Med Phys Pharm 551 L32 Hypertension Pharm Lecture Notes PDF

Lecture #32: Hypertension Pharmacology Julia Hum, PhD Primary Course Instructor Course Meets: Monday/Wednesday/Friday: 2:00-2:50pm Office Hours: Monday/Wednesday/Friday 11:00am-12:00pm (317B or WebEx)  L32: Lea...

Lecture #32: Hypertension Pharmacology Julia Hum, PhD Primary Course Instructor Course Meets: Monday/Wednesday/Friday: 2:00-2:50pm Office Hours: Monday/Wednesday/Friday 11:00am-12:00pm (317B or WebEx)  L32: Learning Objectives 1. Compare and contrast the MOA of the main classes of drugs used to treat hypertension (Diuretics, RAAS inhibitors, Calcium-channel blockers) 2. Relate the MOA of antihypertensive drugs to its underlying physiology of blood pressure 3. Connect key adverse effects back to the MOA of the antihypertensive drugs impact on vasculature physiology Unless otherwise noted, figures in today’s lecture are from: Principles of Pharmacology 3e Baca, Golan, Lippincott Illustrated Reviews: Pharmacology 6e Yellepeddi L32: “Take Home Slide”  Top 10 List of Drugs Prescribed in America 10. Amlodipine – high blood pressure 5. Amoxicillin– infections Ca++ channel blocker Amoxycillin 9. Alprazolam - anxiety Xanax – short acting “benzo” 4. Lisinopril- hypertension, heart failure ACE inhibitor 8. Atorvastatin – high cholesterol Lipitor – “Statins” 3. Prednisone– arthritis/inflammation Delasone – steroid hormone 7. Metformin - T2D Glucophage – first line of defense 2. Levothyroxine - hypothyroidism T4 vs T3 6. Gabapentin – seizures and nerve pain 1. Hydrocodone/Acetaminophen – Pain Neurontin Vicodin/Norco  Summary of Antihypertensive Drugs  Drug Class Mechanisms for Treating Hypertension LO1  Hypertension: Treatment Strategies Goal: reduce cardiovascular and renal morbidity and mortality Current recommendations: Start monotherapy (thiazide diuretic, ACE inhibitor, ARB, or calcium channel blocker) if >130/90 Still uncontrolled: add additional drug, selected based on minimizing adverse effects to reach goal BP If >160/100: dual therapy should be started  Hypertension Management - IRL Treatment of hypertension with concomitant diseases  Hypertension: Diuretics Goal - decreasing blood volume, which leads to decreased blood pressure Low-dose diuretic therapy is safe, inexpensive, and effective in preventing stroke, MI infarction, and HF Routine serum electrolyte monitoring should be done for all patients receiving diuretics LO1  Hypertension: β-Blockers MOA: Reduce BP by decreasing CO by selectively blocking beta adrenergic receptor activity Decrease SNS and inhibit the release of renin from the kidneys Decreasing the formation of angiotensin II and the secretion of aldosterone LO1,2  Hypertension: β-Blockers The “prototype β-blocker” is propranolol acts on both β1 and β2 receptors Metoprolol & atenolol are selective blockers of β1 receptors are among LO1,2 the most commonly prescribed β-blockers  Adverse Effects: β-Blockers May cause bradycardia, hypotension, and CNS side effects (fatigue, lethargy, and insomnia) May also decrease libido and cause erectile dysfunction = reduce patient compliance Adverse effects of can lead to change in drug class to control hypertension LO3  Hypertension: Renin Inhibitors Aliskiren - inhibits renin and, thus, acts earlier in the RAAS Lowers blood pressure about as effectively as ARBs, ACE inhibitors, and thiazides LO1,2  Inhibitors of RAAS - Inhibitor of enzymatic activity of renin Aliskiren is the first approved inhibitor of the enzymatic activity of renin By blocking the activity of renin, aliskiren prevents the conversion of angiotensinogen to angiotensin I Aliskiren is metabolized by CYP 3A4 and is subject to many drug interactions Aliskiren is an effective antihypertensive and may also be useful in slowing the progression of heart failure 2011 – observed kidney complications, high blood K+ 2012 – warning to not be administered with ACE inhibitor or ARBs for patients with kidney problems LO1,2,3  Hypertension: ACE Inhibitors ACE inhibitors are recommended as first-line treatment of hypertension in patients with high coronary disease risk or history of diabetes, stroke, heart failure, myocardial infarction, or chronic kidney disease LO1,2  Inhibitors of RAAS - Angiotensin-converting enzyme inhibitors Angiotensin-converting enzyme (ACE) inhibitors are a part of standard pharmacotherapy in Heart Failure also Lisinopril “-pril” Block the enzyme that cleaves angiotensin I to form the potent vasoconstrictor angiotensin II Vasodilation occurs as a result of decreased levels of the vasoconstrictor angiotensin II SVR = By reducing angiotensin II levels ACE inhibitors also decrease the secretion of aldosterone SVR = LO1,2  Adverse Effects: ACE Inhibitors Dry cough, rash, fever, hypotension (in hypovolemic states), and hyperkalemia The dry cough, (10% of patients) is thought to be due to increased levels of bradykinin in the pulmonary tree Angioedema is a rare but potentially life-threatening reaction that may also be due to increased levels of bradykinin LO3  Hypertension: ARBs MOA: Block the AT1 receptors, decreasing the activation of AT1 receptors by angiotensin II Similar to ACE inhibitors - arteriolar and venous dilation and block aldosterone secretion, lowering blood pressure and decreasing salt LO1,2 and water retention  Inhibitors of RAAS - Angiotensin Receptor Blockers Angiotensin receptor blockers (ARBs) are competitive antagonists of the angiotensin II type 1 receptor Valsartan & Losartan -”sartan” ARBs have the advantage of more complete blockade of angiotensin II action ACE inhibitors inhibit only one enzyme responsible for the production of angiotensin II Clinically ARBs are a substitute for ACE inhibitors in patients who cannot tolerate ACE inhibitors Similar adverse effect profile – except cough LO1,2  Calcium Channel Blockers MOA: limit intracellular calcium = promotes vasodilation of arterioles Block the inward movement of calcium by binding to L-type calcium channels in the heart and in smooth muscle of the coronary and peripheral arteriolar vasculature Phys Reminder - Calcium enters muscle cells through special voltage-sensitive calcium channels (L-type) Triggers release of calcium from the SR, which further increases the cytosolic level of calcium LO1,2  Calcium Channel Blockers Divided into 3 chemical classes, by with different pharmacokinetic properties and clinical indications 1. Diphenylalkylamines: Verapamil Least selective and has significant effects on both cardiac and vascular smooth muscle cells Helps prevent migraine and cluster headaches 2. Benzothiazepines: Diltiazem Affects cardiac and vascular smooth muscle cells, but less pronounced negative inotropic effect on the heart compared to verapamil 3. Dihydropyridines: Nifedipine Much greater affinity for vascular calcium channels than for calcium channels in the heart = particularly beneficial in LO1,2 treating hypertension  Adverse Effects: Calcium Channel Blockers Verapamil and diltiazem should be avoided in patients with heart failure Dizziness, headache, and a feeling of fatigue caused by a decrease in blood pressure Peripheral edema is commonly reported side effect of this class LO3