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PHARMACOLOGY – Simplified, not Mystified

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

  4. Vitamins and herbal supplements…. • Vitamin supplements—A (liver toxicity), B6 (peripheral neuropathy), C (doesn’t work to prevent colds but is an excellent way to help absorb iron when iron supplements are necessary), D for bones, balance, boosting immune system, E (no extra benefit on hearts, and in the very old may actually exacerbate heart failure)…but vitamin E reduces fat in the liver in patients with fatty liver disease (800 IU) • Calcium supplements, iron supplements, soy supplements interfere with levothyroxine (Synthroid)

  5. Speaking of levothyroxine… • Nighttime dosing may be more efficacious than daytime dosing • Most important—take at the same time of day • Adjust doses as the patient ages—why? • Levothyroxine RX can also cause atrial fib if the dose is too high; levothyroxine doses DECREASE with aging; some patients only need 0.5 mcg/kg/day vs. younger adults with 1.7 mcg/kg/day (Prescriber’s Letter July 2011)

  6. The Gs and platelet aggregation • How about the “Gs”?? • Garlic vs. garlic supplements (interfere with all sorts of drugs) • Gingko—not beneficial for dementia, but is beneficial for PAD • grapeseed extract—EAT GRAPES • ginseng –whatever ails ya’; side effects? • Glucosamine--?? • green tea** (a potentially harmful interaction is with green tea and simvastatin—the higher the dose of simvastatin the greater the risk of rhabdomyolysis with green tea)

  7. Plus… • Over 10,000 over-the-counter (OTC) drugs that can wreak havoc—examples: 1) cimetidine (Tagamet)—for heartburn 2) acetaminophen (Tylenol) is in over 300 over-the-counter products (Tylenol)—inadvertent overdoses (narrow therapeutic index—toxic dose is not much higher than therapeutic dose) ….as well as numerous prescription analgesics… Fioricet, Lorcet, Percocet, Propacet, Roxicet, Ultracet (limit “cets” to 325/mg per tab to reduce toxicity)

  8. 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

  9. What’s in a name??? • When you hear “Bayer” what do you think? • ASPIRIN OF COURSE! • Bayer Aspirin is aspirin; but Bayer Select Maximum Strength Headache is acetaminophen and caffeine • Aspirin’s principal use today is in low doses as a platelet inhibitor • Bayer Select Pain Relief is ibuprofen

  10. Non-selective NSAIDs • “profens” Ibuprofen (Advil, Motrin, etc) PO—200 mg = to 650 of ASA; 400 mg superior w/ longer duration of ASA; 400 mg comparable to acetaminophen/codeine combination without the constipation w/ codeine; interferes with ASA cardiovascular prophylaxis; take 2 hours after aspirin IV ibuprofen is Caldolor (400-800 mg q 6h) Flubiprofen (Ansaid)—osteoarthritis, RA Ketoprofen • Diclofenac (Cataflam, Voltaren, Arthrotec (combined with misoprostol to decrease GI toxicity); Flector as a topical patch for minor trauma; gel (Voltaren 1%) for osteoarthritis of knees and hands) • Ketorolac IM, IV, PO—5 –day use only due to GI toxicity; comparable to moderate doses of morphine

  11. More on NSAIDS • Naproxen (Naprosyn, others) • Naproxen sodium (Anaprox)—prescription; 550 mg is superior to 650 of ASA with longer duration of action • Naproxen sodium OTC (Aleve)—440 mg comparable to 400 mg of ibuprofen with longer duration • Celecoxib (Celebrex)—less effective than full doses of naproxen or ibuprofen; less GI toxicity; no platelet effects • All NSAIDS can decrease renal blood flow—may cause hypertension; don’t use in CHF patients; liver toxicity especially with diclofenac Medical Letter, April 2010 (volume 8, issue 92)

  12. 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…

  13. 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

  14. First line therapy for reducing blood pressure—the “prils” • Captopril (Capoten)(1981) • Enalapril (Vasotec)(1983) • Fosinopril (Monopril) • Lisinopril (Prinivil, Zestril) • Perindopril (Aceon) • Moexipril (Univasc) • Benazepril (Lotensin) • Quinapril (Accupril) • Trandolapril (Mavik) • Ramipril (Altace)

  15. A little refresher on the kidney… • At any given moment, the kidney is “sensing” the pressure and volume of blood flow • Low volume or low BP, the kidney will release renin from a small area (the JGA) just inside the afferent arteriole • Renin (the messenger)→(liver) angiotensin I →angiotensin II→ via Angiotensin Converting Enzyme (ACE) (primarily in the pulmonary circulation) • Angiotensin II triggers the release of “AL” (aldosterone) from the adrenal cortex

  16. She “tenses” your “angios”—vasoconstricts your arteries She triggers release of “AL”—aldosterone (from the adrenal cortex to save sodium & H2O in the kidney) She increases inflammation in the arteries She’s prothrombotic She increases tissue resistance to insulin She’s a potent growth factor and “remodels tissues”… What does “angie II” do?

  17. 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. may have elevated RAA systems (renin-angiotensin-aldosterone) • 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….

  18. Remodeling and angiotensin… • Remodels myocardium and disrupts the conduction system…Increases the risk of ventricular dysrrhythmias • Remodeling increases vascular fibrosis—hypertension • Remodeling increases intraglomerular blood pressure resulting in intraglomerular hypertension leading to CKD • BOTTOM LINE?

  19. “Angie” and the healthy kidney… • Afferent arteriole (vasodilated via (prostaglandins) • Blood entering glomerulus • Glomerulus→filter • Efferent arteriole (vasoconstricted via (angiotensin II) • Blood exiting glomerulus PG filter AT II Toilet

  20. “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**

  21. To summarize…ACE inhibitors are used for: • Hypertension (*night time dosing of anti-hypertensive drugs—dippers (10% decline @ night) vs. non-dippers) (American Journal of Kidney Diseases December 2007) • A new, interesting theory of hypertension—CMV infection in epithelial cells results in excess release of renin and angiotensin II, excess production of proinflammatory cytokines, and development of intimal hyperplasia and athersclerosis

  22. To summarize…ACE inhibitors are used for: • Decrease the remodeling of the heart in heart failure patients and post-MI patients (clearly beneficial in MI patients 65-74 years of age, but not so clear in patients older than 75) • Beneficial in patients with anterior ST-elevation MIs and in patients with MIs complicated by HF or significant LV systolic dysfunction with LV ejection fractions less than 40% • Decrease the risk of 1st and 2nd myocardial infarctions in high-risk patients due to anti-inflammatory effects • Stroke prevention • Prevention of diabetic nephropathy • Decrease insulin resistance and reduce the risk of progression to type 2 diabetes

  23. 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

  24. Side effects, of course… • Hyperkalemia (high potassium) (excreting sodium and water and retaining potassium) • Add a thiazide diuretic to the ACE inhibitor • Capozide (captopril + thiazide) • Vaseretic (enalapril +thiazide) • Prinizide (lisinopril + thiazide) • Zestorectic (as above) • Lotensin HCT (benazepril + hydrochlorothiazide)

  25. What about K+ containing foods? • May also contribute to hyperkalemia and cardiac arrhythmias but usually only in patients with renal insufficiency so or in patients who are also on K+ sparing diuretics such as spironolactone (Aldactone) and eprelrenone (Inspra) • Avoid excessive potassium intake when on the above drugs or with renal insufficiency • Advise patients to decrease potassium intake until they can get their potassium checked

  26. High K+ containing foods • Potatoes • Prunes • Raisins • Apricots • Bananas • Halibut • Canteloupe • Oranges • Pasta sauce • for K+ content of 1,200 foods

  27. Side effects, of course… • Cough (gender differences) • ACE inhibitors block angiotensin converting enzyme; but as ACE is inhibited, bradykinin goes UP…bradykinin is a potent bronchoconstrictor • Women have more bradykinin to begin with, therefore the gender disparity in the cough • Rx? Stop drug; can try a nonspecific antitussive; consider indocin, baclofen, aspirin, or sulindac (Clinoril) if the cough persists (Rose BD)

  28. Side effects, of course… • Cough (gender differences) • Life-threatening angioedema (“Does my voice sound funny to you?”)

  29. 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

  30. “Sartans”—Angiotensin II Receptor Blockers • Angiotensin receptor blockers (bypass ACE) and work by blocking the angiotensin II receptors on tissues • Who are they? The “Sartan Sisters”… • losartan—Cozaar • valsartan—Diovan • candesartan—Atacand • irbesartan—Avapro • telmisartan—Micardis • olmesartan—Benicar • azilsartan -- Edarbi • substitute if cough is unbearable on the ACE inhibitors

  31. 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))

  32. 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

  33. “Olols, alols, ilols”—Beta blockers • atenolol (Tenormin) • betaxolol (Kerlone) • bisoprolol (Zebeta) • carvedilol (Coreg) • Esmolol (Brevibloc) • labetalol (Trandate)(Normodyne)—safe during pregnancy • metoprololsuccinate (Toprol XL, Lopressor) • nadolol (Corgard) • nebivolol (Bystolic) • propranolol (Inderal)(1968)(nonselective) • sotalol (Betapace) • timolol (Blocadren)

  34. 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

  35. Fight/flight response • Heart rate goes up • BP goes up • Bronchioles dilate • Increased blood flow to arms and legs • Hair on arms and neck stands up • Tremor • What do your bowels WANT to do?

  36. 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…”

  37. SNS receptors and actions • B1—found on heart muscle; epinephrine binds to B1 and increases heart rate and strength of contraction (chronotropic and inotropic) • B2—skeletal muscle (tremor), bronchioles of the lungs (bronchodilation), large arteries of the legs (vasodilation), piloerection (hairs stand up on back of neck and arms)

  38. Alpha receptors and actions • α1—arteriole smooth muscle (vasoconstriction to increase BP) (alpha 1 receptors are also located on the prostate gland) • α2 (hypothalamus)—regulates CNS output of SNS • Drugs can ‘selectively’ modulate the various receptors

  39. Same slide as the last one—throw in alpha blockers • α1—arteriole smooth muscle (vasoconstriction to increase BP) (alpha 1 are also located on the prostate gland)—the “osins”—(ALPHA-1 BLOCKERS including tamsulosin/Flomax, silodosin/Rapaflo; terazosin (Hytrin), doxazosin/Cardura) • Α2—hypothalamus—regulate CNS output of the SNS—clonidine/Catapres (consider this drug for women on Tamoxifen having hot flashes)

  40. Beta one receptors and cardioselective beta blockers • B1—found on heart muscle; epinephrine binds to B1 and increases heart rate and strength of contraction (chronotropic and inotropic)—– cardiac output falls, heart rate falls (10-15%), blood pressure falls, workload of the heart decreases—angina, SVT, post-MI to protect the heart from remodeling and to reduce heart rate atenolol (Tenormin), metoprolol (Lopressor), betaxolol (Kerlone); bisoprolol (Zebeta), nebivolol (Bystolic)@ doses <10 mg)

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

  42. Why don’t we pick just any old beta blocker? Because the non-cardioselective beta blockers block both the B1 AND B2 receptors and can wreak havoc in certain patient populations • B2 blockade can cause bronchoconstriction and exacerbate COPD & asthma as well as vasoconstrict the femoral artery {exacerbate [peripheral artery disease} propranolol (Inderal), nadolol (Corgard), timolol (Blocadren), carvedilol (Coreg)

  43. 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

  44. 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

  45. Beta-blocker eye drops for glaucoma—second-line therapy--Lower intraocular pressure by 20-25% with once or twice daily dosing • timolol (Timoptic), levobunolol (Betagan), carteolol (Ocupress), metipranolol (Optipranolol) • Timoptic + carbonic anhydrase inhibitor (Trusopt) = Cosopt • Highly lipid-soluble and cross the blood-brain barrier • Can cause bradycardia and anhedonia • So what can you use instead?

  46. The “oprosts”—first line therapy for glaucoma • The “oprosts”—bimatoprost (Lumigan), latanoprost (Xalatan), travoprost (Travatan) • And, unoprostone (Rescula) • Prostaglandin analogues—lower Intraocular pressure by 25-30% • *Latisse for thick, long eyelashes

  47. Long-term use of topical prostaglandin analogs • **Latisse (bimatoprost) for thick, long eyelashes • Conjunctival hyperemia • Darkening of the iris • Increasing the length and number of eyelashes • Iris pigment changes occur most frequently in patients with green-brown, yellow-brown, or blue-gray-brown irides

  48. Calcium Channel Blockers…3 classes; 1st class … DIPHENYALKYLAMINES • Verapamil (Isoptin SR, Verelan and Verelan PM, Calan and Calan SR, Covera-HS)—block calcium channels primarily on the coronary vessels and the AV node—increasing blood flow to the heart and decreasing impulses through the AV node—used to decrease workload of heart and slow the heart rate; HTN, angina, atrial fib • Calcium channels in bowels (elderly)

  49. 2nd class of calcium channel blockers--benzothiazepines • Heart AND peripheral vasculature • Diltiazem—Cardizem LA and CD, Dilacor XR, Tiazac—dilates calcium channels on the coronary arteries and peripheral vessel calcium channels; decreases impulse transmission from atrium to ventricle Clinical uses— Atrial fibrillation, Hypertension, Angina, Vasospasm Less constipation than verapamil

  50. 3rd class--dihydropyridines or the “DIPINES”—Peripheral vessel calcium channel blockers • Amlodipine (Norvasc) • Felodipine (Plendil)** • Nifedipine (Procardia XL, Adalat) • Nicardipine (Cardene) • Isradipine (Dynacirc) • Nisoldipine (Sular) • Clevidipine (Cleviprex) for IV use vs. esmolol or IV nicardipine) • Amlodipine + benazepril=Lotrel • Amlodipine + Atorvastatin=CADUET