1. Hypertension

2. Hypertension
• Hypertension is defined as persistently elevated arterial blood pressure
(BP).
• The seventh report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure (JNC7)
classifies adult BP as shown in Table 10–1.
TABLE 10–1 Classification of Blood Pressure in Adults
Classification Systolic (mm Hg) Diastolic (mm Hg)
Normal <120 and <80
Prehypertension 120–139 or 80–89
Stage 1 hypertension 140–159 or 90–99
Stage 2 hypertension ≥160 or ≥100

3. Hypertension
PATHOPHYSIOLOGY

4. Hypertension
• PATHOPHYSIOLOGY
• Hypertension may result from a specific cause (secondary
hypertension) or from an unknown etiology (primary or essential
hypertension).
• Secondary hypertension (<10% of cases) is usually caused by chronic
kidney disease (CKD) or renovascular disease.

5. Hypertension
• PATHOPHYSIOLOGY
• Other conditions are
- Cushing syndrome,
- coarctation of the aorta,
- obstructive sleep apnea,
- hyperparathyroidism,
- pheochromocytoma,
- primary aldosteronism, and
- hyperthyroidism.

6. Hypertension
• PATHOPHYSIOLOGY
• Some drugs that may increase BP include
corticosteroids,
estrogens,
nonsteroidal anti-inflammatory drugs (NSAIDs),
amphetamines,
sibutramine,
cyclosporine,
tacrolimus,
erythropoietin, and
venlafaxine.

7. Hypertension
• PATHOPHYSIOLOGY
• Factors contributing to development of primary hypertension include:
• Humoral abnormalities involving the renin–angiotensin–aldosterone system (RAAS),
natriuretic hormone, or insulin resistance and hyperinsulinemia;
• Disturbance in the CNS, autonomic nerve fibers, adrenergic receptors, or
baroreceptors;
• Abnormalities in renal or tissue autoregulatory processes for sodium excretion,
plasma volume, and arteriolar constriction;
• Deficiency in synthesis of vasodilating substances in vascular endothelium
(prostacyclin, bradykinin, and nitric oxide) or excess vasoconstricting substances
(angiotensin II, endothelin I);
• High sodium intake or lack of dietary calcium.

8. Hypertension
• PATHOPHYSIOLOGY
• Main causes of death are cerebrovascular accidents, cardiovascular
(CV) events, and renal failure.
• Probability of premature death correlates with the severity of BP
elevation.

9. Hypertension
CLINICAL PRESENTATION

10. Hypertension
• CLINICAL PRESENTATION
• Patients with uncomplicated primary hypertension are usually
asymptomatic initially.
• Patients with secondary hypertension may have symptoms of the underlying
disorder.
• Patients with pheochromocytoma may have headaches, sweating,
tachycardia, palpitations, and orthostatic hypotension.
• In primary aldosteronism, hypokalemic symptoms of muscle cramps and
weakness may be present.
• Patients with Cushing syndrome may have weight gain, polyuria, edema,
menstrual irregularities, recurrent acne, or muscular weakness in addition to
classic features (moon face, buffalo hump, and hirsutism).

11. Hypertension
DIAGNOSIS

12. Hypertension
• Diagnosis
• Elevated BP may be the only sign of primary hypertension on physical
examination.
• Diagnosis should be based on the average of two or more readings
taken at each of two or more clinical encounters.
• Signs of end-organ damage occur primarily in the eye, brain, heart,
kidneys, and peripheral blood vessels.

13. Hypertension
• Diagnosis
• Laboratory tests:
Blood urea nitrogen (BUN)/serum creatinine,
fasting lipid panel,
fasting blood glucose,
serum electrolytes (sodium and potassium),
spot urine albumin-to-creatinine ratio, and
estimated glomerular filtration rate (GFR, using the Modification of
Diet in Renal Disease [MDRD] equation).
A 12-lead electrocardio- gram (ECG) should also be obtained.

14. Hypertension
• Diagnosis
• Laboratory tests to diagnose secondary hypertension:
Plasma norepinephrine and urinary metanephrine levels for
pheochromocytoma,
plasma and urinary aldosterone concentrations for primary
aldosteronism,
plasma renin activity, captopril stimulation test,
renal vein renin, and
renal artery angiography for renovascular disease

15. Hypertension
TREATMENT

16. Hypertension
• TREATMENT
• Goals of Treatment: The overall goal is to reduce morbidity and
mortality by the least intrusive means possible.
• JNC 7 guidelines recommend goal BP
 less than 140/90 mm Hg for most patients,
 less than 140/80 mm Hg for patients with diabetes mellitus, and
 less than 130/80 mm Hg for patients with CKD who have persistent
albuminuria (>30 mg urine albumin excretion per 24 hours).

17. Hypertension
• TREATMENT
• NONPHARMACOLOGIC THERAPY
 Lifestyle modifications:
1) weight loss if overweight,
2) adoption of the Dietary Approaches to Stop Hypertension (DASH) eating plan,
3) dietary sodium restriction ideally to 1.5 g/day,
4) regular aerobic physical activity,
5) moderate alcohol consumption (two or fewer drinks per day), and
6) smoking cessation.
• Lifestyle modification alone is sufficient for most patients with prehypertension
but inadequate for patients with hypertension and additional CV risk factors or
hypertension-associated target-organ damage.

18. Hypertension
• TREATMENT
• PHARMACOLOGIC THERAPY
• Initial drug selection depends on the degree of BP elevation and presence of
compelling indications for selected drugs.
• Angiotensin-Converting Enzyme (ACE) inhibitors,
• Angiotensin II Receptor Block- ers (ARBs),
• Calcium Channel Blockers (CCBs), and
• thiazide diuretics are acceptable first-line options.
• β-Blockers are used to either treat a specific compelling indication or as
combination therapy with a first-line antihypertensive agent for patients without
a compelling indication (Table 10–2)

19. Hypertension
• TREATMENT
• PHARMACOLOGIC THERAPY
• Most patients with stage 1 hypertension should be treated initially with a
first-line antihypertensive drug or a two-drug combination (Fig. 10–1).
• Combination therapy is recommended for patients with stage 2
hypertension, preferably with two first-line agents.
• There are six compelling indications where specific antihypertensive drug
classes provide unique benefits (Fig. 10–2).

20. Hypertension
• TREATMENT
• PHARMACOLOGIC THERAPY
• Most patients with stage 1 hypertension should be treated initially with a
first-line antihypertensive drug or a two-drug combination (Fig. 10–1).
• Combination therapy is recommended for patients with stage 2
hypertension, preferably with two first-line agents.
• There are six compelling indications where specific antihypertensive drug
classes provide unique benefits (Fig. 10–2).

21. Hypertension
• TREATMENT
• PHARMACOLOGIC THERAPY
• Other antihypertensive drug classes
 α1-blockers,
 direct renin inhibitors,
 central α2-agonists,
 peripheral adrenergic antagonists, and
 direct arterial vasodilators
• are alternatives that may be used for select patients after first-line agents (Table 10 – 3).

22. Hypertension
TREATMENT
Angiotensin-Converting Enzyme Inhibitors
(ACE inhibitors)

23. Hypertension
• Angiotensin-Converting Enzyme Inhibitors ( ACE inhibitors )

24. Hypertension
• Angiotensin-Converting Enzyme Inhibitors ( ACE inhibitors )

25. Hypertension
• Angiotensin-Converting Enzyme Inhibitors ( ACE inhibitors )
• ACE inhibitors are a first-line option, and if they are not the first agent used,
they should be the second agent tried in most patients.
• ACE inhibitors block conversion of angiotensin I to angiotensin II, a potent
vasoconstrictor and stimulator of aldosterone secretion.
• ACE inhibitors also block degradation of bradykinin and stimulate synthesis
of other vasodilating substances, including prostaglandin E2 and
prostacyclin.

26. Bradykinin
• Bradykinin is a protein that promotes inflammation.
• It causes arterioles to dilate (enlarge) via the release
of prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing
factor and makes veins constrict, via prostaglandin F2, thereby leading
to leakage into capillary beds, due to the increased pressure in the
capillaries.
• Bradykinin is a physiologically and pharmacologically active peptide
of the kinin group of proteins, consisting of nine amino acids.
• A class of drugs called angiotensin converting enzyme
inhibitors (ACE inhibitors) increase bradykinin levels by inhibiting its
degradation, thereby increasing its blood pressure lowering effect.

27. Hypertension
• Angiotensin-Converting Enzyme Inhibitors ( ACE inhibitors )
• Starting doses should be low with slow dose titration.
• Acute hypotension may occur at the onset of therapy, especially in patients
who are sodium or volume depleted, in HF exacerbation (worsening), very
elderly, or on concurrent vasodilators or diuretics.

28. Hypertension
• Angiotensin-Converting Enzyme Inhibitors ( ACE inhibitors )
• Start administering doses in such patients, using 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 CKD or those also taking
potassium supplements, potassium-sparing diuretics, ARBs, or a direct renin
inhibitor.

29. Hypertension
• Angiotensin-Converting Enzyme Inhibitors ( ACE inhibitors )
• GFR declines in patients receiving ACE inhibitors because of inhibition of
angiotensin II vasoconstriction on efferent arterioles.
• Serum creatinine concentrations often increase, but modest elevations (eg,
absolute increases <1 mg/dL [88 μmol/L]) do not warrant treatment changes.
• Discontinue therapy or reduce dose if larger increases occur.

30. Hypertension
• Angiotensin-Converting Enzyme Inhibitors ( ACE inhibitors )
• Angioedema occurs in fewer than 1% of patients.
• Drug withdrawal is necessary, and some patients may require drug treatment
and/or emergent intubation.
• An ARB can generally be used in patients with a history of ACE inhibitor–
induced angioedema, with careful monitoring.
• A persistent dry cough occurs in up to 20% of patients and is thought to be
due to inhibition of bradykinin breakdown.
• ACE inhibitors (as well as ARBs and direct renin inhibitors) are
contraindicated in pregnancy.

31. Hypertension
TREATMENT
Angiotensin II Receptor Blockers
(ARB)

32. Hypertension
Angiotensin II Receptor Blockers (ARB)

35. Hypertension
Angiotensin II Receptor Blockers (ARB)
• Angiotensin II is generated by the renin–angiotensin pathway (which
involves ACE) and an alternative pathway that uses other enzymes such as
chymases.
• ACE inhibitors block only the renin–angiotensin pathway, whereas ARBs
antagonize angiotensin II generated by either pathway.
• The ARBs directly block the angiotensin II type 1 receptor that mediates the
effects of angiotensin II.

36. Hypertension
Angiotensin II Receptor Blockers (ARB)
• Unlike ACE inhibitors, ARBs do not block bradykinin breakdown. Although
this accounts for the lack of cough as a side effect, there may be negative
consequences because some of the antihypertensive effect of ACE inhibitors
may be due to increased levels of bradykinin.
• All ARBs have similar antihypertensive efficacy and fairly flat dose-response
curves.

37. Hypertension
Angiotensin II Receptor Blockers (ARB)
• Addition of a CCB or thiazide diuretic significantly increases
antihypertensive efficacy.
• ARBs have a low incidence of side effects. Like ACE inhibitors, they may
cause renal insufficiency, hyperkalemia, and orthostatic hypotension.
• ARBs are contraindicated in pregnancy

38. Hypertension
TREATMENT
Calcium channel blockers (CCBs)

39. Hypertension
• Calcium channel blockers (CCBs)

42. Hypertension
• Calcium channel blockers (CCBs)
• Calcium channel blockers (CCBs) cause relaxation of cardiac and smooth
muscle by blocking voltage-sensitive calcium channels, thereby reducing
entry of extracellular calcium into cells.
• This leads to vasodilation and a corresponding reduction in BP.
• Dihydropyridine calcium channel antagonists may cause reflex sympathetic
activation, and all agents (except amlodipine and felodipine) may have
negative inotropic effects.

43. Hypertension
• Calcium channel blockers (CCBs)
• Verapamil decreases heart rate, slows atrioventricular (AV) nodal conduction, and
produces a negative inotropic effect that may precipitate HF in patients with
borderline cardiac reserve.
• Diltiazem decreases AV conduction and heart rate to a lesser extent than verapamil.
• Diltiazem and verapamil can cause cardiac conduction abnormalities such as
bradycardia, AV block, and HF.
• Both can cause anorexia, nausea, peripheral edema, and hypotension.

44. Hypertension
• Calcium channel blockers (CCBs)
• Verapamil causes constipation in ~7% of patients.
• Dihydropyridines cause a baroreceptor-mediated reflex increase in heart rate
because of potent peripheral vasodilating effects.
• Dihydropyridines do not decrease AV node conduction and are not effective
for treating supraventricular tachyarrhythmias.

45. Hypertension
• Calcium channel blockers (CCBs)
• Short-acting nifedipine may rarely increase frequency, intensity, and duration
of angina in association with acute hypotension.
• This effect may be obviated by using sustained-release formulations of
nifedipine or other dihydropyridines.
• Other side effects of dihydropyridines are dizziness, flushing, headache,
gingival hyperplasia, and peripheral edema.

46. Hypertension
TREATMENT
Diuretics

47. Hypertension
• Diuretics

48. Hypertension
• Diuretics
• Acutely, diuretics lower BP by causing diuresis.
• The reduction in plasma volume and stroke volume associated with diuresis decreases
cardiac output and BP.
• The initial drop in cardiac output causes a compensatory increase in peripheral vascular
resistance.
• With chronic therapy, extracellular fluid volume and plasma volume return to near
pretreatment (normal) levels, and peripheral vascular resistance falls below baseline.
• Reduced peripheral vascular resistance is responsible for the long-term hypotensive
effects.

49. •Thiazide diuretics

50. Hypertension
• Diuretics
• Thiazide diuretics are the preferred type of diuretic for most hypertensive
patients. They mobilize sodium and water from arteriolar walls, which may
contribute to decreased peripheral vascular resistance and lowered BP.
• Side effects of thiazides include hypokalemia, hypomagnesemia,
hypercalcemia, hyperuricemia, hyperglycemia, dyslipidemia, and sexual
dysfunction.

51. Thiazide diuretics - MOA
• Thiazide diuretics control hypertension in part by
inhibiting reabsorption of sodium (Na+) and chloride (Cl−) ions from
the distal convoluted tubules in the kidneys by blocking the thiazide-
sensitive Na+-Cl− symporter.
• Symporters are proteins that simultaneously transport two
molecules across a membrane in the same direction.

52. Thiazide diuretics - MOA

53. Thiazide diuretics - MOA
• The sodium-chloride symporter (also known as Na+-
Cl− cotransporter, NCC or NCCT, or as the thiazide-sensitive Na+-
Cl− cotransporter or TSC) in kidney which has the function of
reabsorbing sodium and chloride ions from the tubular fluid into the
cells of the distal convoluted tubule of the nephron.

54. Thiazide diuretics - MOA
• The term "thiazide" is also often used for drugs with a similar action
that do not have the thiazide chemical structure, such
as chlorthalidone and metolazone.
• These agents are more properly termed thiazide-like diuretics.

55. Thiazide diuretics - MOA
• Thiazide diuretics also increase calcium reabsorption at the distal
tubule.
• By lowering the sodium concentration in the tubule epithelial cells,
thiazides indirectly increase the activity of the
basolateral Na+/Ca2+ antiporter to maintain intracellular Na+ level,
facilitating Ca2+ to leave the epithelial cells into the renal interstitium.

56. Thiazide diuretics - MOA
• Thus, intracellular Ca2+ concentration is decreased, which allows more Ca2+ from
the lumen of the tubules to enter epithelial cells via apical Ca2+-selective channels
(TRPV5).
• In other words, less Ca2+ in the cell increases the driving force for reabsorption
from the lumen.
• Thiazides are also thought to increase the reabsorption of Ca2+ by a mechanism
involving the reabsorption of sodium and calcium in the proximal tubule in
response to sodium depletion.
• Some of this response is due to augmentation of the action of parathyroid
hormone.

57. •Loop diuretics

58. Hypertension
• Diuretics
• Loop diuretics are more potent for inducing diuresis but are not ideal
antihypertensives unless relief of edema is also needed. Loops are often
preferred over thiazides in patients with CKD when estimated GFR is less
than 30 mL/min/1.73 m2.
• Loop diuretics have less effect on serum lipids and glucose, but hypokalemia
is more pronounced, and hypocalcemia may occur.

59. Loop diuretics
• Loop diuretics are diuretics that act on the Na-K-Cl cotransporter
(symporter) along the thick ascending limb of the loop of Henle in
the kidney.
• They are primarily used in medicine to
treat hypertension and edema often due to congestive heart
failure or chronic kidney disease.
• While thiazide diuretics are more effective in patients with normal
kidney function, loop diuretics are more effective in patients with
impaired kidney function.

60. Loop diuretics

61. Loop diuretics
• Loop diuretics act on the Na+-K+-2Cl− symporter (NKCC2) in the
thick ascending limb of the loop of Henle to inhibit sodium, chloride
and potassium reabsorption.

62. •Pottasium sparing diuretics
(Aldosterone antagonist)

63. Hypertension
• Diuretics
• Potassium-sparing diuretics (Aldosterone antagonist) are weak
antihypertensives when used alone and provide minimal additive effect when
combined with a thiazide or loop diuretic. Their primary use is in
combination with another diuretic to counteract potassium-wasting
properties.
• Potassium-sparing diuretics may cause hyperkalemia, especially in patients
with CKD or diabetes and in patients receiving concurrent treatment with an
ACE inhibitor, ARB, direct renin inhibitor, or potassium supplement.
Spironolactone
Eplerenone
(Weak antihypertensive)
(Potent antihypertensive)
(Potent antihypertensive)
25 -100
25 -50 2
3
(Aldosterone antagonist)

64. Potassium sparing diuretics
(Aldosterone antagonist)

65. Potassium-sparing diuretics (Aldosterone antagonist)
• Potassium-sparing diuretics are drugs that increase diuresis
(urination) without the loss of potassium.
• They are generally weak diuretics and work by interfering with the
sodium-potassium exchange in the distal convoluted tubule of the
kidneys or as an antagonist at the aldosterone receptor.

66. •Aldosterone antagonists
(Potassium-sparing diuretics)

67. Hypertension
• Diuretics
• Aldosterone antagonists (Potassium-sparing diuretics) (spironolactone and
eplerenone) are also potassium sparing diuretics but are more potent
antihypertensives with a slow onset of action (up to 6 weeks with
spironolactone).
• Spironolactone may cause gynecomastia in up to 10% of patients; this effect
occurs rarely with eplerenone.
• Eplerenone has an increased risk for hyperkalemia and is contraindicated in
patients with impaired renal function or type 2 diabetes with proteinuria.

68. Aldosterone antagonist
Potassium sparing diuretics

69. Gynecomastia
• Gynecomastia (guy-nuh-koh-MAS-tee-uh) is an increase in the
amount of breast gland tissue in boys or men, caused by an imbalance
of the hormones estrogen and testosterone.
• Gynecomastia can affect one or both breasts, sometimes unevenly.

70. Hypertension
TREATMENT
- COMPELLING INDICATIONS

72. Hypertension
TREATMENT
β-Blockers

73. Hypertension
 β-Blockers

74. Hypertension
 β-Blockers
• β-Blockers are only considered appropriate first-line agents to treat specific
compelling indications (eg, post-MI [myocardial infarction], coronary artery
disease).
• Their hypotensive mechanism may involve decreased cardiac output through
negative chronotropic and inotropic effects on the heart and inhibition of
renin release from the kidney.

75. Adrenergic receptors

76. Adrenergic receptors

77. Hypertension
 β-Blockers

78. Hypertension
 β-Blockers
 Cardioselective β-Blockers

79. Hypertension
 β-Blockers
 Cardioselective β-Blockers
• Atenolol, betaxolol, bisoprolol, and metoprolol are cardioselective at low doses and bind
more avidly to β1 -receptors than to β2 -receptors.
• As a result, they are less likely to provoke (induce) bronchospasm and vasoconstriction
and may be safer than nonselective β-blockers in patients with asthma, chronic obstructive
pulmonary disease (COPD), diabetes, and peripheral arterial disease (PAD).
• Cardioselectivity is a dose-dependent phenomenon, and the effect is lost at higher doses.

80. Hypertension
 β-Blockers
 Nonselective β-Blockers
• Nonselective beta blockers display both β1 and β2 antagonism.

81. Hypertension
 β-Blockers
 Cardioselective & non selective β-Blockers
• Atenolol and nadolol have relatively long half-lives and are excreted renally;
the dosage may need to be reduced in patients with renal insufficiency.
• Even though the half-lives of other β-blockers are shorter, once-daily
administration still may be effective.

82. Hypertension
 β-Blockers
 Sympathomimetic β-Blockers

83. Hypertension
 β-Blockers
 Sympathomimetic β-Blockers
• Acebutolol, carteolol, penbutolol, and pindolol possess intrinsic sympathomimetic
activity (ISA) or partial β-receptor agonist activity (β1 – receptor agonist activity).
• When sympathetic tone is low, as in resting states, β-receptors are partially stimulated, so resting heart rate, cardiac output, and peripheral blood flow are
not reduced when receptors are blocked.
• These agents are capable of exerting low-level agonist activity at the β-adrenergic receptor
(β1 – receptor) while simultaneously acting as a receptor site antagonist.
• These agents, therefore, may be useful in individuals exhibiting
excessive bradycardia with sustained beta blocker therapy.

84. Hypertension
 β-Blockers
 Sympathomimetic β-Blockers
• Theoretically, these drugs may have advantages in patients with HF or sinus
bradycardia.
• Unfortunately, they do not reduce CV events and they may increase risk after
MI or in those with high coronary disease risk.
• Thus, agents with ISA are rarely needed.

85. Hypertension
 β-Blockers
 Mixed α- and β-blockers

86. Hypertension
 β-Blockers
 Mixed α- and β-blockers
• Alpha and beta dual receptor blockers for treatment of high blood pressure.
• Alpha and beta dual receptor blockers are a subclass of beta blockers which
are commonly used to treat high blood pressure (BP).

87. Hypertension
 β-Blockers
 Cardioselective and vasodilatory:
 Nebivolol lowers BP with an additional effect on the inner lining of blood vessels to
release a compound called nitric oxide that can relax blood vessels.
 But Cardioselective drugs (ex: atenolol) is a blood pressure reducing agent without the
ability to release nitric oxide and effect additional blood vessel relaxation.

88. Hypertension
 β-Blockers
Adverse effects of β-Blockers
• Myocardial side effects include bradycardia, AV conduction abnormalities,
and acute HF.
• Blocking β2 -receptors in arteriolar smooth muscle may cause cold
extremities and aggravate PAD (peripheral arterial disease) or Raynaud
phenomenon because of decreased peripheral blood flow.

89. Hypertension
 β-Blockers
Adverse effects of β-Blockers
• Abrupt cessation of β-blocker therapy may produce unstable angina, MI, or even
death in patients with coronary disease.
• In patients without heart disease, abrupt discontinuation of β-blockers may be
associated with tachycardia, sweating, and generalized malaise in addition to
increased BP.
• For these reasons, the dose should always be tapered gradually over 1 to 2 weeks
before discontinuation.

90. Hypertension
TREATMENT
α1-Receptor Blockers

91. Hypertension
 α1-Receptor Blockers

92. Hypertension
 α1-Receptor Blockers
Prazosin, terazosin, and doxazosin are selective α1 -receptor
blockers that inhibit catecholamine (dopamine, norepinephrine, and
epinephrine) uptake in smooth muscle cells of peripheral vasculature,
resulting in vasodilation.
A first-dose phenomenon characterized by orthostatic hypotension
accompanied by transient dizziness or faintness, palpitations, and
even syncope (temporary loss of consciousness caused by a fall in
blood pressure) may occur within 1 to 3 hours of the first dose or
after later dosage increases.

93. Catecholamine
• A type of neurohormone (dopamine,
norepinephrine, and epinephrine) (a chemical
that is made by nerve cells and used to send signals
to other cells).
• High levels of catecholamines cause high blood
pressure which can lead to headaches, sweating,
pounding of the heart, pain in the chest, and
anxiety.

94. Orthostatic hypotension
• Orthostatic hypotension — also called postural hypotension — is a
form of low blood pressure that happens when standing after sitting or
lying down.
• Orthostatic hypotension is a form of low blood pressure caused
by blood vessels failing to constrict when the body takes an
upright position.

95. Hypertension
 α1-Receptor Blockers
The patient should take the first dose (and subsequent first
increased doses) at bedtime.
Occasionally, orthostatic dizziness persists with chronic
administration.
Sodium and water retention can occur; these agents are
most effective when given with a diuretic to maintain
antihypertensive efficacy and minimize edema.

96. Hypertension
 α1-Receptor Blockers
Because doxazosin (and probably other α1 -receptor
blockers) may not be 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.
If used to lower BP in this situation, they should only be
used in combination with first-line antihypertensives.

97. Benign prostatic hyperplasia
• Benign prostatic hyperplasia (BPH) — also called prostate gland
enlargement — is a common condition as men get older.
• An enlarged prostate gland can cause uncomfortable urinary symptoms,
such as blocking the flow of urine out of the bladder.
• It can also cause bladder, urinary tract or kidney problems.

98. Hypertension
TREATMENT
Central α2-Agonists

99. Hypertension
 Central α2-Agonists
Guanabenz
Guanfacine

100. Hypertension
 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 reduced sympathetic tone.
Consequently, there may be decrease in heart rate, cardiac
output, total peripheral resistance, plasma renin activity, and
baroreceptor reflexes.
Chronic use results in sodium and fluid retention.

101.  Vasomotor center
• The vasomotor center (VMC) is a portion of the medulla oblongata.
• Together with the cardiovascular center and respiratory center, it regulates blood pressure.
• It also has a more minor role in other homeostatic processes.
 Increase in vagal tone
• Vagal tone is a measure of cardiovascular function that facilitates adaptive responses
to environmental challenge.
• Low vagal tone is associated with poor emotional and attentional regulation in children
and has been conceptualized as a marker of sensitivity to stress.

102. Hypertension
 Central α2-Agonists
Other side effects include depression, orthostatic
hypotension, dizziness, and anticholinergic effects.
Abrupt cessation may lead to rebound hypertension,
perhaps from a compensatory increase in
norepinephrine release that follows discontinuation of
presynaptic α-receptor stimulation.
Methyldopa rarely causes hepatitis or hemolytic
anemia.

103. Hypertension
 Central α2-Agonists
A transient elevation in hepatic transaminases occasionally
occurs.
Discontinue therapy if persistent increases in liver function tests
occur, because this may herald onset of fulminant, life-
threatening hepatitis.
Coombs-positive hemolytic anemia occurs rarely, and 20% of
patients exhibit a positive direct Coombs test without anemia.
For these reasons, methyldopa has limited usefulness except in
pregnancy.

104. Hypertension
TREATMENT
Peripheral adrenergic antagonist

105. Hypertension
 Peripheral adrenergic antagonist
 Reserpine

106. Hypertension
 Peripheral adrenergic antagonist
 Reserpine
 Reserpine depletes norepinephrine from sympathetic nerve endings and
blocks transport of norepinephrine into storage granules.
 When the nerve is stimulated, less than the usual amount of
norepinephrine is released into the synapse.
 This reduces sympathetic tone, decreasing peripheral vascular resistance
and BP.

107. Hypertension
 Peripheral adrenergic antagonist
 Reserpine
 Reserpine has a long half-life that allows for once-daily dosing, but it may take 2 to 6
weeks before the maximal antihypertensive effect is seen.
 Reserpine can cause significant sodium and fluid retention, and it should be given
with a diuretic (preferably a thiazide).
 Reserpine’s strong inhibition of sympathetic activity results in parasympathetic
activity, which is responsible for side effects of nasal stuffiness, increased gastric acid
secretion, diarrhea, and bradycardia.
 Dose-related depression can be minimized by not exceeding 0.25 mg daily.

108. Hypertension
TREATMENT
Direct Renin Inhibitor

109.  Direct Renin Inhibitor
Hypertension

110. Hypertension
 Direct Renin Inhibitor
 Aliskiren blocks the RAAS at its point of activation, resulting in reduced plasma
renin activity and BP.
 BP reductions are comparable to an ACE inhibitor, ARB, or CCB.
 Aliskiren is approved for monotherapy or in combination with other agents.
 It should not be used in combination with an ACE inhibitor or an ARB because
of a higher risk of adverse effects without additional reduction in CV events.

111. Hypertension
 Direct Renin Inhibitor
 Many of the cautions and adverse effects seen with ACE inhibitors and
ARBs apply to aliskiren.
 It is contraindicated in pregnancy.
 Use aliskiren only as an alternative therapy because of lack of long-term
studies evaluating CV event reduction and its significant cost compared
with generic agents that have outcomes data.

112. Hypertension
TREATMENT
Direct Arterial Vasodilators

113. Hypertension
 Direct Arterial Vasodilators

114. Hypertension
 Direct Arterial Vasodilators
 Hydralazine and minoxidil cause direct arteriolar smooth muscle relaxation.
 Compensatory activation of baroreceptor reflexes results in increased
sympathetic outflow from the vasomotor center, increasing heart rate, cardiac
output, and renin release.
 Consequently, hypotensive effectiveness of direct vasodilators diminishes over
time unless the patient is also taking a sympathetic inhibitor and a diuretic.
 Patients taking these drugs for long-term hypertension therapy should first
receive both a diuretic and a β-blocker.

115. Hypertension
 Direct Arterial Vasodilators
 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.

116. Hypertension
 Direct Arterial Vasodilators
 Hydralazine may cause 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 less
than 200 mg. Because of side effects, hydralazine has limited usefulness
for chronic hypertension management.

117. Hypertension
 Direct Arterial Vasodilators
 Minoxidil is a more potent vasodilator than hydralazine, and compensatory increases
in heart rate, cardiac output, renin release, and sodium retention are more dramatic.
Severe sodium and water retention may precipitate congestive HF.
 Severe sodium and water retention may precipitate congestive HF.
 Minoxidil also causes reversible hypertrichosis on the face, arms, back, and chest.
 Reserve minoxidil for very difficult to control hypertension and for patients requiring
hydralazine who experience drug-induced lupus.

118. • Hypertrichosis
• Hypertrichosis is defined as excessive hair growth anywhere on the
body in either males or females