Vasodilators

Vasodilators–Overview
The distribution of blood within the circulation
is a function of vascular caliber.
Venous tone regulates the volume of
blood returned to the heart, hence,
stroke volume and cardiac output. The
luminal diameter of the arterial vasculature
determines peripheral resistance.
Cardiac output and peripheral resistance
are prime determinants of arterial
blood pressure.
In A, the clinically most important
vasodilators are presented in the order
of approximate frequency of therapeutic
use. Some of these agents possess
different efficacy in affecting the venous
and arterial limbs of the circulation
(width of beam).
Possible uses. Arteriolar vasodilators
are given to lower blood pressure in
hypertension, to reduce cardiac
work in angina pectoris, and to
reduce ventricular afterload (pressure
load) in cardiac failure. Venous
vasodilators are used to reduce venous
filling pressure (preload) in angina pectoris
or cardiac failure.
Practical uses are indicated for each
drug group.
Counter-regulation in acute hypotension
due to vasodilators (B). Increased
sympathetic drive raises heart
rate (reflex tachycardia) and cardiac
output and thus helps to elevate blood
pressure. Patients experience palpitations.
Activation of the renin-angiotensin-
aldosterone (RAA) system serves to
increase blood volume, hence cardiac
output. Fluid retention leads to an increase
in body weight and, possibly,
edemas. These counter-regulatory processes
are susceptible to pharmacological
inhibition (!-blockers, ACE inhibitors,
AT1-antagonists, diuretics).
Mechanisms of action. The tonus
of vascular smooth muscle can be decreased
by various means. ACE inhibitors,
antagonists at AT1-receptors and
antagonists at "-adrenoceptors protect
against the effects of excitatory mediators
such as angiotensin II and norepinephrine,
respectively. Prostacyclin analogues
such as iloprost, or prostaglandin
E1 analogues such as alprostanil,
mimic the actions of relaxant mediators.
Ca2+ antagonists reduce depolarizing inward
Ca2+ currents, while K+-channel activators
promote outward (hyperpolarizing)
K+ currents. Organic nitrovasodilators
give rise to NO, an endogenous
activator of guanylate cyclase.
Individual vasodilators. Nitrates
Ca2+-antagonists. "1-
antagonists, ACE-inhibitors, AT1-
antagonists; and sodium nitroprusside
are discussed elsewhere.
Dihydralazine and minoxidil (via
its sulfate-conjugated metabolite) dilate
arterioles and are used in antihypertensive
therapy. They are, however, unsuitable
for monotherapy because of compensatory
circulatory reflexes. The
mechanism of action of dihydralazine is
unclear. Minoxidil probably activates K+
channels, leading to hyperpolarization
of smooth muscle cells. Particular adverse
reactions are lupus erythematosus
with dihydralazine and hirsutism
with minoxidil—used topically for the
treatment of baldness (alopecia androgenetica).
Diazoxide given i.v. causes prominent
arteriolar dilation; it can be employed
in hypertensive crises. After its
oral administration, insulin secretion is
inhibited. Accordingly, diazoxide can be
used in the management of insulin-secreting
pancreatic tumors. Both effects
are probably due to opening of (ATPgated)
K+ channels.
The methylxanthine theophylline,
the phosphodiesterase inhibitor
amrinone, prostacyclins,
and nicotinic acid derivatives
also possess vasodilating activity.

Organic Nitrates
Various esters of nitric acid (HNO3) and
polyvalent alcohols relax vascular
smooth muscle, e.g., nitroglycerin (glyceryltrinitrate)
and isosorbide dinitrate.
The effect is more pronounced in venous
than in arterial beds.
These vasodilator effects produce
hemodynamic consequences that can
be put to therapeutic use. Due to a decrease
in both venous return (preload)
and arterial afterload, cardiac work is
decreased. As a result, the cardiac
oxygen balance improves. Spasmodic
constriction of larger coronary
vessels (coronary spasm) is prevented.
Uses. Organic nitrates are used
chiefly in angina pectoris,
less frequently in severe forms of chronic
and acute congestive heart failure.
Continuous intake of higher doses with
maintenance of steady plasma levels
leads to loss of efficacy, inasmuch as the
organism becomes refractory (tachyphylactic).
This “nitrate tolerance” can
be avoided if a daily “nitrate-free interval”
is maintained, e.g., overnight.
At the start of therapy, unwanted
reactions occur frequently in the form
of a throbbing headache, probably
caused by dilation of cephalic vessels.
This effect also exhibits tolerance, even
when daily “nitrate pauses” are kept.
Excessive dosages give rise to hypotension,
reflex tachycardia, and circulatory
collapse.
Mechanism of action. The reduction
in vascular smooth muscle tone is
presumably due to activation of guanylate
cyclase and elevation of cyclic GMP
levels. The causative agent is most likely
nitric oxide (NO) generated from the organic
nitrate. NO is a physiological messenger
molecule that endothelial cells
release onto subjacent smooth muscle
cells (“endothelium-derived relaxing
factor,” EDRF). Organic nitrates would
thus utilize a pre-existing pathway,
hence their high efficacy. The generation
of NO within the smooth muscle
cell depends on a supply of free sulfhydryl
(-SH) groups; “nitrate-tolerance”
has been attributed to a cellular exhaustion
of SH-donors but this may be not
the only reason.
Nitroglycerin (NTG) is distinguished
by high membrane penetrability
and very low stability. It is the drug
of choice in the treatment of angina pectoris
attacks. For this purpose, it is administered
as a spray, or in sublingual or
buccal tablets for transmucosal delivery.
The onset of action is between 1 and
3 min. Due to a nearly complete presystemic
elimination, it is poorly suited
for oral administration. Transdermal delivery
(nitroglycerin patch) also avoids
presystemic elimination. Isosorbide
dinitrate (ISDN) penetrates well
through membranes, is more stable
than NTG, and is partly degraded into
the weaker, but much longer acting, 5-
isosorbide mononitrate (ISMN). ISDN
can also be applied sublingually; however,
it is mainly administered orally in
order to achieve a prolonged effect.
ISMN is not suitable for sublingual use
because of its higher polarity and slower
rate of absorption. Taken orally, it is absorbed
and is not subject to first-pass
elimination.
Molsidomine itself is inactive. After
oral intake, it is slowly converted
into an active metabolite. Apparently,
there is little likelihood of "nitrate tolerance”.
Sodium nitroprusside contains a
nitroso (-NO) group, but is not an ester.
It dilates venous and arterial beds
equally. It is administered by infusion to
achieve controlled hypotension under
continuous close monitoring. Cyanide
ions liberated from nitroprusside can be
inactivated with sodium thiosulfate
(Na2S2O3).

Calcium Antagonists
During electrical excitation of the cell
membrane of heart or smooth muscle,
different ionic currents are activated,
including an inward Ca2+ current. The
term Ca2+ antagonist is applied to drugs
that inhibit the influx of Ca2+ ions without
affecting inward Na+ or outward K+
currents to a significant degree. Other
labels are Ca-entry blocker or Ca-channel
blocker. Therapeutically used Ca2+ antagonists
can be divided into three
groups according to their effects on
heart and vasculature.
I. Dihydropyridine derivatives.
The dihydropyridines, e.g., nifedipine,
are uncharged hydrophobic substances.
They induce a relaxation of vascular
smooth muscle in arterial beds. An effect
on cardiac function is practically absent
at therapeutic dosage. (However, in
pharmacological experiments on isolated
cardiac muscle preparations a clear
negative inotropic effect is demonstrable.)
They are thus regarded as vasoselective
Ca2+ antagonists. Because of
the dilatation of resistance vessels,
blood pressure falls. Cardiac afterload is
diminished and, therefore, also
oxygen demand. Spasms of coronary arteries
are prevented.
Indications for nifedipine include
angina pectoris and, — when applied
as a sustained release preparation,
— hypertension. In angina pectoris,
it is effective when given either
prophylactically or during acute attacks.
Adverse effects are palpitation (reflex
tachycardia due to hypotension), headache,
and pretibial edema.
Nitrendipine and felodipine are used
in the treatment of hypertension. Nimodipine
is given prophylactically after
subarachnoidal hemorrhage to prevent
vasospasms due to depolarization by
excess K+ liberated from disintegrating
erythrocytes or blockade of NO by free
hemoglobin.
II. Verapamil and other catamphiphilic
Ca2+ antagonists. Verapamil contains
a nitrogen atom bearing a positive
charge at physiological pH and thus represents
a cationic amphiphilic molecule.
It exerts inhibitory effects not only on
arterial smooth muscle, but also on heart
muscle. In the heart, Ca2+ inward currents
are important in generating depolarization
of sinoatrial node cells (impulse
generation), in impulse propagation
through the AV- junction (atrioventricular
conduction), and in electromechanical
coupling in the ventricular cardiomyocytes.
Verapamil thus produces
negative chrono-, dromo-, and inotropic
effects.
Indications. Verapamil is used as
an antiarrhythmic drug in supraventricular
tachyarrhythmias. In atrial flutter
or fibrillation, it is effective in reducing
ventricular rate by virtue of inhibiting
AV-conduction. Verapamil is also employed
in the prophylaxis of angina pectoris
attacks and the treatment
of hypertension. Adverse effects:
Because of verapamil’s effects on
the sinus node, a drop in blood pressure
fails to evoke a reflex tachycardia. Heart
rate hardly changes; bradycardia may
even develop. AV-block and myocardial
insufficiency can occur. Patients frequently
complain of constipation.
Gallopamil (= methoxyverapamil) is
closely related to verapamil in both
structure and biological activity.
Diltiazem is a catamphiphilic benzothiazepine
derivative with an activity
profile resembling that of verapamil.
III. T-channel selective blockers.
Ca2+-channel blockers, such as verapamil
and mibefradil, may block both Land
T-type Ca2+ channels. Mibefradil
shows relative selectivity for the latter
and is devoid of a negative inotropic effect;
its therapeutic usefulness is compromised
by numerous interactions
with other drugs due to inhibition of cytochrome
P450-dependent enzymes
(CYP 1A2, 2D6 and, especially, 3A4).