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Hypertension

is defined as an elevated SBP (≥140 mm Hg), DBP (≥ 90 mm Hg), or both.

- A clinical diagnosis of hypertension is based on the mean of two or more properly

measured seated BP measurements taken on two or more occasions.

- This mean BP is also used to initially classify and stage hypertension.

The JNC-7 classification includes normal BP, prehypertension, stage 1 hypertension, and stage

2 hypertension.

Classification SBP mmHg DBP mmHg

Normal <120 and <80

Prehypertension 120-139 or 80-89

Stage 1 hypertension 140-159 or 90-99

Stage 2 hypertension ≥ 160 or ≥100

Aetiology:

Hypertension is the most common cardiovascular disorder.

1. Primary (or essential) hypertension, constitutes 90-95% of all cases of systemic

hypertension.

- The average age of onset is about 35 years.

- The precise aetiology of essential hypertension is currently unknown,

- Genetic factors clearly play a part as the condition clusters in families, with

hypertension being twice as common in subjects who have a hypertensive parent.

2. Secondary hypertension, accounts for the remaining 5-10% of cases of systemic

hypertension.

- This type usually develops between the ages of 30 and 50.

- There are specific identified causes for the elevated BP & these includes:

Renal diseases

Endocrine diseases

– Steroid excess: hyperaldosteronism (Conn's syndrome)

Hyperglucocorticoidism (Cushing's syndrome)

– Growth hormone excess: acromegaly

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– Catecholamine excess: phaeochromocytoma

– Others: pre-eclampsia

Vascular causes

– Renal artery stenosis: fibromuscular hyperplasia;

Renal artery atheroma;

– coarctation of the aorta

Drugs

– Sympathomimetic amines

– Oestrogens (e.g. combined oral contraceptive pills)

– Ciclosporin

– Erythropoietin

– NSAIDs

– Steroids

White-coat hypertension, refers to patients without target-organ disease who have

consistently elevated BP values measured in a clinical environment (e.g., physician's office)

that are significantly higher than those obtained by either a manual reading outside this

environment (e.g., home) or with 24-hour ambulatory monitoring.

- Patients with white-coat hypertension are at risk for developing hypertension

- Patients with white-coat hypertension are at a higher risk for cardiovascular disease

than normotensive patients.

Hypertensive crises, is situations which arise when measured BP values are excessively high

(> 180/110 mm Hg). It's further classified to:

a) Hypertensive emergency (with acute or chronic end-organ damage), it require

hospitalization for immediate BP lowering using IV medications.

b) Hypertensive urgency (without acute end-organ damage). This does not require

immediate BP lowering; instead, BP should be slowly reduced within 24 hours.

Isolated systolic hypertension (ISH), is defined as an elevated SBP (>140 mm Hg) with a

normal DBP (< 90 mm Hg). This pattern of hypertension is most common in patients older

than 65 yrs.

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Regulation of blood pressure

BP is normally regulated by compensatory mechanisms that respond to changes in cardiac

demand.

MAP = CO x TPR

• an increase in cardiac output (CO) normally results in a compensatory decrease in total

peripheral resistance (TPR).

• an increase in TPR results in a decrease in CO.

• Adverse changes in BP can occur when these compensatory mechanisms are not

functioning properly.

• It has been suggested that in hypertension an initial increase in fluid volume increases CO

and arterial pressure.

• Eventually, with long-standing hypertension, it is believed that TPR increases so that CO

returns to normal.

1- Sympathetic nervous system (controls α- and ß-receptors), which causes contraction and

relaxation of vascular smooth muscle.

Stimulation of α-adrenergic receptors in the central nervous system (CNS) results in a

reflex decrease in sympathetic outflow causing a decrease in BP.

Stimulation of postsynaptic α1-receptors in the periphery causes vasoconstriction.

Stimulation of postsynaptic ß1-receptors (myocardium) causes an increase in heart rate

and contractility.

Stimulation of postsynaptic ß2-receptors in the arterioles and venules results in

vasodilation.

2- Renal function and renal blood flow (influences fluid and electrolyte balance) Increased

fluid volume increases venous system distention and venous return, affecting cardiac output

and tissue perfusion. These changes alter vascular resistance, increasing the blood pressure.

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3- The renin-angiotensin-aldosterone system (RAAS)

Angiotensin-II has several important functions in the regulation of fluid volume:

a. it stimulates the release of aldosterone from adrenal gland, which results in increased

sodium reabsorption, fluid volume, and blood pressure.

b. It constricts resistance vessels, which increases peripheral vascular resistance and arterial

pressure.

c. It stimulates the release of vasopressin, or antidiuretic hormone (ADH), from the

posterior pituitary, which acts within the kidneys to increase fluid retention.

d. It stimulates cardiac hypertrophy and vascular hypertrophy

e. It facilitates norepinephrine release from sympathetic nerve endings and inhibits

norepinephrine reuptake by nerve endings, which enhances sympathetic function.

4. Electrolytes & hypertension

1) Sodium: patients with high dietary sodium intake has a greater prevalence of hypertension

than those with a low sodium intake.

The mechanism by which hypertension is caused by an increase in sodium intake is

hypothesized to involve natriuretic hormone.

Natriuretic hormone might cause an increase in intracellular sodium and calcium,

resulting in increased vascular tone and hypertension.

2) Calcium Epidemiologic evidence and clinical trials have demonstrated an inverse

relationship between calcium and BP.

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One proposed mechanism for this relationship involves an alteration in the balance

between intracellular and extracellular calcium. Increased intracellular calcium

concentrations can increase peripheral vascular resistance, resulting in increased BP.

3) Potassium, a decrease in potassium has been associated with an increase in peripheral

vascular resistance.

It is important that potassium concentrations be maintained within the normal range

because hypokalemia increases the risk of cardiovascular events, such as sudden death.

5- Mosaic theory centers around the fact that multiple factors, rather than one factor alone, are

responsible for sustaining hypertension.

The interactions among the sympathetic nervous system, RAA system & potential defects

in sodium transport within and outside the cell may all play a role in long-term hypertension.

Other vasoactive substances that are involved in the maintenance of normal blood pressure

include:

- Nitric oxide (potent vasodilatling factor): is produced in the endothelium.

Hypothetically, hypertensive patients could have an intrinsic deficiency in NO release

and inadequate vasodilation, which may contribute to hypertension and/or its vascular

complications.

- Endothelin (vasoconstrictor peptide).

- bradykinin (potent vasodilator inactivated by ACE),

- Atrial natriuretic peptide (naturally occurring diuretic).

Hypertension-related target organ damage and major cardiovascular risk

▪ The relationship between elevated blood pressure and CVD was addressed in the JNC-7,

which formalizes the fact that the higher the blood pressure, the greater the chance of a

myocardial infarction (Ml), heart failure (HF), stroke, or kidney disease.

▪ Beginning at a benchmark BP of 115/75 mm Hg, the risk of cardiovascular disease doubles

with every increment of 20/10 mm Hg.

▪ Clinically, it is important to note that having elevated SBP (˃ 140 mm Hg) is a more reliable

predictor of cardiovascular disease than elevated DBP in people older than 50 years of age

(Therefore, SBP is the primary target of evaluation and intervention for most patients).

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Target organ damage

1. Heart

- Indirect effects: by proving atherosclerotic changes (modest elevation of blood pressure)

- Direct effects: via pressure related effects (blood pressure is greatly rising).

Hypertension can promote CVD and increase risk for ischemic events, such as angina and Ml,

LVH, HF, and arrhythmias

2. Brain

Transient ischemic attacks, ischemic strokes, multiple cerebral attacks and hemorrhages.

A sudden, prolonged increase in systolic BP also can cause hypertensive encephalopathy

(hypertensive emergency).

3. Kidney

o Decrease GFR

o Decreased blood flow leads to an increase in RA secretion, which heightens the

reabsorption of sodium and water and increases blood volume.

o Accelerated atherosclerosis decreases the oxygen supply, leading to renal parenchymal

damage with decreased filtration capability and to azoternia. The atherosclerosis also decreases

blood flow to the renal arterioles, leading to nephrosclerosis and, ultimately, renal failure

(acute as well as chronic).

o chronic renal disease, whether mild or severe, can progresses to failure

o Polyuria, nocturia, and diminished ability to concentrate urine; protein and red blood cells

in urine; elevated serum creatinine

4. Peripheral arterial disease

Atherosclerotic vascular disease.

Absence of pulses in extremities with or without intermittent claudication; development of

aneurysm.

5. Eye

Hypertension causes retinopathies that may progress to blindness. Retinopathy is evaluated

according to the Keith, Wagener, and Barker funduscopic classification system.

Grade 1: narrowing of the arterial diameter, indicating vasoconstriction.

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Grade 2: Arteriovenous (AV) nicking indicating atherosclerosis

Grade 3: cotton wool exudates and flame haemorrhages (Longstanding untreated

hypertension or accelerated hypertension)

Grade 4: papilledema (severe cases)

Sign and symptoms

Hypertension is usually asymptomatic until complications develop in target organs. Dizziness,

flushed face, headache, fatigue, epistaxis, and nervousness are not caused by uncomplicated

hypertension.

Malignant (accelerated) hypertension, is an uncommon condition characterised by greatly

elevated blood pressure (usually >220/120 mmHg) associated with evidence of ongoing small

vessel damage.

- Fundoscopy may reveal papilloedema, haemorrhages and/or exudates,

- renal damage can manifest as haematuria, proteinuria and impaired renal function.

- The condition may be associated with hypertensive encephalopathy, which is caused

by small vessel changes in the cerebral circulation associated with cerebral oedema.

The clinical features are confusion, headache, visual loss, seizures and coma.

- Brain imaging (particularly MRI) usually demonstrates extensive white matter

changes.

- it is a medical emergency that requires hospital admission and rapid control of blood

pressure over 12–24 h towards normal levels.

Diagnosis

Hypertension is diagnosed and classified by:

1. Sphygmomanometery: BP must be measured twice—first with the patient supine or seated,

then after the patient has been standing for 2 min—on 3 separate days.

- The average of these measurements is used for diagnosis.

- Ideally, BP is measured after the patient rests > 5 min and at different times of day.

2. History: The history includes the known duration of hypertension and previously recorded

levels; any history or symptoms of CAD, HF, or other relevant coexisting disorders (eg, stroke,

renal dysfunction, peripheral arterial disease, dyslipidemia, diabetes, gout); and a family

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history of any of these disorders. Social history includes exercise levels and use of tobacco,

alcohol, and stimulant drugs (prescribed and illicit). A dietary history focuses on intake of salt

and stimulants (eg, tea, coffee, caffeine-containing sodas, energy drinks).

3. Physical examination: The physical examination includes measurement of height, weight,

and waist circumference; funduscopic examination for retinopathy; and a full cardiac,

respiratory, and neurologic examination. The abdomen is palpated for kidney enlargement and

abdominal masses. Peripheral arterial pulses are evaluated.

4. Testing: The more severe the hypertension and the younger the patient, the more extensive

is the evaluation. Generally, when hypertension is newly diagnosed, routine testing to detect

target-organ damage and cardiovascular risk factors is done. Tests include:

• Multiple measurements of BP to confirm

• Urinalysis & urinary albumin:creatinine ratio; if abnormal, consider renal

ultrasonography

• Blood tests: Fasting lipids, creatinine, K

• If creatinine increased, renal ultrasonography

• If K decreased, evaluate for aldosteronism

• ECG: If left ventricular hypertrophy, consider echocardiography

• Sometimes thyroid-stimulating hormone measurement

• If BP elevation is sudden and labile or severe, evaluate for pheochromocytoma

Assessment of hypertensive patients

First: the presence and absence of various forms of hypertension-related target organ damage

should be assessed.

Second: secondary causes of hypertension, if present, should be identified and managed

accordingly.

Third: major risk factors, concomitant disorders, and lifestyle habits should be evaluated so

that they can be used to guide therapy and influence prognosis.

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Target blood pressure

• Most patients with hypertension have a BP goal of < 140/90 mm Hg.

• The BP goal is < 130/80 mm Hg for patients with diabetes or chronic kidney disease,

because they are at very high risk for target-organ damage.

Goals of Therapy

The ultimate goal of therapy is to lower hypertension-related morbidity and mortality.

a- Lifestyle Modifications

1. Weight reduction (Maintain normal body weight BMI =18.5 to 24.9 kg/m2)

2. Adopt DASH eating plan (Consume a diet rich in fruits, vegetables, and low-fat dairy

products with a reduced content of saturated and total fat)

3. Dietary sodium restriction (Reduce daily dietary sodium intake to 100 mEq (2.4 g

sodium or 6 g sodium chloride)

4. Physical activity (Engage in regular aerobic physical activity at least 30 min/day, most

days of the week)

5. Moderate alcohol consumption

6. Smoking cessation: Smoking result in vasoconstriction and activation of the SNS & is

a major risk factor for cardiovascular disease.

b- Starting Drug Therapy

Stepped care approach, the stepped-care approach has traditionally been used when initiating

therapy.

- A single agent is selected with the dose increased until BP is controlled, the maximum

dose is reached, or dose-limiting toxicity occurs.

- If the goal BP is not achieved, a second drug from a different class is added.

- Theoretically, this process can be continued, if necessary, until three or even four drugs

are used in combination.

Sequential therapy, the sequential therapy approach is similar to the stepped care approach in

that an agent is started and titrated to the maximum dose as needed.

- If goal BP is not achieved, an alternative agent is selected to replace the first.

- Combination drug therapy is reserved for patients who do not achieve goal BP values

after the second agent.

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- Sequential therapy seems most appropriate when the first drug is either poorly tolerated

or results in minimal or no reduction in BP.

Combination Therapy

Starting therapy with a combination of two drugs is now strongly encouraged for

certain patients.

This approach is recommended for all patients with stage 2 hypertension or those who

are far from their goal (e.g., 20 mm Hg from SBP goal or 10 mm Hg from DBP goal,

according to JNC 7).

Initial combination therapy is also an option for patients in whom goal achievement

may be difficult (i.e., diabetes, chronic kidney disease, African Americans) or in

complex patients in whom there are multiple compelling indications for different

antihypertensive agents.

Stepped -Down Therapy

A small number of patients with long-standing hypertension can later have their BP

medications slowly withdrawn, resulting in normal BP values for weeks or months

following discontinuation of their medications. This is called step-down therapy.

Step-down therapy: This consists of attempting to decrease the dosage and/or number

of antihypertensive drugs without compromising BP control. Step-down therapy is

most often successful in patients who have lost significant amounts of weight or have

drastically changed their lifestyle.

Antihypertensive agents

1. Diuretics

When initially started, they induce a natriuresis that decreases plasma volume so cause a

decrease in CO (Diuresis usually depresses after chronic use with some of these agents,

especially with thiazide diuretics).

However, the long-term BP lowering effects are maintained because of a sustained decrease

in peripheral vascular resistance (PVR).

Diuretics are commonly prescribed as the initial antihypertensive drug because:

- They are cheap

- Have low incidence of side effect

- High level of efficacy

- High patients acceptability

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- They reduce morbidity and mortality rates.

- Diuretics are generally well tolerated, and most can be given once daily.

But the biochemical alteration IS a problem and this can be decreased by using a small

dose

Types of diuretics:

1. Thiazides and related diuretics

Thiazide-type diuretics are the diuretics of choice for hypertension.

Goal BP values <140/90 mm Hg are achieved in 45% to 80% of patients who take these

drugs.

They differ primarily in the duration of action:

< 12 hr..... ...chlorthiazides, hydrochlorothiazide, hydroflomethiazide

Up to 24 hr..... ..bendroflumethiazide, benzthiazide, metalazone,

> 12 hrchlorthalidone, polythiazide, cyclothiazide

Properties

- Moderately potent diuretic

- Act within 1-2 hr after oral administration

- Administration should be early in the day (diuresis will not interfere with patients sleep)

Use and choice

They are all similar in effect but differ in the cost

Effective in black patients (HTN is often volume dependent)

Effective in elderly: because of freedom from acute toxicity in low dose

They should not be used in HTN patient with renal failure (creatine clearance< 30)

Side effects

- Decrease Na, Mg, K and hypovolemia o hyperuricemia, hypercholestrolemia, hypertriglyceridemia, hyperglycemia & hypecalcaemia

- Sexual dysfunction - Weakness, muscle cramps, GI disturbance. - Skin rash - Patients with known allergies to sulfa-type drugs should be questioned to determine

the significance of the allergy.

Significant interaction

- NSAIDs, such as ibuprofen, interact to diminish the antihypertensive effects of the

thiazide diuretics.

2. Loop diuretics

- Produce a more potent diuresis, a smaller decrease in PVR, and less vasodilation than

thiazide-type diuretics.

- Their action is more intense but of shorter duration (1-4 hr) than that of the thiazides; they

may also be more expensive.

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Note/ hydrochlorothiazide is more effective than loop diuretic in lowering B.P in most

patients (V.D + longer duration in addition to ↓ Na & water)

Uses Pulmonary edema due to left ventricular failure

CHF

Renal failure (creatine clearance < 30 ml/min)

Examples

Furosemide (lasix), Bumetanide, Torasemide & Ethacrynic acid

Furosemide & Bumetanide, are similar in activity after oral administration the onset is 1 hr

and duration= 6 hr so given twice or once daily without interferences with patients sleep -

I.V administration peak after 30 min.

Side effect

Similar to thiazides but they cause hypocalcaemia

Toxicity/ fuorosemide cause deafness

Bumetanide cause mylagia

Significant interaction

- As with the thiazides, the antihypertensive effect of loop diuretics may be diminished

by NSAIDs.

- Aminoglycoside……. ↑ ototoxicity.

- Digitalis…………... ↑ digitalis toxicity

3. K sparing diuretics (amiloride + triamterine)

▪ They are used for patients who develop hypokalemia while taking diuretics

▪ They are weak diuretics when used alone

▪ They cause retention of K therefore used as a more effective alternative to giving K

supplementation with thiazide or loop diuretic.

▪ These agents are often used in combination with a thiazide diuretic e.g: (thiazide +

amiloride = Moduretic) because they potentiate the effects of the thiazide while

minimizing potassium loss.

Aldosterone antagonists (spironolactone and eplerenone)

They are also classified as potassium sparing diuretics.

Blocking of the aldosterone receptor inhibits Na & water retention, and inhibits

vasoconstriction.

Hyperkalemia is a known dose-dependent effect with these agents that is more prominent

in patients with chronic kidney disease and with eplerenone (compared with spironolactone)

because eplerenone is a more specific aldosterone blocker.

Spironolactone is particularly useful in patients with hyperaldosteronism, as it has direct

antagonistic effects on aldosterone.

Gynecomastia is a side effect of spironolactone that does not occur with eplerenone.

These agents are indicated for hypertension, but their greatest use may be in HF because of

evidence showing reduced morbidity and mortality.

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Significant interaction

Coadministration with ACE inhibitors, Ag II antagonist or potassium supplements

significantly increases the risk of hyperkalemia.

Precautions and monitoring effect

- Potassium-sparing diuretics should be avoided in patients with acute renal failure and

used with caution in patients with impaired renal function (monitor serum creatinine)

because they can retain potassium.

Side effects

Hyperkalemia, GI disturbances, gynecomastia, haisutism and menstrual irregularity

Diuretic induced hypokalemia

The incidence occurs in 14-60% of patients and is dose dependent and this can be managed

by:

1- decreasing the dose

2- K-rich food: dried fruit, bananas & orange juice

3- K-sparing diuretic

4- K-supplementation (oral KCl tablet &syrup , Potassium bicarbonate, gluconate,

acetate and citrate salts)

This management is needed in;

1- patients on digoxin

2- high dose corticosteroid

3- hyperaldosteronism

4- Cirrhosis, D.M, chronic diarrhea, starvation, MI & angina.

Other indications for diuretics

Thiazide diuretics decrease urinary calcium excretion and have been used to prevent

stone formation in patients with calcium-related kidney stones (The resulting elevations in

serum calcium concentrations are usually asymptomatic and of little clinical significance, but

may be beneficial in postmenopausal patients or in patients with osteoporosis).

Contrary to thiazide-type diuretics, loop diuretics increase renal clearance of calcium and

have been used for acute management of severe hypercalcemia.

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2. ß- Blockers

ß- Blockers have several direct effects on the cardiovascular system:

- decrease cardiac contractility and output,

- lower heart rate,

- blunt sympathetic reflex with exercise,

- reduce central release of adrenergic substances,

- inhibit norepinephrine release peripherally,

- decrease renin release from the kidney.

All ß-blockers have similar activity with regard to BP lowering, and patients whose

conditions fail to respond to one generally fail to respond to others.

Pharmacologic difference

Clinically important differences relate primarily to cardioselectivity, intrinsic

sympathomimetic activity (ISA) and relative lipid solubility.

1. CARDIOSELECTIVITY (atenolol, acebutolol, bisoprolol, metoprolol, betaxolol)

o Some ß-blockers demonstrate relative cardioselectivity with greater antagonism of cardiac

β1-receptors and less activity on ß2-receptors in the lung or bronchial tissue. However,

selectivity is not absolute since it is dose-dependent (asthma has been precipitated even with

cardioselective agents when they are used in higher doses, but not with low to moderate doses).

Therefore, no ß -blocker is totally safe in patients with bronchospastic disease—for example

asthma and COPD.

o Nonselective ß-blockers potentially have the disadvantage of blunting the symptoms of

hypoglycemia in patients with type I diabetes.

o β2-blockade from nonselective ß-blockers can lead to unopposed α-induced peripheral

vasoconstriction. This may worsen Raynaud's phenomenon, peripheral arterial disease, or

hypertension caused by catecholamine-producing tumors (pheochromocytoma).

o Nonselective ß-blockers are preferred in patients with noncardiovascular indications for ß

-blocker therapy such as migraine prophylaxis or essential tremor.

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2. INTRINSIC SYMPATHOMIMETIC ACTIVITY (acebutolol, carteolol, penbutolol,

and pindolol)

ISA represent the capacity of ß-blocker to stimulate as well as to block adrenergic receptors.

β-blockers with ISA partially stimulate ß-receptors while attached to this receptor, but much

less than a pure agonist.

When given to a patient with a slow resting heart rate, they can increase the heart rate.

Conversely, these agents can slow heart rate in patients with resting or exercise induced

tachycardia, because β-blocking properties predominate.

They are theoretically less likely to cause bradycardia, bronchospasm, reduced cardiac

output, peripheral vasoconstriction, and increased plasma lipids than non-selective ßblockers.

These agents still might worsen asthma or exacerbate HF or angina in patients with CAD.

They should never be used in patients with a history of MI because they may have

detrimental effects as a result of their agonist properties.

They should be avoided in patients who have contraindications to or adverse reactions with

non-ISA ß-blockers.

Perhaps the only role for ISA ß-blockers is in patients who require a ß-blocker, but

experience severe bradycardia from non-ISA agents.

Pindolol has the greatest ISA.

Celiprolol combine selective ß1-blocker + selective β2 stimulant activity which also

counteract P-vasoconstriction.

3. LIPID SOLUBILITY

▪ Lipophilic ß-blockers (e.g penbutolol & carvidolol & propranolol) have a larger volume of

distribution and undergo more extensive first-pass hepatic metabolism than hydrophilic ß-

blockers (e.g atenolol, nadolol, sotalol).

▪ Highly lipcphilic agents theoretically penetrate the CNS more extensively and readily than

hydrophilic ß-blockers therefore:

- They are preferable for migraine prophylaxis.

- They are associated with increased CNS side effects such as drowsiness, mental

confusion, nightmares, or depression.

▪ Considering lipid solubility is most clinically relevant when selecting a ß-blocker for a

patient with renal or hepatic impairment.

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▪ Highly hydrophilic ß-blockers (e.g., atenolol) are primarily excreted by the kidneys and

may require lower doses in patients with moderate to severe chronic kidney disease.

▪ High lipid soluble drugs are hepatically cleared.

Side effects & contraindications of β-blockers:

Site Side effect Caution &

contraindication

Bronchial smooth muscle Bronchoconstriction COPD & asthma

P- arterioles v-constriction, cold extremities,

muscle weakness, fatigue

PVD, Raynaud's syndrome

Myocardium

-negative inotropic

-negative chronotropic

Fatigue, decrease exercise

tolerance, bradycardia

Caution in HF,

C.In in heart block,

bradycardia

Systemic ß receptors Atherogenic dyslipidemia,

↓ response to hypoglycemia

Care in dyslipidemia

Pancrease ↓ insulin secretion

(herperglycemia)

Type II DM

CNS & others Night mares, confusion,

depression, psychotic reaction,

Impotence

Avoid evening dose and

lipophilic agents

Note/ Nonselective ß-blockers have been associated with increased serum triglycerides and

reductions in HDL—cholesterol. Agents with ISA have little or no effects on lipids, whereas

cardioselective ß-blockers have intermediate effects.

Why should a β-blocker never be abruptly discontinued?

Chronic ß-blocker therapy up regulates the expression of ß-receptors. However, this does not

result in rise of BP while ß-blocker therapy is maintained to occupy the receptors. If ß- blocker

therapy is abruptly stopped more ß-receptors are available to be activated, causing cardiac

stimulation and vasoconstriction & this will cause:

- Rebound hypertension: headache, tachycardia, and possibly anxiety.

- Patients with ischemic heart disease can have significant increases in angina frequency

if ß-blockers are abruptly stopped.

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Therefore ß-blockers should be discontinued by gradually tapering the dose by 50% for 3

days and then another 50% for 3 days. Replacing one ß-blocker with another should not cause

rebound hypertension.

3. Angiotensin-Converting Enzyme Inhibitors (captopril, enalapril, benzapril,

lisinopril, ramipril).

- ACE-inhibitors has a direct local effect on arteriole of systemic and renal vasculature.

- ACE inhibitors are believed to provide unique cardiovascular benefits by improving

endothelial function, promoting LVH regression and collateral vessel development, and

improving insulin sensitivity.

Notes

The effect or response of ACE-I become more pronounced with time, response at 3 months

>> than seen at 2-4 weeks.

This delay may be related to the diuretic effect + slow reversal of V-constrictor effect of

Ag II, catecholamine & vasopressin.

Because there are additional pathways for the formation of angiotensin II, ACE inhibitors

do not completely block the production of angiotensin II.

Bradykinin accumulates in some patients may lead to additive vasodilation by releasing

nitrous oxide; bradykinin can also cause a dry cough in some patients.

ACE inhibitor monotherapy is more effective at lowering BP in young white patients than

in African American or elderly patients (they have low renin hypertension).

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Pharmacological Considerations.

Some of these agents are primarily renally eliminated (benazepril, enalapril, lisinopril,

quinapril, ramipril), and others have mixed hepatic and renal elimination (captopril, fosinopril,

perindopril, trandolapril). Moexipril is the only ACE inhibitor that is almost completely

hepaticaily eliminated.

All ACE-inhibitors are equally effective, but they differ in: (Potency, pharmacokinetic

properties, duration of action, adverse effect & clinical indications)

All of them (except captopril) must be hepatically converted to active substance e.g (enalpril

is hydrolyzed to enaliprilate) so there is delay in onset of action, (but not with chronic therapy)

Newer agents have a slow rate of elimination & long duration of action.

They are associated with fewer incidence of side effects such as rash, taste disturbance

(agensia) and this may be related to the fact that captopril has a sulfhydryl group on its

molecule while other ACE-I don't. This SH group is associated with high incidence of rash,

agensia, proteinuria & neutropenia.

Side effects

Hypotension………..Common especially 1st dose effect

Renal impairment……..Renal insufficiency can occur in patients with predisposing factors,

such as renal stenosis, and when ACE inhibitors are administered with thiazide diuretics, HF

or patients on NSAID.

Hyperkalemia……….Avoid K-sparing diuretics, K-supplementation & NSAID.

Dry cough…………..If persist change to Ag receptor blocker.

Angioedema……….rare (kinin related)

Neutropenia, agranulocytosis (bone marrow toxicity)………rare.

Proteinurea, agensia, skin rash……….rare, only captopril in high doses.

Risk of hypotension Patients who are either volume depleted, hyponatremic, or have an exacerbation of HF, very

elderly, or frail may experience a significant first-dose response to an ACE inhibitor. This can

manifest as orthostatic hypotension, dizziness, or possibly syncope (These patients should

initiate ACE inhibitor therapy at half the normal dose).

Concurrent diuretic therapy may predispose some patients to first-dose hypotension. When

ACE inhibitors were first approved, dosing guidelines recommended starting at half the

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standard dose of the ACE inhibitor, decreasing the dose of the diuretic, or stopping the diuretic

before initiating the ACE inhibitor.

Other considerations

▪ ACE inhibitors are teratogenic in the second and third trimester.

▪ Their use in women of child bearing age is discouraged.

▪ If used in this population, patient education should be explicitly clear regarding risks to the

fetus which include potentially fatal hypotension, anuria, renal failure, and developmental

deformities (A highly effective form of contraception should be strongly recommended).

Indications

- Useful in diabetic nephropathy because they diminish proteinurea and stabilize renal function

(delay in progression of nephropathy)

- Are effective in patients with hypertension related to renal artery disease, however caution

must be taken when use ACE-I in patients with bilateral renal artery stenosis or who have

stenosis in a solitary kidney following nephroctomy.

- They are more effective in young, white patients because elderly, black have low rennin

activity but may respond to ACE-I.

- Following myocardial infarction, they have a direct tissue effect since the wall of artery or

myocardium contain RAAS so ACE-I prevent morphologic changes (remodeling) following

MI or otherwise lead to CHF.

- Decrease morbidity & mortality in CHF & left ventricular dysfunction.

Significant interaction

The antihypertensive effect of ACE inhibitors may be diminished by NSAIDs (e.g., OTC

forms of ibuprofen).

4. Angiotensin II receptor blockers (candesartan, eprosartan, irbesartan, losartan,

olmesartan, telmisartan and valsartan).

They directly block the angiotensin II type 1 receptor site. Therefore, they block angiotensin

II mediated vasoconstriction and aldosterone release.

ARBs are very well tolerated.

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They do not affect bradykinin and, therefore, do not cause a dry cough like ACE inhibitors.

Type I receptor are responsible for most unwanted cardiovascular effect of Ag II, so

inhibition of this receptors have beneficial effect.

So Ag II will bind with Ag type II receptors and produce benefit effects.

Candesartan, irbesartan, and telmisartan have much stronger blockade than either

losartan or valsartan.

Most of these agents can be dosed once daily, except twice daily dosing may be needed

when high doses of candesartan, eprosartan, or losartan are used.

Similar to ACE inhibitors, initial doses may need to be lower in elderly patients and those

who are taking a diuretic or are volume depleted.

Monitoring requirements, contraindications, and side effects (other than cough) are similar

for ARBs and ACE inhibitors.