ANTI HYPERTENSIVE DRUGS | Tutorial B-1 GUS

130110110177|Gabriella Chafrina| 05/05/13

A useful classification of these anti
hypertensive agents categorizes them
according to the principal regulatory site or
mechanism on which they act. Because of
their common mechanisms of action, drugs
within each category tend to produce a similar
spectrum of toxicities. The categories include
the following:
1. Diuretics, which lower blood pressure by
depleting the body of sodium and reducing
blood volume and perhaps by other
mechanisms.
2. Sympathoplegic agents, which lower
blood pressure by reducing peripheral
vascular resistance, inhibiting cardiac
function, and increasing venous pooling in
capacitance vessels. (The latter two
effects reduce cardiac output.) These
agents are further subdivided according to
their putative sites of action in the
sympathetic reflex arc (see below).
3. Direct vasodilators, which reduce
pressure by relaxing vascular smooth
muscle, thus dilating resistance vessels
andto varying degreesincreasing
capacitance as well.
4. Agents that block production or action of angiotensin and thereby reduce peripheral vascular
resistance and (potentially) blood volume.

VASODILATORS
- Mechanism and Site of Action
Class of drugs Used for
Oral vasodilators (hydralazine and minoxidil) long-term outpatient therapy of hypertension
Parenteral vasodilators (nitroprusside, diazoxide,
and fenoldopam)
treat hypertensive emergencies
Calcium channel blockers long-term outpatient therapy of hypertension and
treat hypertensive emergencies
Nitrates in angina

ANTI HYPERTENSIVE DRUGS | Tutorial B-1 GUS

130110110177|Gabriella Chafrina| 05/05/13
Vasodilators work best in
combination with other
antihypertensive drugs that oppose
the compensatory cardiovascular
responses














































- Drugs
Hydralazine
Hydrazine derivative
Hydralazine + nitrates effective in heart failure
Pharmacokinetic and Dosage
Well absorbed and rapidly metabolized by liver during 1
st
pass, so low bioavailability (+25%) and
variable among individuals
Metabolized in part by acetylation at a rate that appears to be bimodally distributed in the population.
As a consequence, rapid acetylators have greater 1
st
-pass metabolism, lower blood levels, and less
antihypertensive benefit from a given dose than do slow acetylators
Half life: 1.5-3 hours, but vascular effects persist longer than do blood concentrations, possibly due to
avid binding to vascular tissue
Usual dosage ranges from 40 mg/d to 200 mg/d, but higher dosages result in greater vasodilation and
may be used if necessary
Dosing two or three times daily provides smooth control of blood pressure

Toxicity
Most common adverse effects: headache, nausea, anorexia, palpitations, sweating, and flushing
In patients with ischemic heart disease, reflex tachycardia and sympathetic stimulation may provoke
angina or ischemic arrhythmias
Dosages of 400 mg/d or more, there is a 1020% incidencechiefly in persons who slowly acetylate
the drugof a syndrome characterized by arthralgia, myalgia, skin rashes, and fever that resembles
lupus erythematosus






ANTI HYPERTENSIVE DRUGS | Tutorial B-1 GUS

130110110177|Gabriella Chafrina| 05/05/13
Minoxidil
Efficacious orally active vasodilator
Minoxidil sulfate (the active metabolite) cause opening of potassium channels in
smooth muscle membranes Increased potassium permeability stabilizes
the membrane at its resting potential and makes contraction less likely
Dilates arterioles but not veins
Minoxidil can replaced hydralazine in patients with renal failure and severe
hypertension, who do not respond well to hydralazine
Pharmacokinetics and Dosage
Associated with reflex sympathetic stimulation and sodium and fluid retention
Must be used in combination with a blocker and a loop diuretic
Toxicity
Tachycardia, palpitations, angina, and edema are observed when doses of blockers and diuretics are
inadequate
Headache, sweating, and hypertrichosis are relatively common
Topical minoxidil (as Rogaine) is used as a stimulant to hair growth for correction of baldness
Sodium nitroprusside
Powerful parenterally administered vasodilator that is used in treating
hypertensive emergencies as well as severe heart failure
dilates both arterial and venous vessels, resulting in reduced peripheral
vascular resistance and venous return
activation of guanylyl cyclase (either via release of nitric oxide or by
direct stimulation of the enzyme) increased intracellular cGMP
relaxes vascular smooth muscle
Pharmacokinetics and Dosage
Nitroprusside: complex of iron, cyanide groups, and a nitroso moiety
rapidly metabolized by uptake into red blood cells with liberation of cyanide. Cyanide in turn is
metabolized by the mitochondrial enzyme rhodanase, in the presence of a sulfur donor, to the less
toxic thiocyanate. Thiocyanate is distributed in extracellular fluid and slowly eliminated by the kidney
rapidly lowers blood pressure, and its effects disappear within 110 minutes after discontinuation
given by intravenous infusion and should be changed after several hours
in aqueous solution is sensitive to light and must therefore be made up fresh before each
administration and covered with opaque foil
Dosage typically begins at 0.5 mcg/kg/min and may be increased up to 10 mcg/kg/min as necessary to
control blood pressure
Toxicity
Most common: excessive blood pressure lowering
Most serious: accumulation of cyanide, metabolic acidosis, arrhythmias, excessive hypotension, and
death







ANTI HYPERTENSIVE DRUGS | Tutorial B-1 GUS

130110110177|Gabriella Chafrina| 05/05/13
Diazoxide
An and relatively long-acting parenterally administered arteriolar dilator
that is occasionally used to treat hypertensive emergencies
Effect: rapid fall in systemic vascular resistance and mean arterial blood
pressure associated with substantial tachycardia and increase in cardiac
output and prevents vascular smooth muscle contraction by opening
potassium channels and stabilizing the membrane potential at the resting
level
Pharmacokinetics and Dosage
Similar chemically to the thiazide diuretics but has no diuretic activity
Bound extensively to serum albumin and to vascular tissue
Partially metabolized, metabolic pathways are not well characterized
The remainder is excreted unchanged
Half life: approx. 24 hours, but the relationship between blood concentration and hypotensive action is
not well established
The blood pressure-lowering effect after a rapid injection is established within 5 minutes and lasts for
412 hours
Toxicity
Most significant: excessive hypotension, resulting from the recommendation to use a fixed dose of 300
mg in all patients
Hypotension has resulted in stroke and myocardial infarction
Diazoxide inhibits insulin release from the pancreas (probably by opening potassium channels in the
beta cell membrane) and is used to treat hypoglycemia secondary to insulinoma hyperglycemia
complicates diazoxide use, particularly in persons with renal insufficiency
Rarely caused renal salt and water retention
Fenoldopam
A peripheral arteriolar dilator used for hypertensive emergencies and postoperative
hypertension
Acts primarily as an agonist of dopamine D
1
receptors, resulting in dilation of peripheral
arteries and natriuresis
Pharmacokinetics and Dosage
Rapidly metabolized, primarily by conjugation
Half life: 10 minutes
Administered by continuous IV infusion
Initiated at a low dosage (0.1 mcg/kg/min), and the dose is then titrated upward every 15 or 20
minutes to a maximum dose of 1.6 mcg/kg/min or until the desired blood pressure reduction is
achieved
Toxicity
Major toxicities: reflex tachycardia, headache, and flushing
Cause increases intraocular pressure
Calcium Channel Blockers
Have antianginal effects, antiarrhythmic effects, and reduce peripheral resistance and blood pressure
Verapamil, diltiazem, and the dihydropyridine family (amlodipine, felodipine, isradipine, nicardipine,
nifedipine, and nisoldipine) are all equally effective in lowering blood pressure
Clevidipine is a newer member of this group that is formulated for intravenous use only
Hemodynamic differences among calcium channel blockers may influence the choice of a
particular agent

ANTI HYPERTENSIVE DRUGS | Tutorial B-1 GUS

130110110177|Gabriella Chafrina| 05/05/13
Nifedipine and the other dihydropyridine agents are more selective as vasodilators and have less
cardiac depressant effect than verapamil and diltiazem
Reflex sympathetic activation with slight tachycardia maintains or increases cardiac output in most
patients given dihydropyridines
Verapamil has the greatest depressant effect on the heart and may decrease heart rate and cardiac
output
Diltiazem has intermediate actions
Intravenous nicardipine and clevidipine are available for the treatment of hypertension when oral
therapy is not feasible; parenteral verapamil and diltiazem can also be used for the same indication
Nicardipine is typically infused at rates of 215 mg/h. Clevidipine is infused starting at 12 mg/h and
progressing to 46 mg/h
Oral short-acting nifedipine has been used in emergency management of severe hypertension

INHIBITORS OF ANGIOTENSIN
- Renin, angiotensin, and aldosterone play important roles in at least some people with essential
hypertension
- Approximately 20% of patients with essential hypertension have inappropriately low and 20% have
inappropriately high plasma renin activity
- Mechanism and Sites of Action
Renin release from the kidney cortex is stimulated by reduced renal arterial pressure, sympathetic
neural stimulation, and reduced sodium delivery or increased sodium concentration at the distal
renal tubule
Renin acts upon angiotensinogen to split off the inactive precursor decapeptide angiotensin I
Angiotensin I is then converted, primarily by endothelial ACE, to the arterial vasoconstrictor
octapeptide angiotensin II angiotensin II which is in turn converted in the adrenal gland to
angiotensin III Angiotensin II and III both stimulate aldosterone release
Angiotensin II has vasoconstrictor and sodium-retaining activity
Angiotensin may contribute to maintaining high vascular resistance in hypertensive states
associated with high plasma renin activity, such as renal arterial stenosis, some types of intrinsic
renal disease, and malignanthypertension, as well as in essential hypertension after treatment with
sodium restriction, diuretics, or vasodilators


















ANTI HYPERTENSIVE DRUGS | Tutorial B-1 GUS

130110110177|Gabriella Chafrina| 05/05/13
A parallel system for angiotensin generation exists in several other tissues (eg, heart) and may be
responsible for trophic changes such as cardiac hypertrophy
The converting enzyme involved in tissue angiotensin II synthesis is also inhibited by ACE inhibitors
Three classes of drugs act specifically on the renin-angiotensin system:
ACE inhibitors; the competitive inhibitors of angiotensin at its receptors, including losartan and other
nonpeptide antagonists; and aliskiren, an orally active renin antagonist
A fourth group of drugs, the aldosterone receptor inhibitors eg, spironolactone, eplerenone)
-blockers, can reduce renin secretion
Angiotensin-Converting Enzyme (ACE) Inhibitors
Captopril and other drugs in this class inhibit the converting enzyme peptidyl dipeptidase that hydrolyzes
angiotensin I to angiotensin II and (under the name plasma kininase) inactivates bradykinin, a potent
vasodilator, which works at least in part by stimulating release of nitric oxide and prostacyclin
The hypotensive activity of captopril results both from an inhibitory action on the renin-angiotensin system
and a stimulating action on the kallikrein-kinin system
Bradykinin receptor antagonist, icatibant, blunts the blood pressure-lowering effect of captopril
Enalapril is an oral prodrug that is converted by hydrolysis to a converting enzyme inhibitor, enalaprilat,
with effects similar to those of captopril
Enalaprilat itself is available only for intravenous use, primarily for hypertensive emergencies
Lisinopril is a lysine derivative of enalaprilat. Benazepril, fosinopril, moexipril, perindopril, quinapril,
ramipril, and trandolapril are other long-acting members of the class. All are prodrugs, like enalapril, and
are converted to the active agents by hydrolysis, primarily in the liver
Angiotensin II inhibitors lower blood pressure principally by decreasing peripheral vascular resistance.
These agents do not result in reflex sympathetic activation may be due to downward resetting of the
baroreceptors or to enhanced parasympathetic activity
ACE inhibitors have a particularly useful role in treating patients with chronic kidney disease because they
diminish proteinuria and stabilize renal function
ACE inhibitors have also proved to be extremely useful in the treatment of heart failure, and after
myocardial infarction, and there is recent evidence that ACE inhibitors reduce the incidence of diabetes in
patients with high cardiovascular risk
Pharmacokinetics and Dosage
Captopril


Enalapril:
Peak concentrations of enalaprilat, the active metabolite of enalapril, occur 34 hours after dosing
with enalapril
Half life: 11 hours
Typical doses of enalapril are 1020 mg once or twice daily
Lisinopril
Half life: 12 hours
Doses of 1080 mg once daily are effective in most patients
All of the ACE inhibitors except fosinopril and moexipril are eliminated primarily by the kidneys; doses
of these drugs should be reduced in patients with renal insufficiency
Toxicity
Severe hypotension can occur after initial doses of any ACE inhibitor in patients who are hypovolemic
as a result of diuretics, salt restriction, or gastrointestinal fluid loss
Other adverse effects common to all ACE inhibitors include acute renal failure (particularly in patients
with bilateral renal artery stenosis or stenosis of the renal artery of a solitary kidney), hyperkalemia,
dry cough sometimes accompanied by wheezing, and angioedema
ANTI HYPERTENSIVE DRUGS | Tutorial B-1 GUS

130110110177|Gabriella Chafrina| 05/05/13
Hyperkalemia is more likely to occur in patients with renal insufficiency or diabetes
ACE inhibitors are contraindicated during the second and third trimesters of pregnancy because of the
risk of fetal hypotension, anuria, and renal failure, sometimes associated with fetal malformations or
death
Captopril, particularly when given in high doses to patients with renal insufficiency, may cause
neutropenia or proteinuria. Minor toxic effects seen more typically include altered sense of taste,
allergic skin rashes, and drug fever, which may occur in up to 10% of patients
Important drug interactions include those with potassium supplements or potassium-sparing diuretics,
which can result in hyperkalemia
Nonsteroidal anti-inflammatory drugs may impair the hypotensive effects of ACE inhibitors by blocking
bradykinin-mediated vasodilation, which is at least in part, prostaglandin mediated
Angiotensin ReceptorBlocking Agents
Losartan and valsartan were the first marketed blockers of the angiotensin II type 1 (AT1) receptor
Candesartan, eprosartan, irbesartan,telmisartan, and olmesartan have no effect on bradykinin metabolism
and are therefore more selective blockers of angiotensin effects than ACE inhibitors and have the
potential for more complete inhibition of angiotensin action compared with ACE inhibitors because there
are enzymes other than ACE that are capable of generating angiotensin II
Angiotensin receptor blockers provide benefits similar to those of ACE inhibitors in patients with heart
failure and chronic kidney disease
Pharmacokinetics and Dosage





Toxicity
Similar to ACE inhibitors, including the hazard of use during pregnancy