of 40-60% of all drugs;
• when grapefruit juice inhibits this enzyme the
drugs are absorbed in a higher bioavailability
Grapefruit juice and drugs
• Interaction with grapefruit/grapefruit juice
may last up to 72 hours—takes this long for
CYP3A4 to recover from as little as 8 ounces of
GJ
• What is it in the grapefruit juice? The
furanocoumarins
(American Journal of Clinical Nutrition May 2006)
Cardiovascular drugs that may interact
with grapefruit
• Very high risk—dronedarone (Multaq)—torsades de
pointes; lovastatin (Mevacor) and simvastatin (700%
increase in bioavailability) (Zocor)—rhabdomyolysis
(check CK if c/o severe muscle aches and pains)
• High risk—amiodarone (Cordarone)-- torsades de
pointes; atorvastatin/Lipitor – rhabdomyolysis;
clopidogrel (Plavix)—loss of efficacy increasing the risk
of a blood clot following angioplasty/stenting;
eplerenone (Inspra)—high serum calcium levels,
serious arrhythmias, ticagrelor (Brilinta)—GI or kidney
bleeding
Cardiovascular drugs that may interact
with grapefruit
• Intermediate risk—felodipine (Plendil),
nifedipine (Procardia)—low BP, peripheral
edema; quinidine (Quinidine)—torsades de
pointes; rivaroxaban (Xarelto)—GI bleeding
• Canadian Medical Association Journal, November 26, 2012
(online)
The proverbial caveat…
One important caveat to consider: There is a large
individual variation in the effect of grapefruit juice on
metabolism. Consequently, someone with a high
intestinal CYP 3A4 activity might tolerate a certain
statin dose but have a marked increase in drug levels
with inhibition via grapefruit juice. Unfortunately, at
this time, pretreatment intestinal CYP 3A4 activity is
not measured in patients commencing drug therapy.
Plus…
• Over 10,000 over-the-counter (OTC) drugs that can
wreak havoc—examples:
1) cimetidine (Tagamet)—1st dose delirium in elderly;
multiple drug interactions
2) acetaminophen (Tylenol) is in over 300 over-thecounter products (Tylenol)—inadvertent overdoses
(narrow therapeutic index—toxic dose is not much
higher than therapeutic dose)
….as well as numerous prescription analgesics…
Fioricet, Lorcet, Percocet, Propacet, Roxicet,
Ultracet (limit “cets” to 325/mg per tab to reduce
toxicity)
Acetaminophen/Tylenol
• “itchy, sneezy, wheezy, snotty, achy, breaky” products
• Vicodin for pain, Excedrin for headache, Theraflu for
cold or flu, Sinutab for allergies, Robitussin for cough,
Allerest for sleep…
• 3,000 mg day is recommended total dose (McNeil
Consumer Healthcare, bulletin on July 28, 2011 to
reduce risk of acetaminophen liver toxicity)—even
less for people who have more than 3 adult
beverages per day
What’s in a name???
• When you hear “Bayer” what do you think?
• ASPIRIN OF COURSE!
• Bayer Aspirin is aspirin; but Bayer Select Maximum
Strength Headache is acetaminophen and caffeine
• Bayer Select Pain Relief is ibuprofen
• Aspirin’s principal use today is in low doses as a
platelet inhibitor and to inhibit colorectal polyps in
high risk patients
Don’t PANIC….
• Know the 30 or 40 drugs you use daily in your
clinical practice as well as the most common
drugs most likely used by your patients…(age
and gender specific)
• Helpful hints…
Generics vs. Brand names
As a general rule, classes of drugs have the same generic “last”
name
• “Prils”—ACE inhibitors (BP + more)
• “Sartans”—ARBs (angiotensin receptor blockers)—BP + more
• “Triptans”—treatment of acute migraine headache
• “Statins”—Lower LDL-cholesterol
• “Dipines”—calcium channel blockers (BP+)
• “Tidines”—H2 blockers reduce nighttime acid
• “Prazoles”—Proton Pump Inhibitors, GERD
• “Azoles”—antifungal
• “Afils”—Erectile dysfunction
• The “osins”, “mabs”, the “nibs”, the “setrons”, etc, etc, etc…
Let’s talk about blood pressure…
• First line therapy for blood pressure today can
be either:
• A thiazide diuretic (HCTZ) or chlorthalidone
(Thalitone)
• ACE inhibitors
• ARBs (angiotensin receptor blockers)
• Calcium channel blockers
• (American Society for Hypertension, Spring 2013)
ACE inhibitors– the “prils”
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Captopril (Capoten)(1981)
Enalapril (Vasotec)(1983)
Fosinopril (Monopril)
Lisinopril (Prinivil, Zestril)
Perindopril (Aceon)
Moexipril (Univasc)
Benazepril (Lotensin)
Quinapril (Accupril)
Trandolapril (Mavik)
Ramipril (Altace)
A little refresher on the kidney…
• At any given moment, the kidney is “sensing” the
pressure and volume of blood flow
• Low volume or low BP, the kidney will release renin
from a small area (the JGA) just inside the afferent
arteriole
• Renin (the messenger)→(liver) angiotensin I
→angiotensin II→ via Angiotensin Converting
Enzyme (ACE) (primarily in the pulmonary
circulation)
What does “angie II” do?
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•
She “tenses” your “angios”—vasoconstricts your
arteries, BP increases
She triggers release of “AL”—aldosterone (from
the adrenal cortex to save sodium & H2O in the
kidney—inncreases BP by increasing volume;
excretes potassium)
She increases inflammation in the arteries—
inflammation = plaque rupture
She’s prothrombotic—increased clotting risk
She increases tissue resistance to insulin—
resulting in hyperglycemia* (T2DM, dementia)
She’s a potent growth factor and “remodels”
(enlarges) tissues…
Is remodeling a GOOD WORD?
But not in your heart, vessels, and
kidneys…
• Remodels myocardium and disrupts the
conduction system…Increases the risk of
ventricular dysrrhythmias
• Remodeling increases vascular fibrosis—
hypertension
• Remodeling increases intraglomerular blood
pressure resulting in intraglomerular
hypertension leading to CKD
• BOTTOM LINE?
So, let’s get back to the original story…Who is
ACE and why do we want to inhibit him?
RENIN
ANGIOTENSIN 1
ACE --
ALDOSTERONE
ANGIOTENSIN 2
So if you were an ACE inhibitor, what would you do?
Inhibit ACE? Inhibit the formation AT angiotensin II
Anti-hypertensive agent via vasodilation (due to inhibiting
angiotensin 2) and inhibition of aldosterone (excrete
SODIUM and H20 BUT you save POTASSIUM)—
(as many as 70% of hypertensive patients in U.S. and Canada
may have elevated renin-angiotensin-aldosterone (RAA)
systems Treatment of heart failure by inhibiting reninangiotensin-aldosterone—CHF is a HYPER-RENINEMIC state
Anti-inflammatory
Anti-thrombotic
Hypoglycemic (be careful when starting ACE inhibitors in
diabetics)
Prevents “remodeling” of the heart, vessels, and kidneys
What does “Angie” do in the healthy
kidney?
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•
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•
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Afferent arteriole
(vasodilated via
(prostaglandins)
Blood entering
glomerulus
Glomerulus→filter
Efferent arteriole
(vasoconstricted via
(angiotensin II)
Blood exiting
glomerulus
PG
filter
AT II
Toilet
“Angie, the “prils” and the Diabetic/hypertensive
Kidney…hyperglycemia/HTN
•
Afferent arteriole
( ↑ vasodilation by
( ↑ prostaglandins)
• Blood entering
glomerulus
• Glomerulus→filter
• Efferent arteriole
( ↑ vasoconstriction via
( ↑ angiotensin II)
• Blood exiting
glomerulus
PRILS inhibit ATII/vasodilate the efferent arteriole
Microalbuminuria
**
To summarize…ACE inhibitors are used
for:
• Hypertension (*night time dosing of antihypertensive drugs—dippers (10% decline @ night)
vs. non-dippers)
(American Journal of Kidney Diseases December
2007)
• Prevention of diabetic nephropathy
• Decrease preload and afterload in the patient with
CHF and decrease the remodeling of the heart
To summarize…ACE inhibitors are used
for:
• Decrease the remodeling of the heart in post-MI
patients (clearly beneficial in MI patients 65-74
years of age, but not so clear in patients older
than 75)
• Beneficial in patients with anterior ST-elevation
MIs and in patients with MIs complicated by HF
or significant LV systolic dysfunction with LV
ejection fractions less than 40%
• Decrease the risk of 1st and 2nd myocardial
infarctions in high-risk patients due to antiinflammatory effects
• Stroke prevention
What’s not to love about the ACE
inhibitors?
Side effects, of course…
• Hypotension—start low and go slow
• Hypoglycemia (low blood sugar)—
only in diabetics on antiglycemic
agents; not a problem in
normoglycemic patients
Side effects, of course…
• Hyperkalemia (high potassium) (excreting sodium
and water and retaining potassium)
• Add a thiazide diuretic to the ACE inhibitor
• Capozide (captopril + thiazide)
• Prinizide (lisinopril + thiazide)
• Zestorectic (as above)
• Lotensin HCT (benazepril + hydrochlorothiazide)
Since ACE inhibitors conserve potassium…What
about K+ containing foods?
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•
•
May contribute to hyperkalemia and cardiac
arrhythmias but usually only in patients with
renal insufficiency or in patients who are also
on K+ sparing diuretics such as spironolactone
(Aldactone) and eplerenone (Inspra)
Avoid excessive potassium intake when on the
above drugs or with renal insufficiency
Advise patients to decrease potassium intake
until they can get their potassium checked
Don’t use Bactrim/Septra for UTIs—it also
increases K+ and can lead to life-threatening
arrhythmias
High K+ containing foods
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Potatoes
Prunes
Raisins
Apricots
Bananas
Halibut
Canteloupe
Oranges
Pasta sauce
Health.harvard.edu/heartextra for K+ content of
1,200 foods
Side effects, continued…
• Cough (gender differences with F > M)
• ACE inhibitors block angiotensin converting enzyme; but as
ACE is inhibited, bradykinin goes UP…bradykinin is a potent
bronchoconstrictor
• Women have more bradykinin to begin with, therefore the
gender disparity in the cough
Side effects, continued…
• Life-threatening angioedema (“Does my voice
sound funny to you?”)
• Usually within the first month (but not the
first week); almost all cases within the first
year
• An exception or two
And ONE OTHER THING:ACE inhibitors (category
D) throughout pregnancy
• Why?
• Angiotensin 2 boosts growth factors
• ACE inhibitors inhibit AT2 and inhibit growth;
ACE inhibitors are teratogenic
•
Cooper WO et al. Major congenital malformations after first-trimester exposure to ACE
inhibitors. N Engl J Med 2006 Jun 8; 354:2498-500
“Sartans”—Angiotensin II Receptor
Blockers
• Angiotensin receptor blockers (bypass ACE) and work
by blocking the angiotensin II receptors on tissues
• Who are they? The “Sartan Sisters”…
• losartan—Cozaar
• valsartan—Diovan
• candesartan—Atacand
• irbesartan—Avapro
• telmisartan—Micardis
• olmesartan—Benicar
• azilsartan -- Edarbi
ARBs as a safe haven for the side effects of
the “prils”
• Are the “sartans” safe for patients with a history
of angioedema from the “prils”?
• Appears to be about an 5 to 8% rate of crossreactivity
• Given this limited percentage, switching to an
ARB should not be considered an absolute
contraindication in all patients with ACE-inhibitor
induced angioedema
• Switch cautiously
• (Prescriber’s Letter 2004; 11(7))
ACE inhibitors vs. ARBs
• New and important info from American
Society of Hypertension Spring meeting 2013
• All ACE are = in lowering BP
• ACE = ARB and both relatively safe; ARBs
with less angioedema
• ARBs may be better after MI
• Both protect after strokes
• No evidence to support combing ACE + ARB
Two other drug categories that influence the
renin-angiotensin-aldosterone system
• The direct renin inhibitors -- aliskirin (Tekturna)
• The aldosterone antagonists – spironolactone
(Aldactone) and eplerenone (Inspra)—be careful with
these drugs when used for CHF in combination with
ACE inhibitors; potassium levels can increase to
dangerous levels and life-threatening cardiac
arrhythmias can occur
• Keep checking the potassium levels
• Stacking diuretics—spironolactone (K+ sparing) with
chlorthalidone (Thalitone) or furosemide to decrease
hyperkalemia (American Society of Hypertension,
Spring 2013)
“Olols, alols, ilols”—Beta blockers
• atenolol (Tenormin) (NO, NO. Raises central pressure despite
lowering brachial pressure—increased risk for CV events
including stroke and MI)
• betaxolol (Kerlone)
• bisoprolol (Zebeta)[Monocor]
• carvedilol (Coreg)—Beta Blocker PLUS (alpha one blocker)
• Esmolol (Brevibloc)
• labetalol (Trandate)(Normodyne)—safe during pregnancy
• metoprolol succinate (Toprol XL, Lopressor)[Betaloc]
• nadolol (Corgard)
• nebivolol (Bystolic)—Beta blocker PLUS (boosts NITRIC
OXIDE)
• propranolol (Inderal)(1968)(nonselective)
• sotalol (Betapace)
• timolol (Blocadren)
•
Sympathetic Nervous System (SNS)—fight/flight
system
• In order to understand the beta blockers, a
quick review of the SNS is in order
• Lock and key theory
• Receptors (lock) and neurotransmitters (key)
• Receptors: beta-1, beta-2, alpha-1, alpha-2
receptors regulate the SNS
• Neurotransmitters are the catecholamines:
epinephrine, norepinephrine
• Scenario: Visit Barb in Chicago
Fight/flight response
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Pupils dilate
Heart rate goes up
BP goes up
Bronchioles dilate
Increased blood flow to arms and legs
Hair on arms and neck stands up
Tremor
What do your bowels WANT to do?
But you have a “mother”—your frontal
lobe…
• “Don’t even think about it…if I have told you
once, I have told you twice…”
SNS receptors – beta 1
• Beta 1 receptors—found on cadiac muscle;
epinephrine binds to B1 and increases heart
rate and strength of contraction
(+chronotropic and + inotropic)
• Beta blockers that JUST block the beta 1
receptors are called cardioselective
Cardioselective beta blockers block the B1
receptors
• Cardioselective beta blockers reduce cardiac
output, heart rate falls (10-15%), blood
pressure falls
• Workload of the heart decreases—used to
treat angina, SVT, post-MI to protect the
heart from remodeling and to reduce heart
rate
• EXAMPLES: atenolol (Tenormin), metoprolol
(Lopressor), betaxolol (Kerlone); bisoprolol
(Zebeta), nebivolol (Bystolic)@ doses <10 mg)
SNS receptors—beta 2
• B2 receptors—found on skeletal muscle, the
bronchioles, large arteries of arms and legs;
when epinephrine binds to B2 the bronchioles
of the lugns dilate, the large arteries of the
arms and legs vasodilate, and hands may
exhibit a slight tremor (skeletal muscle
tremor), and piloerection occurs (hairs stand
up on back of neck and arms)
Non-selective beta blockers block both
beta-1 and beta-2 receptors
• Blocking beta-2?—block skeletal muscle
receptors and decrease the tremor, can cause
bronchoconstriction (problem w/ COPD patients
and asthmatics); can cause vasoconstriction of
the large arteries of the legs—problem with
diabetics or anyone with PAD
• Non-selective beta blockers-- propranolol
(Inderal), nadolol (Corgard), timolol (Blocadren),
carvedilol (Coreg)
• Use CARDIOSELECTIVE beta blockers for diabetics,
asthmatics, and COPD patients
Beta blockers…other properties
• Water-soluble? (low lipophilicity)
atenolol (Tenormin), nadolol (Corgard),
labetalol (Trandate), nebivolol (Bystolic)
• Lipid-soluble? (high lipophilicity--cross the
blood brain barrier)—CNS side effects—
anhedonia (the “Blahs”)—BUT…the lipidsoluble can also “calm down” the brain
• propranolol (Inderal), timolol (Blocadren),
metoprolol (Lopressor, Toprol XL), pindolol
• All of the others are moderately lipophilic
Functions of beta-blockers
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Decrease palpitations during panic attacks
Decrease heart rate in atrial fib
Decrease essential tremors
Decrease situational anxiety
Decrease symptoms of PTSD
Decrease HR in patients with Grave’s disease
Decrease portal pressure in patients with cirrhosis and
esophageal varices
• Decrease migraine headaches by 50% in 50% of the patients
(mechanism unknown)
• Pre-operative beta-blockers—non cardiac surgeries—high risk
pts
Beta Blockers
• Beta blockers have become obsolete for CV
protection. Their “era” did not include
percutaneous coronary interventions (PCI),
statins, antiplatelet therapies, ACE – or ARBs.
• Adding beta blockers to current therapies does
not improve outcomes (REACH registry, JAMA
2012; 309;1340)
• EXCEPTION: Beta blockers still used for
decreasing remodeling of heart in patients with
systolic HF—use the beta blocker PLUS drugs
Beta-blocker eye drops for glaucoma—second-line therapy-Lower intraocular pressure by 20-25% with once or twice daily
dosing
• timolol (Timoptic) [Betimol], ,
levobunolol (Betagan), carteolol
(Ocupress), metipranolol
(Optipranolol)
• Highly lipid-soluble and cross the
blood-brain barrier
• Can cause bradycardia and
anhedonia
• So what can you use instead?
The “oprosts”—first line therapy for
glaucoma
• The “oprosts”—bimatoprost (Lumigan)(Latisse
for eyelashes), latanoprost (Xalatan),
travoprost (Travatan)
• And, unoprostone (Rescula)
• Prostaglandin analogues—lower Intraocular
pressure by 25-30%
• *Latisse for thick, long eyelashes
Calcium Channel Blockers; 2
categories…the nondihydropyridines
1) Verapamil (Isoptin SR, Verelan and
Verelan PM, Calan and Calan SR,
Covera-HS)—block calcium
channels primarily on the coronary
vessels and the AV node—
increasing blood flow to the heart
and decreasing impulses through
the AV node—used to decrease
workload of heart and slow the
heart rate; HTN, angina, atrial fib,
renoprotective
Negative inotropic effect—avoid in
patients with CHF
• Calcium channels in bowels
(elderly)—severe constipation
2nd drug in the non-dihydropyridine
category
• Diltiazem—Cardizem LA and CD,
Dilacor XR, Tiazac—dilates calcium
channels on the coronary arteries
and peripheral vessel calcium
channels; decreases impulse
transmission from atrium to
ventricle
• Negative inotropic effects—avoid
in CHF patients
Clinical uses—
Atrial fibrillation, Hypertension,
Angina, Vasospasm,
renoprotective
Less constipation than verapamil
2nd category—the Dihydropyridines or the
“DIPINES”—Peripheral vessel calcium channel
blockers
• Amlodipine (Norvasc)
• Felodipine (Plendil)**
• Nifedipine (Procardia XL,
Adalat)
• Nicardipine (Cardene)
• Isradipine (Dynacirc)
• Nisoldipine (Sular)
• Clevidipine (Cleviprex) for IV
use vs. esmolol or IV
nicardipine)
Clinical uses of the “dipines”…
• Hypertension
• Vasospasm—Prinzmetal’s angina, Raynaud’s
phenomenon, cocaine-induced vasospasms
• Ureteral spasms in patients with small kidney
stones
• “male contraceptive”
Side effects of CCBs…
• Verapamil—significant constipation; lots of drug
interactions
• Dipines—significant peripheral vasodilation with
headaches; hypotension, and peripheral edema
(swollen feet—pedal edema; (Plendil)
• Diltiazem—less significant constipation than
Verapamil
• All CCBs inhibit calcium-induced contraction of the
LES, resulting in sphincter relaxation and acid reflux
The “Statin Sisters”…
Who are they?
• lovastatin (Mevacor)
• simvastatin (Zocor)
• atorvastatin (Lipitor)
• fluvastatin (Lescol)
• pravastatin (Pravachol)
• rosuvastatin (Crestor)
• pitavastatin (Livalo)
The “Statin Sisters”…what do they do?
• Inhibit an enzyme in the liver responsible for the
production of the LDL-cholesterol; works primarily at
night to reduce LDL, so the “statins” work the best
when taken before bedtime (exceptions to the rule—
atorvastatin/Lipitor and rosuvastatin/Crestor)
LDL-cholesterol
• LDL (low density lipoprotein) is the most atherogenic
of the cholesterol bunch and puts fat right smack dab
into all of the arterial walls; therefore, statins
decrease LDL-cholesterol and reduce the risk of
coronary artery disease, peripheral vascular disease,
renovascular disease and cerebrovascular disease;
they also increase survival rates and improve the
quality and quantity of life
LDL-lowering effects
• If so, how low should your LDL go?
• Atorvastatin/Lipitor 10 mg
= 39%
• Fluvastatin/Lescol 40 mg BID
= 36%
• Fluvastatin XL/Lescol 80 mg
= 35%
• Lovastatin /Mevacor 40 mg
= 31%
• Pitavastatin/Livalo 2 mg
= 36%
• Rosuvastatin/Crestor 5 mg
= 45%
• Simvastatin/Zocor 20 mg
= 38%
(Circulation 2004;110:227-239)
LDL guidelines
• Guidelines—with CAD or a risk equivalent
(PAD, TIA, stroke, abdominal aneurysm), the
LDL should be ~70 mg/dL (2.0 mmol/L or even
lower, perhaps 1.8 mmol/L)
• For the rest of us with other risk factors—100
mg/dL (<2.85 mmol/L)
• Unless you’re perfect…--130 mg/dL (<3.37
mmol/L)
• Particle size is also important (LDL-P)—small
and dense (B pattern) vs. large and loose (A
pattern)
What do the statins do?
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Decrease total cholesterol
Decrease LDL-cholesterol
Decrease oxidation of LDL-cholesterol
Shrink plaques including plaques in the renal artery and
improve blood flow to vital organs
Stabilize fatty plaques and prevent plaques from rupturing (an
inflamed fatty plaque ruptures in a coronary artery triggers
the coagulation cascade and clot formation)
Prevent the formation of new plaques in the renal and other
arteries
Decrease mesangial proliferation in glomerulus and reduce
intraglomerular hypertension
Decrease vascular inflammation
Boost neurogenesis (more later)
Combinations with statins
• Atorvastatin and amlodipine for HTN – Caduet
• Lovastatin and niacin (to lower TG)—Advicor
• Simvastatin and ezetimibe (Zetia) which blocks
cholesterol absorption in GI tract—Vytorin
• Simvastatin and niacine – Simcor
SIDE EFFECTS
• Myalgias **(other causes in elderly patients…)
• About 1/20 patients experience muscle pain or weakness
• Myositis; rhabdomyolysis (rare) (ASA is 100x more likely
to cause a fatal side effect than taking a statin)
• Simvastatin at higher doses is the riskiest “statin” for
rhabdomyolysis—never use the 80 mg dose; lots of drug
interactions; do NOT drink green tea or eat grapefruit or
drink grapefruit juice with this statin
• How about adding CoQ10 for muscle aches and pains?
take 50-100 mg/day of CoQ10
• Either switch statins, lower the dose of statins, consider
every other day dosing
The #1 oral drug for Type 2 DM
• Metformin (Glucophage, Glucophage XR, Fortamet,
Glumetza, Riomet ) does not have any direct effect on
insulin release from the pancreas—doesn’t require
insulin to work
• Primary action: DECREASE hepatic glucose production;
also, decreases glucose absorption via the GI tract, and
may increase sensitivity of insulin receptors
• Problem? GI blues (nighttime dosing/give with food),
need functioning organs--kidneys and heart especially
(check serum creatinine before starting metformin)
• Se Creatinine--Cut-off is 1.4 (50-90 mmol/L) in females
and 1.5 (70-120 mmol/L) in males;
Metformin (Glucophage)
• Cardiovascular benefits: lowers BP, increases
HDL, lowers LDL;
• Metformin and breast and prostate cancer
reduction (54%)—Diabetes Care December
2010
• Metformin and slowing the aging process
• Metformin and neurogenesis
• Metformin and anti-psychotic drugs
• Metformin and HD-Prednisone
• Metformin and PCOS
Downside to Metformin
• B12 deficiency
• Increase in BFR (basal flatal rate)
• Diarrhea (take with food; switch to Glumetza)
Incretin mimetics – the “tides”
• incretins are responsible for approx. 60% of the post-meal
insulin secretion, but the action of the incretins is impaired in
diabetics) ; Acts at the GLP-1 receptor, promoting insulin
release
• Exenatide (Byetta)(2005)—isolated from saliva of a Gila
Monster
• Bydureon (Byetta once a week); Better than Byetta as it
reduces HgA1C 1.6% vs. 0.9% for Byetta; Nausea 14% vs.
Byetta at 35%
• Indications? Type 2 diabetics who are already receiving
metformin, a sulfonylurea, or both and do not have optimal
control
• Weight loss is a + side effect (due to slowing of gastric
emptying and “feeling full”)
Incretin mimetics
• 2nd generation—liraglutide (Victoza)—QD, less
nausea
• PANCREATITIS!
• The “old” face of Victoza—the BUTTER
QUEEN, Paula Deen—she was dumped due to
her legal problems
The “gliptins”
• Weight neutral
• inhibit enzymes in the intestine responsible for
breaking down incretins; incretins potentiate
insulin release
• Sitagliptin (Januvia)
• Saxagliptin (Onglyza)
• Linagliptin (Tradjenta)
• Janumet (Januvia + metformin)
• Kombiglyze (onglyza + metformin)
• Pancreatitis!
OLD Drugs for Type 2 Diabetes
• Sulfonylureas—glimepiride (Amaryl); glipizide,
glyburide
• Major side effects? Weight gain and
hypoglycemia
• Boost release of insulin from remaining islet
cells—high risk of hypoglycemia…use with
caution in the elderly
OLD Drugs…are these even worth using anymore?
Considered third-line therapy…cheap drugs
• Oral sulfonylureas—Glipizide (Glucotrol) and
glyburide (Diabeta, Micronase, Glynase) and
glimipiride (Amaryl)…
• Increase the secretion of insulin from the
pancreas and increase receptor sensitivity
• Problem? Weight gain, hypoglycemia,
increased cardiovascular risk
• glimipiride (Amaryl)—safest use in elderly-decreased incidence of hypoglycemia
(glyburide is NOT safe in the elderly—too
much hypoglycemia)
The “afils”—the Pfizer Riser aka sildenafil (Viagra) and
friends, for erectile dysfunction
• Prior to November 1998
• PDE5 inhibitors which in a round about way boost
nitric oxide—potent vasodilator primarily below the
belt
• What are the causes of ED?
• Athero, neuro, drugs, ↓testo, psychological (the
stamp test)
• Sildenafil (Viagra)(Revatio for pulmonary
hypertension)
• Vardenafil (Levitra, Staxyn)
• Tadalafil (Cialis)—the “weekend warrior” (Adcirca for
PH)
• Can use in patients with stable CHD
Can’t use with nitroglycerin…
•
•
•
•
•
•
•
•
•
“When was your last dose of Viagra?
Can’t use Viagra or Levitra within 24 hours of receiving NTG;
Cialis within 36-48 hours
Side effects
Hypotension
Headaches
GERD
Blue vision
Priapism
A surprise side effect of the “afils”…
Sexually transmitted diseases have increased by over 300% in
the over 60 crowd since the release of Viagra…
•
•
•
•
•
•
•
More sex
No pregnancy worries
Swingin’ singles
Who cares what the neighbors think?
Swimming pools and golf courses
Can you have a heart attack during sex?
Only if…
Drugs and reducing the size of the
“prostrate”
• Alpha one receptors are located on the smooth
muscle cells of the prostate
• Enlarge with aging (BPH)
• Incessant testosterone stimulation over a lifetime
also increases the size of the prostate
• Alpha-one blockers
Tamsulosin (Flomax)
Silodosin (Rapaflo)
Doxazosin (Cardura)
Drugs and reducing the size of the
“prostrate”
• 5-α reductase inhibitors to prevent the
conversion of testosterone to
dihydrotestosterone (DHT)—a more potent
agonist for prostate growth (not only reduce size
of prostate but also decrease the risk of prostate
cancer)
• Dutasteride (Avodart)
Finasteride (Proscar)
• Vitamin D for the prostate
Tamsulosin (Flomax) in women
• NOT to be confused with Flonase
• Can use in women to improve symptoms due
to bladder outlet obstruction
• Help increase urine flow by relaxing the
bladder neck and urethra
• Avoid all decongestants which can lead to
increase tone in the bladder neck and make
symptoms worse + urinary retention
Alpha-one blockers, cataract surgery,
and floppy iris syndrome—
• Who wudda thunk? If you or your patients are going to
have cataract surgery:
• Let the ophthalmologist know if you have EVER taken an
alpha-one blocker or if currently on one (Prescriber’s Letter,
May 2012)
• A history of taking an alpha-one blocker can cause serious
complications (even years later) during cataract
surgery…(atrophy of muscle that holds the iris)
• Procedure is much harder with a floppy iris
• Tamsulosin (Flomax) is the biggest offender
• Silodosin (Rapaflo), Doxazocin (Cardura XL), beta-blocker
with alpha-one blocking properties (carvedilol/Coreg),
labetalol (Trandate), risperidone…
The bisphosphonates for osteoporosis
• The “dronates” for osteoporosis
• Alendronate [Fosavance] (Fosamax + D),
Risedronate (Actonel), ibandronate (Boniva)
• Zoledronic acid (Zometa)– lower dose for
osteoporosis—brand name Reclast [Aclasta]
• Trigger apoptosis of osteoclasts
• Osteoblasts continue to build bone matrix but
without remodeling
• Any downside? Osteonecrosis of jaw
• Subtrochanteric femur fractures? Very low risk
• Can the patient FOLLOW directions with the oral
bisphosphonates?
How long should a patient stay on
bisphosphonates?
• May 9, 2012 online New England Journal of Medicine
• Discuss w/ HCP about staying on longer than 5 years
• May not offer much additional fracture protection
beyond this time period—women who stayed on drugs
had similar fx rates to women who switched to placebo
• Consider continuing drugs in women with low bonemineral density at femoral neck of hip (T-score below 2.5) and in women w/ existing vertebral fx who have T
scores below -2.0.
The “prazoles”—Proton Pump
Inhibitors*
•
•
•
•
•
•
•
Omeprazole (Prilosec)(first released as Losec in U.S.)
Lansoprazole (Prevacid)
DeXlansoprazole (old-Kapidex)(new-Dexilant)
Rabeprazole (Aciphex) [Pariet]
Pantoprazole (Protonix) [Pantoloc]
Esomeprazole (Nexium)-- “the purple pill”
*BIG Exception: Aripiprazole/Abilify—antipsychotic—a
dopamine system stabilizer
The “prazoles”—Proton Pump
Inhibitors
• MOA—Inhibition of the proton pump at the lumenal
surface of the stomach…especially after a meal
H+, Intrinsic Factor-B12
PPIs work here
Lumenal surface
Parietal cell
Basilar surface
H2 receptors
H2
H2 blockers work here
The “prazoles”
•
•
•
•
•
•
•
•
•
Work within 4-7 days to reduce all acid in the stomach; take
30’-60’ before the first meal of the day or before the dinner
meal (especially if nocturnal GERD is a problem)
BUT long-term suppression of acid has been shown to have
significant side effects:
Increased risk of hospital-acquired pneumonia and
community acquired pneumonia (PPI use might be associated
with 33,000 preventable deaths due to pneumonia in
hospitalized patients)(Herzig)
Increased food-borne illness
Increased risk of osteopenia/osteoporosis with long-term use
(in smokers)
Increased risk of B12 deficiency due to blocking the release of
intrinsic factor
Long-term use and iron deficiency anemia
Drug interaction with clopidogrel (Plavix)
Increased risk of Clostridium difficile
**Use of PPIs and clostridium difficile
• Daily PPI use associated with an estimated 74%
increase in Clostridium difficile infection
• People using PPIs while being treated for C. difficile had
a 42 % increased risk of recurrence Archives of Internal
Medicine 2010;170:784-790, 772-778.
• Should all patients be put on PPIs upon admission to
the hospital? NO, it’s NOT necessary…ICU patients?
YES, because they have been shown to have the
highest risk for a GI bleed from stress-induced gastric
ulcers; but not for every bunionectomy,
hemorrhoidectomy, or tonsillectomy
PPIs and Inappropriate subscribing in
hospital patients
• Reid M et all. Inappropriate prescribing of
proton pump inhibitors in hospitalized
patients. J Hosp Med 2012 May/Jun 7:421
• Herzig SJ et al. Acid-suppressive medication
use and the risk for nosocomial
gastrointestinal tract bleeding. Arch Intern
Med 2011 Jun 13;171:991.
The “tidines” (H2 blockers)
• Best to give at night—decrease vagally-induced histamine
release in stomach (double the OTC dose for best results)
• Use PEPCID in patients taking low-dose aspirin therapy for
heart disease prevention
•
•
Cimetidine--Tagamet—can cause delirium in the elderly;
increases the bioavailability of many drugs—beta blockers
and bradycardia, morphine and bradypnea
Other H2 blockers—Ranitidine (Zantac); Nizatidine (Axid);
Famotidine (Pepcid)—safest and most effective
The antifungals--the “azoles”
75% of all women will have at least one vaginal yeast
infection in their life…
• Miconazole (Monistat-7)
• Tioconazole (Vagistat)
• Clotrimazole (Mycelex)
• Fluconazole (Diflucan)
• Itraconazole (Sporanox)
• Ketoconazole (Nizoral)
• Voriconazole (Vfend)
• Posaconazole (Noxafil)—newest of the bunch (HIV)
• DRUG INTERACTIONS
• “You have a yeast infection…”
The antiherpetics—the “cy{i}clovirs”
•
•
•
•
Acyclovir (Zovirax)
Famciclovir (Famvir)
Valacyclovir (Valtrex)
Ganciclovir (Cytovene) – CMV retinitis in HIV
patients; CMV pneumonitis in transplant
patients
The antiherpetics—Varicella Zoster Virus
• Acyclovir (Zovirax)(4000/d)
• Famciclovir (Famvir)(750/d)
• Valacyclovir (Valtrex)(3000/d)
Tx must be started within 48-72 hours after the first signs of a
rash appear.
• +Prednisone
• PREVENTION?
Zostavax the “SHINGLES vaccine”
• Zostavax (Merck) to reduce the incidence of
Herpes Zoster (shingles/Hell’s fire) in people
over 50 (14 x stronger than Varivax)(risk
reduction—50%); reduces severity and
decreases post-herpetic neuralgia
DEPRESSION
“The FDA this week approved the first-ever
transdermal patch for the treatment of
depression. Simply remove the backing and
press the patch firmly over your mother’s
mouth.” Tina Fey, on Saturday Night Live (March 2006)
Drugs for depression
• Serotonin Reuptake Inhibitors (SRIs)—
fluoxetine (Prozac), sertraline (Zoloft),
paroxetine (Paxil)(Seroxat), citalopram
(Celexa), escitalopram (Lexapro)(Cipralax)
• Serotonin Norepinephrine Reuptake
Inhibitors (SNRIs)—venlafaxine (Effexor),
desvenlafaxine (Pristiq), duloxetine
(Cymbalta)
Drugs for depression
• The “other” category—mirtazapine (Remeron),
buproprion (Wellbutrin)
• “old” antidepressants (used primarily for
neuropathic pain)—Tricyclic Antidepressants
(TCAs) such as amitriptyline (Elavil),
nortriptyline (Norpramin, Pamelor)—are
actually SNRIs as they inhibit the re-uptake of
both serotonin and norepinephrine;
• Drugs that block the reuptake of serotonin and
norepinephrine can be used for neuropathic
pain (duloxetine/Cymbalta and amitriptyline
(Elavil) are commonly used for neuropathic pain;
• Milnacipran HCl (Savella, 2009)—SNRI approved
for the management of fibromyalgia (not
approved for kids)
Is there a better SSRI?
• Top two are sertraline and escitalopram (Lancet, Jan. 09)
• Sertraline/Zoloft—short half life; great for use in the elderly;
few drug interactions—(cheapest)
• Escitalopram/Lexapro/Cipralex—few drug interactions, not as
many as Paxil
• Citalopram/Celexa (not to be confused with Celebrex)—very
few drug interactions
• Fluoxetine/Prozac—half-life is too long for elderly
• Paroxetine/Paxil—many, many drug interactions and not good
for use in the elderly; is the most anti-cholinergic of all
(interferes with cholinesterase inhibitors used for Alzheimer’s
disease) and can cause anti-cholinergic side effects in elderly
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)
98
SSRIs—a major side effect
• Boost serotonin
• Makes ya’ happy
• Blocks dopamine though and dopamine in the brain
is responsible for sexual functioning (among other
things)
• Decreases libido, anorgasmia (50-75% of patients)
• However, if premature ejaculation is your problem,
the SSRIs are for you
I’m here for my SSRI prescription…
• Low serotonin is part of the problem with
patients with premature ejaculation
Other side effects of the SSRIs
• Bruxism (due to low dopamine)--morning headaches, jaw
pain, a clicking sound in your jaw, sensitive teeth, and
damaged teeth and crowns. Permanent long-term effects can
include temporomandibular disorder, a painful condition
affecting the jaw and facial muscles, and periodontal disease.
• RLS (restless leg syndrome) due to low dopamine (check iron
levels) (Rx? Dopamine agonists—ropinirole (Requip) or
pramipexole (Mirapex) (p.s. dopamine and addiction)
• SSRIs inhibit platelet aggregation—increased risk for GI bleed
• SSRIs cause hyponatremia—increased risk for delirium,
confusion, and seizures in the elderly
A few more notes on antidepressants
• Give them at least 8 weeks to work—WHY?
Neurogenesis; stay on them for 9-12 months after
improvement in all activities of daily living
• Switching from one SSRI to another SSRI is an
option—another 25% can show benefit by a switch to
another drug in the same class or another
antidepressent in another class
• Augmentation strategies—add buproprion
(Wellbutrin) or buspirone (Buspar), Lithium,
mirtazepine (Remeron)
• Add T3 thyroid hormone (Cytomel)
• Add aripiprazole (Abilify) or other anti-psychotics
The antibiotics—the fluoroquinolones, the
“floxacins”…
•
•
•
•
Ciprofloxacin (Cipro)*(2) (↑ INR)
Lomefloxacin (Maxaquin)(2)
Norfloxacin (Noroxin)*(2)
Ofloxacin (Floxin)(2)*
*uncomplicated UTI if resistance to TMP/SMX is ≥20%
•
•
•
•
Levofloxacin (Levaquin) (3)—too broad spectrum for UTI
Gemifloxacin (Factive)(4)
Moxifloxacin (Avelox)(4)—effective against TB
WARNINGS: C. difficile after the quinolones…
Acute tendonitis in elderly and patients on
corticosteroids
The antibiotics—the macrolides
• Erythromycin—dangerous with many other
drugs due to prolongation of the QT interval;
low-dose increases bowel motility in patients
with gastroparesis
• Azithromycin (Zithromax)—Z-pack (don’t
take with food)
• Clarithromycin (Biaxcin)—take with food!
• Clarithromycin and digoxin toxicity
It’s a “MAB, MAB, MAB” (monoclonal
antibodies) world—immune system
• Infliximab (Remicade)—targeted against TNF-α, the
culprit in Crohn’s disease, Ulcerative colitis,
Rheumatoid Arthritis, psoriatic arthritis; TB and
Hepatitis B testing prior to use
• Adalimumab (Humira)—as above
• certolizumab pegol (Cimzia)—as above
• Golimumab (Simponi)—as above
• Palivizumab (Synagis)—RSV protection for developing
lungs 34-week neonates have just 52% of the
calculated lung volume of full-term infants at birth)
• Omalizumab (Xolair)—mab to IgE
• Belimumab (Benlysta)—SLE (targets B cell activating
factor)
• Tocilizumab (Actemra)
MABs for tumors
• Trastuzumab (Herceptin)—HER2-neu+ Breast
cancers; when given in early stages, prognosis
improves significantly
• Rituximab (Rituxan)—targets CD 20 receptor
on B lymphocytes; used for Non Hodgkin’s
Lymphoma
• Cetuximab (Erbitux)—colon cancer (Martha
Stewart)
• Alemtuzumab (Campath)
• +++++++ more….
It’s a “MAB, MAB, MAB” world
• Bevacizumab (Avastin)—inhibits
angiogenesis; used to inhibit tumor
growth; used to decrease neovascular
growth in the retina; glioblastoma
multiforme (with a tyrosine kinase
inhibitor)
• Abciximab (Reopro)—inhibits platelet
aggregation
The tyrosine kinase inhibitors—the
“nibs”
• Tyrosine kinases act as growth-stimulating factors, and
inhibiting them directly by inhibiting their signal is another
way of zapping the growth of cancer cells
• Imatinib (Gleevec)(2001)—CML (Philadephia chromosome +
t9:20)(complete cytogenetic remissions in 70%)
• Gefitinib (Iressa)—lung cancer (investigational for other
cancers)
• Erlotinib (Tarceva)*--NSCLC
• Crizotinib (Xalkori)—NSCLC w/ specific gene mutation
• Dasatinib (Sprycel)—CML
• Nilotinib (Tasigna)(2007)—CML w/better results and for
resistance to Gleevec)
• Vandetanib (Caprelsa) – medullary thyroid cancer
• *reduced cravings for alcohol (gene in fruit flies, called
happyhour is reduced with erlotinib and gefitinib)
The tyrosine kinase inhibitors—the
“nibs”
• Sunitinib (Sutent)—renal cell carcinoma
• Lapatinib (Tykerb)—HER2/neu+ breast cancer if
the breast cancer doesn’t respond to
trastuzumab
• Sorafenib (Nexavar)—survival benefit in patients
with hepatocellular carcinoma (Journal Watch
Oncology/Hematology 23 Jul 2008); renal cell carcinoma
• Tofacitinib citrate (Xeljanz)—moderate to severe
RA that has not responded to methotrexate (test
for TB before prescribing)
• Vemurafenib (Zelboraf)—metastatic melanoma
5-HT3 (serotonin) receptors and N & V
• 5-HT3 in the CTZ (chemoreceptor trigger zone
of the brain stem) is responsible for vomiting
from chemo and post-anesthesia
• 5-HT3 in the duodenum is responsible for
nausea– “the organ of nausea”
Serotonin antagonists
for 5-HT3
• The “setrons” for chemotherapy, reduced risk of anticipatory
nausea and vomiting, postanesthesia-induced, and migraineinduced nausea and vomiting, morning sickness, and oral
rehydration in kids
• Granisetron (Kytril)
• Ondansetron (Zofran, and generic)—also used for acute n and
v
• Dolasetron (Anzemet)
• Tropisetron (Navoban) (add on to risperidone for chronic
schizophrenia)(Noroozian )
• Palonesetron HCl (Aloxi)—long acting
And last, but not least, an all in one pill for
the stress of being a wonderful nurse…
THANK YOU…and remember…
• “Never under any circumstances take a
sleeping pill and a laxative on the same night.”
• Barb Bancroft, RN, MSN, PNP
• www.barbbancroft.com
• [email protected]
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• Archer SL, Michelakis ED. Phosphodiesterase type 5 inhibitors for
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on serum thyroid hormone profiles in hypothyroid patients. Clin
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• Bonakdar RA. Herb-drug interactions: what physicians need to know.
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• Codario RA. Do we use an ACE, an ARB, or both? What clinical trials tell us.
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• Cramer C et al. Use of statins and incidence of dementia and cognitive
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• DeDea L. How do the dihydropyridine and nondihydropyridine CCBs differ?
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