Antihypertensives Part Two PA 2024 PDF

ANTI-HYPERTENSIVES PART TWO SECOND LINE DRUGS SELECTING ANTIHYPERTENSIVE THERAPY AGENTS FOR  Objectives For each of the drugs to the extent covered in class, distinguish between: Available agents Mechanism of action Clinical indications Adverse/toxic e...

ANTI-HYPERTENSIVES PART TWO SECOND LINE DRUGS SELECTING ANTIHYPERTENSIVE THERAPY AGENTS FOR  Objectives For each of the drugs to the extent covered in class, distinguish between: Available agents Mechanism of action Clinical indications Adverse/toxic effects, contraindications, interactions and precautions Given a clinical scenario, choose the most appropriate therapeutic agent from those listed in the presentation  Required Reading 1.) Pharmacology, Sixth Edition by Brenner, GM. Chapter 10 JNC8 Guidelines  The Line-Up Second-Line Drugs b-blockers a1-blockers Centrally-acting a2 agonists “Other” arterial vasodilators Why are these considered “second- line”? Physiology of Blood Pressure Regulation Key Fundamental Relationships CO X TPR = MAP R=8VL/p r4 HR X SV = CO Physiology of Blood Pressure Regulation  b-Blockers b-blockers have been widely used in the treatment of HTN  They were considered a first-line drug for a number of years and are still considered first- line but only in patients that have hypertension AND other cardiovascular problems: 1. In patients with coronary heart disease, β- blockers reduce myocardial ischemia and lower the risk of myocardial infarction 2. In patients who have had a myocardial infarction, β-blockers are cardioprotective and prevent sudden death, primarily by reducing HR and decreasing the risk of ventricular arrhythmias 3. In patients with heart failure, β-blockers improve symptoms and survival  b-Blockers But………recent evidence has led to their relegation to second-tier status in patients who only have hypertension  They have been shown to be less likely to prevent stroke, MI, and death in patients without coronary heart disease in comparison with CCBs, ACEIs, ARBs and thiazide diuretics. Additionally, their adverse metabolic side effects might be counter-active  increased plasma glucose, increased insulin resistance, decreased HDL-C and increased triglycerides (not all b-blockers necessarily cause all of these) Non-selective b-Blockers for HTN Propanolol (Inderal) Nadalol (Corgard) Pindolol (generic) Penbutolol (Levatol)  Selective b-Blockers for HTN Metoprolol (Lopressor) Atenolol (Tenormin) Acebutolol (Sectral) Bisoprolol (Zebeta) Nebivolol (Bystolic) Betaxolol (generic)  Combined a/b-Blockers Carvedilol (Coreg) Labetalol (Trandate) Both block b1, b2 and a1 receptors Both have been used for the treatment of hypertension Carvedilol also has been shown to have antioxidant and antiapoptotic properties that can prevent myocyte death and reduce infarct size in persons with myocardial  Actions of Non-Selective b- At b1 receptors Blockers Decreased HR, cardiac contractility Decreased renin secretion At b2-receptors Bronchoconstriction (should be avoided in patients with?) Inhibition of glycogenolysis (should be avoided in patients with?)  b-Blockers Mechanism of action Cause ↓ HR and ↓ SV and hence a ↓ CO Cause ↓ in renin secretion and hence a ↓ in plasma angiotensin II and aldosterone May cause an initial reflex response of increased TPR,  b-Blocker Combinations b-blockers are available in fixed dose combinations with diuretics – examples include: Atenolol + chlorthalidone (Tenoretic) Bisoprolol + HCTZ (Ziac) Metoprolol + HCTZ (Lopressor HCT) Nadolol + bendrofluthiazide (Corzide)  b-Blockers – Adverse Effects Non-selective b-blockers are not recommended for hypertensive patients with obstructive airway disease or Type 1 diabetes mellitus – Why ? All b-blockers are usually avoided in patients with a history of: A-V conduction blocks Bradycardia Can reduce exercise capacity in those that are physically active  A Note on CNS Side Effects CNS: drowsiness, fatigue, depression b-blockers that have low lipid solubility (e.g. – atenolol) are less likely to cause CNS side effects Supersensitivity to the Abrupt Withdrawal of Oral b-Blockers Abrupt discontinuation of a b-blocker may cause rebound hypertension (and subsequent stroke) and cardiac arrhythmias, which could lead to sudden death Dosages are usually tapered over 10-14 days prior to discontinuation Education of patients about the risks of sudden withdrawal is important  a1-Blockers (a1-Receptor a1-adrenergicAntagonists) receptor antagonists selectively block a1-adrenergic receptors (particularly on arterioles) without affecting a2-adrenergic receptors Common examples – the "---zosin" drugs Doxazosin (Cardura) Prazosin (Minipress) Terazosin (Hytrin)  a1-Blockers (a1-Receptor Mechanism of Antagonists) action The a1-blockers reduce arteriolar resistance by inducing vasodilation…….B UT……this causes a SNS-reflex increase in heart rate, contractility (inotropy) and plasma renin activity. What could you  a1-Blockers (a1-Receptor Antagonists) Adverse effects "First dose phenomenon" – including: dizziness, headache, weakness, sweating, blurred vision, nausea and vomiting; this reaction can cause syncope due to severe symptomatic postural hypotension The first dose effect is estimated to be seen in 50% of patients After the first few doses, patients generally develop a tolerance to this marked hypotensive response ………. but that’s not always the case  a1-Blockers (a1-Receptor Antagonists) a1-blockers are effective in treating the urinary obstruction of BPH; the MOA in improving urine flow involves partial reversal of smooth muscle contraction in the enlarged prostate and in the bladder base Bottom line  a1-blockers should not be used as first line treatment for HTN; a possible exception is older men who also have symptomatic BPH in whom and an a1-blocker may lead to symptomatic improvement  SIDE NOTE: a1A-Blockers (a1A- Receptor Antagonists) Tamsulosin (Flomax) and alfuzosin (Uroxatral) are highly selective a1A- adrenergic antagonists that were developed to avoid the side effects of a1- adrenergic blockers.  Centrally Acting a2 Agonists Methyldopa (Aldomet), clonidine (Catapres), and guanfacine (Tenex) lower blood pressure by stimulating a2-adrenergic receptors in the vasomotor area of the medulla, thus reducing peripheral sympathetic outflow. These agents are effective as monotherapy for a few patients (e.g., methyldopa in pregnant females), but they are usually employed as second- or third-line agents because of the high frequency of drug intolerance, including sedation, fatigue, impaired mental acuity, dry mouth, postural  Other Arterial Vasodilators Minoxidil and hydralazine relax vascular smooth muscle in arterioles (not veins) and produce peripheral vasodilation. When given alone, they stimulate reflex tachycardia (due to SNS), increase myocardial contractility (also due to SNS), and cause headache, palpitations, flushing and fluid retention (due to activation of the RAA pathway). In patients with ischemic heart disease, reflex tachycardia and sympathetic stimulation may provoke angina or ischemic arrhythmias. Minoxidil may also cause hypertrichosis…… which is what most folks associate with minoxidil. Selection of Antihypertensive Many factors Therapy to consider: Age Ethnicity Severity of HTN Pregnancy Concurrent disease (“compellin g indication”)  Agents for Hypertensive Crises Hypertensive crises are rare but require substantial reduction of blood pressure quickly (but not TOO quickly) to avoid the risk of serious morbidity or death. A hypertensive emergency is considered to be present when severe hypertension (SBP >180; DBP >120) is associated with acute end-organ damage (e.g., subarachnoid or intracerebral hemorrhage, aortic dissection, etc.). A hypertensive urgency is a severe elevation in BP without target organ dysfunction. Immediate but careful reduction in BP is indicated in hypertensive emergencies; an excessive HYPOTENSIVE response may lead to ischemic complications, particularly in the heart, brain and kidneys (which can lead to acute renal failure). The initial goal of treatment of hypertensive  The Line-Up Nitrates (sodium nitroprusside, nitroglycerin) Dopamine-1 (D1) receptor agonists (fenoldopam) Adrenergic blocking agents (labetalol, esmolol) CCBs (clevidipine, nicardipine) Agent of choice is often driven by  Agents for Hypertensive Crises Sodium Nitroprusside Generally the agent of choice for the most serious emergencies because of its immediate (