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Drug Category: Renin Inhibitor.
Indication: Treatment of hypertension, alone or in combination
with other antihypertensive agents.
Hypertension: Initial: 150 mg once daily; may increase to 300 mg once daily (maximum: 300 mg/day). Note: Prior to initiation, correct hypovolemia and/or closely monitor volume status in patients on concurrent diuretics during treatment
Mild-to-moderate impairment [GFR >30 mL/minute and/or Scr <1.7 mg/dL (women); Scr <2 mg/dL (men)]: No dose adjustment required. Severe impairment [GFR<30 mL/minute and/or Scr >1.7 mg/dL (women); Scr >2 mg/dL (men)]: Use caution; not studied in severe renal impairment.
Administration: Administer at the same time daily; may take with or without a meal, but consistent administration with regards to meals is recommended. Avoid taking with high-fat meals.
Supplied: Tablet: 150 mg, 300 mg
bosentan (tracleer ®)
Endothelin receptor antagonist.
Adult (usual) Pulmonary arterial hypertension (PAH): initial, 62.5 mg po bid x 4 weeks. Maintenance (PAH): up to 125 mg po bid. Doses above 125 mg b.i.d. did not appear to confer additional benefit sufficient to offset the increased risk of liver injury.
Monitoring: monitor liver function before and during therapy. Monitor hemoglobin levels after 1 and 3 months, then every 3 months monthly.
[Supplied: 62.5, 125 mg tablets]
clonidine (Catapres ®)
Clonidine stimulates alpha-adrenoreceptors in the brain stem. This action results in reduced sympathetic outflow from the central nervous system and in decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. Clonidine hydrochloride acts relatively rapidly. The patient's blood pressure declines within 30 to 60 minutes after an oral dose, the maximum decrease occurring within 2 to 4 hours. Renal blood flow and glomerular filtration rate remain essentially unchanged. Normal postural reflexes are intact; therefore, orthostatic symptoms are mild and infrequent.
Acute studies with clonidine hydrochloride in humans have demonstrated a moderate reduction (15% to 20%) of cardiac output in the supine position with no change in the peripheral resistance: at a 45° tilt there is a smaller reduction in cardiac output and a decrease of peripheral resistance. During long-term therapy, cardiac output tends to return to control values, while peripheral resistance remains decreased. Slowing of the pulse rate has been observed in most patients given clonidine, but the drug does not alter normal hemodynamic response to exercise.
Tolerance to the antihypertensive effect may develop in some patients, necessitating a re-evaluation of therapy.
Other studies in patients have provided evidence of a reduction in plasma renin activity and in the excretion of aldosterone and catecholamines. The exact relationship of these pharmacologic actions to the antihypertensive effect of clonidine has not been fully elucidated.
Clonidine acutely stimulates growth hormone release in both children and adults, but does not produce a chronic elevation of growth hormone with long-term use.
The plasma level of clonidine peaks in approximately 3 to 5 hours and the plasma half-life ranges from 12 to 16 hours. The half-life increases up to 41 hours in patients with severe impairment of renal function. Following oral administration about 40–60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours. About 50% of the absorbed dose is metabolized in the liver.
INDICATIONS AND USAGE
Clonidine hydrochloride is indicated in the treatment of hypertension. Clonidine hydrochloride may be employed alone or concomitantly with other antihypertensive agents.
DOSAGE AND ADMINISTRATION
Adults: The dose of clonidine hydrochloride must be adjusted according to the patient's individual blood pressure response. The following is a general guide to its administration.
0.1 mg tablet twice daily (morning and bedtime). Elderly patients may benefit from a lower initial dose.
Further increments of 0.1 mg per day may be made at weekly intervals if necessary until the desired response is achieved. Taking the larger portion of the oral daily dose at bedtime may minimize transient adjustment effects of dry mouth and drowsiness. The therapeutic doses most commonly employed have ranged from 0.2 mg to 0.6 mg per day given in divided doses. Studies have indicated that 2.4 mg is the maximum effective daily dose, but doses as high as this have rarely been employed.
Hypertensive urgency: Initial 0.1-0.2 mg x 1, then 0.1 mg q1h prn, to a maximum total dose of 0.6 mg
HOW SUPPLIED (TABLETS)
0.1 mg, 0.2 mg, 0.3 mg
Apply Clonidine Transdermal Systems once every 7 days to a hairless area of intact skin on the upper outer arm or chest. Each new application of Clonidine Transdermal System should be on a different skin site from the previous location. If the system loosens during 7-day wearing, the adhesive cover should be applied directly over the system to ensure good adhesion. There have been rare reports of the need for patch changes prior to 7 days to maintain blood pressure control.
To initiate therapy, Clonidine Transdermal System dosage should be titrated according to individual therapeutic requirements, starting with Clonidine Transdermal System 0.1 mg. If after one or two weeks the desired reduction in blood pressure is not achieved, increase the dosage by adding another Clonidine Transdermal System 0.1 mg or changing to a larger system. An increase in dosage above two Clonidine Transdermal System 0.3 mg is usually not associated with additional efficacy.
When substituting Clonidine Transdermal System for oral clonidine or for other antihypertensive drugs, physicians should be aware that the antihypertensive effect of Clonidine Transdermal System may not commence until 2-3 days after initial application. Therefore, gradual reduction of prior drug dosage is advised. Some or all previous antihypertensive treatment may have to be continued, particularly in patients with more severe forms of hypertension.
Renal Impairment: Dosage must be adjusted according to the degree of impairment, and patients should be carefully monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis.
Clonidine Transdermal Systems 0.1 mg, Clonidine Transdermal Systems 0.2 mg, and Clonidine Transdermal Systems 0.3 mg are supplied as 4 pouched systems and 4 adhesive covers per carton.
Dosage must be adjusted according to the degree of impairment, and patients should be carefully monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis.
epoprostenol (Flolan ®)
Epoprostenol (PGI2, prostacyclin): a naturally occurring prostaglandin
with potent vasodilatory activity and inhibitory activity of platelet
aggregation. Indication: long-term intravenous treatment of primary
pulmonary hypertension and pulmonary hypertension associated with the
scleroderma spectrum of disease in NYHA Class III and Class IV patients
who do not respond adequately to conventional therapy.
Dosage - Adult (usual) Pulmonary hypertension: initial, 2 ng/kg/min IV, titrate upward in increments of 2 ng/kg/min every 15 min or longer until dose-limiting pharmacological effects are elicited or until tolerance develops.
Administration: reconstitute only with supplied diluent; do not give with other parenteral medications. Infuse continuous chronic infusion via a central venous catheter with an ambulatory infusion pump - may be administered peripherally until central catheter established. Avoid abrupt withdrawal. Anticipate need for periodic dose adjustments.
fenoldopam (Corlopam ®)
Mechanism of Action
Fenoldopam is a rapid-acting vasodilator. It is an agonist for D1-like dopamine receptors and binds with moderate affinity to 2-adrenoceptors. It has no significant affinity for D2-like receptors, 1 and adrenoceptors, 5HT1 and 5HT2 receptors, or muscarinic receptors. Fenoldopam is a racemic mixture with the R-isomer responsible for the biological activity. The R-isomer has approximately 250-fold higher affinity for D1-like receptors than does the S-isomer. In non-clinical studies, fenoldopam had no agonist effect on presynaptic D2-like dopamine receptors, or - or -adrenoceptors, nor did it affect angiotensin-converting enzyme activity. Fenoldopam may increase norepinephrine plasma concentration.
In animals, fenoldopam has vasodilating effects in coronary, renal, mesenteric and peripheral arteries. All vascular beds, however, do not respond uniformly to fenoldopam. Vasodilating effects have been demonstrated in renal efferent and afferent arterioles
INDICATIONS AND USAGE
Adult Patients: Fenoldopam is indicated for the in-hospital, short-term (up to 48 hours) management of severe hypertension when rapid, but quickly reversible, emergency reduction of blood pressure is clinically indicated, including malignant hypertension with deteriorating end-organ function. Transition to oral therapy with another agent can begin at any time after blood pressure is stable during fenoldopam infusion.
Pediatric Patients: Fenoldopam is indicated for the in-hospital, short-term (up to 4 hours) reduction in blood pressure (See Package insert for CLINICAL PHARMACOLOGY/Pediatric Patients).
Dosage (adult): Hypertension: initial 0.03-0.1 mcg/kg/min IV; increase every 15 min by 0.05-0.1 mcg/kg/min based on response. Maximum: 1.6 mcg/kg/min. In clinical trials, doses from 0.01-1.6 µg/kg/min have been studied. Most of the effect of a given infusion rate is attained in 15 minutes. A bolus dose should not be used. Hypotension and rapid decreases of blood pressure should be avoided. The initial dose should be titrated upward or downward, no more frequently than every 15 minutes (and less frequently as goal pressure is approached) to achieve the desired therapeutic effect. The recommended increments for titration are 0.05-0.1 µg/kg/min.
[Supplied: 10 mg/ml solution]
hydralazine (Apresoline ®)
Overview: Although the precise mechanism of
action of hydralazine is not fully understood, the major effects are on
the cardiovascular system. Hydralazine apparently lowers blood pressure
by exerting a peripheral vasodilating effect through a direct relaxation
of vascular smooth muscle. Hydralazine, by altering cellular calcium
metabolism, interferes with the calcium movements within the vascular
smooth muscle that are responsible for initiating or maintaining the
The peripheral vasodilating effect of hydralazine results in decreased arterial blood pressure (diastolic more than systolic); decreased peripheral vascular resistance; and an increased heart rate, stroke volume, and cardiac output. The preferential dilatation of arterioles, as compared to veins, minimizes postural hypotension and promotes the increase in cardiac output. Hydralazine usually increases renin activity in plasma, presumably as a result of increased secretion of renin by the renal juxtaglomerular cells in response to reflex sympathetic discharge. This increase in renin activity leads to the production of angiotensin II, which then causes stimulation of aldosterone and consequent sodium reabsorption. Hydralazine also maintains or increases renal and cerebral blood flow.
Hydralazine is rapidly absorbed after oral administration, and peak plasma levels are reached at 1-2 hours. Plasma levels of apparent hydralazine decline with a half-life of 3-7 hours. Binding to human plasma protein is 87% Plasma levels of hydralazine vary widely among individuals. Hydralazine is subject to polymorphic acetylation; slow acetylators generally have higher plasma levels of hydralazine and require lower doses to maintain control of blood pressure. Hydralazine undergoes extensive hepatic metabolism; it is excreted mainly in the form of metabolites in the urine.
Dosing (Adult): Initial (Acute hypertension): 10 mg slow IV bolus ( maximum dose being 20 mg) every 4 to 6 hours as needed. May increase to 40 mg/dose. Change to oral therapy as soon as possible. The fall in blood pressure begins within 10 to 30 minutes and lasts 2 to 4 hours. May also be given IM.
Hypertension (Oral): Initial: 10 mg 4 times/day. Increase by 10-25 mg/dose every 2-5 days (maximum: 300 mg/day). Usual dose range (JNC 7): 25-100 mg/day in 2 divided doses.
Pre-eclampsia/eclampsia: 5 mg/dose (IM, IV) then 5-10 mg every 20-30 minutes as needed.
CHF: Initial dose: 10-25 mg orally 3-4 times/day. Dosage must be adjusted based on individual response. Target dose: 75 mg 4 times daily in combination with isosorbide dinitrate (40 mg 4 times daily). Range: Typically 200-600 mg daily in 2-4 divided doses. Dosages as high as 3 grams per day have been used in some patients for symptomatic and hemodynamic improvement.
Renal dosing: crcl 10-50 ml/min: Administer every 8 hours. crcl <10 ml/min: Administer every 8 to 16 hours in fast acetylators and every 12-24 hours in slow acetylators.
Supplied: Injection (soln): 20 mg/ml (1 ml vial). Tablet: 10 mg, 25 mg, 50 mg, 100 mg.
DOSAGE AND ADMINISTRATION
Initiation of Therapy
The usual starting dosage of methyldopa tablet is 250 mg two to three times a day in the first 48 hours. The daily dosage then may be increased or decreased, preferably at intervals of not less than two days, until an adequate response is achieved. To minimize the sedation, start dosage increases in the evening. By adjustment of dosage, morning hypotension may be prevented without sacrificing control of afternoon blood pressure.
When methyldopa is given to patients on other antihypertensives, the dose of these agents may need to be adjusted to effect a smooth transition. When methyldopa is given with anti-hypertensives other than thiazides, the initial dosage of methyldopa should be limited to 500 mg daily in divided doses; when methyldopa is added to a thiazide, the dosage of thiazide need not be changed.
Maintenance of Therapy
The usual daily dosage of methyldopa is 500 mg to 2 g in two to four doses. Although occasional patients have responded to higher doses, the maximum recommended daily dosage is 3 g. Once an effective dosage range is attained, a smooth blood pressure response occurs in most patients in 12 to 24 hours. Since methyldopa has a relatively short duration of action, withdrawal is followed by return of hypertension usually within 48 hours. This is not complicated by an overshoot of blood pressure.
Occasionally tolerance may occur, usually between the second and third month of therapy. Adding a diuretic or increasing the dosage of methyldopa frequently will restore effective control of blood pressure. A thiazide may be added at any time during methyldopa therapy and is recommended if therapy has not been started with a thiazide or if effective control of blood pressure cannot be maintained on 2 g of methyldopa daily.
Methyldopa is largely excreted by the kidney and patients with impaired renal function may respond to smaller doses. Syncope in older patients may be related to an increased sensitivity and advanced arteriosclerotic vascular disease. This may be avoided by lower doses.
I.V.: 250-1000 mg every 6-8 hours; maximum: 1 g every 6 hours
Methyldopa is an aromatic-aminoacid decarboxylase inhibitor in animals and in man. Although the mechanism of action has yet to be conclusively demonstrated, the antihypertensive effect of methyldopa probably is due to its metabolism to alpha-methylnorepinephrine, which then lowers arterial pressure by stimulation of central inhibitory alpha-adrenergic receptors, false neurotransmission, and/or reduction of plasma renin activity. Methyldopa has been shown to cause a net reduction in the tissue concentration of serotonin, dopamine, norepinephrine, and epinephrine.
Only methyldopa, the L-isomer of alpha-methyldopa, has the ability to inhibit dopa decarboxylase and to deplete animal tissues of norepinephrine. In man, the antihypertensive activity appears to be due solely to the L-isomer. About twice the dose of the racemate (DL-alpha-methyldopa) is required for equal antihypertensive effect.
Methyldopa has no direct effect on cardiac function and usually does not reduce glomerular filtration rate, renal blood flow, or filtration fraction. Cardiac output usually is maintained without cardiac acceleration. In some patients the heart rate is slowed.
Normal or elevated plasma renin activity may decrease in the course of methyldopa therapy.
Methyldopa reduces both supine and standing blood pressure. It usually produces highly effective lowering of the supine pressure with infrequent symptomatic postural hypotension. Exercise hypotension and diurnal blood pressure variations rarely occur.
INDICATIONS AND USAGE
Methyldopa is contraindicated in patients:
– with active hepatic disease, such as acute hepatitis and active cirrhosis.
– with liver disorders previously associated with methyldopa therapy (see package insert for WARNINGS).
– with hypersensitivity to any component of this product.
– on therapy with monoamine oxidase (MAO) inhibitors.
It is important to recognize that a positive Coombs test, hemolytic anemia, and liver disorders may occur with methyldopa therapy.The rare occurrences of hemolytic anemia or liver disorders could lead to potentially fatal complications unless properly recognized and managed. Read this section carefully to understand these reactions.
TABLETS: 250 mg and 500 mg
I.V.: Methyldopate HCl Injection, USP 250 mg/5 mL (50 mg/mL).
minoxidil (Loniten ®)
Severe Hypertension: initial, 5 mg/day orally as single
dose or 2 divided doses. Maintenance (HTN): 10-40 mg/day orally daily in
1-2 divided doses (Maximum: 100 mg/day) . Acts directly on vascular
smooth muscle with selective vasodilatation of the arteriolar resistance
vessels and little or no effects on venous capacitance vessels and does
not effect the functioning of the carotid or aortic baroreceptors.
[Supplied: 2.5, 5, 10mg tablet]
nitroprusside (Nipride ®)
Arteriolar and venous dilator. Considered to be the most effective
parenteral drug for most hypertensive emergencies (except myocardial
ischemia or renal impairment). It dilates both arteries and veins, and
it reduces afterload and preload. Onset: within seconds. Duration: 2-3
minutes. Constant monitoring of the blood pressure is required.
Alternatives to nitroprusside include intravenous labetalol, nicardipine, and fenoldopam. Hypotension is uncommon with these drugs and cyanide toxicity is not an issue.
Dosing (Adults): Initial: 0.3-0.5 mcg/kg/minute. Increase in increments of 0.5 mcg/kg/minute -- titrating to the desired hemodynamic effect or the appearance of headache or nausea. Usual dose: 3 mcg/kg/minute (rarely need >4 mcg/kg/minute). Maximum: 10 mcg/kg/minute.
When treatment is prolonged (>24 to 48 hours) or when renal insufficiency is present, the risk of cyanide and thiocyanate toxicity is increased. Doses > 2 mcg/kg/min exceed the capacity of the body to detoxify cyanide. Maximum doses of 10 mcg/kg/min should never be given for more than 10 minutes. An infusion of sodium thiosulfate can be used in affected patients to provide a sulfur donor to detoxify cyanide into thiocyanate.
Supplied: Injection (Soln): 25 mg/ml - 2 ml (vial).
phentolamine (regitine ®)
Phentolamine mesylate produces an alpha-adrenergic block of relatively short duration. It also has direct, but less marked, positive inotropic and chronotropic effects on cardiac muscle and vasodilator effects on vascular smooth muscle.
Phentolamine has a half-life in the blood of 19 minutes following intravenous administration. Approximately 13% of a single intravenous dose appears in the urine as unchanged drug.
INDICATIONS AND USAGE
Phentolamine Mesylate for Injection is indicated for the prevention or control of hypertensive episodes that may occur in a patient with pheochromocytoma as a result of stress or manipulation during preoperative preparation and surgical excision.
Phentolamine Mesylate for Injection is indicated for the prevention or treatment of dermal necrosis and sloughing following intravenous administration or extravasation of norepinephrine.
Phentolamine Mesylate for Injection is also indicated for the diagnosis of pheochromocytoma by the phentolamine blocking test.
Myocardial infarction, history of myocardial infarction, coronary insufficiency, angina, or other evidence suggestive of coronary artery disease; hypersensitivity to phentolamine or related compounds.
Myocardial infarction, cerebrovascular spasm, and cerebrovascular occlusion have been reported to occur following the administration of phentolamine, usually in association with marked hypotensive episodes.
For screening tests in patients with hypertension, the generally available urinary assay of catecholamines or other biochemical assays have largely replaced the phentolamine and other pharmacological tests for reasons of accuracy and safety. None of the chemical or pharmacological tests is infallible in the diagnosis of pheochromocytoma. The phentolamine blocking test is not the procedure of choice and should be reserved for cases in which additional confirmatory evidence is necessary and the relative risks involved in conducting the test have been considered.
Extravasation - norepinephrine: 5-10 mg in 10 mL saline SC infiltrated within 12 hours into area of extravasation.
Hypertensive crisis: 5-20 mg IV.
Pheochromocytoma (diagnosis): 5 mg IV or IM.
Tissue necrosis prevention: 10 milligrams may be added to each liter of solution containing norepinephrine to prevent dermal necrosis and sloughing associated with intravenous administration of norepinephrine.
treprostinil (Remodulin ®)
Mechanism Of Action
The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic arterial vascular beds, and inhibition of platelet aggregation
Indications: Pulmonary arterial hypertension (PAH) in patients with NYHA Class II-IV symptoms.
Dosage: Pulmonary arterial hypertension: initial, 1.25 ng/kg/min continuous SC infusion; decrease to 0.625 ng/kg/min if initial dose cannot be tolerated. Pulmonary arterial hypertension: adjustments, increase dose in increments of no more than 1.25 ng/kg/min per week for the first 4 weeks and then no more than 2.5 ng/kg/min per week for remaining duration.
Administration: administer by continuous subcutaneous infusion to diminish symptoms associated with exercise. avoid abrupt cessation of infusion. Chronic dosage adjustments should establish a dose at which PAH symptoms are improved, while minimizing side effects. Minimal experience with doses greater than 40 ng/kg/min.
[Supplied (20 ml vials) 1, 2.5 , 5, and 10 mg/ml solution]
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David F. McAuley, Pharm.D., R.Ph. GlobalRPh Inc.