Hypertension is a major risk factor for cardiovascular disease. This document discusses the epidemiology, pathophysiology, classification, and treatment of hypertension. Regarding pathophysiology, factors discussed include intravascular volume, the autonomic nervous system, the renin-angiotensin-aldosterone system, vascular mechanisms, and immune/inflammatory mechanisms. Treatment involves lifestyle modifications and medications such as diuretics, ACE inhibitors, ARBs, calcium channel blockers, and aldosterone antagonists.

1. HYPERTENSION

2. Discussion On:
1. Epidemiology
2. Pathophysiology of hypertension/Mechanisms
Intravascular volume
Autonomic nervous system regulation
Renin-angiotensin aldosterone system
Vascular mechanisms
Immune mechanisms, inflammation and oxidative stress
3. Defining hypertension and classification
4. Primary hypertension
5. Secondary hypertension
6. Treatment

3. EPIDEMIOLOGY :
• 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).
• The likelihood of hypertension increases with age, and among individuals aged ≥60 years, the
prevalence is 65.4%
• According to NHANES (National Health and Nutrition Examination Survey) data, in 2007–2010,
81.5% of those with hypertension were aware they had it, 74.9% were being treated, but only
52.5% were controlled.
• Both environmental and genetic factors may contribute to regional and racial variations in
hypertension prevalence

4. Cntd.
• Obesity and weight gain are strong, independent risk factors for hypertension.
• It has been estimated that 60% of hypertensives are >20% overweight.
• Among populations, hypertension prevalence is related to dietary NaCl intake, and 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.
• The urine sodium-to-potassium ratio is a stronger correlate of blood pressure than is either sodium
or potassium alone.
• Alcohol consumption, psychosocial stress, and low levels of physical activity also may contribute
to hypertension.

5. PATHOPHYSIOLOGY OF HYPERTENSION :
• Cardiac output and peripheral resistance are the two determinants of arterial pressures.
• Cardiac output is determined by stroke volume and heart rate; stroke volume is related to
myocardial contractility and to the size of the vascular compartment.
• Peripheral resistance is determined by functional and anatomic changes in small arteries (lumen
diameter 100–400 μm) and arterioles.

6. 1. INTRAVASCULAR VOLUME
• When NaCl intake exceeds the capacity of the kidney to excrete sodium, vascular volume may
initially expand and cardiac output may increase.
• salt can activate a number of neural, endocrine/paracrine, and vascular mechanisms, all of which
have the potential to increase arterial pressure.
• As arterial pressure increases in response to a high NaCl intake, urinary sodium excretion increases
and sodium balance is maintained at the expense of an increase in arterial pressure.
• NaCl-dependent hypertension may be a consequence of a decreased capacity of the kidney to
excrete sodium.

7. • ESRD is an extreme example of volume-dependent hypertension.
• In ~80% of these patients, vascular volume and hypertension can be controlled with
adequate dialysis.

8. 2. AUTONOMIC NERVOUS SYSTEM
• Norepinephrine, epinephrine, and dopamine all play important roles in tonic and phasic
cardiovascular regulation.
• The activities of the adrenergic receptors are mediated by guanosine nucleotide-binding regulatory
proteins (G proteins) and by intracellular concentrations of downstream second messengers.
• Based on their physiology and pharmacology, adrenergic receptors have been divided into two
principal types: α and β.
• These types have been differentiated further into α1, α2, β1, and β 2 receptors.
• α Receptors are occupied and activated more avidly by norepinephrine than by epinephrine, and
the reverse is true for β receptors.

9. Cntd.
• α1 Receptors are located on post synaptic cells in smooth muscle and elicit vasoconstriction
• α 2 Receptors are localized on presynaptic membranes of postganglionic nerve terminals that
synthesize norepinephrine.
• When activated by catecholamines, α 2 receptors act as negative feedback controllers, inhibiting
further norepinephrine release.
• Different classes of antihypertensive agents either inhibit α 1 receptors or act as agonists of α 2
receptors and reduce systemic sympathetic outflow.
• Activation of myocardial β 1 receptors stimulates the rate and strength of cardiac contraction and
consequently increases cardiac output.
• β 1 Receptor activation also stimulates renin release from the kidney.

10. Cntd.
• Downregulation of receptors may be a consequence of sustained high levels of catecholamines and
provides an explanation for decreasing responsiveness, or tachyphylaxis.
• Several reflexes modulate blood pressure on a minute-to-minute basis.
• One arterial baroreflex is mediated by stretch-sensitive sensory nerve endings in the carotid sinuses
and the aortic arch.
• The rate of firing of these baroreceptors increases with arterial pressure, and the net effect is a
decrease in sympathetic outflow, resulting in decreases in arterial pressure and heart rate.

11. • Patients with autonomic neuropathy and impaired baroreflex function may have extremely labile blood
pressures with difficult-to-control episodic blood pressure spikes associated with tachycardia.

12. 3. 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.
• There are three primary stimuli for renin secretion:
• (1) decreased NaCl transport in the distal portion of the thick ascending limb of the loop of
Henle that abuts the corresponding afferent arteriole (macula densa),
• (2) decreased pressure or stretch within the renal afferent arteriole (baroreceptor mechanism),
• (3) sympathetic nervous system stimulation of renin-secreting cells via β1 adrenoreceptors.

14. Cntd.
• Acting primarily through angiotensin II type 1 (AT1) receptors on cell membranes, angiotensin II is
a potent pressor substance.
• The AT2 receptor induces vasodilation, sodium excretion, and inhibition of cell growth and matrix
formation.
• Angiotensin II is the primary tropic factor regulating the synthesis and secretion of aldosterone by
the zona glomerulosa of the adrenal cortex.
• Aldosterone is a potent mineralocorticoid that increases sodium reabsorption by amiloride-
sensitive epithelial sodium channels (ENaC) on the apical surface of the principal cells.

15. Cntd.
• Electric neutrality is maintained by exchanging sodium for potassium and hydrogen ions.
• These effects are amplified by a high salt intake. In animal models, high circulating aldosterone
levels stimulate cardiac fibrosis and left ventricular hypertrophy, and spironolactone (an
aldosterone antagonist) prevents aldosterone-induced myocardial fibrosis.
• In patients with CHF, low-dose spironolactone reduces the risk of progressive heart failure and
sudden death from cardiac causes by 30%.

16. 4. VASCULAR MECHANISMS
• Vascular radius and compliance of resistance arteries are important determinants of arterial
pressure.
• Resistance to flow varies inversely with the fourth power of the radius, and consequently, small
decreases in lumen size significantly increase resistance
• Hypertrophic or eutrophic vascular remodeling results in decreased lumen size and, hence,
increased peripheral resistance.
• Pulse pressure is related to the functional properties of large arteries and the amplitude and timing
of the incident and reflected waves.
• Due to the timing of these waves, the consequence is augmentation of aortic systolic pressure and a
reduction of aortic diastolic pressure, i.e., an increase in pulse pressure

17. Cntd.
• The aortic augmentation index, a surrogate index of arterial stiffening, is calculated as the ratio of
central arterial pressure-to-pulse pressure.
• Central blood pressure and the aortic augmentation index are strong, independent predictors of
cardiovascular disease and all-cause mortality.
• The vascular endothelium synthesizes and releases several vasoactive substances, including nitric
oxide, a potent vasodilator.
• Endothelium-dependent vasodilation is impaired in hypertensive patients.
• Endothelin is a vasoconstrictor peptide produced by the endothelium, and orally active endothelin
antagonists may lower blood pressure in patients with resistant hypertension.

18. 5. IMMUNE MECHANISMS, INFLAMMATION, AND
OXIDATIVE STRESS
• Patients with primary hypertension have increased circulating levels of autoantibodies.
• Inflammation, vascular stretch, angiotensin II, and salt have all been shown to result in the
generation of reactive oxygen species (ROS), which modify T cell function and further enhance
inflammation.
• Increasing evidence suggests that infiltration of T cells into the renal interstitium contributes to
inflammation and oxidative stress.
• Renal medullary oxidative stress disrupts pressure-natriuresis and contributes to the development
of hypertension.

19. DEFINING HYPERTENSION AND CLASSIFICATION
• Clinically, hypertension may be defined as that level of blood pressure at which the institution of
therapy reduces blood pressure–related morbidity and mortality.
• 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.
• Home blood pressure and average 24-h ambulatory blood pressure measurements are generally
lower than clinic blood pressures.
• Blood pressure tends to be higher in the early morning hours, soon after waking, than at other
times of day.
• Myocardial infarction and stroke are more common in the early morning hours.

20. • Approximately 15–20% of patients with stage 1 hypertension based on office blood pressures have
average ambulatory readings <135/85 mmHg, termed “white coat hypertension”.
• A report of the ACC/AHA task force on clinical practice guideline:

21. PRIMARY HYPERTENSION
• ~80–95% of hypertensive patients are diagnosed as having primary, or “essential,” 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.
• Furthermore, spironolactone, an aldosterone antagonist, may be a particularly effective
antihypertensive agent for some patients with primary hypertension, including some patients with
“drug-resistant” hypertension.
• When plasma renin activity (PRA) is plotted against 24-h sodium excretion, ~10–15% of
hypertensive patients have high PRA and 25% have low PRA.

22. • High-renin patients may have a vasoconstrictor form of hypertension.
Whereas low-renin patients may have volume-dependent hypertension.

23. SECONDARY HYPERTENSION
• In the remaining 5–20% of hypertensive patients, a specific underlying disorder causing the
elevation of blood pressure in the individuals and termed as “secondary” hypertension.
• The constellation of insulin resistance, abdominal obesity, hypertension, and dyslipidemia has been
designated as the metabolic syndrome.
• Renal disease is the most common cause of secondary hypertension.
• Hypertension is present in >80% of patients with chronic renal failure.
• Proteinuria >1000 mg/d and an active urine sediment are indicative of primary renal disease

25. • Approximately 50% of patients with renovascular hypertension have an abdominal or flank bruit.
• If renal artery stenosis is suspected Contrast arteriography remains the “gold standard” for
evaluation.
• Independent of obesity, hypertension occurs in >50% of individuals with obstructive sleep apnea.
• The reported prevalence of primary hyperaldosteronism varies from <2 to ~15% of hypertensive
individuals.
• Primary aldosteronism should be considered in all patients with refractory hypertension.
• Hypertension occurs in 75–80% of patients with Cushing’s syndrome.
• The mechanism of hypertension may be related to stimulation of mineralocorticoid receptors by
cortisol and increased secretion of other adrenal steroids.

26. • Coarctation of the aorta is the most common congenital cardiovascular cause of hypertension. The
incidence is 1–8 per 1000 live births.
• Mild diastolic hypertension may be a consequence of hypothyroidism, whereas hyperthyroidism
may result in systolic hypertension.
• Hypercalcemia of any etiology, the most common being primary hyperparathyroidism, may result
in hypertension.

27. TREATMENT
LIFESTYLE INTERVENTIONS
• Average blood pressure reductions of 6.3/3.1 mmHg have been observed with a reduction in mean
body weight of 9.2 kg.
• Blood pressure may be lowered by 30 min of moderately intense physical activity, such as brisk
walking, 6–7 days a week.
• Based on results of meta-analyses, lowering of blood pressure by limiting daily NaCl intake to 4.4–
7.4 g (75–125 mEq) results in blood pressure reductions of 3.7–4.9/0.9–2.9 mmHg in hypertensive
individuals.

28. Lifestyle Modifications:

29. ACC/AHA Guidelines for Hypertension Management
1. Indications for use of Blood Pressure-Lowering Medications
Secondary prevention of recurrent CVD events in patients with clinical CVD(defined as CHD,
CHF and stroke) and SBP >130 mmHg or DBP >80 mmHg.
Primary prevention in patients with an estimated 10-year ASCVD risk >10% and SBP >130 mmHg
or DBP >80 mmHg.
Primary prevention of CVD and low CVD risk in patients with SBP >140 mmHg or DBP >90
mmHg

30. 2. Blood Pressure Goal for Patients with Hypertension
For adults with confirmed hypertension and known CVD or 10-year ASCVD event risk >10%, a
BP target <130/80 mmHg.
3. Possible Exceptions to Therapeutic Target of <130/80 mmHg
Patients >80 years of age
Patients previously untreated for hypertension who experience an ischemic stroke or TIA and have
blood pressure <140/90 mmHg
Acute therapy of most hypertensive urgencies and emergencies.

31. • Lowering systolic blood pressure by 10–12 mmHg and diastolic blood pressure by 5–6 mmHg
confers relative risk reductions of 35–40% for stroke and 12–16% for CHD within 5 years of the
initiation of treatment. The risk of heart failure is reduced by >50%.

32. Diuretics (Thiazide diuretics, Loop diuretics)
• Low-dose thiazide diuretics may be used alone or in combination with other antihypertensive
drugs.
• Thiazides inhibit the Na+/Cl– pump in the distal convoluted tubule and hence increase sodium
excretion. In the long term, they also may act as vasodilators.
• They provide additive blood pressure–lowering effects when combined with beta blockers,
angiotensin-converting enzyme inhibitors (ACEIs), or angiotensin receptor blockers (ARBs).
• Usual doses of hydrochlorothiazide range from 6.25 to 50 mg/d.
• However, chlorthalidone has a longer half-life (40–60 h vs 9–15 h) and an antihypertensive
potency ~1.5–2.0 times that of hydrochlorothiazide.

33. • The main pharmacologic target for loop diuretics is the Na+-K+-2Cl– cotransporter in the thick
ascending limb of the loop of Henle.
• Loop diuretics generally are reserved for hypertensive patients with reduced glomerular filtration
rates (reflected in serum creatinine >220 μmol/L [>2.5 mg/dL]), CHF, or sodium retention and
edema

34. Blockers of the Renin–Angiotensin System( ACEI and ARB’s)
• ACEIs decrease the production of angiotensin II, increase bradykinin levels, and reduce
sympathetic nervous system activity.
• ARBs provide selective blockade of AT1 receptors, and the effect of angiotensin II on unblocked
AT2 receptors may augment their hypotensive effect.
• May be used as monotherapy or in combination with diuretics, calcium antagonists, and alpha
blocking agents.
• Dry cough occurs in ~15% of patients, and angioedema occurs in <1% of patients taking ACEIs.
• Hyperkalemia due to hypoaldosteronism is an occasional side effect of both ACEIs and ARBs.
• direct renin inhibitors - Aliskiren is the first of a class of oral, nonpeptide, competitive inhibitors of
the enzymatic activity of renin.

35. Aldosterone Antagonists
• Spironolactone is a nonselective aldosterone antagonist.
• It may be a particularly effective agent in patients with low-renin primary hypertension, resistant
hypertension, and primary aldosteronism.
• In patients with CHF, low-dose spironolactone reduces mortality and hospitalizations for heart
failure when given in addition to conventional therapy with ACEIs, digoxin, and loop diuretics.
• Because spironolactone binds to progesterone and androgen receptors, side effects may include
gynecomastia, impotence, and menstrual abnormalities.
• These side effects are circumvented by a newer agent, eplerenone.

36. Beta Blockers
• β-Adrenergic receptor blockers lower blood pressure by decreasing cardiac output owing to a
reduction of heart rate and contractility.
• Beta blockers are particularly effective in hypertensive patients with tachycardia.
• Carvedilol and labetalol block both β receptors and peripheral α-adrenergic receptors.
• Nebivolol represents another class of cardioselective beta blockers that has additional vasodilator
actions related to enhancement of nitric oxide activity.

37. Calcium Channel Blockers
• Calcium antagonists reduce vascular resistance through L-channel blockade, which reduces
intracellular calcium and blunts vasoconstriction.
• Calcium antagonists effectively lower blood pressure.
• Side effects of flushing, headache, and edema with dihydropyridine use are related to their
potencies as arteriolar dilators.

38. RESISTANT HYPERTENSION
• The term resistant hypertension refers to patients with blood pressures persistently >140/90 mmHg
despite taking three or more antihypertensive agents, including a diuretic.
• Resistant hypertension may be related to “pseudoresistance” (high office blood pressures and lower
home blood pressures), nonadherence to therapy, identifiable causes of hypertension (including
obesity and excessive alcohol intake), and the use of any of a number of nonprescription and
prescription drugs.
• In the absence of specific identifiable cause, mineralocorticoid receptor antagonists, especially
spironolactone, have been demonstrated to be the most add on drugs for treatment of resistant
hypertension.

39. HYPERTENSIVE EMERGENCIES
• Severe asymptomatic hypertension(SBP >180 mmHg or DBP >120 mmHg) is considered a
hypertensive “urgency” but when accompanied by acute target damage, it is considered a
hypertensive “emergency”.
• Cerebral and, Renal and coronary blood flow may decrease with overly aggressive acute therapy.
• So, gradually lowered over 24h to ~25% of the initial value.
• Malignant hypertension is an example of hypertensive emergency that is associated with an abrupt
increase of blood pressure in a patient with underlyng hypertension or related to the sudden onset
of hypertension in a previously normotensive individual.
• It is pathologically associated with diffuse necrotizing vasculitis, arteriolar thrombi, and fibrin
deposition in arteriolar walls.

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