Treatment of Hypertension (Drugs)

Classes of antihypertensive drugs:

Diuretics
Centrally-acting Sympathetic Inhibitors
Peripherally-acting Sympathetic Inhibitors
Vasodilators
Calcium channel Inhibitors
ACE Inhibitors

Diuretics:
Reduction in blood volume via facilitation of sodium excretion is
the basic
beneficial response to diuretic administration, usually leading to
a significant drop in BP.
For mild - moderate cases, restriction of dietary sodium may do
the trick.
If not, diuretic therapy alone is often sufficient. In more severe
hypertension,
other drugs are used (eg. ACE inhibitors) together with diuretics,
with the latter
helping to minimize sodium retention that might be triggered by
a drop in renal
blood pressure (while the ACEIs will block the increased release
of renin trigger
by the same drop in renal BP)
- Thiazides (eg. hydrochlorothiazide)

considered most appropriate for mild - moderate

hypertension
with otherwise normal heart and kidney function

numerous attendant side effects: hypokalemia (corrected

using K
supplements); hyperlipidemia; risk of hyperglycemia
(inhibition of
insulin release)
- Loop Diuretics (eg. furosemide)

relied on for severe hypertension; congestive heart failure

K+-sparing Diuretics (eg. spironolactone)

useful in congestive heart failure for patients on digitalis

Centrally-acting Sympathetic Inhibitors:

In moderate to severe hypertension, reduction of sympathetic
outflow would usually be beneficial, but attendant side effects
can be significant, greatly limiting the use of this class of drugs.
Drugs in this class fall into two basic subclasses:
vasomotor center-acting and ganglionic blockers
- Methyldopa

metabolized to methyldopamine and methylnorepinephrine

enters
adrenergic synaptic vesicles, replacing norepinephrine and
acting as a false transmitter (also happens in peripheral
adrenergic nerve
endings, but, there, the false transmitter appears to act
as normal agonist)

stimulate alpha-adrenoceptors (mainly alpha2: action

blocked by
alpha2 antagonists) in the solitary tract nucleus

adverse effects: marked sedation; also nightmares,

depression,
vertigo
- Clonidine

alpha2 agonist will cause transient increase in BP, later

converting to a drop in BP owing to action on alpha2
receptors and imidazoline receptors located in the rostral
ventrolateral medulla to enhance inhibition of sympathetic
outflow. (Newer derivatives selective for the imidazoline
receptor appear to have far few side effects)


other uses: analgesic; reduce withdrawal symptoms with
addictive
drugs; decrease intraocular pressure

adverse effects: strong sedation; dry mouth; depression

rapid withdrawal after chronic use can lead to lifethreatening

hypertensive crisis

Peripherally-acting Sympathetic Inhibitors:

Actually, many of the drugs in this class have actions on both
central and
peripheral adrenergic systems, but their effects are largely if not
completely accounted for by their peripheral action. Most are
used for mild-moderate hypertension; some are also used in
severe hypertension in addition to powerful vasodilators. These
drugs fall into three convenient subclasses: vesicle depletion,
alpha-adrenergic receptor antagonists and beta-adrenergic
receptor antagonists
- Reserpine

of

for mild- moderate hypertension, acts by blocking uptake

biogenic amines (DA, NE, E, and 5-HT) into synaptic

vesicles largely in peripheral synapses, leading to depletion
of these
neurotransmitters loss of NE from sympathetic nerve
endings on
vessels leads to net vasodilatation (with little postural
hypotension
at normal doses)

central action accounts for most side effects: sedation,

depression, parkinsonism

- Selective alpha1 blockers (eg. prasozin; terazosin)

block alpha1 receptors in arterioles and venules, and cause

significant vasodilatation, with empirically less tachycardia

as
found with non-selective blockers or direct-acting
vasodilators;
some risk of significant postural hypotension
- Beta blockers (eg. metoprolol; propanolol; atenolol; pindolol;)

major action in decreasing cardiac output and inhibiting

renin
release
metoprolol (Lopressor), a selective beta1 blocker, with
few side effects
atenolol, a relatively selectively beta1 blocker (#1 beta
blocker antihypertensive), having few side effects but
longer-lasting than metoprolol
propanolol useful in severe hypertension, preventing reflex
tachycardia as well and acting in the kidney to inhibit renin
secretion; little postural hypotension
Vasodilators:
As a group, useful drugs in this class act by dilating arterioles,
reducing
afterload. Vasodilatation by itself will, however, cause
significantly increased sympathetic outflow to the heart (via
baroreceptors and renin release), leading to tachycardia and
increased contraction, which may oppose their hypotensive
action. Consequently, these drugs are used in combination with
beta blockers and diuretics to minimize any compensatory
physiological responses.
Different ways of categorizing these drugs exist: route of
administration;
clinical use; site of action. Orally active drugs (hydralazine and
minoxidil) may be useful for long-term treatment, whereas
parenteral drugs (nitroprusside,nitroglycerin and diazoxide) are
used for hypertensive emergencies. With regard to site of action,
there are two subclasses: dilators of arterioles and dilators of
both arterioles and venules.

- Hydralazine

precise mechanism is not known, but claimed to

antagonize SR IP3
receptors

primarily dilates arteriolar resistance vessels, causing

significant
drop in BP

strong sympathetic reflex: minimized by co-administration

of beta
blocker

risk of lupus-like syndrome in 10-20% of patients receiving

high
dosages
Calcium Channel Inhibitors:
All of these drugs act by blocking voltage-gated calcium channels
in (largely) arterioles and in cardiac muscle, resulting in vessel
relaxation and decreased heart rate and contractility, the latter
minimizing compensatory responses to decreased BP. They
include:

Verapamil (diphenylalkylamine) significant depression of

cardiac function

Diltiazem (benzothiazepines)

The Dihydropyridines (eg.nicardipine)

more effective vasodilators than suppressors of cardiac
function
Main use of calcium channel blockers is in monotherapy (where
appropriate) for mild-moderate hypertension, as alternatives to
diuretics or beta-blockers, particularly in the elderly. Also, quite
useful in patients with concomitant angina.
ACE Inhibitors/ Angiotensin receptor antagonists:
Angiotensin-converting enzyme (ACE) inhibitors (eg. captopril)
are very

effective in reducing hypertension caused by renal artery

stenosis, renal disease and malignant hypertension (arteriole
inflammation), where excessive levels ofrenin are released,
causing high levels of angiotensin II, a potent vasoconstrictor and
releaser of aldosterone. ACE inhibitors lower circulating
angiotensin II and increases bradykinin, a potent vasodilator.
Cardiac output is unaffected in patients with normal heart
function, but is significantly increased in individuals with
congestive heart failure. Hence, the other major use for ACE
inhibitors is for CHF.
Side effects include hyperkalemia, angioedema and dry cough
(due to increased bradykinin)
Antagonists of angiotensin receptors (eg. losartan) are potentially
more
selective (no effect on bradykinin levels, hence no cough; no
angioedema;
independent of ACE).