Antihypertensive drugs
1. Overview
1.1 Definition
Antihypertensive drugs are used to help control blood pressure in people whose blood
pressure is too high.
Hypertension is defined as a sustained diastolic blood pressure greater than 90mmHg
or systolic blood pressure greater than 140mmHg.
1.2 The type of hypertension
Treatments for high blood pressure depend on the type of hypertension. Most cases of
high blood pressure are called essential or primary hypertension, meaning that
patients have no specific cause of the problem. Elevated blood pressure is usually
caused by several abnormalities such as genetic inheritance, psychological stress,
environmental and dietary factors (eg. Increased salt decreased potassium intake).
Such hypertension usually can be controlled by some combination of antihypertensive
drugs and changes in daily habits (such as diet, exercise, and weight control).
Controlling primary hypertension, on the other hand, is usually a lifelong commitment.
Although people may be able to reduce the amount of medicine they take as their
blood pressure improves, they usually must continue taking it for the rest of their
lives.
Secondary hypertension has a specific cause, such as kidney disease, narrowing of
certain arteries, or tumors of the adrenal glands (pheochronocytoma). Correcting these
problems often cures the high blood pressure.
1.3 Major factors influencing blood pressure
Arterial blood pressure is directly proportional to the cardiac output and the peripheral
vascular resistance. The activation of sympathetic nervous system and
renin-angiotensin-aldosterone system is responsible for hypertension. Most
antihypertensive drugs lower blood pressure by reducing cardiac output and/or
decreasing peripheral vascular resistance.
2. Major classes of antihypertensive drugs
2.1 Diuretics
2.1.1 Thiazide Diuretics (moderate efficacy diuretics): hydrochlorothiazide,
chlorothiazide, et al.
2.1.1.1 The mechanism for reduction of BP
(1) Diuretics decreased BP initially by increasing water and sodium excretion
from the kidneys. This causes a decrease in extracellular volume and blood volume,
resulting in a decrease in cardiac output. This in turn decreases the pressure within the
blood vessels and reduces the workload on the heart.
(2) With long-term treatment (6-8weeks), blood volume approaches a normal
value, but peripheral resistance decreases. Sodium is believed to contribute to it by
increasing Na+--Ca2+ exchange with a resultant decrease in intracellular Ca2+.
decrease Na+ of vessel wall ------ Na+-Ca2+ exchange----reduce intracellular
Ca2+concentration (smooth muscle cell)----- decrease peripheral resistance.
(3) Some diuretics such as indapamide have direct vasodilating effects in addition
to their diuretic action.
(4) Amiloride inhibits smooth muscle responses to contractile stimuli (eg. NE).
2.1.1.2 Clinical uses
(1)Low-dose of thiazide diuretic therapy is safe and effective for hypertension.
Thiazide diuretics are appropriate for most patients with mild or moderate
hypertension, particularly elderly patients. Low doses of hydrochlorothiazide
(25-50mg/d) exert as much antihypertensive effect as do higher doses.
(2) Thiazides are useful in combination therapy with other antihypertensive drugs
including β-Blockers and ACE inhibitors.
2.1.1.3 adverse effects
(1) Thiazide diuretics induce electrolyte disturbance: hypokalemia (potassium
depletion), hypomagnesaemia, hyposodium et al.
(2) Thiazide diuretics can increase TC, TG, LDL level and renin activity; impair
glucose tolerance. Therefore diuretics should be avoided in treatment of hypertensive
diabetics or patients with hyperlipidemia.
2.1.2 Loop diuretics (high efficacy diuretics): furosemide, etacrynic acid.
The loop diuretics act promptly and can be used in hypertensive emergencies or
hypertension combined with renal function failure.
2.1.3 Potassium-sparing diuretics (low efficacy diuretics): spironolactone,
amiloride.
Potassium-sparing diuretics are useful both to avoid excessive potassium
depletion and to enhance the natriuretic effect of other diuretics.
2.2 β-receptor blockers (adrenergic antagonist): propranolol, atenolol, metoprolol.
2.2.1 The mechanism of antihypertensive action
(1) β-Blockers reduce BP primarily by decreasing cardiac output.
(2) β-Blockers also inhibit the release of rennin from the kidneys.
(3) β-Blockers block peripheral β-adrenoceptor in presynaptic membrane to
reduce sympathetic vasoconstrictor never activity by inhibitting noradrenaline release.
(4) β-Blockers block β receptor in CNS to inhibit vasomotor center.
2.2.2 Pharmacokinetics
The β-Blockers are orally active. Propranolol undergoes extensive first-pass
elimination. The β-Blockers may take several weeks to develop their full effects.
2.2.3 Clinical use and evaluation
The β-Blockers are more effective for treating hypertension in young patients
compared to the elderly.
The β-Blockers are useful in treating conditions that may coexist with
hypertension, such as superventricular tachyarrhythma, previous myocardial
infarction, angina pectoris, glaucoma, migraine headache.
2.2.4 Application attention:
(1) Beginning with small dose (individual variation is larger)
(2) Combining with diuretics
2.2.5 Adverse effects
(1) Common effects:
CNS side effects: fatigue, lethargy, insomnia;
Sexual dysfunction can severely reduce patient compliance.
(2)Alteration in serum lipid patterns: decrease HDL and increase plasma
triacylglycerol(TG).
(3)Drug withdrawal: Abrupt withdrawal may cause rebound hypertension,
probably as a result of up-regulation of β receptor.
2.2.6 Contraindication:
serious AV conduction block, bradycardia, bronchial asthma, peripheral vascular
disease, et al.
2.3 Angiotensin converting enzyme inhibitors (ACEI)
2.3.1.Drugs including Catopril, Enalapril, Cilazapril, Benazapril, Ramipril
2.3.2. The mechanism of antihypertensive action
(1) These drugs inhibit angiotensin converting enzyme that cleaves angiotensin I
to form the potent vasoconstrictor, angiotensin II(Ang-II) both in circulating system
and local tissue.
(2) These inhibitors also diminish rate of bradykinin inactivation----increase
bradykinin levels----release of NO, EDHF PGE2
(3) By reducing circulating Ang-II levels, ACEI also decrease the secretion of
aldosterone, resulting in decreased sodium and water retention.
2.3.3. Clinical use
(1) The ACE inhibitors are appropriate for most patients with mild or moderate
hypertension, particularly hypertension with high rennin activity.
(2) The ACE inhibitors are useful in treating conditions that may coexist with
hypertension, such as CHF, myocardial infarction.
2.3.4. The merits of treatment of hypertension: The ACE inhibitors
(1)have no tachycardia
(2)have no lipid metabolism disturbance
(3)Inhibit proliferation and hypertrophy of vascular smooth muscle cells and
myocardial cells
(4)improve life quality , decrease mortality
2.3.5. Adverse effects
(1) Common side effects: hypotension(2%), dry cough(5-20%), rashes, fever,
hyperkalemia,
(2) angioedema, fetotoxic (influence on development of fetus)
2.4 Angiotensin II type 1 receptor antagonists
2.4.1. Drugs: Losartan, Valsartan, Irbesartan
2.4.2. Clinical use and evaluation
Its pharmacological effects are similar to ACEI, while its adverse effects profile is
improved over ACEI and dose not cause cough and angioedema although it is
fetotoxic. Losartan can promote excrention of uric acid.
2.5. Calcium channel blockers
2.5.1. drugs: nifedipine, amlodipine, verapamil, diltiazem
2.5.2. The mechanism of antihypertensive action
Calcium antagonists block the inward movement of calcium by binding to L-type
calcium channel in the heart and in smooth muscle of the coronary and peripheral
vessel. This cause vascular relaxation and lower blood pressure. Blocks the entry of
calcium into the smooth muscle of the blood vessels, causing it to dilate or relax.
Certain types such as verapamil and diltiazem can also slow the heart rate.
2.5.3 Therapeutic uses
Calcium channel blockers are useful in the treatment of hypertensive patients who
also have asthma, diabetes, angina, and/or peripheral vascular disease.
2.5.4 Characters of every drug
Nifedipine belongs to short-acting calcium channel blockers which are associated
with an increased risk of myocardial infarction and can increase mortality if used for
long time.
(1)It is more selective to vessels; therefore its action of dilating vessel is stronger
than verapamil and diltiazem.
(2) Complication: tachycardia, increasing renin activity and cardiac output
(3) Treatment of mild and moderate hypertension.
Amlodipine belongs to short-acting calcium channel blockers which are better
than nifedipine.
(1) It takes effect slowly (1--2w), lower BP steadily and continuously
(2) It does not affect heart obviously.
(3) It can reverse myocardial hypertrophy.
2.6 α-Blockers: Prazosin, Terazosin, oxazosin.
2.6.1. phyarmacological action: α-blockers inhibit the effect of norepinephrine, a
hormone that causes constriction of blood vessels, by blocking α1-R selectively. In
this way, dilate the arteries and decrea blood pressure, but not decrease cardiac output
renal blood flow (renal dysfunction). Moreover, prazosin also decrease plasma TG,
TC, LDL, VLDL level and rise HDL.
2.6.2. Clinical use
α-Blockers are used to treat moderate hypertension and is prescribed in
combination with β-R blockers or diuretics for additive effects.
2.6.3. Adverse effects
(1) nasal congestion, dry mouth, drowsiness, headache, diarrhoea et al.
(2) first dose phenomenon: postural / orthostatic hypotension, reflex tachycardia
2.6.4. α β- adrenergic receptor antagonist: Labetalol blocks both α-R and β-R.
Labetalol blocks β-R more than α-R, blocks β1-R and β2-R in the equal potency,
blocks α1-R more than α2-R. Mechanism of lowing BP is due to blocking α1-R and
β1-R.
2.7. Centrally-acting drugs:
2.7.1 Clondine
2.7.1.1. pharmacological action
(1)antihypertensive effect( iv or oral)
(2)sedative effect
(3)inhibit gastrointestenal secretion and motion
2.7.1.2 The mechanism of action
(1) activate imidazoline I1receptor of rostral ventrolateral medulla (RVLM)
(2) excite α2-R of RVLM
(3) excite α2-R and imidazoline I1 receptor of peripheral sympathetic synaptic
premembrane---- decrease release of NA
(4) increase the release of endogenous opioid peptides, such as enkephalin
2.7.1.3. clinical use
(1)moderate hypertension
(2)morphine addiction
2.7.1.4. adverse effects
(1)dry mouth, sedation, headache, sexual dysfunction, constipation.
(2)withdrawal reaction: tachycardia, sweating, acute rising in BP,
2.7.2 Methyldopa is used to treat moderate hypertension, particularly with renal
function failure complication.
2.7.3 Moxonidine is belong to secondary central hypotensor, mainly excite I1
imidazoline receptor of rostral ventrolateral medulla oblongata. Actions on central and
peripheral α2-R are very weak, so the adverse reaction is rare.
2.8. Vasodilators
2.8.1 Hydralazine mainly dilate arteriols but not veins, is useful to treat moderate
hypertension, often being combined with other hypotensors. Its can cause resembles
erythematosus(10-20%) in large dose.
2.8.2 Sodium nitroprusside lowers BP rapidly by releasing NO. It take effects
rapidly(1-2min after iv), the effects disappear quickly too(5min after stopping iv).
Sodium nitroprusside is always used to treat hypertensive emergency and severe
cardiac failure.
2.8.3 Minoxidil belongs to potassium channel openers. It can promote the growth
of hair besides its antihypertensive effect. Treating obstinate hypertension must
combine with diuretics and β-R blockers; male alopecia
2.9 Ganglionic blocking agent
2.10 Adrenergic neuron blocking agents: Reserpine and quanethidine have been
rarely used because of their severe adverse reaction, reserpine is used in some
traditional compounds sometimes.
3. The antihypertensive treatment strategies
3.1 To normalize blood pressure effectively.
3.2 Controlling hypertension is usually a lifelong treatment (patient compliance)
3.3 To prevent target-organ damage to the heart, brain, kidneys and blood vessels.
3.4 To decrease the blood pressure steadily.
3.5 Individualized care.
3.6 To achieve this with no or minimal side effects by combination administration.