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 β-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.).
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 (
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 β-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.
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