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.

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-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• 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”

• 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? • 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?

ANGIOTENSIN 1

ANGIOTENSIN 2

RENIN

ALDOSTERONE

ACE --

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 renin-angiotensin-aldosterone—CHF is a HYPER-RENINEMIC state

Anti-inflammatoryAnti-thromboticHypoglycemic (be careful when starting ACE inhibitors in

diabetics)Prevents “remodeling” of the heart, vessels, and kidneys

What does “Angie” do in 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)

• 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 anti-inflammatory 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?

• 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

• 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 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))

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

• 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 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 • 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?• 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 bone-mineral 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

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 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 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)• 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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