GUS4 Antihypertensive Drugs

8/11/2019 GUS4 Antihypertensive Drugs

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ANTI HYPERTENSIVE DRUGS| Tutorial B-1 GUS

130110110177|Gabriella Chafrina| 05/05/13

A useful classification of these antihypertensive agents categorizes themaccording to the principal regulatory site ormechanism on which they act. Because oftheir common mechanisms of action, drugswithin each category tend to produce a similar

spectrum of toxicities. The categories includethe following:1. Diuretics,which lower blood pressure by

depleting the body of sodium and reducingblood volume and perhaps by othermechanisms.

2. Sympathoplegic agents,which lowerblood pressure by reducing peripheralvascular resistance, inhibiting cardiacfunction, and increasing venous pooling incapacitance vessels. (The latter two

effects reduce cardiac output.) Theseagents are further subdivided according totheir putative sites of action in thesympathetic reflex arc (see below).

3. Direct vasodilators,which reducepressure by relaxing vascular smoothmuscle, thus dilating resistance vesselsandto varying degreesincreasingcapacitance as well.

4. Agents that block production or action of angiotensinand thereby reduce peripheral vascularresistance 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 andtreat hypertensive emergencies

Nitrates in angina


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Vasodilators work best incombination with otherantihypertensive drugs that opposethe compensatory cardiovascularresponses

- Drugs HydralazineHydrazine derivativeHydralazine + nitrateseffective in heart failurePharmacokinetic and Dosage Well absorbed and rapidly metabolized by liver during 1stpass, 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 1st-pass metabolism, lower blood levels, and lessantihypertensive 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 acetylatethe drugof a syndrome characterized by arthralgia, myalgia, skin rashes, and fever that resembleslupus erythematosus


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MinoxidilEfficacious orally active vasodilatorMinoxidil sulfate (the active metabolite) cause opening of potassium channels in

smooth muscle membranesIncreased potassium permeabilitystabilizesthe 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 severehypertension, who do not respond well to hydralazine

Pharmacokinetics and DosageAssociated with reflex sympathetic stimulation and sodium and fluid retentionMust 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 nitroprussidePowerful parenterally administered vasodilator that is used in treating

hypertensive emergencies as well as severe heart failuredilates both arterial and venous vessels, resulting in reduced peripheral

vascular resistance and venous returnactivation 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 moietyrapidly 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 lesstoxic 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 discontinuationgiven 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 foilDosage 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


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DiazoxideAn and relatively long-acting parenterally administered arteriolar dilator

that is occasionally used to treat hypertensive emergenciesEffect: rapid fall in systemic vascular resistance and mean arterial blood

pressure associated with substantial tachycardia and increase in cardiacoutput and prevents vascular smooth muscle contraction by opening

potassium channels and stabilizing the membrane potential at the restinglevel

Pharmacokinetics and DosageSimilar chemically to the thiazide diuretics but has no diuretic activityBound extensively to serum albumin and to vascular tissuePartially metabolized, metabolic pathways are not well characterizedThe remainder is excreted unchangedHalf life: approx. 24 hours, but the relationship between blood concentration and hypotensive action is

not well establishedThe blood pressure-lowering effect after a rapid injection is established within 5 minutes and lasts for

412 hoursToxicityMost significant: excessive hypotension, resulting from the recommendation to use a fixed dose of 300

mg in all patientsHypotension has resulted in stroke and myocardial infarctionDiazoxide inhibits insulin release from the pancreas (probably by opening potassium channels in the

beta cell membrane) and is used to treat hypoglycemia secondary to insulinomahyperglycemiacomplicates diazoxide use, particularly in persons with renal insufficiency

Rarely caused renal salt and water retention FenoldopamA peripheral arteriolar dilator used for hypertensive emergencies and postoperative

hypertensionActs primarily as an agonist of dopamine D1receptors, resulting in dilation of peripheral

arteries and natriuresisPharmacokinetics and DosageRapidly metabolized, primarily by conjugationHalf life: 10 minutesAdministered by continuous IV infusionInitiated 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 isachieved

ToxicityMajor toxicities: reflex tachycardia, headache, and flushingCause increases intraocular pressure

Calcium Channel BlockersHave antianginal effects, antiarrhythmic effects, and reduce peripheral resistance and blood pressureVerapamil, diltiazem, and the dihydropyridine family (amlodipine, felodipine, isradipine, nicardipine,

nifedipine, and nisoldipine) are all equally effective in lowering blood pressureClevidipine is a newer member of this group that is formulated for intravenous use onlyHemodynamic differences among calcium channel blockers may influence the choice of a

particular agent


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Nifedipine and the other dihydropyridine agents are more selective as vasodilators and have lesscardiac depressant effect than verapamil and diltiazem

Reflex sympathetic activation with slight tachycardia maintains or increases cardiac output in mostpatients given dihydropyridines

Verapamil has the greatest depressant effect on the heart and may decrease heart rate and cardiacoutput

Diltiazem has intermediate actionsIntravenous nicardipine and clevidipine are available for the treatment of hypertension when oraltherapy 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 andprogressing 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 essentialhypertension

- Approximately 20% of patients with essential hypertension have inappropriately low and 20% haveinappropriately 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 distalrenal tubule

Renin acts upon angiotensinogen to split off the inactive precursor decapeptide angiotensin IAngiotensin I is then converted, primarily by endothelial ACE, to the arterial vasoconstrictoroctapeptide angiotensin II angiotensin II which is in turn converted in the adrenal gland toangiotensin IIIAngiotensin 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 withsodium restriction, diuretics, or vasodilators


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A parallel system for angiotensin generation exists in several other tissues (eg, heart) and may beresponsible 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) InhibitorsCaptopril 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 potentvasodilator, 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 systemand a stimulating action on the kallikrein-kinin system

Bradykinin receptor antagonist, icatibant, blunts the blood pressure-lowering effect of captoprilEnalapril is an oral prodrug that is converted by hydrolysis to a converting enzyme inhibitor, enalaprilat,

with effects similar to those of captoprilEnalaprilat 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, andare 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 thebaroreceptors or to enhanced parasympathetic activity

ACE inhibitors have a particularly useful role in treating patients with chronic kidney disease because theydiminish proteinuria and stabilize renal function

ACE inhibitors have also proved to be extremely useful in the treatment of heart failure, and aftermyocardial infarction, and there is recent evidence that ACE inhibitors reduce the incidence of diabetes inpatients with high cardiovascular risk

Pharmacokinetics and Dosage

Captopril

Enalapril:Peak concentrations of enalaprilat, the active metabolite of enalapril, occur 34 hours after dosing

with enalaprilHalf life: 11 hoursTypical doses of enalapril are 1020 mg once or twice daily

Lisinopril

Half life: 12 hoursDoses 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; dosesof these drugs should be reduced in patients with renal insufficiency

ToxicitySevere 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 lossOther 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


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Hyperkalemia is more likely to occur in patients with renal insufficiency or diabetesACE 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 ordeath

Captopril, particularly when given in high doses to patients with renal insufficiency, may causeneutropenia 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 blockingbradykinin-mediated vasodilation, which is at least in part, prostaglandin mediated

Angiotensin ReceptorBlocking AgentsLosartan and valsartan were the first marketed blockers of the angiotensin II type 1 (AT1) receptorCandesartan, 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 thepotential for more complete inhibition of angiotensin action compared with ACE inhibitors because thereare 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 diseasePharmacokinetics and Dosage

ToxicitySimilar to ACE inhibitors, including the hazard of use during pregnancy

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GUS4 Antihypertensive Drugs