HYPERTENSION

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The disease Pathology Diagnosis
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 INTRODUCTION
Hypertension is one of the leading causes of the global
burden of disease. Elevated blood pressure affectsmore
than one billion individuals and causes an estimated 9.4
million deaths per year. Hypertension doubles the risk
of cardiovascular diseases, including coronary heart
disease (CHD), congestive heart failure (CHF), ischemic
and hemorrhagic stroke, renal failure, and peripheral
arterial disease (PAD).

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 EPIDEMIOLOGY
Blood pressure levels, the rate of age-related increases in blood pressure
and the prevalence of hypertension vary among countries and
among subpopulations within a country. Hypertension is present in all
populations except for small numbers of individuals living in isolated
societies. In industrialized societies, blood pressure increases steadily during
the first two decades of life. In children and adolescents,
blood pressure is associated with growth and maturation, and blood
pressure “tracks” over time in children and between adolescence and
young adulthood

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Clinical criteria for defining hypertension generally have been based on the average of two or more seated blood
pressure readings during each of two or more outpatient visits.

One recent classification recommends hypertension be defined as systolic blood pressure ≥130 mmHg or
diastolic blood pressure ≥80 mmHg.

previous guidelines defined hypertension as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90
mmHg.

Cardiovascular disease risk doubles for every 20-mmHg increase in systolic and 10-mmHg increase in diastolic
pressure.
 PRIMARY HYPERTENSION

Primary hypertension tends to be familial and is likely to be the

consequence of an interaction between environmental and genetic
factors. The prevalence of primary hypertension increases with age, and
individuals with relatively high blood pressures at younger ages are at
increased risk for the subsequent development of hypertension.
 SECONDARY HYPERTENSION

an underlying disorder causing the elevation of blood pressure can be

called secondary hypertension.specific mechanism for the blood pressure
elevation is often more apparent. secondary hypertension is due to
endocrine causes, renal causes, coarctation of aorta, obstructive sleep
apnea.
RISK FACTORS

RISK FACTORS FOR DEVELOPMENT PRIMARY HYPERTENSION

*Obesity and weight gain are strong, independent risk factors for hypertension.
*Hypertension prevalence is also related to dietary NaCl intake,
* the age-related increase in blood pressure may be augmented by
a high NaCl intake.
*Low dietary intakes of calcium and potassium also may contribute to the risk of hypertension.
RISK FACTORS FOR SECONDARY HYPERTENSION
 MECHANISMS OF HYPERTENSION
INTRAVASCULAR VOLUME:

The kidney is both a target and a cause of hypertension. Primary

renal disease is the most common etiology of secondary hypertension.
Mechanisms of kidney-related hypertension include a diminished
capacity to excrete sodium, excessive renin secretion in relation to
volume status, and sympathetic nervous system overactivity. Sodium
is predominantly an extracellular ion and is a primary determinant of
the extracellular fluid volume. When NaCl intake exceeds the capacity
of the kidney to excrete sodium, vascular volume may initially expand
and cardiac output may increase.
 AUTONOMIC NERVOUS SYSTEM
The activities of the adrenergic receptors are mediated by guanosine nucleotide-binding regulatory proteins (G
proteins) and by intracellular concentrations of downstream second messengers.
● α1Receptors are located on postsynaptic cells in smooth muscle and elicit vasoconstriction.
● α2 Receptors are localized on presynaptic membranes of postganglionic nerve terminals
that synthesize norepinephrine.
● β1 receptors stimulates the rate and strength of cardiac contraction and consequently increases cardiac
output. β1 Receptor activation also stimulates renin release from the kidney. Another class of
antihypertensive agents acts by inhibiting β1 receptors. Activation of β2receptors by epinephrine
relaxes vascular smooth muscle and results in vasodilation.
 RENIN-ANGIOTENSIN-ALDOSTERONE
*The renin-angiotensin-aldosterone system contributes to the regulation of arterial pressure primarily via the
vasoconstrictor properties of angiotensin II and the sodium-retaining properties of aldosterone.

*Angiotensin II is the primary tropic factor regulating the synthesis and secretion of aldosterone by the zona
glomerulosa of the adrenal cortex. Aldosterone synthesis is also dependent on potassium, and aldosterone
secretion may be decreased in potassium-depleted individuals.

*Increased activity of the renin-angiotensin-aldosterone axis is not invariably associated with hypertension. In
response to a low-NaCl diet or to volume contraction, arterial pressure and volume homeostasis may be
maintained by increased activity of the renin-angiotensinaldosterone axis
 PATHOLOGIC CONSEQUENCES OF
HYPERTENSION
HEART

Heart disease is the most common cause of death in hypertensive patients. Hypertensive heart disease is the
result of structural and functional adaptations leading to leftventricular hypertrophy, increased atrial size,
CHF, atherosclerotic coronary artery disease, microvascular disease, and cardiac arrhythmias, including atrial
fibrillation.

BRAIN

*Elevated blood pressure is the strongest risk factor for stroke. Approximately 85% of strokes are due
to infarction, and the remainder are due to either intracerebral or subarachnoid hemorrhage.

*Hypertension is also associated with impaired cognition in an aging population, and longitudinal studies
support an association between midlife hypertension and late-life cognitive decline.
KIDNEY

*Hypertension is a risk factor for renal injury and ESRD. The increased risk associated with high blood
pressure is graded, continuous, and present throughout the distribution of blood pressure above optimal
pressure.

*Clinically, macroalbuminuria (a random urine albumin/creatinine ratio >300 mg/g) and microalbuminuria (a
random urine albumin/creatinine ratio 30–300 mg/g) are early markers of renal injury. They are also risk
factors for renal disease progression and cardiovascular disease.

PERIPHERAL ARTERIES

Blood vessels are a target organ atherosclerotic disease secondary to long-standing elevated blood pressure.
Independent of blood pressure, arterial stiffness is associated with target organ disease, including stroke,
heart disease, and renal failure. Hypertensive patients with arterial disease of the lower extremities are also at
increased risk of future cardiovascular disease.
INTIAL DIAGNOSTICS
 TREATMENT PLAN
Lifestyle Modifications to Manage Hypertension :

*Weight reduction :Attain and maintain BMI <25 kg/m2

*Dietary salt reduction : <6 g NaCl/d

*Adapt DASH-type dietary plan : Diet rich in fruits, vegetables, and low-fat dairy
products with reduced content of saturated and
total fat. Diet is also rich in potassium, calcium, and
magnesium.
*Moderation of alcohol consumption : For those who drink alcohol, consume ≤2 drinks/d in
men and ≤1 drink/d in women
*Physical activity : Regular aerobic activity, e.g., brisk walking for 30 min/d
 MEDICAL
MANAGEMENT
 VASODILATORS

• Direct vasodilators decrease peripheral resistance

and activate mechanisms that defend arterial
pressure, notably the sympathetic nervous system,
the renin- angiotensin-aldosterone system, and
sodium retention.
• Usually, they are not considered first-line agents but
are most effective when added to a combination that
includes a diuretic and a beta blockers.
 DIURETICS
• INITIAL ACTION OF THIAZIDE DIURETICS: decreases extracellular
volume by interacting with a thiazide-sensitive NCC (SLC12A3) expressed in
the distal convoluted tubule in the kidney, enhancing Na+ excretion in the
urine, and leading to a decrease in cardiac output
• the hypotensive effect is maintained during long-term therapy due to decreased vascular
resistance; cardiac output returns to pretreatment values, and extracellular volume
returns to almost normal due to compensatory responses such as activation of the RAS
 DIURETICS
• explanation for the long-term vasodilation induced by
thiazide diuretics is unknown
• Hydrochlorothiazide
• may open Ca2+-activated K+ channels, leading to hyperpolarization of vascular smooth
muscle cells, which leads in turn to closing of L-type Ca2+ channels and lower probability of
opening, resulting in decreased Ca2+ entry and reduced vasoconstriction
• REGIMEN FOR ADMINISTRATION OF THE THIAZIDE CLASS
DIURETICS
• Similar pharmacological effects: generally viewed as interchangeable with appropriate
adjustment of dosage
• Urinary K loss: pose a problem
• ACE inhibitors and ARBs: attenuate diuretic induced loss of potassium, consideration if a
second drug is required to achieve further blood pressure reduction beyond that attained
with diuretic alone
• ACE inhibitors or ARBs with K sparing agents or with K supplements, combination with
K sparing drugs : requires great caution, cause dangerous hyperkalemia
• Severe hypertension unresponsive to 3 or more drugs (state in which blood pressure is
volume dependent): require large doses of thiazide class diuretics
• Most patients: respond to diuretics with reduction in BP within about 4-6
weeks
• Doses should not be increased more often than 4-6 weeks
• Unlikely to be effective as sole therapy in patients with stage 2
hypertension
ADVERSE EFFECTS AND PRECAUTIONS
• Erectile dysfunction
• Gout: due hyperuricemia induced by diuretics
• K+ depletion: dose dependent, variable among patients, may
lead to arrythmias
• Changes in plasma lipids and glucose tolerance
• Cross the placenta, no direct effects on the fetus, risk of transient volume
depletion leading to placental hypoperfusion
 DIURETICS
• Loop Diuretics
• furosemide and bumetanide
• Thiazide diuretics are more effective antihypertensive agents than
are the loop diuretics
• a single daily dose of loop diuretics does not cause a significant net loss of Na+ for an entire
24-h period because the strong initial diuretic effect is followed by a rebound mediated by
activation of the RAS
 DIURETICS
• K-sparing diuretics
• amiloride and triamterene
• K+-sparing diuretics that have little value as antihypertensive monotherapy
• important in combination with thiazides to antagonize urinary K+ loss and
the concomitant risk of ventricular arrhythmias
 DIURETICS
• K-sparing diuretics
• Spironolactone: K sparing diuretic, effects in men: erectile dysfunction, gynecomastia,
benign prostatic hyperplasia
• Renal insufficiency: relative contraindication to the use of K sparing diuretics
• Concomitant use od an ACE inhibitor or an angiotensin receptor antagonist
magnifies the risk of hyperkalemia with these agents
• DIURETIC ASSOCIATED DRUG INTERACTION
• K+ and Mg 2+ depleting effects of the thiazides and loop diuretics:
potentiate arrythmias that arise from digitalis toxicity
• Corticosteroids: amplify hypokalemia produced by diuretics
• Decrease the clearance of Li+ resulting in increased plasma
concentrations of Li+ and potential toxicity
• NSAIDS: inhibit the synthesis of prostaglandins reduce the
antihypertensive effects of diuretics
• B receptor antagonists and ACE inhibitors: reduce plasma
concentrations of aldosterone, potentiate the hyperkalemic effects of K
sparing diuretic
 BETA-BLOCKERS
• LOCUS AND MECHANISM OF ACTION: blockade of β receptors
of the juxtaglomerular complex, reducing renin secretion and thereby
diminishing production of Angiotensin II
• Labetalol: α receptor antagonist
• Nebivolol: promotes endothelial cell dependent vasodilation activation
of the NO pathway
 BETA-BLOCKERS
• THERAPEUTIC USES
• Therapy for all grades of hypertension
• Sufficient duration to permit once or twice daily administration
• Usually do not cause retention of salt and water and administration with
diuretic not necessary to avoid edema or the development of tolerance
• Combination with b receptor antagonist, diuretic and a vasodilator:
effective for patients who require a third drug
 a1 BLOCKERS
Selectively block α1adrenergic receptors without affecting α2receptors

• PHARMACOLOGICAL EFFECTS: initially, reduce arteriolar resistance and increase

venous capacitance causing a sympathetically mediated reflex increase in heart rate
ad plasma renin activity

• Long term: vasodilation persists but cardiac output, heart rate and plasma renin as activity return to normal
• Reduce plasma concentration of TGL and total LDL and increase HDL
 a1 BLOCKERS
• ADVERSE EFFECTS: major precaution “first dose phenomenon”
symptomatic orthostatic hypotension occurs within 30-90 mins of the
initial dose, after the first few doses, patients develop tolerance

• THERAPEUTIC USES: not recommended as monotherapy for

hypertension, used primarily in conjunction with diuretics, B blockers
and other antihypertensive agents
 SYMPATHOLYTICS
METHYLDOPA
• Centrally acting anti-hypertensive;prodrug and exerts action via active metabolite
• ABSORPTION, METABOLISM AND EXCRETION:
• Peak concentration in plasma: 2-3 hours; t1/2 of -2 hours
• Excreted in the urine as the sulfate conjugate (50-70%) and as the parent drug
(25%), remaining excreted as metabolites
• Peak effect 6-8 hours, duration of single dose: 24 hours permitting once or twice
daily dosing
• With renal failure: more sensitive to the effect
• ADVERSE EFFECTS AND PRECAUTIONS
• Transient sedation, diminution of psychic energy and depression in some
patients
• Adverse: diminished libido, parkinsonian signs and hyperprolactinemia; may be
pronounced to cause gynecomastia and galactorrhea.
 CLONIDINE & MOXONIDINE
• Stimulate α2A adrenergic receptors in the brainstem, resulting in a reduction
in sympathetic outflow from the CNS
• PHARMACOLOGICAL EFFECTS:
• Lower arterial pressure by an effect on both cardiac output and peripheral
resistance; supine position (low sympathetic tone to vasculature)-reduce heart rate
and stroke volume; upright- reduce vascular resistance

• ADVERSE EFFECTS AND PRECAUTIONS

• Sedation and xerostomia with dry nasal mucosa, dry eyes and parotid gland swelling
and pain, postural hypotension and erectile dysfunction

• THERAPEUTIC USES
• Not a leading option for monotherapy for hypertension; absence of evidence in
reduction in risk of adverse cardiovascular events
ANGIOTENSIN CONVERTING ENZYME INHIBITORS:

•ACEIs decrease the production of angiotensin II, increase bradykinin levels, and
reduce sympathetic nervous system activity.
•Enhance the efficacy of diuretic drugs.
•Preferred initial agent: chronic renal disease
•Treatment Post MI: improve ventricular function and reduce morbidity and
mortality
•Blunt the rise in aldosterone concentrations in response to Na loss, normal role
of aldosterone to oppose diuretic induced natriuresis is diminished.
 ANGIOTENSINIGEN II RECEPTOR ANTAGONIST

• Antagonizing the effects of ANG II: relax smooth muscle and promote vasodilation and
increase renal and salt water excretion, reduce plasma volume and decrease cellular
hypertrophy
• ARBs provide selective blockade of AT1 Rs, and the effect of angiotensin II on
unblocked AT2 Rs may augment their hypotensive effect.
• AT1 receptor: located predominantly in vascular and myocardial tissue, brain, kidney
and adrenal glomerulosa which secrete aldosterone
• AT2: anti-proliferative responses
 CALCIUM CHANNEL
BLOCKERS
• Basis: hypertension is the result of increased peripheral vascular
resistance

• Vascular smooth muscle contraction dependent on free

intracellular concentration of calcium

• Lower blood pressure by relaxing arteriolar smooth muscle

and decreasing peripheral vascular resistance

• Tachycardia: minimal to absent with verapamil and diltiazem

because of the direct chronotropic effects of these drugs
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