R.

YE / Antihypertensive Agents

PHARMACOLOGY OF ANTIHYPERTENSIVE AGENTS

UIC Dept of Pharmacology

Richard D. Ye
312-996-5087

CMW 406

yer@uic.edu

Hypertension: Systolic BP 140 mm Hg and/or diastolic BP 90 mm Hg

Approximately 24% of the U.S. population (~60 million) have hypertension
Burt et al., Hypertension 25:305-313 (1995)

Classification of hypertension for adults:

Category

Systolic (mm Hg)

Optimal BP
Normal BP
High-normal BP
Stage 1 (mild)
Stage 2 (moderate)
Stage 3 (severe)

Diastolic (mm Hg)

< 120
< 130
130 139
140 159
160 179
180

AND
AND
OR
OR
OR
OR

< 80
< 85
85 - 89
90 - 99
100 - 109
110

Archives Int. Med. 157:2413-2446 (1997)

Sustained arterial hypertension damages blood vessels in kidney, heart, and brain, and
leads to an increased incidence of renal failure, coronary disease, cardiac failure, and
stroke.
Drug treatment of hypertension factors to consider:
Primary (essential hypertension) vs. secondary (10-15% patients)
e.g. pheochromocytoma, renal artery constriction, Cushings syndrome

Diagnosis (based on 3 separate office visits) and severity of hypertension

Individualization (age, gender, ethnicity) and patient compliance
Pre-existing risk factors and medical conditions
Smoking, hyperlipidemia, diabetes, congestive heart failure, asthma, current medication

Single-drug therapy (monotherapy) vs. multiple-drug therapy (polypharmacy)

Currently used antihypertensive agents:
I. Diuretics: bumetanide, furosemide, hydrochlorothiazide, spironolactone, triamterene
II. Sympathoplegic agents: methodopa, clonidine, guanfacine, thrimethaphan, guanethidine,
propranolol, reserpine, methoprolol, nadolol, carteolol, pindolol, labetalol, prazosin
III. Direct vasodilators: hydralazine, minoxidil, sodium nitroprusside, diazoxide
IV. ACE inhibitors and angiotensin receptor antagonists: captopril, enalapril, benazepril, quinapril,
losartan, valsartan, saralasin

R. YE / Antihypertensive Agents
I.

DIURETICS
First-line drug for hypertension. Relatively safe and effective. Suitable for older adults.
Given orally, alone or together with other antihypertensive agents.

Mechanism of action:
Diuretics lower BP by depleting body sodium stores. Effects take 2 stages: (1) reduction of
total blood volume and therefore cardiac output; initially causes increase of peripheral
vascular resistance; (2) when CO returns to normal level (6-8 wks), PVR declines.
Therapeutic use:
Thiazide diuretics, such as hydrochlorothiazide, act on distal convoluted tubule and
inhibit Na+-Cl- symport. They can counteract the Na+ and H2O retention effect of
hydralazine (direct vasodilator), and therefore are suitable for combined use. Thiazides are
particularly useful for elderly patients, but not effective when kidney function is inadequate.
Thiazides reduce blood K+ and Mg2+ levels, and induce hypokalemia and hyperuricemia.
Thiazides retain Ca2+ and decrease urine Ca2+ content. Use carefully and monitor serum K+
level in patients with cardiac arrhythmias and when digitalis is in use.
Loop diuretics, such as fusosemide and bumetanide, are more powerful than thiazides.
Often used for treatment of severe hypertension when direct vasodilators are administered
and Na+ and H2O retention becomes a problem. They can be used in patients with poor renal
function and those not respond to thiazides. Loop diuretics increase urine Ca2+ content.
K-sparing diuretics include triamterene, amiloride (both are Na+ channel inhibitors), and
spironolactone (aldosterone antagonist). Used for treating hypertension in patients given
digitalis. Also enhance the natriuretic effects of other diuretics (e.g., thiazides) and
counteract the K+-depleting effect of these diuretics.
Adverse effects and toxicity:
(1) Depletion of K+ (except K+-sparing diuretics), leading to hypokalemia. (2) Increase uric
acid concentration and precipitate gout. (3) Increase serum lipid concentrations. Diuretics
are not used for treating hypertension in patients with hyperlipidemia or diabetes.
II.

SYMPATHOPLEGIC AGENTS
A. Centrally-acting adrenergic drugs (2-agonists such as clonidine and -methyldopa).
B. Drugs that act on peripheral nervous system (-blockers; 1-blockers; ganglionblocking agents; agents that block adrenergic neurotransmitter synthesis and/or release)

R. YE / Antihypertensive Agents
A.

Centrally-acting antihypertensive agents

1. Clonidine. A 2-imidazoline derivative that reduces sympathetic and increases
parasympathetic tone, leading to BP lowering and bradycardia.

Mechanism of action: Clonidine binds 2-AR with higher affinity than

1-AR. The 2-agonistic activity contributes to its BP-lowering
effect due to negative feedback at the presynaptic neurons. When
given i.v., clonidine induces a brief rise of BP, which is followed
by proloned hypotension. In addition, clonidine is thought to bind
imidazoline receptors (IR) that have not been molecularly cloned.

Cl

N
NH
N

Cl

Therapeutic use: Clonidine reduces CO due to decreased heart rate and relaxation of capacitance
vessels. It is used for treatment of mild to moderate hypertension, often together with
diuretics. Because it decreases renal vascular resistance, it maintains renal blood flow and
glomerular filtration. Its lipid-soluble and enters brain readily. Half-life is 8-12 h.
Adverse effects and toxicity: Sedation, dry mouth. Clonidine also causes Na+ and H2O retention.
Abrupt withdrawal may induce hypertensive crisis. Do not give to patients who are at risk
of mental depression, or are taking tricyclic antidepressants.
2. Methyldopa. A prodrug that exers its antihypertensive action via an active metabolite.
Mechanism of action: The metabolite, -methylnorepinephrine, is stored in neurosecretory vesicle
in place of NE. When released, -methyl-NE is a potent -AR agonist and in PNS is a
vasoconstrictor. Its CNS effect is mediated by 2-AR, resulting in reduced adrenergic outflow from
the CNS and an overall reduced total peripheral resistance.
-methyldopa
HO
HO

-methyldopamine
H

CH3

NH2

COOH

HO
HO

Aromatic L-amino acid

decarboxylase

CH3

NH2

-methylnorepinephrine
OH CH3
NH2

HO
HO

NH2

NH2

Dopamine
-oxidase

Therapeutic use: This drug does not alter most of the cardiovascular reflexes. Cardiac output and
blood flow to vital organs are maintained. It reduces renal vascular resistance and can be used in
patients with renal insufficiency. Given orally. Effect reaches maximum in 4-6 h and continues to
24 h. Not used as first drug in monotherapy, but effective when used with diuretics.

R. YE / Antihypertensive Agents
Adverse effects and toxicity: Sedation, lassitude, nightmares, lactation (due to inhibition of
dopaminergic neuron in hypothalamus). Long-term use may cause development of autoantibodies
against Rh locus and give positive Coombs test.

B.

Antihypertensive agents that act on peripheral nervous system

1. -blockers. Propranolol, metoprolol, nadolol, carteolol, atenolol, betaxolol,
bisoprolol,pindolol, acebutolol, penbutolol, labetalol, carvedilol.

Mechanism of action: (1) Reduce cardiac output; (2) inhibit renin release and AT-II and
aldosterone production, and lower peripheral resistance; (3) may decrease adrenergic
outflow from the CNS.
Therapeutic use: Recommended as first-line antihypertensive agents. Combined use with diuretics
are common. More effective in treating hypertension in white than black patients, and in
young patients than elderly (due to high occurrence of chronic lung and heart diseases in the
elderly). Especially useful in treating hypertension with preexisting conditions such as
previous myocardia infarction, angina pectoris, migraine headache.
Propranolol: Prototype -blocker; antagonizes 1 and 2 AR. It inhibits renin production
(due to 1-antagonistic activity) and is used in patients with high renin level. It causes no
prominent postural hypotension in mild to moderate hypertension patients.
Metoprolol: Much less 2-antagonistic than propranolol, thus can be used in patients who
also suffer from asthma, diabetes, or peripheral vascular diseases.
Nadolol, carteolol, atenolol, betaxolol, bisoprolol: Slower metabolism and longer half-life
for these drugs. They can be administered once daily. The underlined are 1-selective
antagonists.
Pindolol, acebutolol, penbutolol: Antagonistic effect is combined with partial agonistic
effect on 2-AR. Particularly useful for patients with cardiac failure, bradyarrhythmias, or
peripheral vascular disease.
Labetalol, carvedilol: These are given as racemic mixture of isomeric compounds. A major
advantage is combined and blockers and therefore these are more powerful drugs.
Labetalol also has some 2-agonistic effects. Labetalol is used in treating hypertensive
emergencies (injection) or hypertension resulting from pheochromocytoma. Carvedilol can
be used in patients with congestive heart failure.
Adverse effects and toxicity: (1) Withdrawal syndrome (nervousness, tachycardia, angina, BP
increase). (2) Reduced myocardial reserve and peripheral vascular insufficiency; exacerbate
asthma, diabetes. (3) Increased plasma triglycerides and decreased HDL cholesterol
(propranolol). (4) CNS effects: lassitude, mental depression, insomnia, nightmares. (5) GI
effects: diarrhea, constipation, nausea, vomiting.
4

R. YE / Antihypertensive Agents
2. 1-blockers. Prazosin, tetrazosin, doxazosin, phentolamine, phenoxybenzamine.
Mechanism of action: The underlined are competitive antagonists for 1-AR. Phentolamine is
antagonist for both 1 and 2-AR. Phenoxybenzamine is an irreversible blocker for 1-AR
and 2-AR. Blocking 1-AR leads to relaxation of both arterial and venous smooth muscles
and thereby reduces PVR.
Therapeutic use: Prazosin is used for treating mild to moderate hypertension. Combined use with
propranolol or diuretics may produce additive effects. Long-term use is not likely to cause
significant changes in cardiac output and renal blood flow. Thus there is less likelihood to
have tachycardia and increased renin release for long-term users. Phentolamine and
phenoxybenzamine are used for treatment of pheochromocytoma.
Adverse effects and toxicity: (1) For prazosin, tetrazosin, doxazosin: First dose syncope and reflex
tachycardia are common (first time use with clinic monitoring recommended). Concomitant
use with a -blocker may be necessary. (2) For phentolamine, increased cardiac stimulation
(by blocking 2-AR negative feedback) can cause severe tachycardia, arrhythmias, and
myocardial ischemia. For phenoxybenzamine, postural hypotension may occur. CNS
symptoms, such as fatigue sedation and nausea, are also seen in patients using
phenoxybenzamine.
3. Ganglion-blocking agents. Not currently in use clinically because of toxicity.
Trimethaphan is one example. It competitively blocks nicotinic cholinergic receptors on
postganglionic neurons, in both sympathetic and parasympathetic ganglia. The
antihypertensive effect is due to pooling of blood in capacitance vessels. Antihypertensive
effect is rapid, but excessive hypotension may occur. Adverse effects: (1) sympathoplegia
(excessive orthostatic hypotension, sexual dysfunction); (2) parasympathoplegia
(constipation, urinary retention, dry mouth, precipitation of glaucoma, etc.)
4. Agents that block adrenergic neurotransmitter synthesis and / or release. Reserpine,
guanethidine, pargyline.
Reserpine
Mechanism of action: Interferes with the Mg2+- and ATP-dependent uptake of biogenic amines,
thereby depleting NE, dopamine, and serotonin. The effect is universal and irreversible.
Reserpine decreaes both cardiac output and PVR.

R. YE / Antihypertensive Agents

Therapeutic use: Reserpine can be used for treatment of mild to moderate hypertension. The effect
stays long after the drug disappears from circulation. Effective daily dose is low (0.25 mg).
Reserpine is now used less frequently in the clinic due to availability of better drugs.
Adverse effect and toxicity: Enters into brain easily and can produce sedation, mental depression,
Parkinsons like symptom. Reserpine should not be given to patients with mental
depression or peptic ulcer (for its GI-stimulating effect).
Guanethidine and guanadrel
N

Guanethidine

CH2

CH2

NH
H
N C
NH2

Mechanism of action: Guanethidine (1) inhibits NE release from sympathetic nerve ending; (2)
gradually depletes NE stores in the nerve ending. The latter effect depends on Uptake 1,
which also transports released NE and can be blocked by cocaine and tricyclic
antidepressants (TCA). Drugs that displace amines from nerve terminal (e.g., amphetamine)
also block the effect of guanethidine.

Therapeutic use: Used for outpatient treatment of severe hypertension. It reduces cardiac output
due to bradycardia and relaxation of capacitance vessels. Long-term use leads to reduced
PVR. Guanethidine does not enter CNS and all effects are local.
Adverse effects and toxicity: Postural hypotension and decreased blood flow to heart and brain. It
causes delayed ejaculation in men, increased GI motility and diarrhea. Supersensitivity of
effector cells (smooth muscle) occurs following long-term use, reminiscent of surgical
sympathectomy. Sodium and water retention are often seen. Not to be used together with
drugs that act on Uptake 1 such as TCA, or certain over-the-counter cold medicine
(phenylpropanolamine). Not suitable for patients with pheochromocytoma.
6

R. YE / Antihypertensive Agents

III.

DIRECT VASODILATORS

Mechanism of action: Relax smooth muscle (SM) of arterioles (and sometimes veins), thereby
reduce systemic vascular resistance. Compensatory responses occur as shown below:

Therapeutic use:
Hydralazine: Dilates arterioles but not veins. Effect does not last long when used alone
(tachyphylaxis); but combination therapy can be very effective for even severe hypertension.
Minoxidil: Opens K+ channels in SM by its active metabolite, minoxidil sulfate, and
stabilizes membrane at its resting potential. Patients with renal failure and severe
hypertension, who do not respond well to hydralazine, may be given minoxidil. Best effect
is achieved when used together with -block and loop diuretics.
Sodium nitroprusside: Parenterally administered (i.v.), powerful vasodilator for treatment
of hypertensive emergencies. Works by increasing intracellular cGMP and dilates both
arterial and venous vessels. Also used in patients with cardiac failure because cardiac output
increases due to afterload reduction. Effects last only less than 10 minutes after
discontinuation.
Diazoxide: Stimulates opening of K+ channels and stabilizes membrane potential at resting
level. A long-lasting antihypertesive agent (effective from 4-12 h, with half-life of 24 h).
Can be used for treating hypertensive emergencies (i.v.).
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R. YE / Antihypertensive Agents
Calcium channel blockers: These include verapamil, diltiazem and the dihydropyridine
(eg, nifedipine) family. In addition to their antianginal and antiarrhythmic effects, these
calcium channel blockers also dilate peripheral arterioles and thereby reduce BP by
inhibiting calcium influx into arterial SM cells. Among these, verapamil has more cardiac
effect (decreasing CO) and nifedipine has more vasodilating effect.
Adverse effects and toxicity: Cardiac side effects have been seen with many vasodilators:
tachycardia, palpitation, angina. Excessive hypotension occurs with diazoxide. Diazoxide
also retains sodium and water. Accumulation of cyanide, metabolic acidosis have been
observed with patients using sodium nitroprusside. Minoxidil causes hypertrichosis (hairgrowing), an effect now used for correction of baldness (Rogaine).

III.

ACE INHIBITORS AND ANGIOTENSIN RECEPTOR ANTAGONISTS

Angiotensinogen

Kininogen

Renin

Kallikrein

Angiotensin-I

Bradykinin
Prostaglandin
synthesis

ACE
(kininase-II)
Angiotensin-II

Vasoconstriction

Inactive
products
Vasodilation

Aldosterone
secretion

PVR
Na+ and H2O
retension

PVR

BP
BP

The renin-angiotensin-aldosterone pathway showing sites of ACE action ()

Angiotensin-I:
Angiotensin-II:

NH2-Asp-Arg-Val-Tyr-Ile-His-Pro-PheHis-Leu-COOH
NH2-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-COOH

R. YE / Antihypertensive Agents
ACE inhibitors. Captopril, enalapril (lisinopril is a lysine-derivative), benazepril,
fosinopril, moexipril, quinapril and ramipril
Mechanism of action: Captopril and other ACE inhibitors are competitive inhibitors of ACE,
mimicking the structure of its substrate. Captopril and lisinopril are active molecules.
Others listed above are prodrugs that need to be converted to active metabolites (di-acids)
for functions. ACE inhibitors (1) directly block the formation of AT-II, (2) at the same time
increase bradykinin level. The net results are reduced vasoconstriction, reduced sodium and
water retension, and increased vasodilation (through bradykinin).
Therapeutic use: Primarily used when the first-line diuretics or -blockers are ineffective or
contraindicated. Most effective in white and young hypertensive patients. This difference
diminishes when ACE inhibitors are used together with diuretics. ACE inhibitors are also
more effective in patients with higher renin level. Commonly used in patients following
myocardial infarction, and in patients with chronic congestive heart failure.
Adverse effects and toxicity: In hypovolemic patients, severe hypotension may occur after initial
doses. ACE inhibitors are fetotoxic and should not be used in pregnant women. Other
adverse effects: Angioedema (rare), dry cough, rashes, altered taste, and proteinuria,
hyperkalemia. Countraindication: spironolactone (K-sparing diuretic agent).
Angiotensin-II antagonists. Losartan (FDA approved in 1995) and valsartan are nonpeptide antagonists of AT-II receptor. Other non-peptide antagonists of this class include
candesartan, irbesartan, telmisartan, eprosartan, and zolasartan; some of these are in various
stages of clinical development. Saralasin is a peptide analog and competitive inhibitor of
AT-II receptor, but is orally ineffective and requires continuous intravenous infusion.
Saralasin also has partial agonist activity, and is not currently in use for hypertension
treatment.
Mechanism of action: Competitive inhibition of AT-II receptor (Type 1). Effect is more specific on
AT-II action, and less or none on bradykinin production or metabolism.
Therapeutic use: Clinical use is similar to ACE inhibitors. Compared to ACE inhibitors, losartan
has the advantage of not causing cough and angioedema, which are effects of bradykinin.
Adverse effects and toxicity: Similar to those of ACE inhibitors. AT-II antagonists are also
fetotoxic and should not be used for treating hypertension in pregnant women.

BP = CO PVR

CNS / sympathetic nerves

Baroreceptor
reflex arc

Heart rate
contractility

Aortic arch
carotid sinuses

Peripheral
resistance

1-AR

1-AR

Stroke
volume

Baroreceptors

Na+/Ca2+

Cardiac
output

Arterial
Blood
Pressure

exchange
Reninangiotensinaldosterone

Sodium/
volume

Venules
capacitance

SUMMARY - AHD Mechanisms

Methyldopa, clonidine,
guanabenz, guanfacine

Reserpine,
guanethidine,
granadrel

Propranolol,
other -blockers

Trimethaphan

Prazosin, other
1-blockers
AT-II receptor
antagonists
(losartan)

Thriazide,
other diuretics

ACE inhibitors
(captopril)

Hydralazine,
minoxidil,
nitroprusside,
diazoxide
Calcium channel
blockers