Treatment of Hypertension

Evaluation of the Hypertensive Patient

identify known causes of HTN, assess end organ damage, identify other cardiovascular risk factors

complete Hx and physical examination

laboratory studies:

routine – urinalysis; complete blood count; serum Na⁺, K⁺, creatinine, fasting glucose, cholesterol, HDL cholesterol; EKG

optional – 24-hour urine for creatinine clearance, total protein; serum Ca⁺⁺, uric acid; TSH; glycohemoglobin

Rationale for Antihypertensive Therapy

Cardiovascular morbidity and mortality correlates with increased blood pressure; likewise, antihypertensive therapy reduces cardiovascular disease and death

(1) VA Cooperative Study – severe stage 3 HTN

Diastolic BP 115 – 129 mmHg Þ unequivocal benefit

Hypertensive complications were significantly less in the treated groups as opposed to the placebo groups

Diastolic BP 90 – 114 mmHg Þ benefits less apparent

(2) Australian National Blood Pressure Study – stage 2 HTN

3,500 patients, average diastolic BP 100 mmHg
Drug Treatment significantly decreased cardiovascular morbidity and mortality significantly more in treated than in placebo groups (although placebo group had a significant response as well)

(3) Treatment of Mild Hypertension Study (TOMHS) – stage 1 HTN

Purpose: Define the role of life-style modification and compare 5 newer antihypertensive agents in the management of mild HTN

Design: randomized, double-blind, placebo-controlled clinical trial

Inclusive criteria: men and women (45 – 70 yo); free of cardiovascular disease; diastolic BP was stage 1
All patients – diastolic BP 90 – 99 mmHg
All received nonpharmacologic treatment plus placebo or one of 5 drug classes

Nonpharmacologic treatment = weight loss, sodium restriction, alcohol intake reduction, exercise
treatment group had in addition antihypertensive meds

Results

Non-drug therapy lowered BP in both groups to some degree
Further reduction with drug treatment
Greater decrease in cardiovascular morbidity in drug treatment group after 5 years enrollment

(4) Meta-analysis of Drug Therapy in HTN

Stroke – 42% reduction
Coronary disease – 14% reduction

Nonpharmacologic Therapy

Aerobic exercise

Limitation of alcohol intake

Weight reduction

Multiple studies show significant ß in BP with 4.5 – 20 kg weight loss (methodologic flaws – non-randomized)

(placebo + weight reduction diet) vs (placebo + usual diet) Þ significant reduction in BP

independent of dietary salt intake

Salt restriction

Decreased salt intake Þ decreased BP

effect proportional to severity of HTN

80 – 100 mmol sodium diet will reduce BP in 50 – 60% of hypertensives

rank according to effectiveness Þ decreased weight > decreased alcohol > sodium intake, physical exercise > potassium intake, decreased fat intake, relaxation therapies

Suggested Approach to Treatment of Hypertension – JNCV

begin or continue lifestyle modifications Þ not at goal BP Þ initial drug choices Þ not at goal BP Þ substitute drug from different class (if no response or troublesome side effects) or add 2^nd drug from another class (if inadequate response but well tolerated) Þ not at goal BP Þ continue adding agents from other classes. Consider referral to a hypertension specialist

Pharmacologic Therapy – Eight Categories of Antihypertensive Drug Therapy

(1) Diuretics

Categories Þ thiazides and related sulfonamide diuretics; loop diuretics; potassium-sparing diuretics Þ excellent first line of defense drugs

Thiazide diuretics – work primarily by ß plasma volume Þ ß TPR

Advantages – effective, low cost; once a day dosing

Side effects – general (muscle cramps, impotence, gout); metabolic; electrolyte imbalance Þ hypokalemia, hyperuricemia, hyperlipidemia

(2) b-Adrenoreceptor Antagonists (Propranolol, Atenolol, Metoprolol) Þ ß cardiac output

Side effects: bronchospasm, cold extremities, fatigue, sleep disturbance, vivid dreams
well tolerated and effective

(3) Centrally acting a ₂-agonists (Clonidine, Methyldopa) – indirectly inhibit sympathetic vasoconstriction

stimulate a ₂ receptors in brainstem Þ decrease in central sympathetic outflow

Side effects Þ dry mouth, depression, sexual dysfunction, decreased mental acuity

not considered first line defense due to side effects

(4) a₁-Adrenoreceptor Antagonists (Prazosin, Doxazosin) – directly inhibit sympathetic vasoconstriction

Postsynaptic a ₁ blockade of vascular smooth muscle

Side effects: orthostatic hypotension, tachycardia, edema

Not for first line defense

(5) ACE inhibitors (Benazepril, Captopril, Enalapril, Fosinopril, Lisinopril, Ramipril) – inhib. vasoconst.; ß volume

Effect of Captopril on the RAA system Þ inhibits conversion of angiotensin I to angiotensin II Þ decreases blood pressure directly also indirectly by inhibiting salt retention through aldosterone

When combined with Thiazide diuretics Þ have better effects than either of the 2 by themselves (excellent combination therapy) Þ ameliorate biochemical side effects of Thiazides

Side effects: cough (5-15%), angioedema, fetal injury and death when administered in the 2^nd or 3^rd trimesters, hyperkalemia, hypotension, renal insufficiency

(6) Angiotensin II Receptor Antagonists (Losartan, Valsarten, Irbesartan) – inhib. vasoconstriction

Block binding of Angiotensin II to AT₁ Receptor
additionally, does not inhibit the breakdown of bradykinin which was seen in the ACE inhibitors
ARBs summary: effective antihypertensive agents, BP response at least equal to other classes, placebo-like adverse effects, true QD dosing (for some ARBs), no metabolic effects

(7) Calcium Channel Antagonists (Diltiazem, Amlodipine, Nicardipine, Nifedipine, Isradipine, Verapamil) – inhibit vasoconstriction

Mech of action: ß Ca⁺⁺ influx into vascular smooth cells Þ relax vascular smooth muscle Þ ß TPR

Especially effective in elderly and patients with low renin hypertension

Side effects Þ vasodilation-related (edema, flushing, headache); other (dizziness, GI disturbances – constipation, changes in HR – tachycardia)

(8) Vasodilators (Hydralazine, Minoxidil) – directly vasodilate

last line therapy due to side effects

Side effects: edema, reflex tachycardia; Hydralazine – lupus-like syndrome; Minoxidil – treatment for hair loss

Malignant HTN

severe HTN with at least grade 3 or grade 4 retinopathy (with retinal hemorrhages, exudates, and papilledema)

incidence – 1% of hypertensive populations

mortality – untreated 90% at 2 years

etiology – renal disease (70%), essential HTN (10%), other causes (20%)

therapy for asymptomatic malignant HTN: decrease BP over 24-48 hours; oral agents (Clonidine, etc.)

Associated Hypertensive Emergencies

severe hypertension with cerebrovascular or cardiovascular dysfunction
blood pressure – lowered within one hour
ex: hypertensive encephaolpathy, intracranial hemorrhage, acure MI, pulmaory edema, aortic dissection, eclampsia

therapy: immediate reduction of blood pressure; Nitroprusside, Labetalol, Nitroglycerin