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 11,000…• 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, HAART (highly active anti-retroviral therapy) for AIDS patients, and Combined Oral Contraceptives

• Side effect?

Vitamins and herbal supplements….

• Vitamin supplements—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)

• Calcium supplements, iron supplements, soy supplements interfere with levothyroxine (Synthroid)

Speaking of levothyroxine…

• Nighttime dosing may be more efficacious than daytime dosing

• Most important—take at the same time of day• 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• How about the “Gs”?? • 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--??• green tea** (a potentially harmful interaction is with green

tea and simvastatin—the higher the dose of simvastatin the greater the risk of rhabdomyolysis with green tea)

Plus…• Over 10,000 over-the-counter (OTC) drugs that can

wreak havoc—examples: 1) cimetidine (Tagamet)—for heartburn 2) acetaminophen (Tylenol) is in over 300 over-the-

counter 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• Aspirin’s principal use today is in low doses as a platelet

inhibitor• Bayer Select Pain Relief is ibuprofen

Non-selective NSAIDs• “profens” Ibuprofen (Advil, Motrin, etc) PO—200 mg = to 650 of ASA; 400 mg

superior w/ longer duration of ASA; 400 mg comparable to acetaminophen/codeine combination without the constipation w/ codeine; interferes with ASA cardiovascular prophylaxis; take 2 hours after aspirin

IV ibuprofen is Caldolor (400-800 mg q 6h) Flubiprofen (Ansaid)—osteoarthritis, RA Ketoprofen• Diclofenac (Cataflam, Voltaren, Arthrotec (combined with

misoprostol to decrease GI toxicity); Flector as a topical patch for minor trauma; gel (Voltaren 1%) for osteoarthritis of knees and hands)

• Ketorolac IM, IV, PO—5 –day use only due to GI toxicity; comparable to moderate doses of morphine

More on NSAIDS• Naproxen (Naprosyn, others)• Naproxen sodium (Anaprox)—prescription; 550 mg is

superior to 650 of ASA with longer duration of action• Naproxen sodium OTC (Aleve)—440 mg comparable to

400 mg of ibuprofen with longer duration• Celecoxib (Celebrex)—less effective than full doses of

naproxen or ibuprofen; less GI toxicity; no platelet effects

• All NSAIDS can decrease renal blood flow—may cause hypertension; don’t use in CHF patients; liver toxicity especially with diclofenac

Medical Letter, April 2010 (volume 8, issue 92)

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

First line therapy for reducing blood pressure—the “prils”

• 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)

• Angiotensin II triggers the release of “AL” (aldosterone) from the adrenal cortex

What does “angie II” do? • She “tenses” your “angios”—

vasoconstricts your arteries• She triggers release of “AL”—

aldosterone (from the adrenal cortex to save sodium & H2O in the kidney)

• She increases inflammation in the arteries

• She’s prothrombotic• She increases tissue resistance to insulin• She’s a potent growth factor and

“remodels tissues”…

So if you were an ACE inhibitor, what would you do? Inhibit ACE? Inhibit the formation AT angiotensin II

1. 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. may have elevated RAA systems (renin-angiotensin-aldosterone)

1. Treatment of heart failure by inhibiting renin-angiotensin-aldosterone—CHF is a HYPER-RENINEMIC state

2. Anti-inflammatory3. Anti-thrombotic4. Hypoglycemic (be careful when starting ACE inhibitors in

diabetics)5. Decrease growth of tissues or “remodeling” Is “remodeling” a good word? Hmmmmm….

Remodeling and angiotensin…

• 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?

“Angie” and the healthy kidney…

• Afferent arteriole (vasodilated via (prostaglandins)• Blood entering glomerulus• Glomerulus→filter• Efferent arteriole (vasoconstricted via (angiotensin II)• Blood exiting glomerulus

PG

AT II

Toilet

filter

“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 glomerulusPRILS inhibit ATII/vasodilate the efferent arteriole

Microalbuminuria**

To summarize…ACE inhibitors are used for:

• Hypertension (*night time dosing of anti-hypertensive drugs—dippers (10% decline @ night) vs. non-dippers)

(American Journal of Kidney Diseases December 2007)

• A new, interesting theory of hypertension—CMV infection in epithelial cells results in excess release of renin and angiotensin II, excess production of proinflammatory cytokines, and development of intimal hyperplasia and athersclerosis

To summarize…ACE inhibitors are used for:

• Decrease the remodeling of the heart in heart failure patients and 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 anti-inflammatory effects

• Stroke prevention• Prevention of diabetic nephropathy• Decrease insulin resistance and reduce the risk of

progression to type 2 diabetes

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)• Vaseretic (enalapril +thiazide)• Prinizide (lisinopril + thiazide)• Zestorectic (as above)• Lotensin HCT (benazepril + hydrochlorothiazide)

What about K+ containing foods?

• May also contribute to hyperkalemia and cardiac arrhythmias but usually only in patients with renal insufficiency so or in patients who are also on K+ sparing diuretics such as spironolactone (Aldactone) and eprelrenone (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

High K+ containing foods

• Potatoes• Prunes• Raisins• Apricots • Bananas• Halibut• Canteloupe• Oranges • Pasta sauce• Health.harvard.edu/heartextra for K+ content

of 1,200 foods

Side effects, of course…

• Cough (gender differences)• 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

• Rx? Stop drug; can try a nonspecific antitussive; consider indocin, baclofen, aspirin, or sulindac (Clinoril) if the cough persists (Rose BD)

Side effects, of course…

• Cough (gender differences)• Life-threatening angioedema (“Does my

voice sound funny to you?”)

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• substitute if cough is unbearable on the ACE inhibitors

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 cross-reactivity

• 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))

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

“Olols, alols, ilols”—Beta blockers• atenolol (Tenormin)• betaxolol (Kerlone)• bisoprolol (Zebeta)• carvedilol (Coreg) • Esmolol (Brevibloc)• labetalol (Trandate)(Normodyne)—safe during

pregnancy• metoprolol succinate (Toprol XL, Lopressor)• nadolol (Corgard)• nebivolol (Bystolic)• 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

• 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 and actions

• B1—found on heart muscle; epinephrine binds to B1 and increases heart rate and strength of contraction (chronotropic and inotropic)

• B2—skeletal muscle (tremor), bronchioles of the lungs (bronchodilation), large arteries of the legs (vasodilation), piloerection (hairs stand up on back of neck and arms)

Alpha receptors and actions

• α1—arteriole smooth muscle (vasoconstriction to increase BP) (alpha 1 receptors are also located on the prostate gland)

• α2 (hypothalamus)—regulates CNS output of SNS

• Drugs can ‘selectively’ modulate the various receptors

Same slide as the last one—throw in alpha blockers

• α1—arteriole smooth muscle (vasoconstriction to increase BP) (alpha 1 are also located on the prostate gland)—the “osins”—(ALPHA-1 BLOCKERS including tamsulosin/Flomax, silodosin/Rapaflo; terazosin (Hytrin), doxazosin/Cardura)

• Α2—hypothalamus—regulate CNS output of the SNS—clonidine/Catapres (consider this drug for women on Tamoxifen having hot flashes)

Beta one receptors and cardioselective beta blockers

• B1—found on heart muscle; epinephrine binds to B1 and increases heart rate and strength of contraction (chronotropic and inotropic)—– cardiac output falls, heart rate falls (10-15%), blood pressure falls, workload of the heart decreases—angina, SVT, post-MI to protect the heart from remodeling and to reduce heart rate

atenolol (Tenormin), metoprolol (Lopressor), betaxolol (Kerlone); bisoprolol (Zebeta), nebivolol (Bystolic)@ doses <10 mg)

• B2—skeletal muscle (tremor), bronchioles of the lungs (bronchodilation), large arteries of the legs (vasodilation), piloerection (hairs stand up on back of neck and arms)—NONSELECTIVE BETA BLOCKERS

Why don’t we pick just any old beta blocker? Because the non-cardioselective beta blockers block both the B1 AND B2 receptors and can wreak havoc in certain patient populations

• B2 blockade can cause bronchoconstriction and exacerbate COPD & asthma as well as vasoconstrict the femoral artery {exacerbate [peripheral artery disease}

propranolol (Inderal), nadolol (Corgard), timolol (Blocadren), carvedilol (Coreg)

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 lipid-soluble 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• Decrease palpitations during panic attacks• Decrease heart rate in atrial fib• Decrease essential tremors• Decrease situational anxiety• Decrease symptoms of PTSD • Episodic dyscontrol syndrome• 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-blocker eye drops for glaucoma—second-line therapy--Lower intraocular pressure by 20-25% with once or twice daily

dosing

• timolol (Timoptic), levobunolol (Betagan), carteolol (Ocupress), metipranolol (Optipranolol)

• Timoptic + carbonic anhydrase inhibitor (Trusopt) = Cosopt

• 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), latanoprost (Xalatan), travoprost (Travatan)

• And, unoprostone (Rescula)• Prostaglandin analogues—lower Intraocular pressure

by 25-30%• *Latisse for thick, long eyelashes

Long-term use of topical prostaglandin analogs

• **Latisse (bimatoprost) for thick, long eyelashes• Conjunctival hyperemia• Darkening of the iris• Increasing the length and number of eyelashes • Iris pigment changes occur most frequently in patients with

green-brown, yellow-brown, or blue-gray-brown irides

Calcium Channel Blockers…3 classes; 1st class …

DIPHENYALKYLAMINES• 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

• Calcium channels in bowels (elderly)

2nd class of calcium channel blockers--benzothiazepines

• Heart AND peripheral vasculature• 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

Clinical uses— Atrial fibrillation, Hypertension,

Angina, Vasospasm

Less constipation than verapamil

3rd class--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)• Amlodipine + benazepril=Lotrel• Amlodipine +

Atorvastatin=CADUET

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• Dipines—significant peripheral vasodilation with

headaches; hypotension, and peripheral edema (swollen feet—pedal edema; (Plendil)

• Diltiazem—less significant constipation than Verapamil

• The GRAPEFRUIT connection

The liver, drugs and the cytochrome P450 system (CYP450)

• Family of isoenzymes that metabolize drugs--CYP• CYP3A4—40-60% of total hepatic and extrahepatic enzymes;

the extrahepatic enzymes are located primarily along the brush border of the small intestine

• Drugs/foods can be either inducers or inhibitors of the enzyme system

• The most famous inhibitor of this enzyme in the small intestines is grapefruit juice—if you inhibit the enzyme, drugs are absorbed in greater amounts resulting in a higher bioavailability and greater toxicity

The small intestine and metabolism of drugs

• When grapefruit juice or grapefruit inhibits CYP3A4, drugs are absorbed in a higher bioavailability

• 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)

Grapefruit juice interactions increase bioavailability and increase the risk for toxicity

• Amiodarone HCl—increased absorption with GFJ increasing risk of adverse effects and toxicities:

pulmonary toxicity, hypotension, and cardiac arrhythmias, (TSH). Avoid using Amiodarone in patients who may not understand the toxic potential of this interaction.

• Felodipine (Plendil), nisoldipine (Sular), nicardipine HCl (Cardene), nifedipine (Procardia), isradipine (Dynacirc)—increased toxicity with headaches and peripheral edema

• Simvastatin (Zocor)—300% increase in bioavailability with grapefruit vs. atorvastatin (Lipitor) 25% increase; rosuvastatin (Crestor)—no interaction

Grapefruit juice/grapefruit

• Avoid grapefruit juice and grapefruit with antibiotics

• One interaction is especially dangerous• Interaction between grapefruit juice and

erythromycin• Accumulates and may cause tachycardia• Prolongs QT interval and may cause death

from “torsades de points”

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 (exception to the rule—atorvastatin/Lipitor)

• 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 and cerebrovascular disease; they also increase survival and improve the quality of life

The “Statin Sisters”

• Anti-inflammatory effects• Reduce total cholesterol levels• Decrease fatty plaque formation in the arteries• Stabilize fatty plaques and prevent plaques from

rupturing (an inflamed fatty plaque ruptures in a coronary artery triggers the coagulation cascade and clot formation)

• Shrink plaques in all arteries (prevent strokes and heart attacks)

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 with this statin

• How about adding CoQ10 for muscle aches and pains? Either switch statins, lower the dose of statins, consider every other day dosing or take 50-100 mg/day of CoQ10

The “afils”—the Pfizer Riser aka sildenafil (Viagra) and friends, for erectile dysfunction

• Prior to November 1998• What are the causes of ED?• Athero, neuro, drugs, ↓testo, psychological (the stamp

test)• Sildenafil (Viagra)(Revatio for pulmonary hypertension)• Vardenafil (Levitra)• Tadalafil (Cialis)—the “weekend warrior” (Adcirca for

PH)• PDE5 inhibitors which in a round about way boost nitric

oxide—potent vasodilator primarily below the belt• 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 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 blockers Tamsulosin (Flomax) Silodosin (Rapaflo) Doxazosin (Cardura)• Testosterone blockers Dutasteride (Avodart) Finasteride (Proscar)

• Vitamin D for the prostate

The bisphosphonates for osteoporosis• The “dronates” for osteoporosis• Alendronate [Fosavance] (Fosamax + D), Risedronate

(Actonel), ibandronate (Boniva)• zoledronic acid (Zometa) and pamidronate (Aredia)—

hypercalcemia of cancer • Zoledronic acid – lower dose for osteoporosis—brand

name Reclast• Trigger apoptosis of osteoclasts• Osteoblasts continue to build bone matrix but

without remodeling • Any downside?• Subtrochanteric femur fractures? Very low risk• Can the patient FOLLOW directions with the oral

bisphosphonates?

Bisphosphnates— “dronates”• 1/100,000 patients per year on oral bisphosphonates• 94% of cases are on Zometa or Aredia for

hypercalcemia of cancer• To minimize risk: 1) get dental exam before starting drugs 2) good dental hygiene reduces risk 3) might not help to do a drug holiday as these

drugs stay in the bones for years (esp. Fosamax)

The “prazoles”—Proton Pump Inhibitors*

Who are they?• Omeprazole (Prilosec)(first released as Losec in U.S.)• Lansoprazole (Prevacid) • Deslansoprazole (old-Kapidex)(new-Dexilant)• Rabeprazole (Aciphex)• Pantoprazole (Protonix)• 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

Parietal cell

Lumenal surface

Basilar surface

H2 receptors H2

H+, Intrinsic Factor-B12PPIs work here

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 suppressing 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 foodborne illness• Increased risk of osteopenia/osteoporosis with long-

term use• Increased risk of B12 deficiency due to blocking the

release of intrinsic factor

What happens when you have B12 deficiency?

• B12 is necessary for the healthy production of RBCs and for the maintenance of the central and peripheral nervous system (cognitive function in the CNS and motor/sensory function of spinal cord and peripheral nerves)

• B12 deficiency is the number one cause of nutritional dementia

• B12 deficiency is one of the top 3 causes of peripheral neuropathy in the elderly

• B12 deficiency causes macrocytic anemia (MCV greater than 120)

• B12 is stored in the liver for ~ 5 years—takes a long time of PPI use to cause B12 deficiency

Combine long-term use of PPIs with other risk factors…

• 39% of the population over 50 has a B12 deficiency• Patients on glucophage (Metformin) for longer than

3 years should also have B12 levels measured (and the peripheral neuropathy of diabetes may actually be a B12 deficiency neuropathy—give diabetics B12—improves any neuropathy they have)

• Patients with malabsorption; gastrectomy; gastric surgery; atrophic gastritis

Should we all be taking B12?

• If so, how can we take it? • Supplements?• The 4 S’s…• How much? For dementia? For peripheral neuropathy?• For daily maintenance? • Can you overdose on B12? The one dreaded side effect is…

The “tidines” (H2 blockers)

• Cimetidine--Tagamet—can cause delirium in the elderly; increases the bioavailability of many drugs—beta blockers, morphine

• Other H2 blockers—Ranitidine (Zantac); Nizatidine (Axid); Famotidine (Pepcid)

• Best to give at night—decrease vagally-induced histamine release in stomach (double the OTC dose for best results)

• (not to be confused with the “tadines”—amantadine and rimantadine which are the antiviral drugs, Symmetrel and Flumadine for Influenza A)

The antifungals--the “azoles”• Miconazole (Monistat)• 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?

SHINGLES PREVENTION

• 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), citalopram (Celexa), escitalopram (Lexapro)

• Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)—venlafaxine (Effexor), desvenlafaxine (Pristiq), duloxetine (Cymbalta)

Drugs for depression• The “other” category—mirtazapine (Remeron),

buproprion (Wellbutrin)• “old” antidepressants—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

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—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 (see next slide)

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

Two other side effects of reduced dopamine from SSRIs

• Bruxism--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)

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

• Azithromycin (Zithromax)—Z-pack (don’t take with food)

• Clarithromycin (Biaxcin)—take with food!• Important drug/food interactions with the second

generation macrolides; • 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, RA, psoriasis; TB 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 (Zolair)—mab to IgE• Belimumab (Benlysta)—SLE (targets B cell

activating factor)

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)

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

• Ranibizumab (Lucentis)—wet macular degeneration

The “triptans”--5-HT (5-Hydroxytryptamine) (serotonin) 1B/1D

agonists-- vasoconstriction of peripheral arteries and coronary arteries

• Sumatriptan (Imitrex)(64-70% response rate at 2°) • (Treximet—Imitrex (85 mg) + naprosyn (500 mg)• Naratriptan(Amerge)(fewer HA recurrences than

Imitrex)(45% response rate at 2 hours)• Zolmitriptan (Zomig, Zomig ZMT)* (dissolves)• Rizatriptan (Maxalt,Maxalt MLT)* (dissolves)• Almotriptan (Axert)(dec. chest pain, tightness,

pressure)• Eletriptan (Relpax)—faster acting than oral Imitrex• Frovatriptan (Frova) (longest half-life)(45%

response rate at 2°

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 migraine-induced 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)• Palonesetron HCl (Aloxi)

And last, but not least, an all in one pill for stress…

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• BBancr9271@aol.com

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