HTN

DR
Vishvas
HTN Treatment
• Initial drug selection depends on the degree of BP elevation and the presence of compelling indications for
selected drugs.
• Most patients with stage 1 hypertension should be treated initially with a thiazide diuretic, angiotensin-
converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB), or calcium channel blocker
(CCB)

• Combination therapy is recommended for patients with stage 2 disease, with one of the agents being a
thiazide-type diuretic unless contraindications exist.

• Diuretics, ACE inhibitors, ARBs, and CCBs are primary agents acceptable as first-line options based on
outcome data demonstrating CV risk reduction benefits
• b-Blockers may be used either to treat a specific compelling indication or as combination therapy with a
primary antihypertensive agent for patients without a compelling indication.

• a1-Blockers, direct renin inhibitors, central a2-agonists, peripheral adrenergic antagonists, and direct
arterial vasodilators are alternatives that may be used in select patients after primary agents
Diuretics

• Thiazides are the preferred type of diuretic for treating hypertension, and all are equally effective in lowering
BP.

• Potassium-sparing diuretics are weak antihypertensives when used alone but provide an additive
hypotensive effect when combined with thiazide or loop diuretics. Moreover, they counteract the potassium-
and magnesium losing properties and perhaps glucose intolerance caused by other diuretics.

• Aldosterone antagonists (spironolactone, eplerenone) are also potassium- sparing diuretics but are more
potent antihypertensives with a slow onset of action (up to 6 weeks with spironolactone
• The reduction in plasma volume and stroke volume associated with diuresis decreases cardiac output and,
consequently, BP.
• The initial drop in cardiac output causes a compensatory increase in peripheral vascular resistance.

• When diuretics are combined with other antihypertensive agents, an additive hypotensive effect is usually
observed because of independent mechanisms of action.

• Side effects of thiazides include hypokalemia, hypomagnesemia, hypercalcemia, hyperuricemia,

hyperglycemia, hyperlipidemia, and sexual dysfunction.
• Loop diuretics have less effect on serum lipids and glucose, but hypocalcaemia may occur.
• Eplerenone has an increased risk for hyperkalemia and is contraindicated in patients with impaired renal
function or type 2 diabetes with proteinuria. Spironolactone may cause gynecomastia in up to 10% of
patients, but this effect occurs rarely with eplerenone.
Angiotensin-Converting Enzyme Inhibitors

• ACE facilitates production of angiotensin II, which has a major role in regulating arterial BP.

• ACE is distributed in many tissues and is present in several different cell types, but its principal location is in
endothelial cells.

• Therefore, the major site for angiotensin II production is in the blood vessels, not the kidney.
• ACE inhibitors block the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor and
stimulator of aldosterone secretion.
• ACE inhibitors also block the degradation of bradykinin and stimulate the synthesis of other vasodilating
substances including prostaglandin E2 and prostacyclin

• The fact that ACE inhibitors lower BP in patients with normal plasma renin activity suggests that bradykinin
and perhaps tissue production of ACE are important in hypertension.

• Starting doses of ACE inhibitors should be low with slow dose titration. Acute hypotension may occur at the
onset of ACE inhibitor therapy,
• especially in patients who are sodium- or volume-depleted, in heart failure exacerbation, very elderly, or on
concurrent vasodilators or diuretics.
• Patients with these risk factors should start with half the normal dose followed by slow dose titration
• ACE inhibitors decrease aldosterone and can increase serum potassium concentrations.
• Hyperkalemia occurs primarily in patients with chronic kidney disease or diabetes and in those also taking
ARBs, NSAIDs, potassium supplements, or potassium-sparing diuretics.

• GFR decrease because of inhibition of angiotensin II vasoconstriction

on efferent arterioles Scr are often increase.
• Dry cough occur in up to 20% of patient and though to inhibition of
bradykinin breakdown
Angiotensin II receptor blocker
• Angiotensin II is generated by the renin-angiotensin pathway (which involves ACE) and an alternative
pathway that uses other enzymes

• ACE inhibitors block only the renin-angiotensin pathway, whereas ARBs antagonize angiotensin II generated
by either pathway

• The ARBs directly block the angiotensin type 1 receptor that mediates the known effects of angiotensin II
(vasoconstriction, aldosterone release, sympathetic activation, antidiuretic hormone release, and constriction
of the efferent arterioles of the glomerulus).
• ARBs do not block the breakdown of bradykinin

• All drugs in this class have similar antihypertensive efficacy and fairly flat dose-response curves. The
addition of low doses of a thiazide diuretic can increase efficacy significantly.

• In patients with type 2 diabetes and nephropathy, ARB therapy has been shown to significantly reduce
progression of nephropathy. For patients with LV dysfunction, ARB therapy has also been shown to reduce
the risk of CV events when added to a stable regimen of a diuretic, ACE inhibitor, and Beta blocker or as
alternative therapy in ACE inhibitor-intolerant patients.
• S/E hyperkalemia, orthostatic hypotension, angioedema
• ARB should not be used in pregnancy
Calcium Channel Blocker
• CCBs cause relaxation of cardiac and smooth muscle by blocking
voltage sensitive calcium channels.
• There by reducing the entry of extracellular calcium into cells
• Vascular smooth muscle relaxation leads to vasodilation and a
corresponding reduction BP.
• Verapamil decrease HR, slow atrioventricular nodal conduction
• Diltiazem and verapamil can cause cardiac abnormalities such as
bradycardia, AV block and health failure.
• Both drug can cause anorexia, nausea and edema and hypotension
Beta- Blocker
• Extra hypotensive effect now know of this drug but may involves
decreased cardiac output through negative chronotropic and
inotropic effect on heart and inhibition of renin release from kidney.

• Atenolol, betaxolol, bisoprolol, and metoprolol are cardio selective at low doses and bind more
avidly to b1-receptors than to b2-receptors.
• As a result, they are less likely to provoke bronchospasm and vasoconstriction and may be safer than
nonselective b-blockers in patients with asthma, chronic obstructive pulmonary disease, diabetes,
• There are pharmacokinetic differences among b-blockers in first-pass metabolism,
serum half-lives, degree of lipophilicity, and route of elimination.

• Propranolol and metoprolol undergo extensive first-pass metabolism.

• Atenolol and nadolol have relatively long half-lives and are excreted renally; the
dosage may need to be reduced in patients with moderate to severe renal insufficiency.

• Even though the half-lives of the other b-blockers are much shorter, once-daily
administration still may be effective. b-Blockers vary in their lipophilic properties and
thus CNS penetration.
• Increases in serum lipids and glucose appear to be transient and of little clinical importance.

• b-Blockers increase serum triglyceride levels and decrease high-density lipoprotein cholesterol levels slightly.
b-Blockers with a-blocking properties (carvedilol and labetalol) do not affect serum lipid concentrations.
Alpha receptor blocker
• Prazosin, terazosin, and doxazosin are selective a1-receptor blockers that inhibit
catecholamine uptake in smooth muscle cells of the peripheral vasculature, resulting in
vasodilation.

• A potentially severe side effect is a first-dose phenomenon characterized by orthostatic

hypotension accompanied by transient dizziness or faintness, palpitations, and even syncope
within 1 to 3 hours of the first dose or after later dosage increases.
• Sodium and water retention can occur with chronic administration. These agents are most
effective when given with a diuretic to maintain antihypertensive efficacy and minimize
potential edema.
• Because data suggest that doxazosin (and probably other a1-receptor blockers) are not as
protective against CV events as other therapies, they should be reserved as alternative agents
for unique situations, such as men with benign prostatic hyperplasia.
Direct Renin Inhibitor
• Aliskiren
blocks the renin-angiotensin-aldosterone system at its point of a
activation, which results in reduced plasma renin activity and BP.

• It provides BP reductions comparable to an ACE inhibitor, ARB, or

CCB.
• It also has additive antihypertensive effects when used in combination
with thiazides, ACE inhibitors, ARBs, or CCBs. It is approved for
monotherapy or in combination with other agents.
• Many of the cautions and adverse effects seen with ACE inhibitors and
ARBs apply to aliskiren. It is contraindicated in pregnancy.

• At this time, aliskiren should be used only as an alternative therapy

because of the lack of long-term studies evaluating CV event
reduction and its significant cost compared to generic agents with
outcomes data.
Central α2-Agonists
• Clonidine, guanabenz, guanfacine, and methyldopa

• lower BP primarily by stimulating α2-adrenergic receptors in the

brain, which reduces sympathetic outflow from the vasomotor center
and increases vagal tone.

• Stimulation of presynaptic α2-receptors peripherally may contribute

to the reduction in sympathetic tone.
• Consequently, there may be decreases in heart rate, cardiac output,
total peripheral resistance, plasma renin activity, and baroreceptor
reflexes.

• Chronic use results in sodium and fluid retention. Other side effects
may include depression, orthostatic hypotension, dizziness, and
anticholinergic effects.
• Abrupt cessation may lead to rebound hypertension, which is thought
to result from a compensatory increase in norepinephrine release
that follows discontinuation of presynaptic α-receptor stimulation.

• However the drug should be quickly discontinued if persistent

elevation in serum hepatic transaminase or alkaline phosphate are
detected.
• Many research suggest that methyldopa can cause hepatitis and
hemolytic anemia
Direct arterial vasodilation
• Hydralazine and minoxidil cause direct arteriolar smooth muscle
relaxation.
• Compensatory activation of baroreceptor reflexes results in increased
sympathetic outflow from the vasomotor center, producing an
increase in heart rate, cardiac output, and renin release.
• Consequently, the hypotensive effectiveness of direct vasodilators
diminishes over time unless the patient is also taking a sympathetic
inhibitor and a diuretic.
• All patients taking these drugs for long-term hypertension therapy
should first receive both a diuretic and a β-blocker.
• The diuretic minimizes the side effect of sodium and water retention.
• Direct vasodilators can precipitate angina in patients with underlying
coronary artery disease unless the baroreceptor reflex mechanism is
completely blocked with a β-blocker.
• Nondihydropyridine CCBs can be used as an alternative to β-blockers
in patients with contraindications to β-blockers.

• Hydralazine may cause a dose-related, reversible lupus-like syndrome,

which is more common in slow acetylators.
• Lupus-like reactions can usually be avoided by using total daily doses
of less than 200 mg.
• Other hydralazine side effects include dermatitis, drug fever,
peripheral neuropathy, hepatitis, and vascular headaches.

• For these reasons, hydralazine has limited usefulness in the treatment

of hypertension.

• However, it may be useful in patients with severe chronic kidney

disease and in kidney failure.
• Minoxidil is a more potent vasodilator than hydralazine, and the
compensatory increases in heart rate, cardiac output, renin release,
and sodium retention are more dramatic.

• Severe sodium and water retention may precipitate congestive heart

failure.
• Minoxidil also causes reversible hypertrichosis on the face, back, and
chest
COMPELLING INDICATIONS

• The compelling indications identified by JNC 7 represent specific comorbid

conditions for which clinical trial data support using specific antihypertensive
drug classes to treat both hypertension and the compelling indication
• Left Ventricular Dysfunction (Systolic Heart Failure):
• ACE inhibitor with diuretic therapy is recommended as the first-line regimen of
choice.
• ACE inhibitors have numerous outcome data showing reduced CV morbidity and
mortality. Diuretics provide symptomatic relief of edema by inducing diuresis.
• Loop diuretics are often needed, especially in patients with more advanced
disease.
• Because of the high renin status of patients with heart failure, ACE
inhibitors should be initiated at low doses to avoid orthostatic
hypotension.
• b Blocker therapy is appropriate to further modify disease in LV
dysfunction and is a component of this first-line regimen (standard
therapy) for these patients.
• Because of the risk of exacerbating heart failure, they must be started
in very low doses and titrated slowly to high doses-based tolerability.
Bisoprolol, carvedilol, and metoprolol succinate are the only beta-
blockers proven to be beneficial in LV dysfunction.
• ARBs are acceptable as alternative therapy for patients who cannot
tolerate ACE inhibitors and possibly as add-on therapy for those
already receiving a standard three-drug regimen

• An aldosterone antagonist may be considered in addition to a

diuretic, ACE inhibitor or ARB, and b-blocker. Regimens employing
both an aldosterone antagonist and ARB are not recommended
because of the potential risk of severe hyperkalemia.
Post myocardial Infarction

• b-Blocker and ACE inhibitor therapy is recommended. b- Blockers decrease cardiac adrenergic stimulation
and reduce the risk of a subsequent MI or sudden cardiac death.

• ACE inhibitors improve cardiac function and reduce CV events after MI. ARBs are alternatives to ACE
inhibitors in postmyocardial patients with LV dysfunction.

• The aldosterone antagonist eplerenone reduces CV morbidity and mortality in patients soon after an acute MI
Coronary Artery Disease

• b-Blockers are first-line therapy in chronic stable angina and have the ability to reduce BP, improve
myocardial consumption, and decrease demand

• Long-acting CCBs are either alternatives (the no dihydropyridines verapamil and diltiazem) or add-on
therapy (dihydropyridines) to b-blockers in chronic stable angina.

• Once ischemic symptoms are controlled with b-blocker and/or CCB therapy, other antihypertensive drugs
(e.g., ACE inhibitor, ARB) can be added to provide additional CV risk reduction.

• For acute coronary syndromes, first-line therapy should consist of a b- blocker and ACE inhibitor; the
combination lowers BP, controls acute ischemia, and reduces CV risk.
Diabetes Mellitus

• The BP goal in diabetes is less than 130/80 mm Hg.

• All patients with diabetes and hypertension should be treated with either an ACE inhibitor or an ARB. Both
classes provide nephroprotection and reduced CV risk.

• A thiazide-type diuretic is recommended as the second agent to lower BP and provide additional CV risk
reduction

• CCBs are useful add-on agents for BP control in hypertensive patients with diabetes. Limited data suggest
that no dihydropyridines may have more renal protective effects than dihydropyridines
Chronic Kidney Disease

• Either an ACE inhibitor or ARB is recommended as first-line therapy to control BP and preserve kidney
function in chronic kidney disease. Some data indicate that the combination of an ACE inhibitor and ARB
may be more effective than either agent alone. However, routine use of the combination is controversial

• Because these patients usually require multiple-drug therapy, diuretics and a third antihypertensive drug class
(e.g., b-blocker, CCB) are often needed.
Older People

• Elderly patients may present with either isolated systolic hypertension or an elevation in both SBP and DBP.
Epidemiologic data indicate that CV morbidity and mortality are more closely related to SBP than to DBP in
patients 50 years of age and older.

• Diuretics and ACE inhibitors provide significant benefits and can be used safely in the elderly, but smaller-
than-usual initial doses might be needed, and dosage titrations should occur over a longer period to minimize
the risk of hypotension.

• Centrally acting agents and b-blockers should generally be avoided or used with caution because they are
frequently associated with dizziness and postural hypotension.
Children and Adolescents

• Secondary hypertension is much more common in children than in adults. Kidney disease (e.g.,
pyelonephritis, glomerulonephritis) is the most common cause of secondary hypertension in children.

• Medical or surgical management of the underlying disorder usually restores normal BP.

• Nonpharmacologic treatment (particularly weight loss in obese children) is the cornerstone of therapy of
primary hypertension

• ACE inhibitors, ARBs, b-blockers, CCBs, and thiazide-type diuretics are all acceptable drug therapy choices
• ACE inhibitors, ARBs, and direct renin inhibitors are contraindicated in sexually active girls because of
potential teratogenic effect and in those who might have bilateral renal artery stenosis ( Heart valve disease)
Pregnant Women

• Preeclampsia, defined as BP ≥140/90 mm Hg that appears after 20 weeks’ gestation accompanied by new-
onset proteinuria (≥300 mg/24 hours), can lead to life-threatening complications for both the mother and
fetus

• Definitive treatment of preeclampsia is delivery, and this is indicated if pending or frank eclampsia
(preeclampsia and convulsions) is present.

• management consists of restricting activity, bedrest, and close monitoring.

• Salt restriction or other measures

• Antihypertensives are used prior to induction of labor if the DBP is >105–110 mm Hg, with a target DBP of
95–105 mm Hg.

• IV hydralazine is most commonly used; IV labetalol is also effective.

• Methyldopa is considered the drug of choice because of experience with its use. b-Blockers, labetalol, and
CCBs are also reasonable alternatives.

• ACE inhibitors and ARBs are known teratogens and are absolutely contraindicated. The direct renin inhibitor
aliskiren also should not be used in pregnancy.
HYPERTENSIVE URGENCIES AND EMERGENCIES

• Acute administration of a short-acting oral drug (captopril, clonidine, or labetalol) followed by careful
observation for several hours to ensure a gradual BP reduction is an option.

• ✓ Oral captopril doses of 25 to 50 mg may be given at 1- to 2-hour intervals. The onset of action is 15 to 30
minutes.

✓ For treatment of hypertensive rebound after withdrawal of clonidine, 0.2 mg is given initially, followed
by 0.2 mg hourly until the DBP falls below 110 mm Hg or a total of 0.7 mg has been administered; a single dose
may be sufficient.

✓ Labetalol can be given in a dose of 200 to 400 mg, followed by additional doses every 2 to 3 hours.
Case study
• A 59-year-old man with type 2 diabetes presents with concerns about
high blood pressure (BP). At a recent visit to his dentist, he was told
his BP was high. He was reclining in the dentist’s chair when his BP
was taken, but he doesn’t remember the exact reading. He has no
symptoms. He has never taken medications for high BP. He takes
metformin for type 2 diabetes.
• His BP is measured once at 146/95 mm Hg in the left arm while
sitting. Physical exam is unremarkable except for obesity.
• A 62 year old African-American woman with prediabetes presents for
her annual physical. She has no complaints. The average of 2 BP
readings in her right arm is BP 143/88. Her physical exam is
unremarkable except for obesity. She has no history of myocardial
infarction, stroke, kidney disease, or heart failure. After the visit, she
measures her BP at home and returns 1 month later. The average BP
from multiple clinic and home readings is 138/86.
• Her total cholesterol is 260 mg/dL, HDL 42 mg/dL, and LDL 165
mg/dL. She does not smoke.