PATHOPHYSILOGY OF HYPERTENSION

MS. SHIVANGI MISTRY
M.PHARM (PHARMACOLOGY)
ASSISTANT PROFESSOR
BHAGWAN MAHAVIR COLLEGE OF PHARMACY

CHAPTER 2 BP304TT CARDIOVASCULAR SYSTEM
Bmcp, Surat. Pathophysiology Page 2
HYPERTENSION :
 INTRODUCTION:
 Hypertension is defined by persistent elevation of arterial blood pressure (BP). The
Seventh Report of the Joint National Committee on the Detection, Evaluation, and
Treatment of High Blood Pressure (JNC 7) classifies adult BP as shown in Table.
 Patients with diastolic blood pressure (DBP) values <90 mm Hg and systolic blood
pressure (SBP) values ≥140 mm Hg have isolated systolic hypertension.
 A hypertensive crisis (BP >180/120 mm Hg) may be categorized as either a hypertensive
emergency (extreme BP elevation with acute or progressing target organ damage) or a
hypertensive urgency (severe BP elevation without acute or progressing target organ
injury).
 EPIDEMIOLOGY :
 The prevalence of hypertension differs based on age, sex, and ethnicity. As individuals
become older, their risk of high blood pressure increases.
 Individuals 55 years of age who do not have hypertension are estimated to have a lifetime
risk of 90% of eventually developing hypertension.
 The National Health and Nutrition Examination Survey from 1999 to 2000 indicated that
hypertension is slightly more prevalent in men (30.1%) than women (27.1%). However,
the prevalence increased by 5.6% in women and has remained unchanged in men from
1988 to 2000.
 Hypertension prevalence is highest in African-Americans when compared to non-
Hispanic whites and Mexican-Americans.

 Hypertension is strongly associated with type 2 diabetes. The added comorbidity of
hypertension in diabetes leads to a higher risk of cardiovascular disease (CVD), stroke,
renal disease, and diabetic retinopathy leading to greater health care costs.
 ETIOLOGY : (CAUSES OF DIEASES):

 PATHOPHYSIOLOGY :

1. GENETIC FACTOR :
 It is estimated that up to 30% to 50% of variability in blood pressure may have a genetic
basis. The majority of these polymorphisms appear to be involved directly or indirectly in
renal sodium re-absorption, which may represent future therapeutic drug targets.
 In addition, the identification of genetic factors contributing to variability in response to
drug therapy should allow for specific tailoring of individual patient therapy, thereby
optimizing the effectiveness of antihypertensive therapy while minimizing costs and
adverse events.
2. CARDIAC OUTPUT :
 Factors which elevate cardiac output may, in theory, contribute to the development of
primary hypertension.
 Increases in cardiac output and subsequent blood pressure may arise from factors that
increase preload (fluid volume) or contractility of the heart.
3. SODIUM REGULATION :
 The contribution of sodium to the development of primary hypertension is related to
excess sodium intake and/or abnormal sodium excretion by the kidneys.
 It is generally accepted that dietary salt is associated with increases in blood pressure that
can be lowered with reduction of sodium intake.
 There appears to be a threshold effect of sodium intake in the range of 50 to 100
mmol/day [1.2 to 2.4 grams of sodium per day is equivalent to 3 to 6 grams of sodium
chloride per day (50 to 100 mmol/day)] and its impact on blood pressure.
 The proposed mechanisms behind high sodium intake and blood pressure include
increases in intracellular calcium, insulin resistance, paradoxical rise in atrial natriuretic
peptide, and other pressor effects.
 Proposed mechanisms behind salt sensitivity include a defect in renal sodium excretion
and an increased rate of proximal sodium reabsorption, among others.
 Other theories supporting abnormal renal sodium retention suggest a congenital reduction
in the number of nephrons, enhanced renin secretion from nephrons that are ischemic, or
an acquired compensatory mechanism for renal sodium retention.
 One such system which is central to the understanding of hypertension and drug therapies
is the renin-angiotensinaldosterone system (RAAS).

4. Renin-Angiotensin-Aldosterone System :
 Renin is produced and stored in the juxtaglomerular cells of the kidney, and its release is
stimulated by impaired renal perfusion, salt depletion, and β1- adrenergic stimulation.
 The release of renin is the rate-limiting step in the eventual formation of angiotensin II,
which is primarily responsible for the pressor effects mediated by the RAAS (Fig.)
 The role of the RAAS in primary hypertension is supported by the presence of high levels
of renin, suggesting that the system is inappropriately activated.
 Proposed mechanisms behind this inappropriate activation include increased sympathetic
drive, defective regulation of the RAAS (non-modulation), and the existence of a sub-
population of ischemic nephrons which release excess renin.
5. Sympathetic Overactivity :
 Over-activation of the sympathetic nervous system (SNS) may also play a role in the
development and maintenance of primary hypertension for some individuals.
 Among other effects, direct activation of the SNS may lead to enhanced sodium
retention, insulin resistance, and baro-receptor dysfunction.

 Regardless of which mechanism(s) underlie the role the SNS may play in the
development of primary hypertension, the SNS remains a target of many antihypertensive
agents.
6. Peripheral Resistance :
 Elevated peripheral arterial resistance is a hallmark of primary hypertension. The increase
in peripheral resistance typically observed may be due to a reduction in the arterial lumen
size as a result of vascular remodeling.
 This remodeling, or change in vascular tone, may be modulated by various endothelium
derived vasoactive substances, growth factors, and cytokines.
 This increase in arterial stiffness or reduced compliance results in the observed increase
in systolic blood pressure.
7. Other Contributing Processes and Factors :
 Obesity appears to promote the development of primary hypertension via activation of
the SNS and the RAAS and is well-recognized as a global risk factor for CVD.
 Many other processes are proposed to contribute to the development of hypertension,
including physical inactivity, insulin resistance, potassium and magnesium depletion,
chronic moderate alcohol consumption, and transient effects of cigarette smoking and
caffeine intake.
 Some people develop excessive and unrepresentative blood pressure when attending the
Doctor’s surgery, so called “White Coat Hypertension”.
 TREATMENT :
(A)NONPHARMACOLOGIC THERAPY
 All patients with prehypertension and hypertension should be prescribed lifestyle
modifications, including
(1) weight reduction if overweight,
(2) adoption of the Dietary Approaches to Stop Hypertension eating plan,
(3) dietary sodium restriction ideally to 1.5 g/day (3.8 g/day sodium chloride),
(4) regular aerobic physical activity,
(5) moderate alcohol consumption (two or fewer drinks per day), and
(6) smoking cessation.
 Lifestyle modification alone is appropriate therapy for patients with prehypertension.

 Patients diagnosed with stage 1 or 2 hypertension should be placed on lifestyle
modifications and drug therapy concurrently.
(B) PHARMACOLOGICAL THERAPY :

 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, angio tensin II receptor blocker
(ARB), or calcium channel blocker (CCB) (Fig.).
 Combination therapy is recommended for patients with stage 2 disease, with one of the
agents being a thiazide-type diuretic unless contraindications exist.
 There are six compelling indications where specific antihypertensive drug classes have
shown evidence of unique benefits.
 Diuretics, ACE inhibitors, ARBs, and CCBs are primary agents acceptable as first-line
options based on outcome data demonstrating CV risk reduction benefits.
 β-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.
 α1-Blockers, direct renin inhibitors, central α2-agonists, peripheral adrenergic
antagonists, and direct arterial vasodilators are alternatives that may be used in select
patients after primary agents.

1. 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 magnesiumlosing 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).
 Acutely, diuretics lower BP by causing diuresis. 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.
 With chronic diuretic therapy, the extracellular fluid volume and plasma volume return
almost to pretreatment levels, and peripheral vascular resistance falls below its
pretreatment baseline.
 The reduction in peripheral vascular resistance is responsible for the long-term
hypotensive effects.
 Thiazides lower BP by mobilizing sodium and water from arteriolar walls, which may
contribute to decreased peripheral vascular resistance.
 When diuretics are combined with other antihypertensive agents, an additive hypotensive
effect is usually observed because of independent mechanisms of action.
 Furthermore, many nondiuretic antihypertensive agents induce salt and water retention,
which is counteracted by concurrent diuretic use.
 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 hypocalcemia may occur.
 Hypokalemia and hypomagnesemia may cause muscle fatigue or cramps.
 Serious cardiac arrhythmias may occur, especially in patients receiving digitalis therapy,
patients with LV hypertrophy, and those with ischemic heart disease.
 Low-dose therapy (e.g., 25 mg hydrochlorothiazide or 12.5 mg chlorthalidone daily)
rarely causes significant electrolyte disturbances.
 Potassium-sparing diuretics may cause hyperkalemia, especially in patients with
chronic kidney disease or diabetes, and in patients receiving concurrent treatment with an
ACE inhibitor, ARB, NSAID, or potassium supplement.

 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.
2. 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 (e.g., 6-week intervals).
 All 10 ACE inhibitors available in the United States can be dosed once daily for
hypertension except captopril, which is usually dosed two or three times daily.
 The absorption of captopril (but not enalapril or lisinopril) is reduced by 30% to 40%
when given with food.
 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.

 Acute renal failure is a rare but serious side effect of ACE inhibitors; preexisting kidney
disease increases the risk. Bilateral renal artery stenosis or unilateral stenosis of a solitary
functioning kidney renders patients dependent on the vasoconstrictive effect of
angiotensin II on efferent arterioles, making these patients particularly susceptible to
acute renal failure.
 The GFR decreases in patients receiving ACE inhibitors because of inhibition of
angiotensin II vasoconstriction on efferent arterioles.
 Serum creatinine concentrations often increase, but modest elevations (e.g., absolute
increases of less than 1 mg/dL) do not warrant changes. Therapy should be stopped or the
dose reduced if larger increases occur.
 Angioedema is a serious potential complication that occurs in less than 1% of patients. It
may be manifested as lip and tongue swelling and possibly difficulty breathing.
 Drug withdrawal is necessary for all patients with angioedema, and some patients may
also require drug treatment and/or emergent intubation. Cross-reactivity between ACE
inhibitors and ARBs has been reported.
 A persistent dry cough occurs in up to 20% of patients and is thought to be due to
inhibition of bradykinin breakdown.
 ACE inhibitors are absolutely contraindicated in pregnancy because of possible major
congenital malformations associated with exposure in the first trimester and serious
neonatal problems, including renal failure and death in the infant, from exposure during
the second and third trimesters.
3. Angiotensin II Receptor Blockers
 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 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).
 Unlike ACE inhibitors, ARBs do not block the breakdown of bradykinin.

 While 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.
 Bradykinin may also be important for regression of myocyte hypertrophy and fibrosis,
and increased levels of tissue plasminogen activator.
 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 β-blocker or
as alternative therapy in ACE inhibitor-intolerant patients.
 ARBs appear to have the lowest incidence of side effects compared with other
antihypertensive agents. Because they do not affect bradykinin, they do not cause a dry
cough like ACE inhibitors.
 Like ACE inhibitors, they may cause renal insufficiency, hyperkalemia, and orthostatic
hypotension.
 Angioedema is less likely to occur than with ACE inhibitors, but crossreactivity has been
reported. ARBs should not be used in pregnancy.
4. Calcium Channel Blockers
 CCBs cause relaxation of cardiac and smooth muscle by blocking voltagesensitive
calcium channels, thereby reducing the entry of extracellular calcium into cells. Vascular
smooth muscle relaxation 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 demonstrate negative inotropic
effects.
 Verapamil decreases heart rate, slows atrioventricular (AV) nodal conduction, and
produces a negative inotropic effect that may precipitate heart failure 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 heart failure.
 Both can cause anorexia, nausea, peripheral edema, and hypotension. Verapamil causes
constipation in about 7% of patients.
 Dihydropyridines cause a baroreceptor-mediated reflex increase in heart rate because of
their potent peripheral vasodilating effects. Dihydropyridines do not decrease AV node
conduction and are not effective for treating supraventricular tachyarrhythmias.
 Short-acting nifedipine may rarely cause an increase in the frequency, intensity, and
duration of angina in association with acute hypotension.
 This effect may be obviated by using sustained-released formulations of nifedipine or
other dihydropyridines. Other side effects of dihydropyridines include dizziness, flushing,
headache, gingival hyperplasia, and peripheral edema.
 Side effects due to vasodilation such as dizziness, flushing, head ache, and peripheral
edema occur more frequently with dihydropyridines than with verapamil or diltiazem.


PATHOPHYSILOGY OF HYPERTENSION

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