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. The Numbers… • 35 years ago there were 900 drugs to choose from in the PDR • Today there are over 11,000… • Plus….there are over 10,000 OTC drugs and 600 herbal products • Rule #1…don’t PANIC

3. Organizing by Categorizing… • Teach Generics NOT brand/trade names • The “PRILs”—the ACE inhibitors • The “SARTANs”—Angiotensin Receptor Blockers (ARBs) • The “OLOLs, ALOLs, ILOLs”—Beta Blockers • The “DIPINEs”—The calcium channel blockers • The “TRIPTANs”—serotonin agonists for migraines • The “STATINs”—HMG Co-A reductase inhibitors • The “NIBS”—tyrosine kinase inhibitors for cancer • The “MABS”—monoclonal antibodies • The “AZOLES”—antifungal drugs • The “PRAZOLES”—anti-GERD drugs

4. Rule #2…Use a little humor in the title of your lectures… • Who is ACE and why do we want to inhibit him? Or the story of “Angie and Al” • Who is “Sara”(tonin) and why does she make us so happy? • Who put the “dope” in dopamine? • Hormonal chaos • Shove it up your acid-base… • The “Statin Sister’s”—lova, simva, fluva, atorva, rosuva, prava) • From the devil weed to the poppy seed • Corny, but…it WORKS

5. #3—Historical highlights and hysterical highlights…nothin’ like a good story… • Cows, sweet clover, rat poison, and the President of the United States • Dicumarol, WARFarin/Coumadin • Rats in England

6. The “dropsy”… • Serendipitous findings • William Withering, M.D. and botanist treated his patients with “dropsy” by leaching them • Meanwhile, in the village of Shropshire, a local witch brewed up a concoction that she dispensed to anyone knocking at her door complaining of the “dropsy” • 16 ingredients—one active • The FOXGLOVE

7. “Witche’s brew”—atropine (deadly nightshade), henbane (scopolamine— “twilight sleep”), mandrake (+/- hemlock) • 9th to the 13th century-- Surgical patients inhaled “soporific” sponges infused with opium, marijuana, hemlock, or henbane (scopolamine) • Witche’s brew was also a popular analgesic and hallucinatory potion—what was in it? • Physician to Pope Julius III wrote that he used Witche’s brew to anoint (from head-to-toe), the wife of a hangman • How was it administered?

8. Historical highlights –36 years ago…PAIN management in the early 70s • The days of starting with the smallest dose possible…RX: Demerol 50 to 150 mg q 3-4 PRN • Patients waited too long to call nurse—wait and tolerate pain • Or, more likely, the nurse took too long to respond, OR the dosing interval was inappropriate… • The Limbic system --interpretation of pain…Mutha…@!%&**(@!!!! I NEED IT NOW!! • PRN took on a new meaning for me…PER REGISTERED NURSE… • “If we give ‘em too much, they’re going to become addicts...”

9. The days of yesteryear… • Around-the-clock vs. PRN • Patient-controlled analgesia— “they will be pushing that button all day and they’re going to become addicts!!” (140 mg/24 vs. 48 mg/24) • Pre-emptive analgesia—give ‘em something before they even hurt…

10. Pain and newborns • The circumcision decision • Why bother giving the little guys something for pain??? • “It’s such a short procedure and newborns don’t feel pain anyway…” • Babies circumcised without anesthesia/analgesia experience more pain during routine vaccinations 4-6 months later • Pain and ADD?? • Sugar-coated pacifiers; EMLA cream

11. Historical highlights • In the 2nd century AD the Greek physician Galen prescribed opium for just about anything that ails ya’—from asthma to epilepsy; dropsy to diarrhea and for the… • “troubles to which women are subject..”

12. All of the Asian countries started growing their own poppy plants after introduction into their countries • Opium was used primarily as a sedative and as a treatment for diarrhea when they weren’t hanging around opium dens

13. Fast forward to today’s bowels… • Codeine—not that great for pain management because of its side effects; as the dose escalates, so do the side effects; major side effect is constipation • Morphine—major side effect is constipation • Lomotil for diarrhea (atropine sulfate + diphenoxylate HCl) • “Lomotil is so good, it will…” • Loperamide (Imodium) • Undiarrhea (Taiwan) • Stopit (Israel) • New drug for opiate-induced constipation--RELISTOR

14. The approach… • Divide and conquer 1) Prescription drugs—a Class Act; the “statins”, the “prils”, the “sartans”, the “azoles”, the “afils”, the “olols, alols, and ilols”, the “triptans”… 2) OTC drugs—the most common; acetaminophen, aspirin, NSAIDS, and anti-histamines should top the list 3) Herbal products—the top 10

15. Let’s put all of the rules together… • Don’t panic…start with the basics • Use humor in the title • Tell a story • Let’s try it with the ACE inhibitors…

16. “The Prils”—The ACE inhibitors (Brazilian pit viper—Bothrops jararaca)) • The Brazilian rain forest • Pit viper venom and hypotension • Tested in VA hospitals to treat what was known in the 50’s and 60’s as “the SILENT KILLER”, (hypertension)

17. Who are the ACE inhibitors? Pick a “pril” any “pril”… • Captopril (Capoten) • Enalapril (Vasotec) • Lisinopril (Prinivil, Zestril) • Perindopril (Aceon) • Moxepril (Univasc) • Benazepril (Lotensin) • Quinapril (Accupril) • Trandolapril (Mavik) • Ramipril (Altace) • Etc…

18. 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

19. What does “angie’ do? • “Tenses” your “angios”—vasoconstricts • (  BP) • 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”

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

21. Functions of ACE Inhibitors • Anti-hypertensive agents 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—why? (low volume/low pressure presented to the kidney from the failing heart triggers renin release) • Anti-inflammatory • Anti-thrombotic • Hypoglycemic (be careful when starting ACE inhibitors in diabetics) • Decreases “remodeling” of tissues Is “remodeling” a good word? Hmmmmm….

22. Remodeling and angiotensin… • Remodels myocardium and disrupts the conduction system… • Increases the risk of ventricular dysrhythmias • Increases vascular fibrosis—hypertension • Increases intraglomerular blood pressure resulting in intraglomerular hypertension leading to CKD

23. “Angie” and the healthy kidney… • Afferent arteriole (vasodilated via (prostaglandins) The analogy—3 lanes in • Blood entering glomerulus • Glomerulus→filter • Efferent arteriole (vasoconstricted via (angiotensin 2) • Blood exiting glomerulus-one lane out PG filter AT2 Toilet

24. “Angie, the “prils” and the Diabetic/hypertensive Kidney…hyperglycemia/HTN • Afferent arteriole (  vasodilation by (  prostaglandins) • Blood entering glomerulus 6 lanes in • Glomerulus→filter • Efferent arteriole (  vasoconstriction via  angiotensin-2) Shoulder of the road exiting Microalbuminuria**

25. Side effects… • Hypotension • Hypoglycemia • Cough • Angioedema (“Does my voice sound funny to you?”) • Hyperkalemia (excreting sodium and water and retaining potassium)

26. Side effects…Rx of hyperkalemia Hyperkalemia-- Add a thiazide diuretic to the “pril” and voilá! • Capozide (captopril + thiazide) • Vaseretic (enalapril +thiazide) • Prinizide (lisinopril + thiazide) • Zestorectic (as above) • Lotensin HCT (benazepril + hydrochlorothiazide)

27. Adding drugs that block aldosterone in CHF patients—spironolactone (Aldactone) and eprelrenone (Inspra) • Be really careful to check K+ levels within the first week after adding Aldactone or Inspra to an ACE inhibitor • RALES (1999) (Random Aldactone Evaluation Study)—adding Aldactone postpones or prevents 200 deaths/1000 people w/CHF • BUT…For every 1000 new spironolactone RX in heart failure patients, there are 50 more hospitalizations for hyperkalemia

28. Decrease the intake of foods with high potassium in patients on ACE-+ Aldactone… • Banana (1 m) 422 mg • Potatoes (with skin) 540 mg • French fries (1 med) 924 mg • Halibut (3 oz) 490 mg • Spinach (1c) 839 mg • Pasta sauce (1c) 940 mg • Oranges 1 m 237 mg • Prunes (elderly) 10 615 mg • Health.harvard.edu/heartextra for K+ content of 1,200 foods

29. Other potential K+ boosters… • Stop taking any K+ supplements including salt substitutes such as K+ iodide • Go easy on the NSAIDS (decrease GFR) with retention of fluids and electrolytes (including K+) • Herbal or natural remedies with hefty doses of potassium include noni juice, Siberian ginseng, hawthorn berries • Licorice can also “save” potassium (Harvard Heart Letter, December 2004)

30. ACE inhibitors (category D) in pregnancy • Why? • Inhibit growth factors • Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 354;23:2443-51. • Friedman JM. ACE inhibitors and congenital anomalies. N Engl J Med 2006 (June 8);354:23.

31. “Sartans”—ARBs • Angiotensin Receptor Blockers (bypass ACE) and work by blocking the tissue receptors • Who are they? The “Sartan Sisters”… • losartan—Cozaar • valsartan—Diovan • candesartan—Atacand • irbesartan—Avapro • telmisartan—Micardis • olmesartan—Benicar • Can use with “prils” for additive effect; Less side effects—may substitute if cough is unbearable

32. “Olols, alols, ilols”—Beta blockers • propranolol (Inderal)(1968) • nadolol (Corgard) • timolol (Blocadren) • atenolol (Tenormin) • metoprolol succinate and tartrate (Toprol XL, Lopressor) • betaxolol (Kerlone) • bisoprolol (Zebeta) • carvedilol (Coreg) • labetalol (Trandate) • acebutolol (Sectral), • penbutolol (Levatol) • pindolol (generic) • nebivolol (Bystolic)

33. 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: dopamine, epinephrine, norepinephrine • Scenario: Visit Barb in Chicago

34. B1—found on heart muscle; epinephrine binds to B1 and increases heart rate and strength of contraction (chronotropic and inotropic) • B2—skeletal muscle, bronchioles of the lungs (bronchodilation), large arteries of the legs (vasodilation) • Alpha 1—arteriole smooth muscle (vasoconstriction to increase BP) • Alpha 2 (hypothalamus)—regulates CNS output of SNS • Drugs can ‘selectively’ modulate the various receptors

35. “Olols, alols, ilols”… • Cardioselective? (B1 receptors)—if you block the B1 receptors on the heart, the heart rate and contractile state decrease – cardiac output falls, blood pressure falls, workload of the heart decreases atenolol (Tenormin), metoprolol (Lopressor), betaxolol (Kerlone); bisoprolol (Zebeta), nebivoloil (Bystolic)@ doses <10 mg) • Used for blood pressure control, angina, situational anxiety, hyperthyroidism (with heart rates that can reach 200+)

36. Why don’t we pick just any old beta blocker? Because the non-cardioselective block both the B1 AND B2 receptors and can wreak havoc in certain patient populations • (bronchoconstrict { exacerbate COPD, asthma}, vasoconstrict the femoral artery {exacerbate PAD}) propranolol (Inderal), nadolol (Corgard), timolol (Blocadren), carvedilol (Coreg)

37. Beta blockers…other properties • Water-soluble? (low lipophilicity) atenolol (Tenormin), nadolol (Corgard), labetalol (Trandate) • 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—anxiety (panic and situational) attacks, PTSD, episodic dyscontrol, essential tremor • propranolol (Inderal), timolol (Blocadren), metoprolol (Lopressor, Toprol XL), pindolol • All of the others are moderately lipophilic

38. Beta-blocker eyedrops • Timolol (Timoptic), betaxolol (Betoptic), levobunolol (Betagan), carteolol (Ocupress) • Highly lipid-soluble and cross the blood-brain barrier • Can cause bradycardia and anhedonia • What can you use instead?

39. The “oprosts”… • The “oprosts”—bimatoprost (Lumigan), latanoprost (Xalatan), travoprost (Travatan)** • Prostaglandin analogues for glaucoma • **Not to be confused with the new “oprost” (Iloprost or Ventavis)—it, too, is a synthetic prostaglandin analogue (PG-12) but it dilates the systemic and pulmonary vascular beds—used for the treatment of pulmonary arterial hypertension

40. Speaking of eye drops…one gtt or two? • The volume of a single drop can vary with the viscosity of the solution, the design of the dropper, and patient technique. • A second eye drop either washes out the first or increases the possibility of systemic toxicity, and doubles the cost • When two different types of drops are being used, they should be instilled at least 5 minutes apart. • The Medical Letter, June 19, ‘06

41. Calcium channel blockers • What are the calcium channel blockers? • Where are the calcium channels located? • Heart vessels and AV node, peripheral blood vessels, bowels

42. 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) 3 Classes of Calcium Channel Blockers…

43. 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

44. 3) “DIPINES”—Peripheral vessel calcium channel blockers • Amlodipine (Norvasc) • Felodipine (Plendil)** • Nifedipine (Procardia) • Nicardipine (Cardene) • Isradipine (Dynacirc) • Nisoldipine (Sular) • MOA: Block the peripheral vascular calcium channels • Amlodipine + Atorvastatin=CADUET

45. Case study: • 93-year-old male with severely edematous feet • HCT given to decrease swelling—didn’t work • Motrin (ibuprofen) given for the pain and “edema” • Taking felodipine (Plendil) for HTN • Eating grapefruit or drinking grapefruit juice every day for breakfast • What is wrong with this picture?

46. What’s wrong? • Motrin (ibuprofen)—vasoconstricts the renal artery by blocking the vasodilating prostaglandins—fluid retention • felodipine is the most potent of all “dipines” and therefore the most vasodilation • Grapefruit juice increases the bioavailability of felodipine and increases toxicity • What should be done?

47. Clinical uses of the “dipines”… • Hypertension • Vasospasm—Prinzmetal’s angina, Raynaud’s phenomenon, cocaine-induced vasospasms • FYI: Ureteral spasm in patients with small kidney stones (try slow release nifedipine 30 mg qd x 5-7 days) • “male contraceptive”

48. Side effects of CCBs… • Verapamil—significant constipation; blocks Ca+ channels in bowel • Dipines—significant peripheral vasodilation with headaches; hypotension, and peripheral edema (swollen feet—pedal edema; (Plendil) • Diltiazem—less significant constipation than Verapamil

49. The “Statin Sisters”… The weaker “sisters”… • lovastatin (Mevacor) • fluvastatin (Lescol) • pravastatin (Pravachol) The stronger “sisters”… • simvastatin (Zocor) • atorvastatin (Lipitor) • rosuvastatin (Crestor)

50. The “Statin Sisters”…what do they do? Reduce LDL cholesterol • Inhibit the enzyme HMG-CoA reductase in the liver • This enzyme in the liver is responsible for the production of LDL-cholesterol; • 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 • Works primarily at night to produce LDL, so the “statins” work the best when taken before bedtime (exception to the rule is Lipitor—has a much longer half-life) • Statins decrease CHD, PAD, CVD risk and increasesurvival rates • What else do the statins do?