Hypertension (Arterial Hypertension)-Pathophysiology


Hypertension (Personal Notes)

-A person is considered hypertensive if three sets of BP measurements over at least a 3 month period are higher than 140/90 mmHg (instruments used includes sphygomomanometers).

-Prevalence increases with advancing age. All adults should have their BP routinely measured at least every 50 years until the age of 80. If found to be borderline, the measurements should be made every 3-12 months.

*** Non-Pharmacological therapy is important in treatment of all patients with hypertension which includes weight loss, restricting sodium intake, exercise, moderating alcohol consumption, 

Drugs that lower BP do so via (a) lowering TPR (b) CO (c) both

-Hemodynamic effects of anti-hypertensive agents provide a rationale for complementary effects of concurrent therapy with two or more drugs.

-Concurrent use of drugs from different classes is effective in achieving effective control of BP while minimising dose-related side effects.

Part 1:

  • Primary Hypertension

-‘Idiopathic’ hypertension (sudden and obscure cause), accounts for 95% of hypertension

-Hypertension must involve either elevated cardiac output or elevated total peripheral vascular resistance

-However, it is often diagnosed several years after any tendency towards it has started (A little too late because secondary compensatory physiological mechanisms have been initiated such that these fundamental abnormalities are not clearly identifiable).

Effects: Presence of hypertension will cause arterial and arteriolar wall thickening. In early stages of hypertension, cardiac output is only slightly elevated whereas in late stages, cardiac output tends to fall and TPR rises.

These effects are mediated by Insulin, catecholamines, angiotensin, growth hormones which stimulate vascular hypertrophy and vasoconstriction


  • Some factors likely to result in hypertension:

(a) Genetic: Western blacks are more predisposed to hypertension and have increased morbidity and mortality (suggests possible genetic differences)

-Possible mutations in angiotensinogen gene but disease is likely to be polygenic

(b) Geographic and environmental

-South American Indians have significant lower BP which raised less with age than in Western societies

(c) Fetal

-Low birth weight appears to predispose to hypertension later in life.

(d) Sex

-Hypertension is less common in pre-menopausal women than in men suggesting hormonal influences.

(e) Sodium intake

-Role of sodium is well supported. This could possibly be due to genetic or an acquired inability to excrete sodium load efficiently.

-Presence of natriuretic hormone which inhibits sodium pump ATPase activity and has a pressor effect?

-Reducing salt intake can help reduce BP.

*(f) Renin-Angiotensin System

-Renin stimulates production of angiotensin (pressor agent) and aldosterone (promotes sodium and water retention).

-Due to homeostatic effects of negative feedback mechanism to volume overload and increase in BP, renin production is suppressed (thus large proportion of patients with primary hypertension have normal or low renin levels).

  • Angiotensin II is derived from angiotensinogen (produced in the liver)
  • Renin is released from the kidneys (DCT), cleaves the decapeptide Angiotensin I from angiotensinogen.
  • ACE enzyme converts Angiotensin I to Angiotensin II
  • Angiotensin II acts on ATI receptors (binds to two GPCRs)–>Stimulates Gq, Activates Phospholipase C and increases cytoplasmic Calcium–>Activates PKC–>Various Physiological Responses
  • Angiotensin II is degraded subsequently via proteolysis

-Angiotensin II receptor Type 1 (AT1 Receptors) can be in the heart, blood vessels, kidney, adrenal cortex, lung and brain and mediates the vasoconstrictor effects

 (angiotensin II-Octapeptide)

Physiological impacts of Angiotensin II

1. Vasoconstriction (Altered TPR)

-Rapid Pressor Reponse (Angiotensin II increases TPR rapidly-maintains arterial blood pressure when blood is lost rapidly or vasodilation)

(a) Direct Vasoconstriction

-AngII increases TPR by constricting precapillary arterioles and to a lesser extent, post-capillary venules by activating AT1 receptors on vascular smooth muscle cells.

-AngII has effects on vascular beds. Kidneys and splanchnic bed constrict markedly, thus decreasing blood flow

-High circulating concentrations of AngII may decrease cerebral and coronary blood flow.

(b) Enhancement of sympathetic output/transmission

-Increased NAdr release, Inhibition of NAdr reuptake, Increased vascular responsiveness

-AngII augments NA release from sympathetic nerve terminals

-Inhibits the reuptake of NA into nerve terminals, enhancing the vascular response to NA

-Intracoronary AngII potentiates sympathetic NS system-induced vasoconstriction.

(c) Increased sympathetic discharge (CNS)

(d) Released of catecholamines from adrenal medulla

-AngII stimulates catecholamine release from the adrenal medulla by depolarising chromaffin cells (found in medulla of adrenal gland)

-This response may produce dangerous reactions to people esp. with pheochromocytoma (Tumour of the adrenal gland)

-Tumour is benign but results in hypertension, headaches, tachycardia, apprehension and facial flushing.



2. Salt retention (Altered Renal Function)

Slow Pressor response (chronic response to maintain BP)

-Continuous infusion of initially subpressor doses of Ang II gradually increases blood pressure over a period of days.

-This slow pressor response is mediated by decreases in renal excretion that shifts the renal pressure (natriuresis) curve to the right.

(a) Direct increase in sodium reabsorption in proximal tubules

-At very low concentrations of AngII, stimulates the Na+/H+ exchanger in the PCT tubule. Thus increasing  sodium, chloride and bicarbonate reabsorption.

-AngII increases expression of the Na+/glucose symporter in the PCT (significance: increased reabsorption of sodium and glucose)

-AngII directly stimulates Na+/K+/2Cl- symporter in the TAL of the PCT.

-PCT and liver secretes angiotensinogen and the connect tubule releases renin which cleaves it into angiotensin I. Thus, a paracrine (neighbouring cell signalling) renin-angiotensin system modulates sodium reabsorption.


(b) Release of aldosterone from adrenal cortex leads to increase Na+ reabsorption and K+ excretion

-AngII stimulates zona glomerula of adrenal cortex to increase secretion of aldosterone


-Aldosterone acts on distal and collecting tubules to cause retention of sodium and excretion of K+ and H+.

Note: Increased output of Aldosterone is due to AngTII which has little/no impact on BP.


-Ang-II induced stimulation of aldosterone synthesis is enhanced by hyponatremia or hyperkalemia.


(c) Altered renal hemodynamics

-Direct Renal vasoconstriction (Constrict renal smooth muscle directly)

-Enhancement of sympathetic NAdr output/transmission in kidney

-Increased renal sympathetic tone (CNS), facilitates noradrenergic transmission

-Constriction of vasa recta AT1 receptors. Reduce blood flow, reduce Na+ excretion, facilitates reabsorption back into blood.

Ang II influence GFR

-It constricts either afferent or efferent arterioles depending on the situation. Constricting afferent arterioles, decrease GFR. Constricting efferent arterioles, increase GFR. Contraction of mesengial cells decreases capillary S.A. within glomerulus for filtration and tend to reduce GFR

-PGI2/PGE2 counteracts constriction at whichever side (compensatory vasodilation)

Effects of these opposing effects depends on physiological state. GFR is slightly reduced by AngII. However, during renal artery hypotension, effects of AngII on efferent arteriole predominate and Ang II increases GFR. 

∴Blockage of RAS may cause acute renal failure in patients with bilateral/unilateral renal artery stenosis (i.e. AngII cannot have its effects)



3. Vascular growth

-Left Ventricular Hypertrophy and Hyperplasia (Extensive Proliferation of cells)

-Increased collagen deposition by cardiac fibroblasts.

-Increased wall to lumen ratio

-Concentric Hypertrophy (No expansion)

-Eccentric Hypertrophy and fibrosis

-Thickening of the intimate surface of the blood vessel (associated with artherosclerosis and angioplasty)

*RAS contributes to these changes, AngII stimulates migration, proliferation, hypertrophy, synthetic capability of myocytes, fibroblasts, smooth muscle cells



(a) Increased expression of proto-oncogenes, growth factors

(b) Increased synthesis of extracellular matrix proteins

(c) Increased afterload, increased wall tension (Hemodynamic effects)

-Cardiac Preload (volume expansion due to sodium retention-Increased venous return)

-Afterload (Increased arterial blood pressure)

∴Leads to cardiac remodelling and hypertrophy

*Hypertension also directly contributes to hypertrophy and remodelling of blood vessels.



What causes renin to be released? (Increased arterial blood pressure)

1. Decreased Na+ reabsorption in the PCT

2. Increased Blood Pressure in pre-glomerular vessels

3. Increased sympathetic tone which leads to activation of B1 Adrenergic Receptors on JGCs

(g) Sympathetic hyperactivity

-Catecholamine overproduction which stimulates renin production in the JGA cells.

-These catecholamines (NA and NAdr) stimulates vasodilation in blood vessels due to activation of β2 receptors (dilates smaller coronary arteries, dilutes hepatic artery) and β1 receptors (due to renin released in JGA cells)

To be confirmed: Constriction of arterioles and veins which result in an increase in cardiac output

(h) Insulin resistance/hyperinsulinaemia

-The association of primary hypertension and insulin resistance has been noted for years especially in obese people

-Studies showing how insulin affects reabsorption at the PCT level to increase volume reabsorption.

-Insulin is a pressor itself and increases levels of catecholamines and renal sodium reabsorption.

Link: http://www.medscape.org/viewarticle/513877


What is the effect of RAS on maintaining Blood pressure despite extremes in dietary sodium intake?

-When dietary sodium intake is low, renin is released, AngII acts on the kidneys to shift the renal pressure-natriuresis curve to the right (vice versa is true)

-Thus, despite large swings in dietary sodium intake, it does not deviate too far from the set point of BP.

*However, if RAS is blocked by drugs, there will be a great effect on BP if changes in salt intake are done!!!






(i) Endothelial cell dysfunction

-Hypertensives may have reduced vasodilatory responses to Nitric Oxide and endothelium contains local vasoconstrictor substances such as endothelin-1.

*The presence of headaches has been found to poorly correlate with the level of Blood Pressure.

*Organ damage (cardiac, cerebral and renal) is related to the severity of hypertension.

Note: To effectively treat hypertension in the presence of insulin resistance, body composition must also be taken into account. Insulin resistance is proportional to body fat. 

Obesity results in downregulation of insulin receptors, reduction in number of GLUT4 molecules, reduced sensitivity of insulin-dependent enzymes like lipoprotein lipase, glycosylation of various proteins (receptors and enzymes) and associated with left ventricular hypertrophy (via sodium retention, renin-angiotensin system). Results in insulin-resistance.

In diabetic patients, troglitazone (but not glyburide) lowered resting blood pressure and stress-induced high blood pressure. Troglitazone improved insulin resistance but not glycemic control.


Cardiac damage and remodeling:

-Left ventricular hypertrophy results in increase wall stiffness to diastolic filling

-Diastolic filling decreases and results in a prominent ‘a’ wave (atrial systole) on echocardiography (lowered E/A ratio)

-Left Ventricular failure (systolic and diastolic dysfunction) may follow often with a ventricle that is not dilated

****Note: Coronary artery disease is also common in hypertensive patients as hypertension is a risk factor

-Risk of cardiac events (death, myocardial infarction, heart failure, Ventricular arrhythmias) decreases when BP is lowered

Altered Renal Function:

-Gradual development of renal impairment and renal failure is frequently seen in long-standing hypertension

-Loss of urinary concentrating ability may cause nocturia to develop (need/impulse to get up at night to urinate thus interrupting sleep)

****Note: Chronic Renal Disease/Chronic Kidney Disease is also common in hypertensive patients as hypertension is a risk factor. Chronic Kidney Disease can be diagnosed via blood test for creatinine (Higher creatinine indicates lower GFR)

-Microalbuminuria (kidney leaks small amount of albumin into urine-abnormally high permeability to albumin) progresses to more severe proteinuria (protein in urine) and creatinine clearance decline. Eventually end-stage renal failure may occur and dialysis is necessary.

-In accelerated severe hypertension, acute renal failure may occur and dialysis may be necessary and immediate medical treatment should be sought!

Cerebral Effects:

-Strokes and transcient ischemic attacks are more common in hypertensives

-During a stroke, BP may increase acutely and caution must be taken in lowering it too rapidly

****Note: Hypertension is an important, known risk factor for STROKE.

-Cerebral vascular resistance will be increased due to effects of hypertension as well as the possible effects of Cerebral Oedema (swelling of the brain due to excess fluid accumulation) and if a reduction in cerebral arterial perfusion pressure is too great, cerebral ischemia may occur.


Table 1: Retinopathy associated with hypertension (persistent and acute damage to the retina results in vascular remodeling)

Grade 1: Mild narrowing or sclerosis of the retinal arteriolar lumen producing a ‘silver’ wiring effect
Grade 2: Moderate to marked sclerosis of the arterioles, visible as arteriovenous ‘nipping’
Grade 3: Progressive retinal changes resulting in oedema, ‘cotton wool’ spots and hemorrhages
Grade 4: All of the above with papilloedema (swelling of the optic disc)


****Note: Hypertension is also a risk factor of retinopathy

Tests for hypertension:

-Urinalysis for blood and protein (albumin), blood electrolytes (Na+) and creatinine [May indicate renal disease either causing or caused by hypertension, rarely may suggest adrenal hypertension]

-Blood glucose levels [To exclude diabetes or glucose intolerance]

-Serum total and high density lipoprotein (HDL) cholesterol (leads to artherosclerosis) [To help assess future cardiovascular risk]

-ECG [May suggest left ventricular hypertrophy]

***Accelerated (malignant) hypertension

***Suspected secondary hypertension                                All these requires specialist referral

***Therapeutic problems or failures

***Special circumstances (e.g. pregnancy)

Indications for treatment

-Benefits achieved by lowering BP are the greatest for those with the highest pressures

-Risks of future cerebral and cardiac events are significant when the diastolic pressure is elevated for a prolonged period by >10mmHg

-Drug therapy should be commenced if lifestyle changes cannot control increase in BP

-60% of hypertensives fall into the category of 80-85 mmHg diastolic pressure. Thus there is a cost-effective  question on whether drug treatment is necessary.

-As a general guide, almost all treated patients should have diastolic pressures <85-90 mmHg and systolics <140-140 mmHg AND IN DIABETICS THE TARGET SHOULD BE <140/80



Part 2: Mild/Borderline/Stage 1 Hypertension

-BP range from 140/90 to 149/99 mmHg

-If life style changes are ineffective, drug treatment is indicated in this group under the following circumstances

  • Evidence of target organ damage is present (i.e. retinopathy, renal failure, left ventricular hypertrophy, proteinuria, microalbuminuria)
  • If diabetes mellitus is present
  • If there are established cardiovascular complications (previous stroke or known ischemic heart disease)
  • If the 10 year coronary heart disease risk is 15% or more

Part 3: Hypertension in the elderly

>50% of men and women above the age of 60 years will have isolated systolic hypertension (systolic BP 160mmHg and diastolic BP 160 mmHg)

-Elderly patients with this BP require treatment urgently

-Lowering BP has been shown to reduce dementia and may help preserve cognitive function

Part 4: Secondary hypertension/Inessential hypertension

-Defined as hypertension with known/identifiable secondary causes

-Only affects 5% of hypertensive patients

-Many different causes including endocrine diseases, kidney problems and side effect of many medications

  1. Renal parenchymal disease (3%)

-Any cause of renal failure (glomerulonephritis, pyelonephritis, obstructive causes) that involves parenchymal  (tissue portion of organ) damage would tend to cause hypertension which leads to renal damage.

  1. Renal Vascular disease

-Encompasses and deals with renal blood supply and can be divided broadly into artherosclerosis (affects proximal third of the renal artery) and fibrodysplasia (mainly affects the distal 2/3, commonly found in younger individuals esp. women)

Reduced renal blood supply stimulates ipsilateral (same side) production of renin and hence elevation of BP

Should be suspected of Fibrodysplasia or arterosclerosis if there is an abrupt onset, refractory to treatment and appears to normalize with ACE inhibitors. It is also severe or accelerated and if an abdominal bruit (Term for the unusual sound that blood makes when it rushes past an obstruction-turbulent flow)is detected

  1. Endocrine disorders

-Consider primary aldosteronism (Conn’s syndrome)when hypokalemia is associated with hypertension

-Usually hypertension results in hypokalemia due to excretion of potassium ions

-Thus when high aldosterone and low renin levels present, it results in sodium and water overload

-This is due to a solitary benign adrenal adenoma (Benign tumour-Conn’s syndrome) or bilateral idiopathic adrenal hyperplasia (Most common causes of primary aldosteronism)

-Diagnosis is aided by computerized tomographic (CT) scan or MRI scanning. Treatment is by tumour resection or use of aldosterone antagonist (NOT ARB)–>e.g. Spironolactone (Steroidal Anti-mineralocorticoid agent)àAnti-hypertensive

  1. Cushing’s Syndrome

-Due to bilateral adrenal hyperplasia caused by adrenocorticotropic hormone (ACTh) secreting pituitary adenoma in 2/3 of the cases

-Pirmary adrenal tumour account for the remaining

-Suspected if hypertension is associated with thinning of skin, obesity, easy bruising, moon face, osteoporosis, muscle weakness

Diagnosis-Via 24 hour urinary cortisol and dexamethasone suppression test, then pituitary and adrenal CT or MRI if cortisols are abnormal

  1. Congenital adrenal hyperplasia-Rare childhood hypertension
  2. Phaeochromocytoma

– Catecholamine-secreting tumour in the chromaffin cells of neural origin, 90% in the adrenals. The rest occurs somewhere in the sympathetic N.S.

-10% of tumours are bilateral and 10% are malignant

-Suspected phaeochromocytoma if BP fluctuates occurs with tachycardia, sweating or sometimes pulmonary edema due to cardiac failure

Diagnosis is by 24 hour or spot-urine measurement of total metanephrine (Catecholamine metabolite) although levels may be affected by certain antihypertensive drugs (esp. Labetalol). Once diagnosed, attempt to locate the secreting tumour using CT, MR or radioisotope scanning.

-Remove tumour ASAP

  1. Coarctation (Narrowing) of the aorta

-Aortic Coarctatoin means narrowing in the area where the ductus arteriosus inserts

-It is a congenital condition which occurs when the ductus arteriosus is inserted and results in a narrowing of the aorta or distal to the left subclavian artery

-When a patient has coarctation, the left ventricle has to work harder and since the aorta is narrowed, the left ventricle must generate much higher pressure than normal

-Results in hypertension in arms and lower pressures in legs, with weak or absent femoral arterial pulses

-Systemic arterial vasoconstriction occurs due to stimulation of renin-angiotensin system  (due to low renal arterial perfusion pressure and sympathetic hyperactivity)

Diagnosis by CT or MR scanning and/or contrast aortography

-Hypertension may often persist even after successful surgical resection

  1. Pregnancy Related

-Gestational hypertension occurs up to 10% of first pregnancies which is more common in younger mothers

-Most likely due to poor uteroplacental blood flow and generally occurs in last trimester or early post-partum period (post pregnancy stage of mother)

-Associated with proteinuria, increased serum urate levels and when severe causes the syndrome of pre-eclampsia (high blood pressure and significant amounts of protein in the urine of a pregnant woman-may lead to eclampsia which means seizures)

-May also worsen pre-existing primary hypertension and this ‘acute on chronic’ variety occurs in more common older, multigravida (pregnant many times) mothers

-Anti-hypertensives should be avoided in pregnancy esp ARBs and ACE-inhibitors.

-Hypertension should be treated with ample bed rest and fetal monitoring

Drug therapy preferred: Methyldopa and Labetalol

  1. Drug induced

-Oral contraceptive pill (OCP) and steroids with around 5% of women developing hypertension within 5 years of starting

-Older women >35 years old are predispose, BP will fall to normal in 50% within 3-6 months  of stopping OCP

-Post menopausal women taking oestrogen is cardioprotective and does not increase BP

-NSAIDs, certain anti-depressants can also cause hypertension

-Cyclosporin (Immunospressant) and sudden withdrawl of anti-hypertensive medications (e.g. clonidine and methyl-dopa) leads to  rebound hypertension

-Clonidine [alpha 2 selective adrenergic receptor agonist]

causes an acute rise in BP due to the activation of post-synaptic alpha 2 receptors in vascular smooth muscle (after parenteral administration, the transient vasoconstriction outflow is followed by a prolonged hypotensive response that is due to decreased sympathetic outflow from CNS-activation of a2 receptors in the lower brainstem region)

-Clonidine also stimulates parasympathetic outflow, which may contribute to slowing of the heart rate. Some anti-hypertensive effects of clonidine may be due to activation of pre-synaptic a2 receptors that suppresses the release of NAdr, ATP and Neuropeptide Y from post-ganglionic nerves

-Clonidine also decreases plasma concentration of NAdr and reduces its excretion in urine.

  1. Sleep apnea



Part 5: Accelerated hypertension

-Malignant hypertension (condition arises when BP rises rapidly due to diastolic levels above 130-140mmHg)

-Occurs in 1% of patients with primary hypertension but commonly in secondary hypertension (esp. phaechromocytoma and chronic renal failure)

-Retinal hemorrhages and exudates are common and papilloedema will follow

-Initially, cerebral vessels constrict with increasing hypertension (autoregulation) but in accelerated cases, vessels cannot without rapidly rising pressure and dilate (resulting cerebal hyperperfusion and cerebral odema)

-Symptoms of headache, irritability and alterations in consciousness

-If left untreated, accelerated hypetension will lead to progressive renal damage, hyperaldosteronism due to renal ischemia, microangiopathic hemolytic anemia (disease of small blood vessels in body) and disseminated intravascular coagulation (DIC)


Part 6: Management of hypertension

  1. Non-Pharmacological approach (Lifestyle modifications)

-Reducing Weight, Exercise

-Reducing Alcohol Intake

-Reducing Salt intake, Reducing saturated fat intake

-Increasing intake of fruits and vegetables, avoiding smoking, reducing stress

  1. Pharmacological therapy (Drug therapy)

*Use the lowest dose initially and increase incrementally depending on the response to treatment

-Allow at least 4 weeks to see the effect, unless a more pressing/urgent need to reduce BP is needed

-In general, medication should be taken in the morning rather than at night (since BP is lowest at night, prevents exacerbation of morning drop in BP during 5-8 am)

-Most physicians tend to prescribe diuretics or B-blockers as first line therapy because they are the agents with the most research supporting benefit. What?

  • ACE Inhibitors

-Captapril, Enalapril, Tranalapril, Quinapril, Ramipril etc

-Blocks the production of angiotensin II by inhibiting the conversion of ANGIOTENSIN IàAngiotensin II

-Angiotensin II is a potent vasoconstrictor and stimulates the production of aldosterone

****ACE-inhibitors are very useful for diabetic nephropathy, where efferent arteriolar dilation slows the progressive loss of renal function and may reduce proteinuria.

**** May also increase sensitivity to insulin and have no effect on serum lipids or urate


Adverse effects:

  1. Hypotension
  2. Intractable cough due to bradykinin production
  3. Angioedema
  4. Acute Renal failure
  5. Skin Rashes
  6. Fetal Toxicity
  7. Interaction with other drugs
  • Angiotensin II receptor Blockers (ARBs)
  • Alpha-Adrenergic inhibitors

May act Centrally on the vasomotor centre in the brain stem, peripherally on neuronal catecholamine release or by blocking alpha receptors

-In vascular smooth muscle, alpha stimulation causes vasoconstriction and beta stimulation causes vasodilation

-In the vasomotor centre, sympathetic outflow is inhibited by alpha stimulation

Mechanism of Action:

  1. Inhibits the activation of alpha adrenergic receptors in vascular smooth muscle results in less contraction. Decreased peripheral vascular resistance (Decreased TPR)
  2. Blood Pressure decreases
  • Beta-adrenergic blockers

-Widely used as hypertensives and some have greater selectivity than others (some cardioselective and some non-cardioselective)

-Some beta-blockers have intrinsic sympathomimetic activity (ISA) [e.g. pindolol, oxprenolol, acebutalol and celiprolol]

*ISA refers to beta blockers that can show both agonism and antagonism at a given beta receptor, depending on the concentration of the agent and the concentration of the antagonized agent (NAdr or Adr) àPartial agonist

ISA beta-blockers result in less fall in heart rate, cardiac output and renin for a similar change in BP when compared to B-blockers without ISA

Adverse effects:

-Beta blockers may worsen bronchospasm, claudication (limping, impairment or discomfort) and untreated congestive cardiac failure

Symptoms of hypoglycemia in diabetics may be blunted and thus relatively contraindicated

-Glucose control may be worsened due to interference with insulin sensitivity

-Fatigue, Insomnia, Nightmares, Hallucinations, Depression and impotence

-Relatively ineffective in elderly care hypertensive

  • Calcium channel blockers

-Amlodipine, Felodipine, Nifedipine etc (Dihydropyridine class)

-Verapamil, Diltiazem (Non-Dihydropyridine)

-Able to slow heart rate (negative chronotropism), reducing myocardial contractility (negative inotropism)

-For elderly patients, nifedipine is the second drug of choice after diuretics

Adverse effects:

-Facial flushing, Peripheral odema, Constipation

  • Diuretics

-All diuretics lower BP acutely by salt and water loss but over 4-6 weeks equilibrium is restored and BP returns to previous levels

-However, thiazides have a direct vasodilatory effect on arterioles which results in a sustained hypotensive effect

-Thiazides reduce serum potassium and tend to increase blood glucose, urate, insulin, cholesterol and calcium

****Note: For treatment of hypertension use the longer acting thiazides such as hydrochlorothiazide (12.5-50mg/day) or bendrofluazide (2.5-5.0mg/day) perhaps with addition of a potassium sparing agent such as amiloride unless an ACE-inhibitor is used

-Indapamide is a sulphonamide diuretic with actions similar to thiazides but with little side effects on glucose or cholesterol

****Thiazides are the first drug of choice in elderly patients followed by nifedipine

Adverse effects:

Nearly 25% of men suffer impotence

  • Endothelin and Vasodilators

Part 6: Choice of drug agents

-Many hypertensive patients will require drug combinations to achieve adequate BP control

-Drug classes generally have additive effects when prescribed together so submaximal doses of two drugs result in a larger BP response and fewer side effects

-Thus two classes of anti-hypertensives often prescribed

Rational combinations:

  1. Thiazide diuretic and a B-Blocker
  2. Thiazide diuretic and an A-Blocker
  3. ACE inhibitor and an A-blocker
  4. Alpha blocker and calcium antagonist
  5. B-blocker and calcium antagnonist

-Each hypertensive patient needs to be considered separately when considering the choice of therapy

-Choice being determined by factors such as age, comorbidity (e.g. diabetis, coronary heart disease, asthma)

-Thiazide diuretic should be chosen because it has been shown to be effective, reduce long term complications of hypertension, well tolerated and cost effective


Part 7: Hypertensive crisis

-When the BP rises over a few days to levels above 180/120 mmHg, RENAL FAILURE AND HYPERTENSIVE ENCEPHALOPATHY MAY OCCUR.

-It is important to lower BP but do so in as gradual and controlled manner because rapid reduction in BP will cause cerebral and renal under perfusion

-Intravenous agents such as Labetalol, Diazoxide, Esmalol, Nicardipine and sodium nitroprusside are used.

-Use of Sodium nitroprusside should be only limited to a few days because of the risk of thiocyanate accumulation

  • Additional Drug Therapy

Aspirin (NSAID) is widely used for secondary prevention of cardiovascular disease

Hypertension Optimal Treatment (HOT) trial 75mg of aspirin reduced major cardiovascular events but not fatal events but with also a significant increase in the risk of bleeding events.

-Thus Aspirin is not recommended for routine prophylaxis but used for:

  • Primary Prevention in controlled hypertensive patients  <50 years who have evidence of targeted organ damage, diabetes or a 10 year cardiovascular risk of >15%
  • Secondary Prevention in hypertensive patients where there is evidence of existing cardiovascular disease (e.g. angina, myocardial infarction)

-Statins (lipid lowering group of drugs reduces coronary events, all-cause mortality and strokes in Coronary heart disease patients)

Thus Statins are recommended for the following circumstances:

  • Primary prevention in those <70 years with total fasting cholesterol >5.0mmol/L and a 10 year  cardiovascular risk of >30%
  • Secondary prevention in hypertensives <75 years with evidence of existing cardiovascular disease and total fasting cholesterols >5.0mmol/L

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