PHARMACOLOGY – Simplify don’t Mystify

1. PHARMACOLOGY – Simplify don’t Mystify • “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. Taking a “drug” history • Over-the-counter? • Includes “alternative” herbal therapies • Prescription? • Illicit drugs? Potent vasoconstrictors—increased risk of coronary events • Any drugs you have borrowed from friends?

3. The Numbers… • 40 years ago there were 900 drugs to choose from in the PDR • Today there are over 12,000… • Plus….

4. 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: Digoxin, Cyclosporine, tamoxifen, HIV therapy, and COCs (combined oral contraceptives) • Side effect?

5. Plus…over 10,000 OTC drugs that can wreak havoc—2 examples: 1) cimetidine (Tagamet)—makes drugs MORE toxic—don’t use in elderly patients; first dose delirium in elderly patients 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…Darvocet, Fioricet, Lorcet, Percocet, Propacet, Roxicet, Ultracet (limit “cets” to 325 mg/tab to reduce toxicity

6. And acetaminophen is especially toxic when combined with … • At least 3 adult beverages a day…

7. What to do? Don’t PANIC…. • Helpful hints… • Learn drugs by their CLASS “last” (generic) names…

8. Generics vs. Brand names As a general rule, classes of drugs have the same generic “last” name • “Prils”—ACE inhibitors • “Sartans”—ARBs (angiotensin receptor blockers) • “Triptans”—treatment of acute migraine headache • “Statins”—Lower LDL-cholesterol • “Dipines”—calcium channel blockers • “Tidines”—H2 blockers reduce nighttime acid • “Prazoles”—Proton Pump Inhibitors, GERD • “Azoles”—antifungal • “cyclovirs” – anti-herpetic drugs • The MABs, the NIBS, the “afils”…

9. “Prils”—The ACE inhibitors (Brazilian pit viper) • Captopril (Capoten)(1985) • Enalapril (Vasotec) • Lisinopril (Prinivil, Zestril) • Perindopril (Aceon) • Moxepril (Univasc) • Benazepril (Lotensin) • Quinapril (Accupril) • Trandolapril (Mavik) • Ramipril (Altace)

10. A little refresher on the kidney… • At any given moment, the kidney is “sensing” the pressure and volume of blood flow throughout the body • 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 1→angiotensin 2→ via Angiotensin Converting Enzyme (ACE) • Angiotensin 2 triggers the release of “AL” from the adrenal cortex ALDOSTERONE

11. “Tenses” your “angios”—vasoconstricts the arterioles and increases blood pressure Triggers release of “AL”—aldosterone (from the adrenal cortex to save Na+ & H2O ( BP) and excrete K+…but that’s not all… ANGIOTENSIN 2 ALSO… Increases inflammation in the arteries Prothrombotic Increases tissue resistance to insulin Potent growth factor— “remodels tissues” What does “angie’ do?

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

13. So, if you were an ACE inhibitor, what would you do? • Anti-hypertensive agent via vasodilation and inhibition of aldosterone (Na+ and H20 diuresis) • 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) • Decrease growth of tissues or “remodeling” Is “remodeling” a good word? Hmmmmm….yes, in your…

14. But NOT… • In your heart after a myocardial infarction, OR • In your heart with chronic heart failure, OR • In your blood vessels with hypertension, • OR • In your kidneys with diabetes • “Angie is a bad girl…”

15. To summarize…ACE inhibitors are used for: • Hypertension • Decrease the remodeling of the heart in heart failure patients and post-MI patients • 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

16. Side effects, of course… • Hypotension • Cough (gender differences) • Hyperkalemia (excreting sodium and water and retaining potassium)—add a thiazide diuretic • Angioedema (“Does my voice sound funny to you?”)

17. “Sartans”—ARBs—if you can’t stand the cough or angioedema is a problem • Angiotensin receptor blockers (bypass ACE) and work by blocking the angiotensin-2 receptors on tissues • Who are they? The “Sartan Sisters”… • losartan—Cozaar • valsartan—Diovan • candesartan—Atacand • irbesartan—Avapro • telmisartan—Micardis • olmesartan—Benicar • eprosartan--Tevetan

18. “Olols, alols, ilols”—Beta blockers • acebutolol (Sectral) • atenolol (Tenormin) • betaxolol (Kerlone) • bisoprolol (Zebeta) * • carvedilol (Coreg) (non selective, alpha-1 blocker)* • Esmolol (Brevibloc) • labetalol (Trandate)(Normodyne)—safe during pregnancy • metoprololsuccinate* and tartrate (Toprol XL, Lopressor) *(for CHF) • *EBM (evidence-based medicine) for heart failure to prevent remodeling of the heart

19. Beta-blockers, continued… • nadolol (Corgard) • nebivolol (Bystolic) • oxprenolol (Trasicor, Slow-Trasicor) • penbutolol (Levatol) • pindolol {Visken}—intrinsic sympathomimetic activity (increases HR) • propranolol (Inderal)(1968)(nonselective) • timolol (Blocadren)

20. 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

21. Sympathetic nervous system—fight/flight response • The scenario • Visit Barb in Chicago • Pupils dilate • Heart rate increases • BP increases • Bronchodilate • Vasodilate the large arteries of legs • Hairs stand up on neck and arms • What do your bowls WANT to do?

22. Beta one receptors and cardioselective beta blockers • B1—beta blockers—reduce cardiac output, 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 • acebutolol (Sectral), atenolol (Tenormin), metoprolol (Lopressor), betaxolol (Kerlone); bisoprolol (Zebeta), esmolol (Brevibloc), nebivolol (Bystolic)@ doses <10 mg)

23. Why don’t we just choose any old beta blocker? Nonselective beta blockers NONSELECTIVE BETA BLOCKERS block B2—reduce skeletal muscle tremor, BUT.. • can also cause bronchoconstriction in patients with COPD and vasoconstriction of the large arteries of the legs in patients with PAD • Propranolol/Inderal, nadalol (Corgard), timolol (Blocadren), carvedilol (Coreg), levobunolol (Betagan), sotalol (Betapace)

24. 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—norepinephrine is the neurotransmitter of energy and zest; lipid soluble beta blockers block norepinephrine in the brain and cause 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

25. 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

26. Another major function of beta blockers is to: • Block “re-modeling” of the heart in patients with CHF, and post-MI • The compensatory mechanism of the stress response enlarges the myocardial fibers leading to cardiomegaly • Big hearts = cardiac arrhythmias • Beta blockers block the “re-modeling” • Bisoprolol, carvedilol, metoprolol

27. 3 Classes of Calcium Channel Blockers… • Verapamil (Isoptin SR, Verelan and Verelan PM, Calan and Calan SR, Apo-Verap, Novo-Veramil, Nu-Verap,)—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)

28. 2) Diltiazem—Cardizem, Dilacor XL—dilates calcium channels on the coronary (1/5 affinity for coronary channels) and peripheral vessel calcium channels; Clinical uses— Atrial fibrillation, Hypertension, Angina, Vasospasm Less constipation

29. 3) “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) • MOA: Block the peripheral vascular calcium channels

30. Clinical uses of the “dipines”… • Hypertension • Vasospasm—Prinzmetal’s angina, Raynaud’s phenomenon, cocaine-induced vasospasms • “male contraceptive”

31. The “Statin Sisters”… Who are they? • lovastatin (Mevacor) • simvastatin (Zocor) • atorvastatin (Lipitor) • fluvastatin (Lescol) • pravastatin (Pravachol) • rosuvastatin (Crestor) • pitavastatin (Livalo)

32. The “Statin Sisters”…what do they do? • Inhibit the enzyme HMG-CoAreductase in the liver • HMG-CoAreductase is responsible for the production of the bad guy—LDL-cholesterol; works primarily at night to produce LDL, so the “statins” work the best when taken before bedtime (exception to the rule--atorvastatin) • LDL 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 • Statinsdecrease CAD, PVD, CVD risk and increase survival rates

33. Did your MD or NP start you on lipid-lowering medications? • If so, how much should your LDL go down? • 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

34. 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; Green tea and grapefruit juice • 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

35. One other drug we should all be taking… • Beside the obvious use for Type 2 diabetes • Why are oncologists excited about this drug? • Why are neurologists excited about this drug? • Why are geriatricians excited about this drug? • Why are weight-loss experts excited about this drug? • Why are psychiatrists excited about this drug?

36. SO… • Why are oncologists excited about this drug? prevention of breast cancer and prostate cancer, slowing the growth of lung, pancreatic • Why are neurologists excited about this drug? boosts neurogenesis • Why are geriatricians excited about this drug? slows down the aging process (omega-3s, too)

37. Speaking of metformin… • Why are weight-loss experts excited about this drug? 1-4 pounds per week • Why are OB-GYN HCPs excited about this drug? PCOS (polycystic ovary syndrome)

38. Speaking of metformin • Why are psychiatrists excited about this drug? Prevents weight gain and secondary diabetes secondary to atypical anti-psychotic use • Clozapine (Clozaril) • Olanzapine (Zyprexa) • High-dose prednisone also causes weight gain • Not to mention diabetologists…

39. Other drugs that diabetics are on… • The “gliptins”—sitagliptin/Januvia, saxagliptin/Onglyza, linagliptin/Tradjenta • The “tides”—exanetide (Bydureon), and liraglutide (Victoza)—daily/weekly injections (from the saliva of a Gila Monster)(induce satiety)(significant weight loss with Victoza)

40. The “afils”—1998 and the Pfizer Riser (Viagra)…Erectile dysfunction • Prior to November 1998… • What are the causes of ED? Athero, neuro, drugs, ↓testo, psychological These drugs are used to improve blood flow…(nothing to do with neuropathy) • Sildenafil (Viagra)(Revatio for pulmonary vasodilation and pulmonary hypertension) • Vardenafil (Levitra) • Tadalafil (Cialis)—the “weekend warrior”(Adcirca for pulmonary HTN) • Boost nitric oxide—potent vasodilator

41. 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

42. Surprise side effect of the “afils”? Fastest rising group for sexually transmitted disease is the “over 60” crowd… • More sex • No pregnancy worries • Swingin’ singles • Who cares what the neighbors think? • So since this is an older age group…the question begs to be asked… • Can you have a heart attack during sex? • Only if…

43. Drugs to reduce the size of the prostate—the “osins” • The prostate gland is composed of smooth muscle fibers with alpha-one receptors • Alpha-one blockers reduce the size of the prostate • tamsulosin (Flomax) (not to be confused with Flonase) • silodosin (Rapaflo) (Older drugs for BPH were doxazosin (Cardura) and terazosin (Hytrin)—too many problems with BP, although Cardura ER is still used—slower release, longer acting, BP not a problem)

44. 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

45. Alpha-one blockers, cataract surgery, and floppy iris syndrome— • Who wuddathunk? • Let your 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…

46. The “dronates” for osteoporosis • The “dronates” for osteoporosis • Alendronate [Fosavance] (Fosamax + D), clodronate [Ostac,Bonefos), Risendronate (Actonel), ibandronate (Boniva) • zoledronic acid (Zometa) and pamidronate (Aredia)--cancer • Trigger apoptosis of osteoclasts • Osteoblasts continue to build bone matrix but without remodeling • CAN THE PATIENT FOLLOW INSTRUCTIONS?

47. Don’t forget calcium and vitamin D • Try to get all of your calcium in FOOD, not supplements • SPF and vitamin D • Get out in the sun!

48. The “prazoles”—Proton Pump Inhibitors* • Who are they? • Omeprazole[Losec] (Prilosec)(first released as Losec in U.S.) • Lansoprazole (Prevacid) • Dexlansoprazole (Dexilant) • Rabeprazole (Aciphex) • Pantoprazole (Protonix) • Esomeprazole (Nexium)-- “the purple pill” • *BIGException:Aripiprazole/Abilify—an new antipsychotic—a dopamine system stabilizer

49. The “prazoles”—the PPIs • Work within 4-7 days to reduce 90-100% of the acid pumped into the lumen of the stomach after a meal; take 30’-60’ before the first meal of the day or 30’ to 60’ before the dinner meal (especially if nocturnal GERD is a problem) • Significant GERD? Take twice a day—one before breakfast and one before dinner • Take an OTC “tidine” at bedtime to reduce nocturnal acid secretion via the vagus nerve—cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid)

50. Short-term and long-term side effects of the “prazoles” • BUT suppressing acid has been shown to have significant side effects: • Drugs that need acid for absorption don’t work as well or at all (drugs for fungal infections) • 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 • Increased risk of B12 deficiency due to blocking the release of intrinsic factor