3. *
*These drugs lower blood pressure by reduction
of blood volume and probably also by a direct
vascular effect.
*The diuretics most important for treating
hypertension are the thiazides (eg,
chlorthalidone, hydrochlorothiazide) and the
loop diuretics (eg, furosemide).
6. *
*Sympathoplegic drugs interfere with
sympathetic (SANS) control of cardiovascular
function.
*The result is a reduction of one or more of the
following: venous tone, heart rate, contractile
force of the heart, cardiac output, and total
peripheral resistance.
7. *
*A few natural products, such as veratrum
alkaloids, appear to increase sensitivity of
baroreceptor sensory nerves and reduce SANS
outflow while increasing vagal tone to the
heart.
*These agents are toxic and no clinically
available drugs act at this site.
8. *
*Alpha2-selective agonists (eg, clonidine, methyldopa)
cause decrease in sympathetic outflow by activation of
α2 receptors in the CNS.
*These drugs readily enter the CNS when given orally.
* Methyldopa is a prodrug; it is transported into the
brain and then converted to methylnorepinephrine.
*Clonidine and methyldopa reduce blood pressure by
reducing cardiac output, vascular resistance, or both.
*The major compensatory response is salt retention.
Sudden discontinuation of clonidine causes rebound
hypertension, which may be severe.
9. *
*Nicotinic blockers that act in the ganglia are
very efficacious, but because their adverse
effects are severe, they are now considered
obsolete.
10. *
*Drugs that deplete the adrenergic nerve terminal of
its norepinephrine stores (eg, reserpine) or that
deplete and block release of the stores (eg,
guanethidine, guanadrel) can lower blood
pressure.
*The major compensatory response is salt and water
retention.
*In high dosages, these drugs are very efficacious but
produce severe adverse effects and are now
considered obsolete for hypertension.
11. *
*Alpha1-selective agents (eg, prazosin,
doxazosin, terazosin) are moderately
effective antihypertensive drugs. Alpha
blockers reduce vascular resistance and venous
return.
*The nonselective α blockers (phentolamine,
phenoxybenzamine) are of no value in chronic
hypertension because of excessive tachycardia.
12. *Beta blockers are used very heavily in the
treatment of hypertension.
*Propranolol is the prototype, and atenolol,
metoprolol, and carvedilol are among the
most popular.
*They initially reduce cardiac output, but in
chronic use their action may include a
decrease in vascular resistance as a
contributing effect.
13. *
*Drugs that dilate blood vessels by acting
directly on smooth muscle cells through
nonautonomic mechanisms are useful in
treating some hypertensive patients.
*Vasodilators act by four major mechanisms:
blockade of calcium channels, release of nitric
oxide, opening of potassium channels (which
leads to hyperpolarization), and activation of
D1 dopamine receptors.
15. *
*Calcium channel blockers (eg, nifedipine,
verapamil, diltiazem) are effective
vasodilators.
* Because they are moderately efficacious and
orally active, these drugs are suitable for
chronic use in hypertension of any severity.
Verapamil and diltiazem also reduce cardiac
output in most patients.
16. *
*These older vasodilators have more effect on
arterioles than on veins.
*They are orally active and suitable for chronic
therapy.
*Hydralazine apparently acts through the release of
nitric oxide from endothelial cells.
*It causes significant baroreceptor homeostatic
responses and must be combined with other drugs,
usually diuretics and β blockers.
* However, it is rarely used at high dosage because of
its toxicity.
17. *
*These parenteral vasodilators are used in
hypertensive emergencies.
*Nitroprusside is a light-sensitive, short-acting
agent that must be infused continuously.
*The release of nitric oxide (from the drug
molecule itself) stimulates guanylyl cyclase
and increases cyclic guanine monophosphate
(cGMP) concentration and relaxation in
vascular smooth muscle.
18. *Dopamine D1 receptor activation by
fenoldopam causes prompt, marked arteriolar
vasodilation.
*This drug is given by intravenous infusion. It
has a short duration of action (10 min) and,
like nitroprusside and diazoxide, is used for
hypertensive emergencies.
19. *
*The two primary groups of angiotensin antagonists
are the angiotensin-converting enzyme (ACE)
inhibitors and the angiotensin II receptor blockers
(ARBs).
*ACE inhibitors (eg, captopril), which inhibit the
enzyme variously known as angiotensin- converting
enzyme, kininase II, and peptidyl dipeptidase, cause
a reduction in blood levels of angiotensin II and
aldosterone and an increase in endogenous
vasodilators of the kinin family.
20. *The ACE inhibitors are useful in heart failure
and diabetes as well as in hypertension.
*The toxicities of ACE inhibitors include cough,
hyperkalemia, and renal damage in occasional
patients with preexisting renal vascular
disease.
*They cause major renal damage in the fetus
and are absolutely contraindicated in
pregnancy.
21. *The second group of angiotensin antagonists,
the receptor blockers, is represented by the
orally active agents losartan, valsartan,
irbesartan, candesartan, and other ARBs, which
competitively inhibit angiotensin II at its AT1
receptor site.
*ARBs appear to be as effective in lowering
blood pressure as the ACE inhibitors and have
the advantage of a lower incidence of cough,
although they do cause hyperkalemia.
22.
23. *
*A. Stepped Care (Polypharmacy)
*Drugs are added to a patient’s regimen in stepwise
fashion; each additional agent is chosen from a
different subgroup until adequate blood pressure
control has been achieved.
*The usual steps include (1) lifestyle measures such
as salt restriction and weight reduction, (2)
diuretics (a thiazide), (3) sympathoplegics (a β
blocker), (4) ACE inhibitors, and (5) vasodilators.
*The vasodilator chosen first is usually a calcium
channel blocker.
24. *B. Monotherapy
*It has been found in large clinical studies that many
patients do well on a single drug (eg, an ACE
inhibitor, calcium channel blocker, or combined α
and β blocker).
*This approach to the treatment of mild and
moderate hypertension has become more popular
than stepped care because of its simplicity, better
patient compliance, and—with modern drugs—a
relatively low incidence of toxicity.
25. *
*Hypertensive emergency (formerly called malignant
hypertension) is an accelerated form of severe
hypertension associated with rising blood pressure and
rapidly progressing damage to vessels and end organs.
*Management of hypertensive emergency must be
carried out on an urgent basis in the hospital.
*Powerful vasodilators (nitroprusside, fenoldopam, or
diazoxide) are combined with diuretics (furosemide)
and β blockers to lower blood pressure to the 140–
160/90–110 mm Hg range promptly (within a few
hours).
* Further reduction is then pursued more slowly.
