antihypertensiv drugs(vasodilators)

                 Vasodilator Drugs

Therapeutic Use and Rationale

Therapeutic Uses of Vasodilators

·         Systemic and pulmonary hypertension

·         Heart failure

·         Angina

As the name implies, vasodilator drugs relax the smooth muscle in blood vessels, which causes the vessels to dilate. Dilation of arterial (resistance) vessels leads to a reduction in systemic vascular resistance, which leads to a fall in arterial blood pressure. Dilation of venous (capacitance ) vessels decreases venous blood pressure.

Vasodilators are used to treat hypertension, heart failure and angina; however, some vasodilators are better suited than others for these indications. Vasodilators that act primarily on resistance vessels (arterial dilators) are used for hypertension and heart failure, but not for angina because of reflex cardiac stimulation. Venous dilators are very effective for angina, and sometimes used for heart failure, but are not used as primary therapy for hypertension. Most vasodilator drugs are mixed (or balanced) vasodilators in that they dilate both arteries and veins; however, there are some very useful drugs that are highly selective for arterial or venous vasculature. Some vasodilators, because of their mechanism of action, also have other important actions that can in some cases enhance their therapeutic utility as vasodilators or provide some additional therapeutic benefit. For example, some calcium channel blockers not only dilate blood vessels, but also depress cardiac mechanical and electrical function, which can enhance their antihypertensive actions and confer additional therapeutic benefit such as blocking arrhythmias.

Arterial dilators

Arterial dilator drugs are commonly used to treat systemic andpulmonary hypertension, heart failure and angina. They reduce arterial pressure by decreasing systemic vascular resistance. This benefits patients in heart failure by reducing the afterload on the left ventricle, which enhances stroke volume and cardiac output and leads to secondary decreases in ventricular preload and venous pressures. Anginal patients benefit from arterial dilators because by reducing afterload on the heart, vasodilators decrease the oxygen demand of the heart, and thereby improve the oxygen supply/demand ratio. Oxygen demand is reduced because ventricular wall stress is reduced by arterial dilators. Some vasodilators can also reverse or prevent arterial vasospasm (transient contraction of arteries), which can precipitate anginal attacks.

Most drugs that dilate arteries also dilate veins; however, hydralazine, a direct acting vasodilator, is highly selective for arterial resistance vessels.

The effects of arterial dilators on overall cardiovascular function can be depicted graphically using cardiac and systemic vascular function curves as shown to the right. Selective arterial dilation decreases systemic vascular resistance, which increases the slope of the systemic vascular function curve (red line) without appreciably changing the x-intercept (mean circulatory filling pressure). This alone causes the operating point to shift from A to B, resulting in an increase in cardiac output (CO) with a small increase in right atrial pressure (P_RA). The reason for the increase in P_RA is that arterial dilation increases blood flow from the arterial vasculature into the venous vasculature, thereby increasing venous volume and pressure. However, arterial dilators also reduce afterload on the left ventricle and therefore unload the heart, which enhances the pumping ability of the heart. This causes the cardiac function curve to shift up and to the left (not shown in figure). Adding to this afterload effect is the influence of enhanced sympathetic stimulation due to a baroreceptor reflex in response to the fall in arterial pressure, which increases heart rate and inotropy. Because of these compensatory cardiac responses, arterial dilators increase cardiac output with little or no change in right atrial pressure (cardiac preload). Although cardiac output is increased, systemic vascular resistance is reduce relatively more so arterial pressure falls. The effect of reducing afterload on enhancing cardiac output is even greater in failing heartsbecause stroke volume more sensitive to the influence of elevated afterload in hearts with impaired contractility.

Venous dilators

Drugs that dilate venous capacitance vessels serve two primary functions in treating cardiovascular disorders:

1.     Venous dilators reduce venous pressure, which reduces preload on the heart thereby decreasing cardiac output. This is useful in angina because it decreases the oxygen demand of the heart and thereby increases the oxygen supply/demand ratio. Oxygen demand is reduced because decreasing preload leads to a reduction in ventricular wall stress by decreasing the size of the heart.

2.     Reducing venous pressure decreases proximal capillary hydrostatic pressure, which reduces capillary fluid filtration and edema formation. Therefore, venous dilators are sometimes used in the treatment of heart failure along with other drugs because they help to reduce pulmonary and/or systemic edema that results from the heart failure.

Although most vasodilator drugs dilate veins as well as arteries, some drugs, such as organic nitrate dilators are relatively selective for veins.

The effects of selective venous dilators on overall cardiovascular function in normal subjects can be depicted graphically using cardiac and systemic vascular function curves as shown to the right. Venous dilation increasesvenous compliance by relaxing the venous smooth muscle. Increased compliance causes a parallel shift to the left of the vascular function curve (red line), which decreases the mean circulatory filling pressure (x-intercept). This causes the operating point to shift from A to B, resulting in a decrease in cardiac output (CO) with a small decrease in right atrial pressure (P_RA). The reason for these changes is that venous dilation, by reducing P_RA, decreases right ventricular preload, which decreases stroke volume and cardiac output by the Frank-Starling mechanism. Although not shown in this figure, reduced cardiac output causes a fall in arterial pressure, which reduces afterload on the left ventricle and leads to baroreceptor reflex responses, both of which can shift the cardiac function curve up and to the left. Sympathetic activation can also lead to an increase in systemic vascular resistance. The cardiac effects (decreased cardiac output) of venous dilation are more pronounce in normal hearts than in failing hearts because of where the hearts are operating on their Frank-Starling curves (cardiac function) curves (click here for more information).

Therefore, the cardiac and vascular responses to venous dilation are complex when both direct effects and indirect compensatory responses are taken into consideration. The most important effects in terms of clinical utility for patients are summarized below.

Venous dilators reduce:

1.     Venous pressure and therefore cardiac preload

2.     Cardiac output

3.     Arterial pressure

4.     Myocardial oxygen demand

5.     Capillary fluid filtration and tissue edema

Mixed or "balanced" dilators

As indicated above, most vasodilators act on both arteries and veins, and therefore are termed mixed or balanced dilators. Notable exceptions are hydralazine (arterial dilator) and organic nitrate dilators (venous dilators).

The effects of mixed dilators on cardiac and systemic vascular function curves are shown in the figure to the right. The red line represents a systemic function curve generated when there is both venous dilation (increased venous compliance) and arterial dilation (reduced systemic vascular resistance) - the  mean circulatory filling pressure (x-axis) is decreased and the slope is increased. Point B represents the new operating point, although it is important to note that where this point lies depends on the relative degree of venous and arterial dilation. If there is more arterial dilation than venous dilation, then point B may be located slightly above point A where the cardiac function curve intersects with the new vascular function curve.

To summarize the effects of mixed vasodilators, we can say that in general they decrease systemic vascular resistance and arterial pressure with relatively little change in right atrial (or central venous) pressure (i.e., little change in cardiac preload), and they have a relatively little effect on cardiac output.

Side-Effects of Vasodilators

There are three potential drawbacks in the use of vasodilators:

1.     Systemic vasodilation and arterial pressure reduction can lead to a baroreceptor-mediated reflex stimulation of the heart (increased heart rate and inotropy). This increases oxygen demand, which is undesirable if the patient also has coronary artery disease.

2.     Vasodilators can impair normal baroreceptor-mediated reflex vasoconstriction when a person stands up, which can lead to orthostatic hypotension and syncope upon standing.

3.     Vasodilators can lead to renal retention of sodium and water, which increases blood volume and cardiac output and thereby compensates for the reduced systemic vascular resistance.

Drug Classes and General Mechanisms of Action

Vasodilator drugs can be classified based on their site of action (arterial versus venous) or by mechanism of action. Some drugs primarily dilate resistance vessels (arterial dilators; e.g., hydralazine), while others primarily affect venous capacitance vessels (venous dilators; e.g., nitroglycerine). Most vasodilator drugs, however, have mixed arterial and venous dilator properties (mixed dilators; e.g., alpha-adrenoceptor antagonists, angiotensin converting enzyme inhibitors).

It is more common, however, to classify vasodilator drugs based on their primary mechanism of action. This type of classification scheme leads to the following drug classes: (Click on the drug class for more details)

·         Alpha-adrenoceptor antagonists (alpha-blockers)

·         Angiotensin converting enzyme (ACE) inhibitors

·         Angiotensin receptor blockers (ARBs)

·         Beta₂-adrenoceptor agonists (β₂-agonists)

·         Calcium-channel blockers (CCBs)

·         Centrally acting sympatholytics

·         Direct acting vasodilators

·         Endothelin receptor antagonists

·         Ganglionic blockers

·         Nitrodilators

·         Phosphodiesterase inhibitors

·         Potassium-channel openers

·         Renin inhibitors

·          

Hydralazine

Hydralazine (Apresoline) is a direct-acting smooth muscle relaxant used to treat hypertensionby acting as a vasodilator primarily in arteries and arterioles. By relaxing vascular smooth muscle, vasodilators act to decrease peripheral resistance, thereby lowering blood pressure and decreasing afterload

Mechanism of action

Hydralazine increases guanosine monophosphate levels, decreasing the action of the second messenger IP₃, limiting calcium release from the sarcoplasmic reticulum of smooth muscle. This results in an vessel relaxation. It dilates arterioles more than veins.

It recently has been identified as a nitric oxide donor.

Activation of hypoxia-inducible factors has been suggested as a mechanism

Clinical Use

Hydralazine is not used as a primary drug for treating hypertension because it elicits a reflexsympathetic stimulation of the heart (the baroreceptor reflex). The sympathetic stimulation may increase heart rate and cardiac output, and in patients with coronary artery disease may causeangina pectoris or myocardial infarction. Hydralazine may also increase plasma reninconcentration, resulting in fluid retention. In order to prevent these undesirable side-effects, hydralazine is usually prescribed in combination with a beta-blocker (e.g., propranolol) and adiuretic.

Hydralazine is used to treat severe hypertension, but again, it is not a first-line therapy for essential hypertension. However, hydralazine is the first-line therapy for hypertension in pregnancy, with methyldopa.

Pre-clinical research

Multiple sclerosis: Due to its ability to damage myelin nerve sheaths, acrolein may be a factor in the development of multiple sclerosis. Hydralazine, a known scavenger of acrolein, was found to reduce myelin damage and significantly improve behavioral outcomes in a mouse model of multiple sclerosis (experimental autoimmune encephalomyelitis).

Side effects

Common side-effects include:

§                     Diarrhea

§                     Compensatory tachycardia due to baroreceptor reflex ->Angina

§                     Headache

§                     Loss of appetite

§                     Nausea or vomiting

§                     Depression

§                     Pounding heartbeat

§                     Drug-Induced Lupus Erythematosus

§                     ANCA-associated Vasculitis - Generally MPO-ANCA positive

Patients given hydralazine over a period of six months may develop a lupus-like syndrome or other immune-related diseases that, in general, are reversible with withdrawal. Hydralazine is differentially acetylated by fast and slow acetylator phenotypes, hence incidence of lupus-like disease in slow acetylators

Minoxidil

Minoxidil (trade names Rogaine, Regaine, Avacor, Loniten (orally), and Mintop among others-- now that Minoxidil is off patent) is an antihypertensive vasodilator medication also known for its ability to slow or stop hair loss and promote hair regrowth. It is available over the counterfor treatment of androgenic alopecia, among other baldness treatments, but measurable changes disappear within months after discontinuation of treatment.

History

Minoxidil was first used exclusively as an oral drug (trade name Loniten) to treat high blood pressure. However, it was discovered to have an interesting side-effect:Minoxidil may cause increased growth or darkening of fine body hairs. When the medication is discontinued, the hair will return to normal within 30 to 60 days. Upjohn Corporation produced a topical solution that contained 2% minoxidil to be used to treat baldness and hair loss, under the brand name Rogaine in the United States and Canada, and Regaine in Europe and the Asia-Pacific. Treatments usually include a 5% concentration solution that is designed for men, whereas the 2% concentration solutions are designed for women. The patent on minoxidil expired on February 11, 1996.

In 2007 a new foam-based formulation of 5% minoxidil was shown to be as effective as the liquid-based treatment for male pattern baldness

While the drug is available in the United Kingdom, it cannot be prescribed on the NHS, so patients must either buy it over-the-counter or have a private prescription for it.

Results

One study in healthy males aged 18–50 years with androgenic alopecia (male pattern baldness) found that compared to a baseline of 103 to 106 hairs/cm², those who applied a 5% solution of minoxidil for 32 weeks increased their non-vellus hair counts by an average of 39 hairs/cm², in contrast to 5 hairs/cm² in subjects who received a placebo.

Mechanism

The mechanism by which minoxidil promotes hair growth is not fully understood. Minoxidil contains the nitric oxide chemical moeity and may act as a nitric oxide agonist. Similarly, Minoxidil is a potassium channel opener, causing hyperpolarization of cell membranes. Minoxidil is less effective when there is a large area of hair loss. In addition, its effectiveness has largely been demonstrated in younger men (18 to 41 years of age). Minoxidil use is indicated for central (vertex), or top of head, balding only.

Minoxidil is also a vasodilator^{[citation needed]}. It is speculated that by widening blood vessels and opening potassium channels, it allows more oxygen, blood, and nutrients to the follicle. This can also cause follicles in the telogen phase to shed, usually soon to be replaced by new, thicker hairs (in a new anagen phase).

Side effects

Common side effects of minoxidil include burning or irritation of the eye; itching; redness or irritation at the treated area; unwanted hair growth elsewhere on the body. Users should seek medical attention right away if they experience the severe side effects: Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain; dizziness; fainting; fast heartbeat; sudden, unexplained weight gain; swollen hands or feet.

Alcohol present in topical preparations may dry the scalp, resulting in dandruff. Side effects of oral minoxidil may include swelling of the face and extremities, rapid and irregular heartbeat, lightheadedness, cardiac lesions, and focal necrosis of the papillary muscle and subendocardial areas of the left ventricle. There have been cases of allergic reactions to minoxidil or the non-active ingredient propylene glycol, which is found in some forms of topical Rogaine.

Pseudoacromegaly is an extremely rarely reported side effect of large doses of oral minoxidil.

Ironically, hair loss is a common side effect of minoxidil treatment. Manufacturers note that minoxidil-induced hair loss is a common side effect and describe the process as 'shedding'. Although this phenomenon demonstrates that minoxidil is indeed affecting hair follicles, manufacturers offer no guarantee that the new hair loss will be replaced with hair growth.

The speculated reason for this "shedding" is the encouragement of hairs already in the telogen phase to shed early, before often beginning a fresh, healthier anagen phase

Toxic effects

Minoxidil is highly toxic to, and may cause death in, cats and rats.

Application

[This section does not cite any sources] Minoxidil needs to be applied once or twice daily for hair gained to be maintained. For maximum effect, the solution should be in contact with the scalp for four hours before being washed out. It does not seem capable of reducing DHT or the enzyme responsible for its accumulation around the hair follicle, 5-alpha reductase, which are the main causes of male pattern baldnessin genetically susceptible individuals. Therefore, when treatment is stopped, the DHT already accumulated around the follicle has its expected effect, and the follicle usually shrinks again and eventually dies.

Minoxidil solutions are sold under many brand names. Many high priced as well as generic brands of minoxidil regrowth solutions exist and do not differ in their active ingredient or concentration (except differing versions within each brand).

Minoxidil products involve contact with hair strands, which may cause problems with hair styling since minoxidil must be in an alcohol solution. If the solution is not a problem, hair styling devices can be used as soon as the minoxidil solution has dried.

Sodium nitroprusside

Sodium nitroprusside is the inorganic compound with the formula Na₂[Fe(CN)₅NO]·2H₂O. This red-coloured salt, which is often abbreviated SNP, is a potent vasodilator.

Structure and properties

Nitroprusside is a complex anion that features an octahedral ferrous center surrounded by five tightly bound cyanide ligands and one linear nitric oxide ligand. The molecular symmetry is C_4v.Linear nitrosyl ligands are assigned a single positive charge, thus the iron is assigned an oxidation state of 2+. As such it has a low-spin d⁶ electron configuration and is diamagnetic. Its chemical reactions are mainly associated with the NO ligand.

The sodium salt dissolves in water and to a lesser extent in ethanol to give solutions containing the dianion [Fe(CN)₅NO]²⁻. This metal nitrosyl complex is the active agent in medical applications.

Medical pharmacology

Sodium nitroprusside (SNP) has potent vasodilating effects in arterioles and venules (arterioles more than venules). It is administered intravenously in cases of acute hypertensive emergency. SNP breaks down in circulation to release nitric oxide (NO). NO activates guanylate cyclase in vascular smooth muscle and increases intracellular production of cGMP. cGMP stimulates calcium movement from the cytoplasm to the endoplasmic reticulum and reduces calcium available to bind with calmodulin. Vascular smooth muscle relaxes and vessels dilate.

In the human heart, nitric oxide reduces both total peripheral resistance as well as venous return, thus decreasing both preload and afterload. For this reason, it can be used in severe cardiogenic heart failure where this combination of effects can act to increase cardiac output. In situations where cardiac output is normal, the effect is to reduce blood pressure.

Metabolism and toxicity

Sodium nitroprusside slowly breaks down to release 5 cyanide ions, especially upon exposure to UV light. Despite the toxic potential of cyanide, nitroprusside remains an effective drug in certain clinical circumstances such as malignant hypertension or for rapid control of blood pressure during vascular surgery and neurosurgery. The cyanide can be detoxified by reaction with a sulfur-donor such as thiosulfate, catalysed by the enzyme rhodanese. In the absence of sufficient thiosulfate, cyanide ions can quickly reach toxic levels.^[4] The half-life of nitroprusside is 1–2 minutes, but the metabolite thiocyanate has an excretion half-life of several days.

Use in research

In physiology research, sodium nitroprusside is frequently used to test endothelium-independent vasodilation. Iontophoresis, for example, allows local administration of the drug, preventing the systemic effects listed above but still inducing local microvascular vasodilation.

Sodium nitroprusside is also used in the presence of buffers as a reagent for ketone strips, which test the ketone levels in the urine of a diabetic. Color change on the strip indicates the relative concentration of ketones.

Sodium nitroprusside is often used as a reference compound for the calibration of Mössbauer spectrometer. It is also used as an analytical reagent in qualitative organic analysis.

In combination with acetaldehyde it is also used as a color reagent in the development of thin layer chromtography plates, particularly for N-heterocyclic compounds.

Sodium nitroprusside is also used in a urinalysis test, called the cyanide nitroprusside test, also known as Brand's test. In this test sodium cyanide is added first to urine and let stand for approximately 10 minutes. In this time disulfide bonds will be broken by the released cyanide. The destruction of disulfide bonds liberates cysteine from cystine and homocysteine from homocystine. Next sodium nitroprusside is added to the solution and it reacts with the newly freed sulfhydrylgroups. The test will turn a red/purple color if the test is positive indicating that there was significant amounts of amino acid in the urine (aminoaciduria). Cysteine, cystine, homocysteine andhomocystine all react when present in the urine when this test is performed. This test can indicate inborn errors of amino acid transporters such as cystinuria, which results from pathology in the transport of dibasic amino acids.

SNP is also used in microbiology, where it has been linked with the dispersal of Pseudomonas aeruginosa biofilms by acting as a nitric oxide donor.

Diazoxide

iazoxide is a potassium channel activator, which causes local relaxation in smooth muscle by increasing membrane permeability to potassium ions. This switches off voltage-gated calciumion channels which inhibits the generation of an action potential.

Uses

It is used as a vasodilator in the treatment of acute hypertension or malignant hypertension.

It is also used to decrease hypoglycemia due to the secretion of insulin in disease states such as insulinoma (a tumor producing insulin) or congenital hyperinsulinism.

Fenoldopam

enoldopam (Corlopam) is a drug and synthetic benzazepine derivative which acts as aperipheral selective D₁ receptor weak partial agonist/antagonist and is used as anantihypertensive

Indications

Fenoldopam is used as an antihypertensive agent postoperatively, and also via IV to treathypertensive crisis.

Pharmacology

By activating peripheral D₁ receptors, fenoldopam causes arterial/arteriolar vasodilation leading to a decrease in blood pressure. It is particularly effective in dilating the renal, mesenteric, andcoronary arteries, where D₁.receptors are found. It decreases afterload and also through specific dopamine receptors along the nephron promoting sodium excretion.^[

Side effects

Adverse effects include headache, flushing, angina, hypotension, reflex tachycardia, and increased intraocular pressure.

Contraindications

Contraindicated with patients who suffers from glaucoma.