Chapter 11 Hypertension Treatment PDF

Chapter 11: Hypertension Treatment HLSC3P19 Hui Di Wang Health Sciences Brock University  Objectives (1) List the four major groups of antihypertensive drugs and give examples of drugs in each group. Describe the compensatory responses to each of the...

Chapter 11: Hypertension Treatment HLSC3P19 Hui Di Wang Health Sciences Brock University  Objectives (1) List the four major groups of antihypertensive drugs and give examples of drugs in each group. Describe the compensatory responses to each of the four major types of antihypertensive drugs. List the major sites of action of sympathoplegic drugs and give examples of drugs that act at each site. List the three mechanisms of action of vasodilator drugs. 2  Objectives (2) - List the major antihypertensive vasodilator drugs and describe their effects. Describe the differences between the two types of angiotensin antagonists. Describe the PK, PD, therapeutic use of methyldopa and Aliskiren. List the major toxicities of the prototype antihypertensive agents. Explain why some combinations of antihypertensive drugs are rational and appropriate and others are not. 3 What Constitutes Hypertension? BP Systolic BP Diastolic BP Classification (mmHg) (mmHg) Normal 100 hypertension Hypertension emergencies (malignant hypertension) are defined as severe hypertension coupled with acute end-stage organ damage. 4 How Common is Hypertension? -Hypertension affects approximately 20% of adult Canadian population. -The lifetime risk of developing hypertension is approximately 90%. 5 8  Ethnicity Variations A more recent analysis comparing age groups by ethnicity concluded that in African American subjects, SBP was the best predictor of CHD mortality in all age groups. In contrast, in Caucasian subjects DBP was significantly associated with CHD in subjects 30 to 39 years of age, and SBP was the only significant blood pressure variable associated with CHD in all older age groups (Paultre & Mosca, 2006). 9 Excess body weight Excess dietary sodium intake 10 adapted from: Adrogue & Medias, 2007  Aerobic physical inactivity aerobic activity such as brisk walking at least 30 mins/day most days of the week can lower SBP by 4-9 mm Hg Excess alcohol intake ↑Ang II, vascular inflammation, endothelial injury (Husain et al., 2010)) 11  What are the signs and symptoms of hypertension? -”Silent killer”. -The exception is malignant hypertension, which can cause headache, congestive heart failure, stroke, seizure, papilledema (optical disc swelling caused by increased intracranial pressure), renal failure and anuria. 12 Principal determinants of BP Arterial Cardiac Peripheral Pressure = Output x Resistance 13  Four Possible Mechanisms for Hypertension Blood Peripheral Venous Cardiac volume resistance tone output -Fluid -Sympathetic -? -not typical retention nervous system -Aldosterone activity -ADH -Renin/Ang II -occur infrequently 14  Four major classes of antihypertensive drugs 1. Diuretics 2. Sympatholytics 3. Angiotensin Inhibitors: ACE inhibitors and ARBs 4. Vasodilators 15  There are three different classes of diuretics: 1. Thiazide and related diuretics (Hydrochlorothiazide, commonly used) 2. Loop diuretics (furosemide, less commonly used) 3. Potassium sparing diuretics (Spirnolactone) 16 Thiazide and related diuretics Short term effectiveness Inhibit reabsorption of Na+ and Cl- in distal tubule  sodium and water excretion  when first taken by the patient it  blood volume which in turn 17  cardiac output Thiazide and related diuretics Long term effectiveness  Na+ content of smooth muscle cells   Muscle sensitivity to vasopressors  Peripheral vascular resistance  Peripheral vascular resistance 18 Thiazide and related diuretics -PK -Among the most common used drugs -Lost effectiveness when GFR is low -Protection against osteoporosis 19  Side effects & toxicity of thiazides – Hypokalemia When used in low dose – hypercalcemia such as 25-50mg/day – Hyponatremia of hydrochlorothiazide, – Hyperglycemia the side effects seem – Hyperlipidemia to be minimized. – hyperuricemia Less common: renin release 20  Loop diuretics less effective than thiazide diuretics with treatment of hypertensive patients with normal renal function when given to patients with poor renal function loop diuretics maintain its effectiveness whereas thiazide diuretics do not 21  Loop diuretics (eg furosmide) Inhibit the Na+/K+/Cl- cotransporter in the ascending limb of the loop of Henle. Strong diuretic, but their antihypertensive effects are not strong Acute iv would cause vasodilation by unknown mechanisms Often as part of the treatment for severe hypertension and hypertension with hypervolemia (renal insufficiency),or HT with HF, (patients with severe edema) 22  Side effects & toxicity of loop diuretics – hypokalemia Not recommended as – hypocalcemia initial monotherapy. – Hyponatremia – Hyperglycemia – Hyperlipidemia – hyperuricemia 23  Potassium-Sparing Diuretics (e.g., spironolactone) have a mild natriuretic and antihypertensive effect compared to thiazide and loop diuretics decrease renal potassium excretion thereby preventing hypokalemia Particular care must be taken when given to patients on ACE inhibitors, since both classes cause increase in serum potassium. 24 PK  SYMPATHOLYTIC DRUGS (ADRENERGIC RECEPTOR ANTAGONISTS DRUGS) -Alpha blockers (prazosin, terazosin, dexazosin) -beta-blocker (propranolol, metoprolol, atenolol) -Mixed alpha and beta blockers (labetalol, carvedilol) -Central sympatholytics (clonidine) 25  ADRENERGIC RECEPTOR ANTAGONISTS DRUGS Alpha 1 adrenergic Blocking Agents PRAZOSIN  Sympathetic tone on vasculature Dilating arterioles & veins Does not block Alph2 pre-synaptic receptors Much less tachycardia than the nonselective alpha-lockers 26  ADRENERGIC RECEPTOR ANTAGONISTS DRUGS Alpha 1 adrenergic Blocking Agents PRAZOSIN Not preferred as initial treatment due to: – May evoke relfex activity of sympathetic activity (HR, heart contractivity and circulating norepinephrine level)-> increase oxygen demand->Not used in patients with ischemia – Used with diuretic because they activate angiotenII system and cause water retention 27  ADRENERGIC RECEPTOR ANTAGONISTS DRUGS (cont’) Alpha 1 adrenergic Blocking Agents PRAZOSIN Orthostatic hypotension Used for short term management of hypertensive episode caused by pheochromocytoma Contraindications: 28  Beta-adrenergic Drugs (beta- receptor blockers: -olol) Propranolol (nonselective), metoprolol (selective), atenolol (selective) For chronic use, blocks beta-adrenergic receptors in the heart & kidneys  CO &  myocardial O2 consumption and  release of rennin &  BP 29  Beta-adrenergic Drugs (beta1 receptor blockers: -olol) -increase triglycerin and reduce HDL -glucose intolerance -impotence -depression -non-selective can't be used in patients prone to bronchospasm (ie, asthmatics) The side effects often dictate drug choices PK 30 ADRENERGIC RECEPTOR ANTAGONIST DRUGS Mixed Alpha- and beta-adrenergic Blocking Agents labetalol Blocks both Alpha- and beta- receptors No tachycardia Can cause orthostatic hypotension Very effective iv antihypertensive drug; less frequently use as a chronic oral antihypertensive drug. 31  Centrally acting adrenergic drugs CLONADINE stimulates CNS alpha2 Inhibits sympathetic cardiovascular & vasoconstrictor center  sympathetic outflow from the CNS 32  Centrally acting adrenergic drugs: side effects CLONADINE Effective but usually not for first line therapy; only used in patients resistant to other medications, due to the following side effects and : -Sedation -rebound hypertension 33  Angiotensin Antagonists Angiotensin-Converting Enzyme Inhibitors (ACE Inhibitors: “pril”) - Captopril Angiotensin Receptor Antagonist/Blockers (ARBs) - Losartan 34 Angiotensinogen (liver, vessel, brain) Renin (kidney) Angiotensin I Bradykinin (active vasodilator; it could induce cough) (lung and vasculature) ACE Inactive metablolites enhanced SNS Angiotensin II AII Receptor vasoconstriction Aldosterone Na+ retention 35 Angiotensinogen (liver, vessel, brain) Renin (kidney) Angiotensin I Bradykinin (active vasodilator; it could induce cough) (lung and vasculature) ACE - Inactive metablolites enhanced SNS ACE Inhibitors Angiotensin II AII Receptor - vasoconstriction AT1-blockers Aldosterone Na+ retention 36  The AT1 receptors are coupled with enzymes that: Increase the formation of (IP3) Increase various arachidonic acid metabolites Decrease the formation of (cAMP) 37  Renin-Angiotensin-Aldosterone- Axis cont. Activation of AT1 receptors causes synthesis and release of aldosterone Activation of AT1 receptors causes vasoconstriction. Via IP3-mediated release of intracellular Ca+, AT1 receptors mediate cardiac, renal, and CNS effects. The function of AT2 receptors is unclear. 38 Angiotensinogen (liver, vessel, brain) Renin (kidney) Angiotensin I Bradykinin (active vasodilator) (lung and vasculature) ACE - Inactive metablolites ACE Inhibitors enhanced SNS Angiotensin II AII Receptor - vasoconstriction AT1-blockers Aldosterone Na+ retention 39  Mechanism of ACE Inhibitors (1) Inhibit Angiotensin Converting Enzyme to decrease blood level of Ang II and aldosterone Increase in endogenous vasodilators of the kinin family by Inhibiting the degradation of bradykinin. 40  Mechanism of ACE Inhibitors (2) Antihypertensive effect by – reducing peripheral vascular resistance, – promoting natriuresis and hyperkalemia since a reduction in Ang II leads to a reduction in aldosterone, – Breading down bradykinin to cause more vasodilation 41  Actions of ACE Inhibitors ↓ cardiac afterload ↑ cardiac output ↓ the risk of death in patients with heart failure reduce the incidence of heart failure and significant LV dysfunction Improve renal functions in patients with diabetes 42  Indications of ACE Inhibitors -Mild to sever hypertension Benificial in patients with coexisting heart failure, myocardia infarction, chronic kidney diseases, or diabetes. 43  ACE Inhibitors Adverse Effects cough (5-10% of patients) Fetal and neonatal morbidity and mortality (contraindication for pregnant women) Renal failure in patients with pre-existing bilateral renal artery stenosis hyperkalemia 44  Mechanism & Action of AT1- receptor inhibitors Inhibit the AT1 receptors in the vascular smooth muscle, and in the adrenal cortex, causing vasodilatation and a decrease in aldosterone secretion 45  AT1-receptor antagonist Efficacy: Similar to ACE Inhibitors -Indications: Hypertension -Interactions: serum levels for AT1-receptor inhibitors are increased by cimetidine and decreased by Phenobarbital -Contraindications: same as ACE Inhibitors -Bradykinin is not increased 46  AT1-receptor antagonist Adverse Effects: Hyperkalemia Only rarely causes a chronic cough Relatively free of other adverse effects Vast majority of patients tolerate them well 47  What is Methyldopa? 48  Mechanism of Action of Vasodilators: 1) Reduction of calcium influx, examples: Verapamil, Diltiazem, Nifedipine 2) Hyperpolarization of smooth muscle through increasing potassium permeability, examples: Minoxidil Sulfate (Hypertrichosis), diazoxide 3) Release of nitric oxide, examples: Hydralazine, nitroprusside, nitrates 4) Activation of dopamine receptors (renal D1, Gs, increase cAMP): Fenoldopam 49  Side effects & toxicity of direct vasodilators for oral agents: tachycardia, palpitations, angina, sweating, headache, edema for parenteral agents: excessive hypotension for Ca+ channel blockers: cardiac depression=decreased heart rate and decreased output 54  Compensatory Mechanisms Reflex tachycardia Fluid retention by the kidneys Activation of the rennin – angiotensin – aldosterone axis. 55  Management of Hypertension: Recommendations Diuretic or calcium channel blocker, ACE inhibitors be used initially for most hypertensive patients. Beta-Blocker use: younger patients