Loretta Walker, Ph.D.

ANTIHYPERTENSIVE DRUGS
Reading:

Rang & Dales Pharmacology, 6th Edition, Chap.17, 19, 24 (ignore

endothelin); review background on NO; also, review basic diuretic and
adrenergic mechanisms

Objectives:
1.
2.
3.

To understand the basic controls in regulating blood pressure

To know the categories of various antihypertensive drugs
To know the actions and uses of antihypertensive drugs

DRUGS
Hydrochlorothiazide
Furosemide
Spironolactone
Nitroprusside
Verapramil
Diltiazem
Nicardipine

Clonidine
Methyldopa
Prazosin
Terazosin

Atenolol**
Metoprolol
Propanolol
Pindolol
Labetolol

Hydralazine
Minoxidil
Diazoxide
Captopril
Losartan

Basic Physiology of Blood Pressure Control:

BP =Heart Output X Peripheral Vascular Resistance
The control of blood pressure requires constant adjustment of cardiac
output and peripheral resistance. Output of blood from the heart via the aorta is
dependent upon ventricular filling pressure, which is a direct function of atrial
pressure (=preload), ventricle contractility (=force of contraction), heart rate, and
vascular resistance (=afterload). Though it may be confusing that output is
dependent upon vascular resistance while the product of output and resistance
determines blood pressure, simply think of the output of blood from the heart as a
force and the blood-filled narrow vessels into which the newly oxygenated blood is
pumped as a variably opposing force (or a variable volume of liquid <=different
mass> having momentary inertia, for those of you more inclined toward physics).
More important to the present discussion, there are two structural
components to the vascular system essential for determining overall resistance:

narrow arterioles, which exert the major force of resistance to cardiac output,
and the large capacitance venules, which determine the volume and pressure of
the blood returning to the heart. Overall blood volume, the third essential
component in determining blood pressure, is regulated by electrolyte balance by
the kidney via aldosterone whose level is controlled by angiotensin II, generated
by the renin-angiotensinogen system, and K+.
Hypertension
Most instances of hypertension (=chronically elevated blood pressure) result
from increased arterial resistance, while cardiac output is in the normal range.
Hence, the some of the most effective antihypertensive drugs act by decreasing
this resistance, but not necessarily via direct vasodilation, though the end result is
just that. One basic problem in treating hypertension is that in the vast majority
of cases (90%) the basis for the chronically elevated blood pressure is
unidentified, termed primary, or essential, hypertension. Many of the interacting
control mechanisms mentioned above are altered, and often adjusting two or more
of these processes is required to lower the BP. In a minority of cases, the
hypertension is a consequence of a disease state, hence it is termed secondary
hypertension. Obviously, the disease is addressed first, and its resolution will
usually alleviate the secondary hypertension. If not, additional, direct intervention
would then be considered.
Classification of hypertension based on blood pressure:
Status

Systolic pressure
mm Hg

Normal
Prehypertension
Hypertension:
Stage 1 (Mild)
Stage 2 (Moderate)
Stage 3 (Severe)
Stage 4 (Very severe)

Diastolic pressure
mm Hg

< 130
120 to 139

< 85
80 to 90

140 to 159
160 to 179
180 to 209
> 210

90 to 99
100 to 109
110 to 119
> 120

Risk

None
Slight
Long-term
50% in 5 years
40% in 2 years
Emergency

Risk = stroke, cardiac failure, renal insufficiency or failure

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 a
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 life-threatening
hypertensive crisis
- Ganglionic blockers (eg. mecamylamine)
historically, first effective antihypertension drugs; now used to
explore function of central neuronal nicotinic acetylcholine receptors

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
for mild- moderate hypertension, acts by blocking uptake of
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;
labetalol)
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
o side effects: reduced cardiac reserve; possible bronchial
constriction

pindolol, a partial agonist, lowers BP with less attendant
depression of cardiac
output due to stronger
agonist action at beta1 than beta2.