Lecture 8 - Antihypertensive Agents

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Antihypertensive

Agents

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Hypertension is defined as either a sustained systolic blood
pressure (SBP) of greater than 140 mm Hg or a sustained
diastolic blood pressure (DBP) of greater than 90 mm Hg.

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Classification of Blood Pressure

Hypertension is classified into four categories for the


purpose of treatment management.
The categories are normal (SBP/DBP, <120/<80), prehypertension
(SBP/DBP, 120 -139/80 - 89), stage 1 hypertension (SBP/DBP, 140 -
159/90 - 99) and stage 2 hypertension (SBP/DBP >160 / > 100).

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Etiology of Hypertension
Primary Hypertension
 Specific cause unknown
 90% of the cases
 Also known as essential or idiopathic
hypertension
Secondary Hypertension
 Cause is known (such as eclampsia of pregnancy,
renal artery disease, pheochromocytoma)
 10% of the cases

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Major factors influencing blood pressure

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Antihypertensive Agents:
Categories
1. Adrenergic antagonists
2. Angiotensin-converting enzyme inhibitors
3. Angiotensin II receptor blockers
4. Calcium channel blockers
5. Diuretics
6. Vasodilators

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1. Adrenergic antagonists:
A. Beta-blockers
Reduce blood pressure primarily by decreasing cardiac
output. They may also decrease sympathetic outflow from
CNS and inhibit the release of renin from the kidneys,
thus decreasing the formation of angiotensin II and the
secretion of aldosterone.
The prototype is propranolol, which acts at both β1 and
β2 receptors. Selective blockers of β1 receptors, such as
metoprolol and atenolol are among the most commonly
prescribed β2-blockers. The selective β2-blockers may be
administered cautiously to hypertensive patients who also
have asthma, for which propranolol is contraindicated due
to its blockade of β2-mediated bronchodilation.

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Adverse effects
1. Common effects: They may cause bradycardia and CNS side
effects such as fatigue, lethargy, insomnia, and hallucinations; these
drugs can also cause hypotension
2. Alterations in serum lipid patterns: They may disturb lipid
metabolism, decreasing high-density lipoprotein cholesterol and
increasing plasma triacylglycerol.
3. Drug withdrawal: Abrupt withdrawal may induce angina,
myocardial infarction, or even sudden death in patients with
ischemic heart disease. Therefore, the dose of these drugs must be
tapered over 2 to 3 weeks in patients with hypertension and
ischemic heart disease. 10
α1-Adrenoceptor Blocking Agents
ᴥ Prazosin, doxazosin and terazosin produce a competitive block of
α1-adrenoceptors.

ᴥ They decrease peripheral vascular resistance and lower arterial


blood pressure by causing relaxation of both arterial and venous
smooth muscle.

ᴥ These drugs cause only minimal changes in cardiac output, renal


blood flow and glomerular filtration rate.

ᴥ Postural hypotension may occur in some individuals. Reflex


tachycardia and first-dose syncope are almost universal adverse
effects. 11
Centrally Acting Adrenergic Drugs
ᴥ They are α2-agonist which diminish the central
adrenergic outflow.
ᴥ Clonidine and α- Methyldopa are examples of this
group.
α- Methyldopa has been used in hypertensive pregnant
patients.

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2. Angiotensin-Converting Enzyme Inhibitors
(ACE Inhibitors)

RAAS: Renin Angiotensin-Aldosterone System


 When the enzyme angiotensin I is converted to
angiotensin II, the result is vasoconstriction and
stimulation of aldosterone
 Result of vasoconstriction: increased systemic
vascular resistance and increased afterload.
Therefore, increased BP
 Aldosterone stimulates water and sodium
resorption.
 Result: increased blood volume, increased preload,
and increased BP
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 ACE Inhibitors block the angiotensin-converting
enzyme, thus preventing the formation of
angiotensin II.
 Also prevent the breakdown of the vasodilating
substance, bradykinin

Result: vasodilation: decreased systemic vascular


resistance (afterload), and decrease water resorption.
therefore, decreased blood pressure

 Large group of safe and effective drugs


 Often used as first-line agents for CHF and HTN
 May be combined with a thiazide diuretic or calcium
channel blocker
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ACE Inhibitors
 Captopril
Short half-life, must be dosed more frequently
than others
 Enalapril
The only ACE inhibitor available in oral and
parenteral forms
 Lisinopril
 Quinapril
Newer agents, long half-lives, once daily dose
 Several other agents available

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ACE Inhibitors: therapeutic uses
 Drugs of choice in HTN patients with CHF

Side Effects:
Fatigue Dizziness
Headache Hyperkalemia
Impaired tasteRash
Dry cough due to increased levels of bradykinin in
the pulmonary tree.

NOTE: first-dose hypotensive effect may occur!!

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3. Angiotensin II Receptor Blockers (ARBs)

1. Allow angiotensin I to be converted to angiotensin II,


but block receptors that receive angiotensin II.
2. Their pharmacologic effects are similar to those of ACE
inhibitors in that they produce arteriolar and venous
dilation and block aldosterone secretion, thus lowering
blood pressure and decreasing salt and water retention.
3. ARBs do not increase bradykinin levels.
4. ARBs decrease the nephrotoxicity of diabetes, making
them an attractive therapy in hypertensive diabetics.
5. Their adverse effects are similar to those of ACE
inhibitors, although the risks of cough and angioedema
are significantly decreased.
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Angiotensin II Receptor Blockers:
 Losartan
 Valsartan
 Candesartan
 Eposartan
 Irbesartan
 Telmisartan

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4. Calcium Channel Blockers
 Cause smooth muscle relaxation by blocking the
binding of calcium to its receptors, preventing
muscle contraction
 This causes decreased peripheral smooth muscle
tone, decreased systemic vascular resistance.
Result: decreased blood pressure

Therapeutic uses:
 Angina
 Hypertension
 Dysrhythmias
 peripheral vascular disease
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Classes of Calcium Channel Blockers
 Benzothiazepines:
 Diltiazem (Cardizem)
 Diphenylalkamines:
 Verapamil (Isoptin)
 Dihydropyridines:
 Amlodipine , Bepridil,
Nicardipine
 Nifedipine, Nimodipine

Side Effects
Hypotension, palpitations, tachycardia, constipation,
nausea, rash, peripheral edema, dermatitis
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5. Diuretics
 Drugs that accelerate the rate of urine
formation through removal of sodium and
water.
 Decrease the plasma and extracellular fluid
volumes
 Results: decreased preload
decreased cardiac output decreased
workload of the heart decreased blood
pressure

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 Loop Diuretics
 Furosemide (Lasix)
Act directly on the ascending loop of Henle to inhibit sodium
and chloride resorption.

 Potassium-Sparing Diuretics
 Spironolactone (Aldactone)
Work in collecting ducts and distal convoluted tubules.
Interfere with sodium-potassium exchange

 Thiazide
 Chlorothiazide
Act primarily in the ascending loop of Henle and early distal
tubule. Inhibit tubular sodium and chloride resorption.
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6. Vasodilators
 Directly relaxes arteriolar smooth muscle
 Result: Peripheral vasodilation
Decreased systemic vascular resistance
Decreased afterload
● It is almost always administered in combination with a
β-blocker, such as propranolol (to balance the reflex
tachycardia), and a diuretic (to decrease sodium
retention).
 Examples:
 Diazoxide
 Hydralazine
 Minoxidil
 Sodium Nitroprusside
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 IV sodium nitroprusside and diazoxide are used for the
management of hypertensive emergencies

Side effects:
 Hydralazine:
 Dizziness, headache, tachycardia, nausea, sweating,
arrhythmia, and precipitation of angina.

 Sodium nitroprusside:
Bradycardia, hypotension, possible cyanide toxicity

 Minoxidil causes serious sodium and water retention, leading


to volume overload, edema, and congestive heart failure.
 [Note: Minoxidil treatment also causes hypertrichosis (the
growth of body hair). This drug is now used topically to treat
male pattern baldness.] 27
Hypertensive Emergency
Hypertensive emergency is a rare but life-threatening
situation in which the DBP is either >150 mm Hg
(with SBP >210 mm Hg) in an otherwise healthy
person or >130 mm Hg in an individual with
preexisting complications, such as encephalopathy,
cerebral hemorrhage, left ventricular failure, or
aortic stenosis. The therapeutic goal is to rapidly
reduce blood pressure.
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- Nitroprusside is administered intravenously and causes
prompt vasodilation with reflex tachycardia. It is capable of
reducing blood pressure in all patients regardless of the cause
of hypertension.

- Labetalol is both an α1 and a β-blocker and is given as an


intravenous bolus or infusion in hypertensive emergencies.
Labetalol does not cause reflex tachycardia.
- Fenoldopam is a peripheral dopamine-1 receptor agonist that
is given as an intravenous infusion.
- Nicardipine, a calcium-channel blocker, can be given as an
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intravenous infusion.

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