Chapter 44 - Vasodilators

CHAPTER 44

VASODILATORS

Some of these drugs act primarily on arterioles, some act primarily on veins and some dilate both types of vessels. - widely used, with indications ranging from hypertension to angina pectoris to heart failure

I.

BASIC CONCEPTS

IN

VASODILATOR PHARMACOLOGY

A.

SELECTIVITY OF VASODILATORY EFFECTS - vasodilators differ from one another with respect to the types of blood vessels they affect - some agents produce selective dilation of arterioles - some agents produce selective dilation of veins - some agents dilate arterioles and veins - selectivity determines its hemodynamic responses and effects - drugs that dilate resistance vessels (arterioles) cause a decrease in cardiac afterload (the force against which the heart must work to pump blood) - by decreasing afterload, arteriolar dilators reduce cardiac work while causing cardiac output and tissue perfusion to increase - drugs that dilate capacitance vessels (veins) reduce the force with which blood is returned to the heart, reducing ventricular filling - this filling decreases cardiac preload (the degree of stretch of the ventricular muscle prior to contraction), decreasing the force of ventricular contraction - - venous dilators cause a decrease in cardiac work, along with a decrease in cardiac output and tissue perfusion B.

OVERVIEW OF THERAPEUTIC USES - principal indications: essential hypertension

hypertensive

crisis angina pectoris heart failure myocardial infarction - additional indications: pheochromocytoma peripheral vascular disease production of controlled hypotension during surgery - specific applications are determined by pharmacologic profile - profile facets: route of administration, site of vasodilation (arterioles, veins or both), and intensity and duration of effects C.

ADVERSE EFFECTS RELATED

TO

VASODILATION

1. Postural Hypotension – a fall in blood pressure brought on by moving from a supine or seated position to an upright position - cause is relaxation of smooth muscle in veins - because of venous relaxation, gravity causes blood to “pool” in veins, decreasing venous return to the heart which causes a decrease in cardiac output and a corresponding drop in blood pressure - symptoms: lightheadedness, dizziness - advise patient to sit or lie down if these occur - can be minimized by avoiding abrupt transitions from a supine or seated position to an upright position

2.

Reflex Tachycardia – produced by dilation of arterioles or veins Mechanism: - arteriolar dilation causes a direct decrease in arterial pressure - venous dilation reduces cardiac output, reducing arterial pressure - baroreceptors in the aortic arch and carotid sinus sense the drop in pressure and relay this information to the vasomotor center of the medulla - in an attempt to bring blood pressure back up, the medulla sends impulses along sympathetic nerves instructing the heart to beat faster - undesirable because: a) tachycardia can put an unacceptable burden on the heart b) if the vasodilator was given to reduce blood pressure, tachycardia would raise pressure and thereby counteract beneficial effects - pretreatment with a beta blocker, which will block sympathetic stimulation of the heart, will help prevent this condition 3. Expansion of Blood Volume – prolonged use of arteriolar or venous dilators can cause an increase in blood volume (secondary to prolonged reduction of blood pressure) - this increase represents an attempt by the body to restore blood pressure to pretreatment levels Mechanism: aldosterone by the adrenal

a) - reduced blood pressure triggers secretion of

glands - aldosterone then acts on the kidney to promote retention of sodium and water, increasing blood volume b) - by reducing arterial pressure, vasodilators decrease renal blood flow and glomerular filtration rate - because filtrate volume is decreased, the kidney is able to reabsorb an increased fraction of filtered sodium and water, causing blood volume to expand - increased plasma volume can negate the beneficial effects of vasodilator therapy - to prevent the kidney from neutralizing the benefits, patients often receive concurrent therapy with a diuretic

II.

PHARMACOLOGY

A.

ARTERIAL VASODILATORS 1. Hydralazine trade name: Apresoline a. Hydralazine Cardiovascular Effects - causes selective dilation of arterioles - has little or no effect on veins - results from a direct action on vascular smooth muscle

OF

INDIVIDUAL VASODILATORS

(VSM) - arteriolar dilation responses:

peripheral resistance

and arterial blood pressure fall heart rate and myocardial contractility increase - minimal postural hypotension due to arteriole selectivity

b.

Hydralazine Pharmacokinetics - readily absorbed following oral administration - effects begin within 45 minutes and persist for 6 hours

or more - with parenteral administration, effects begin rapidly (within 10 minutes) and last for 2 – 4 hours - inactivated by metabolic process (acetylation)

- slow acetylators = higher blood levels of drug which can result in excessive vasodilation and other undesired effects c.

Hydralazine Therapeutic Uses i. Essential Hypertension – oral administration can

be used to lower

ii.

blood pressure - regimen almost always includes a beta blocker - regimen may also include a diuretic Hypertensive Crisis – parenteral administration is

used to lower blood pressure rapidly in severe hypertensive episodes - should be administered in small, incremental doses - in excessive doses hypotension may replace hypertension iii.

Heart Failure – hydralazine can be used short term

to reduce afterload in patients with heart failure - with prolonged therapy, tolerance develops d.

Hydralazine Adverse Effects i. Reflex Tachycardia – by lowering arterial blood

pressure, hydralazine can trigger reflex stimulation of the heart, causing cardiac work, and myocardial oxygen demand to increase - drug is usually combined with a beta blocker ii.

Increased Blood Volume – hydralazine can cause

iii.

retention and a corresponding increase in blood volume - can be prevented with a diuretic Systemic Lupus Erythematosus-like Syndrome –

sodium and water

hydralazine can cause an acute rheumatoid syndrome that closely resembles systemic lupus erythematosus (SLE) - characterized by muscle pain, joint pain, fever, nephritis, pericarditis, and the presence of antinuclear antibodies

- occurs most frequently in slow acetylators and is rare when dosage is kept below 200 mg/day - symptoms are usually reversible but may take 6 or more

iv.

months to resolve - rheumatoid symptoms may persist for years Others – headache, dizziness, weakness, and

fatigue e.

Hydralazine Drug Interactions - combined with a beta blocker to protect against reflex

tachycardia - combined with a diuretic to prevent sodium and water retention and expansion of blood volume - drugs that lower blood pressure will intensify hypotensive responses - care is needed to avoid excessive hypotension f.

Hydralazine Preparations, Dosage and Administration - dispensed in tablets for oral use - dispensed in solution for parenteral administration (IV

and IM) - - reserved for hypertensive crises - available in fixed dose combinations 2.

Minoxidil - trade name: Loniten - produces more intense vasodilation than hydralazine but also causes more severe adverse reactions - very effective and very dangerous - reserved for patients with severe hypertension that has been refractory to safer drugs a.

Minoxidil Cardiovascular Effects - produces selective dilation of arterioles - little or no venous dilation - decreases peripheral resistance and arterial blood

pressure - reflex mechanisms increase in heart rate and myocardial contractility - these responses can increase cardiac oxygen demand, exacerbating angina pectoris - vasodilation results from a direct action on VSM - minoxidil must first be metabolized to minoxidil sulfate

- this metabolite causes potassium channels in VSM to open - resultant efflux of potassium hyperpolarizes VSM cells, reducing their ability to contract b.

Minoxidil Pharmacokinetics - rapidly and completely absorbed following oral

administration - maximal within 2 – 3 hours, then gradually declines c.

Minoxidil Therapeutic Uses - only cardiovascular indication is severe hypertension - reserved for patients who have failed to respond to

safer drugs - to minimize adverse responses (reflex tachycardia, expansion of blood volume, peripheral effusion), drug should be used with a beta blocker plus intensive diuretic therapy - topical formulation (Rogaine, Minoxidil for Men) is used to promote hair growth d.

Minoxidil Adverse Effects i. Reflex Tachycardia – blood pressure reduction

triggers this condition - serious side effect - can be minimized by concurrent use of a beta blocker ii.

Sodium and Water Retention – fluid retention is

common and serious - volume expansion can be so severe as to cause cardiac decompensation - management requires a high ceiling diuretic used alone or in combination with a thiazide diuretic - if diuretics are inadequate, dialysis must be employed or withdraw the medication iii.

Hypertrichosis (excessive growth of hair) - condition develops after 4 wks or more of use - growth begins on the face and later

develops on the arms, legs, and back

- appears to result from proliferation of epithelial cells at the base of the hair follicle - vasodilation may also be involved - cosmetic problem and may be controlled by shaving or using a depilatory - most patients (primarily women) find condition both

iv.

unmanageable and intolerable and refuse to continue treatment Pericardial Effusion (fluid accumulation beneath

pericardium) - rarely occurs - asymptomatic - in some cases, fluid accumulation becomes so great as to cause cardiac tamponade (compression of the heart with a resultant decrease in cardiac performance) - if tamponade occurs, it must be treated by v.

pericardiocentesis or surgical drainage Others – nausea, headache, fatigue, breast

tenderness, glucose intolerance, thrombocytopenia, skin reactions (rashes, Stevens-Johnson syndrome),and hemorrhagic cardiac lesions B.

MIXED ARTERIAL AND VENOUS DILATION 1. Sodium Nitroprusside – trade name: Nitropress - potent and efficacious vasodilator - fastest acting antihypertensive agent - drug of choice for hypertensive emergencies a.

Nitroprusside Cardiovascular Effects - causes venous dilation in addition to arteriolar dilation - reflex tachycardia is minimal - administration is by IV infusion - onset of effects is immediate - by adjusting infusion rate, blood pressure can be depressed to almost any level desired - when infusion stops, blood pressure returns to pretreatment levels in minutes

- can trigger retention of sodium and water; furosemide can help offset this effect b.

Nitroprusside Mechanism of Action - breaks down to release nitric oxide - activates guanylate cyclase, an enzyme present in VSM - guanylate cyclase catalyzes the production of cyclic

GMP, which, through a series of reactions, causes vasodilation - similar to nitroglycerin c.

Nitroprusside Therapeutic Uses i. Hypertensive Emergencies – used to lower blood

pressure rapidly in hypertensive emergencies - oral antihypertensive medication should be initiated simultaneously - during treatment, furosemide may be needed to prevent excessive retention of fluid ii.

Other Uses – approved for production of controlled

hypotension during surgery (to reduce bleeding in the surgical field) - employed to treat severe, refractory congestive heart failure and myocardial infarction