Direct vasodilators: hydralazine and minoxidil
Pharmacology and mechanism of action
These two agents are no more “direct” than any of the other vasodilating drugs, but they differ from the others in that their actual mechanisms of action remain uncertain. For hydralazine, the mechanism by which it relaxes arterial smooth muscle is unknown. On the other hand, it is now known that an active metabolite of minoxidil — minoxidil N-O sulfate — opens ATP-modulated potassium channels in arteries. Enhanced efflux of potassium from smooth muscle cells tends to hyperpolarize the smooth muscle cells, which in turn lowers intracellular calcium concentrations and inhibits smooth muscle contraction. Interestingly, hydralazine and minoxidil are highly selective for arterial rather than venous smooth muscle. This selective action tends to cause reflex sympathetic activation and venoconstriction with attendant increases in venous return. In turn, cardiac output increases and limits the antihypertensive effectiveness of the vasodilators. The reflex sympathetic effects on the heart increase myocardial contractility and rate and add to the mechanisms of increased cardiac output. At the same time, the kidney retains salt and water, further increasing blood volume and secondarily venous return. The renin system is stimulated by the sympathetic activity. For all these reasons, these agents are not useful as monotherapy and should generally be combined with a diuretic and an adrenergic-inhibiting agent such as a β-adrenergic receptor antagonist. Both hydralazine and minoxidil are well absorbed and have antihypertensive effects for 6 to 12 hours or more. Hydralazine is excreted in the urine mainly as metabolites. Twenty percent of minoxidil is metabolized, 60–70% is conjugated and eliminated, and approximately 10% is excreted unchanged.
Clinical use and adverse effects of vasodilators
Because these drugs are almost always used as third- or fourth-line therapy, this section concentrates on the use of minoxidil and hydralazine in that context. In comparison with a-adrenergic antagonists, hydralazine produces similar antihypertensive effects with comparatively similar incidences of adverse effects. Trials comparing hydralazine to prazosin showed similar antihypertensive efficacy, but only prazosin was associated with regression of left ventricular hypertrophy. Nifedipine as the third drug in a regimen may be more effective than hydralazine.
Minoxidil is a very efficacious orally active antihypertensive agent. Its use originally was reserved to treat refractory hypertension. In large-scale trials, as a third drug given to patients with resistant hypertension, minoxidil produced effective control of blood pressure in over 70% of patients. Minoxidil has been more effective than captopril or hydralazine in double-blind, randomized, control studies of treatment-resistant patients. Minoxidil may have particular utility in patients with renal insufficiency and hypertension refractory to other drugs. Most studies using minoxidil as a third drug have combined it with β-adrenergic antagonists. Patients refractory to β-adrenergic antagonists plus diuretics and minoxidil have responded to the addition of an Angiotensin-converting enzyme inhibitor as the fourth drug in the regimen.
Excessive reduction of blood pressure results in orthostatic hypotension. This can be minimized by starting at low doses (e.g., 1.25 mg minoxidil, 25 mg hydralazine). Salt and water retention can occur and may manifest as severe peripheral edema, occasionally with ascites, associated with loss of control of blood pressure. Concomitant use of loop diuretics will be needed in almost all patients with functioning kidneys who respond to minoxidil to reverse the effects of plasma volume expansion. Reflex sympathetic effects can occur and include flushing, palpitations, anxiety, tremulousness, and headache. These are controlled by β-adrenergic antagonists or other antiadrenergic agents. It may be possible to reduce the dose of β-adrenergic antagonists once blood pressure is stabilized. Hydralazine and minoxidil in the absence of a sympathetic inhibitor drug can be associated with increasing left ventricular wall mass and ECG changes of left ventricular hypertrophy.
These agents are contraindicated in patients with aortic dissection because they increase cardiac inotropy and lead to increased shear force on the aortic wall. Patients taking hydralazine may develop positive antinuclear antibody, typically occurring only when doses are greater than 200 mg/day. However drug-induced lupus occurs in only 5–10% of those with positive antinuclear antibody, usually spares the kidney, and is generally reversible on discontinuation of the drug.
Principles
Many syndromes produced by drugs look like spontaneously produced syndromes, but the drugs do not reproduce the pathogenesis, morbidity, or mortality of the disease they mimic. Be aware of the differences between simulating the facade of a disease and causing the disease when it comes time to treat the adverse effect or decide on whether the offending drug can be continued.
Minoxidil may cause pericardial effusion, usually in patients who have renal failure, heart failure, or severe hypertension requiring high doses. Finally, hirsutism is common with minoxidil, is dose-dependent, and is an important limiting factor to using the drug in women. In fact, minoxidil is now used topically to promote hair growth.
Principles
Note how adversity can be put to use for unexpected alternative indications.
Recommendations
Hydralazine should be started at a dosage of 25 mg twice a day and increased gradually to a maximum of 200 mg/day in patients who already are taking diuretics and antiadrenergic therapy. The drug is safe, effective, and relatively inexpensive in this setting. Its use has declined because alternative vasodilators such as Angiotensin-converting enzyme inhibitors, α-adrenergic antagonists, and calcium channel blockers have become available. Hydralazine, in combination with isosorbide dinitrate, is useful in patients with congestive heart failure who cannot tolerate Angiotensin-converting enzyme inhibitors (see the section on Congestive Heart Failure in this chapter). Typically, minoxidil has been reserved to treat refractory hypertensive patients. It may be especially useful in patients with stage 3 hypertension and renal insufficiency. Use of this highly efficacious drug may allow reduction in dosage of other drugs and improvement in the quality of life of patients. The initial dosage should be from 1.25 to 2.5 mg/day, with titration in 2.5- to 5-mg increments up to a maximum dosage of 40–80 mg/day. Obviously, this approach should be highly individualized, especially because less is known about the safety of the systemic administration of minoxidil than for many other antihypertensive drugs. Patients who are taking direct vasodilators but have inadequate control of their blood pressure should have their plasma volume status carefully evaluated. If the patient is volume-overloaded, diuretics should be increased and euvolemia restored before increasing dosage of the vasodilator.
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