PHARMACOLOGY – Simplified, not Mystified

1. 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)

2. The Numbers… • 30 years ago there were 900 drugs to choose from in the PDR • Today there are over 12,000… • Plus….

3. 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?

4. I’m PREGNANT!!! • CONFUCIUS say: • “It take many nail to build crib; only one screw to fill it.”

5. 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

6. 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)

7. 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)

8. 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

9. 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)

10. 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

11. 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)

12. 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.

13. 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)

14. 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

15. 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

16. 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…

17. 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…

18. 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)

19. 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)

20. 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)

21. 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? What does “angie II” do?

22. 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?

23. So, let’s get back to the original story…Who is ACE and why do we want to inhibit him? ACE --

24. 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-inflammatory Anti-thrombotic Hypoglycemic (be careful when starting ACE inhibitors in diabetics) Prevents “remodeling” of the heart, vessels, and kidneys

25. 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 filter AT II Toilet

26. “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**

27. 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

28. 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

29. What’s not to love about the ACE inhibitors?

30. 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

31. 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)

32. 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

33. 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

34. 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

35. 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

36. 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

37. “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

38. 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))

39. 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

40. 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)

41. “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 • metoprololsuccinate (Toprol XL, Lopressor)[Betaloc] • nadolol (Corgard) • nebivolol (Bystolic)—Beta blocker PLUS (boosts NITRIC OXIDE) • propranolol (Inderal)(1968)(nonselective) • sotalol (Betapace) • timolol (Blocadren)

42. 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

43. 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?

44. 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…”

45. 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

46. 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)

47. 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)

48. 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

49. 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

50. 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