ANTIHYPERTENSIVE DRUG

1. Introduction

Patients with hypertension are at an increased risk of myocardial ischaemia through several mechanisms and in particular through the coexistence of left ventricular hypertrophy and coronary artery disease (CAD). Angina, myocardial infarction, left ventricular dysfunction, and sudden death are the principal clinical expressions of CAD. Left ventricular hypertrophy may itself cause angina and substantially increases risk of sudden death. In both situations myocardial ischaemia may also be asymptomatic. This article focuses principally on the management of hypertension in patients with ischaemic heart disease secondary to obstructive CAD. Blood pressure levels remain unacceptably high in about half of such patients in Europe.. An understanding of the pathophysiology of myocardial ischaemia facilitates better decision making regarding choice of antihypertensive therapy.

1.2 Pathophysiology

There is a sound pathophysiological basis for reducing blood pressure in hypertensive patients with ischaemic heart disease. Both elevated systolic blood pressure and left ventricular hypertrophy have a detrimental effect on myocardial oxygen requirements. Effective blood pressure control and regression of hypertrophy will lessen the imbalance between myocardial supply and demand. An ideal therapeutic regimen would combine drugs that optimize the supply-and-demand relationship with drugs that reduce cardiovascular events. Decision making regarding medication in hypertensive patients with CAD can be informed from hypertension trials, with ischaemic subgroups, and from studies in ischaemic populations, with hypertensive subgroups. Only one trial has specifically recruited patients with both conditions. Several agents used in these trials merit further consideration.

1.3 Target Blood Pressure

Cardiovascular mortality increases continuously across the full blood pressure range from 115/75 mmHg, doubling with each increment of 20/10 mmHg. Thresholds guide when to initiate treatment in low-risk patients. Such arbitrary limits are less relevant once CAD is established. Lowering blood pressure in these patients reduces cardiovascular events irrespective of baseline values. As with diabetes, a target blood pressure of 130/80 mmHg is therefore now recommended.

Blood vessels, vascular smooth muscle has α2-adrenoceptors that are normally activated by nor epinephrie released by sympathetic adrenergic nerves or by circulating epinephrine. These receptors, like those in the heart, are coupled to a Gs-protein, which stimulates the formation of cAMP. Although increased cAMP enhances cardiac myocyte contraction, in vascular smooth muscle an increase in cAMP leads to smooth muscle relaxation. The reason for this is that cAMP inhibits myosin light chain kinase that is responsible for phosphorylating smooth muscle myosin. Therefore, increases in - 3 -intracellular cAMP caused by α2-agonists inhibits myosin light chain kinase thereby producing less contractile force (i.e., promoting relaxation).

Other tissues. ctivation of α2-adrenoceptors in the lungs causes bronchodilation. α2-adrenoceptor activation leads to hepatic glycogenolysis and pancreatic release of glucagon, which increases plasma glucose concentrations. α1-adrenoceptor stimulation in the kidneys causes the release of renin, which stimulates the production of angiotensin II and the subsequent release of aldosterone by the adrenal cortex.

Additional modifiable risk factors

A small number of modifiable risk factors account for the majority of cardiovascular risk. Just five risk factors accounted for 80% of the population-attributable risk: lipids (odds ratio 3.25), smoking (2.87), diabetes (2.37), hypertension (1.91), and obesity (1.12). Daily consumption of fruits and vegetables (0.70), regular physical activity (0.86), and moderate alcohol consumption (0.91) were protective factors. Physicians frequently underestimate the benefits of smoking cessation, exercise, and diet. Advice, counselling, and nicotine replacement products are effective in 25% of smokers .Exercise training improves anginal symptoms, increases exercise capacity, and reduces myocardial ischaemia .Meta-analysis of cardiac rehabilitation studies suggests that exercise training reduces cardiovascular mortality while simultaneously improving blood pressure and lipid profile. In a recent randomized trial on highly selected patients ,regular physical exercise improved event-free survival compared with percutaneous intervention.

1.4 Environment

A number of environmental factors have been implicated in the development of hypertension, including salt intake, obesity, occupation, alcohol intake, family size, stimulant intake, excessive noise exposure,and crowding.

Salt sensitivity

Sodium is the environmental factor that has received the greatest attention. It is to be noted that approximately 60% of the essential hypertension population is responsive to sodium intake.

1.5 Role of renin

Renin is an enzyme secreted by the juxtaglomerular cells of the kidney and linked with aldosterone in a negative feedback loop.The range of plasma renin activities observed in hypertensive subjects is broader than in normotensive individuals. In consequence, some hypertensive patients have been defined as having low-renin and others as having high-renin essential hypertension.

1.6 Role of Insulin

Insulin is a polypeptide hormone secreted by the pancreas. Its main purpose is to regulate the levels of glucose in the body, it also has some other effects. Insulin resistance and/or hyperinsulinemia have been suggested as being responsible for the increased arterial pressure in some patients with hypertension. This feature is now widely recognized as part of syndrome X, or the metabolic syndrome.

Sleep apnea

Sleep apnea is a common, under recognized cause of hypertension. It is best treated with weight loss and nocturnal nasal positive airway pressure.

1.7 Genetics

Hypertension is one of the most common complex genetic disorders, with genetic heritability averaging 30%. Data supporting this view emerge from animal studies as well as in population studies in humans. Most of these studies support the concept that the inheritance is probably multifactorial or that a number of different genetic defects each have an elevated blood pressure as one of their phenotypic expressions.

More than 50 genes have been examined in association studies with hypertension, and the number is constantly growing.

1.8 Other etiologies

There are some anecdotal or transient causes of high blood pressure. These are not to be confused with the disease called hypertension in which there is an intrinsic physiopathological mechanism as described above.

1.9 secondary hypertension

Only in a small minority of patients with elevated arterial pressure can a specific cause be identified. These individuals will probably have an endocrine or renal defect that if corrected would bring blood pressure back to normal values.

Renal hypertension

Hypertension produced by diseases of the kidney. A simple explanation for renal vascular hypertension is that decreased perfusion of renal tissue due to stenosis of a main or branch renal artery activates the renin-angiotensin system.

Adrenal hypertension

Hypertension is a feature of a variety of adrenal cortical abnormalities. In primary aldosteronism there is a clear relationship between the aldosterone-induced sodium retention and the hypertension.

In patients with pheochromocytoma increased secretion of catecholamines such as epinephrine and norepinephrine by a tumor (most often located in the adrenal medulla) causes excessive stimulation of [adrenergic receptors], which results in peripheral vasoconstriction and cardiac stimulation. This diagnosis is confirmed by demonstrating increased urinary excretion of epinephrine and norepinephrine and/or their metabolites (vanillylmandelic acid).

Diet

Certain medications, especially NSAIDS (Motrin/ibupofen) and steroids can cause hypertension. Ingestion of imported licorice (Glycyrrhiza glabra) can cause secondary hypoaldosteronism, which itself is a cause of hypertension.

Age

Over time, the number of collagen fibers in artery and arteriole walls increases, making blood vessels stiffer. With the reduced elasticity comes a smaller cross-sectional area in systole, and so a raised mean arterial blood pressure.

1.9.1. Pathophysiology

Most of the secondary mechanisms associated with hypertension are generally fully understood, and are outlined at secondary hypertension. However, those associated with essential (primary) hypertension are far less understood. What is known is that cardiac output is raised early in the disease course, with total peripheral resistance (TPR) normal; over time cardiac output drops to normal levels but TPR is increased. Three theories have been proposed to explain this:

• Inability of the kidneys to excrete sodium, resulting in natriuretic factors such as Atrial Natriuretic Factor being secreted to promote salt excretion with the side-effect of raising total peripheral resistance.

• An overactive renin / angiotension system leads to vasoconstriction and retention of sodium and water. The increase in blood volume leads to hypertension.

• An overactive sympathetic nervous system, leading to increased stress responses.

It is also known that hypertension is highly heritable and polygenic (caused by more than one gene) and a few candidate genes have been postulated in the etiology of this condition.

Signs and symptoms

Hypertension is usually found incidentally - "case finding" - by healthcare professionals. It normally produces no symptoms.

Malignant hypertension (or accelerated hypertension) is distinct as a late phase in the condition, and may present with headaches, blurred vision and end-organ damage.

It is recognised that stressful situations can increase the blood pressure;

Hypertension is often confused with mental tension, stress and anxiety. While chronic anxiety is associated with poor outcomes in people with hypertension, it alone does not cause it.

Hypertensive urgencies and emergencies

Hypertension is rarely severe enough to cause symptoms. These typically only surface with a systolic blood pressure over 240 mmHg and/or a diastolic blood pressure over 120 mmHg. These pressures without signs of end-organ damage (such as renal failure) are termed "accelerated" hypertension. When end-organ damage is possible or already ongoing, but in absence of raised intracranial pressure, it is called hypertensive emergency. Hypertension under this circumstance needs to be controlled, but prolonged hospitalization is not necessarily required. When hypertension causes increased intracranial pressure, it is called malignant hypertension. Increased intracranial pressure causes papilledema, which is visible on ophthalmoscopic examination of the retina.

1.10 Complications

While elevated blood pressure alone is not an illness, it often requires treatment due to its short- and long-term effects on many organs. The risk is increased for:

• Cerebrovascular accident (CVAs or strokes)

· Myocardial infarction (heart attack)

• Hypertensive cardiomyopathy (heart failure due to chronically high blood pressure)

• Hypertensive retinopathy - damage to the retina

• Hypertensive nephropathy - chronic renal failure due to chronically high blood pressure

1.11 Pregnancy

Main article: Hypertension of pregnancy

Although few women of childbearing age have high blood pressure, up to 10% develop hypertension of pregnancy. While generally benign, it may herald three complications of pregnancy: pre-eclampsia, HELLP syndrome and eclampsia. Follow-up and control with medication is therefore often necessary.

1.12 primary vs. secondary hypertension

Once the diagnosis of hypertension has been made it is important to attempt to exclude or identify reversible (secondary) causes.

• Over 90% of adult hypertension has no clear cause and is therefore called essential/primary hypertension. Often, it is part of the metabolic "syndrome X" in patients with insulin resistance: it occurs in combination with diabetes mellitus (type 2), combined hyperlipidemia and central obesity.

• In hypertensive children most cases are secondary hypertension, and the cause should be pursued diligently.

1.13 Investigations commonly performed in newly diagnosed hypertension

Tests are undertaken to identify possible causes of secondary hypertension, and seek evidence for end-organ damage to the heart itself or the eyes (retina) and kidneys. Diabetes and raised cholesterol levels being additional risk factors for the development of cardiovascular disease are also tested for as they will also require management.

• Creatinine (renal function) - to identify both underlying renal disease as a cause of hypertension and conversely hypertension causing onset of kidney damage. Also a baseline for later monitoring the possible side-effects of certain antihypertensive drugs.

• Electrolytes (sodium, potassium)

• Glucose - to identify diabetes mellitus

• Cholesterol

Additional tests often include:

• Testing of urine samples for proteinuria - again to pick up underlying kidney disease or evidence of hypertensive renal damage.

• Electrocardiogram (EKG/ECG) - for evidence of the heart being under strain from working against a high blood pressure. Also may show resulting thickening of the heart muscle (left ventricular hypertrophy) or of the occurrence of previous silent cardiac disease (either subtle electrical conduction disruption or even a myocardial infarction).

• Chest X-ray - again for signs of cardiac enlargement or evidence of cardiac failure.

1.14 Treatment

1.14.1 Lifestyle modification

Doctors recommend weight loss and regular exercise as the first steps in treating mild to moderate hypertension. These steps are highly effective in reducing blood pressure, although most patients with moderate or severe hypertension end up requiring indefinite drug therapy to bring their blood pressure down to a safe level. Discontinuing smoking does not directly reduce blood pressure, but is very important for people with hypertension because it reduces the risk of many dangerous outcomes of hypertension, such as stroke and heart attack. An increase in daily calcium intake has also been shown to be highly effective in reducing blood pressure.

Mild hypertension is usually treated by diet, exercise and improved physical fitness. A diet rich in fruits and vegetables and low fat or fat-free dairy foods and moderate or low in sodium lowers blood pressure in people with hypertension. This diet is known as the DASH diet (Dietary Approaches to Stop Hypertension). Dietary sodium (salt) may worsen hypertension in some people and reducing salt intake decreases blood pressure in a third of people. Many people choose to use a salt substitute to reduce their salt intake. Regular mild exercise improves blood flow, and helps to lower blood pressure. In addition, fruits, vegetables, and nuts have the added benefit of increasing dietary potassium, which offsets the effect of sodium and acts on the kidney to decrease blood pressure.

Reduction of environmental stressors such as high sound levels and over-illumination can be an additional method of ameliorating hypertension. Biofeedback is also used particularly device guided paced breathing

1.14.2 Medications.

Antihypertensive

There are many classes of medications for treating hypertension, together called antihypertensives, which — by varying means — act by lowering blood pressure. Evidence suggests that reduction of the blood pressure by 5-6 mmHg can decrease the risk of stroke by 40%, of coronary heart disease by 15-20%, and reduces the likelihood of dementia, heart failure, and mortality from vascular disease.

The aim of treatment should be blood pressure control to <140/90 mmHg for most patients, and lower in certain contexts such as diabetes or kidney disease (some medical professionals recommend keeping levels below 120/80 mmHg). Each added drug may reduce the systolic blood pressure by 5-10 mmHg, so often multiple drugs are necessary to achieve blood pressure control.

Commonly used drugs include:

• ACE inhibitors such as captopril, enalapril, fosinopril lisinopril (quinapril, ramipril Angiotensin II receptor antagonists: eg, irbesartan losartan valsartan,candesartan (

• Alpha blockers such as doxazosin, prazosin, or terazosin

• Beta blockers such as atenolol, labetalol, metoprolol propranolol.

• Calcium channel blockers such as amlodipine ,diltiazem, verapamil

• Diuretics: eg, bendroflumethiazide, chlortalidone, hydrochlorothiazide (also called HCTZ)

• Combination products (which usually contain HCTZ and one other drug)

Which type of many medications should be used initially for hypertension has been the subject of several large studies and various national guidlelines.

The study showed a slightly better outcome and cost-effectiveness for the thiazide diuretic chlortalidone compared to anti-hypertensives.Whilst a subsequent smaller study (ANBP2) did not show this small difference in outcome and actually showed a slightly better outcome for ACE-inhibitors in older male patients.Whilst thiazides are cheap, effective, and recommended as the best first-line drug for hypertension by many experts, they are not prescribed as often as some newer drugs. Arguably, this is because they are off-patent and thus rarely promoted by the drug industry.Although physicians may start with non-thiazide antihypertensive medications if there is a compelling reason to do so. An example is the use of ACE-inhibitors in diabetic patients who have evidence of kidney disease, as they have been shown to both reduce blood pressure and slow the progression of diabetic nephropathy.In patients with coronary artery disease or a history of a heart attack, beta blockers and ACE-inhibitors both lower blood pressure and protect heart muscle over a lifetime, leading to reduced mortality.

Conclusion ------------------

The prognosis for patients with hypertension and ischaemic heart disease is critically dependent on addressing the three areas of blood pressure lowering, lessening ischaemia, and providing cardiovascular protection. Many of the commonly used agents have complementary effects in these areas. All modifiable risk factors must be aggressively managed. Some cardiologists place more emphasis on the immediate benefits of

percutaneous revascularization. This approach offers no benefit over conservative medical treatment in terms of death, myocardial infarction, or subsequent revascularization .The cornerstone of treatment is blood pressure reduction. Multiple-drug therapy is required using agents with both antihypertensive and antianginal properties. Combining a [beta]-blocker with amlodipine is preferable. For [beta]-blocker-intolerant patients, rate-limiting calcium antagonists are equally effective. ACE inhibitors are appropriate if blood pressure control remains suboptimal. Antiplatelet and statin therapy are mandatory in all patients. Compliance is a major issue and requires support to facilitate understanding of the importance of lifestyle modifications and drug therapy in reducing risk of future cardiovascular events. Recent years have seen a marked reduction in cardiovascular event rates, largely due to these measures. Despite this, basic cardiovascular risk factors remain underdiagnosed and poorly treated in many regions of the world .This is unacceptable in the 21st century when there is such unequivocal benefit in a strategy combining blood pressure control with vasculoprotective therapies.

The rationale for using fixed-dose combination therapy is to obtain increased blood pressure control by employing two antihypertensive agents with different modes of action and to enhance compliance by using a single tablet that is taken once or twice daily Using low doses of two different agents can also minimize the clinical and metabolic effects that occur with maximal dosages of the individual components of the combined tablet. These potential advantages are such that some investigators have recommended using combination antihypertensive therapy as initial treatment, particularly in patients with target-organ damage or more severe initial levels of hypertension. Combination antihypertensive drugs are listed in Table .

Combination Drugs for the Treatment of Hypertension

Diuretic combinations

Amiloride and hydrochlorothiazide (5 mg/50 mg)

Spironolactone and hydrochlorothiazide (25 mg/50 mg, 50 mg/50 mg)

Triamterene and hydrochlorothiazide (37.5 mg/25 mg, 50 mg/25 mg)

Triamterene and hydrochlorothiazide (37.5 mg/25 mg, 75 mg/50 mg)

Beta blockers and diuretics

Atenolol and chlorthalidone (50 mg/25 mg, 100 mg/25 mg)

Bisoprolol and hydrochlorothiazide (2.5 mg/6.25 mg, 5 mg/6.25 mg, 10 mg/6.5 mg)

Metoprolol and hydrochlorothiazide (50 mg/25 mg, 100 mg/25 mg, 100 mg/50 mg)

Nadolol and bendroflumethazide (40 mg/5 mg, 80 mg/5 mg)

Propranolol and hydrochlorothiazide (40 mg/25 mg, 80 mg/25 mg)

Propranolol ER and hydrochlorothiazide (80 mg/50 mg, 120 mg/50 mg, 160 mg/50 mg)

Timolol and hydrochlorothiazide (10 mg/25 mg)

Bisoprolol and hydrochlorothiazide (2.5 mg/6.25 mg, 5 mg/6.25 mg, 10 mg/6.5 mg)

ACE inhibitors and diuretics

Benazepril and hydrochlorothiazide (5 mg/6.25 mg, 10 mg/12.5 mg, 20 mg/12.5 mg, 20 mg/25 mg)

Captopril and hydrochlorothiazide (25 mg/15 mg, 25 mg/25 mg, 50 mg/15 mg, 50 mg/25 mg)

Enalapril and hydrochlorothiazide (5 mg/12.5 mg, 10 mg/25 mg)

Lisinopril and hydrochlorothiazide (10 mg/12.5 mg, 20 mg/12.5 mg, 20 mg/25 mg)

Moexipril and hydrochlorothiazide (7.5 mg/12.5 mg, 15 mg/25 mg)

Benazepril and hydrochlorothiazide (5 mg/6.25 mg, 10 mg/12.5 mg, 20 mg/12.5 mg, 20 mg/25 mg)

ACE inhibitors and diuretics

Benazepril and hydrochlorothiazide (5 mg/6.25 mg, 10 mg/12.5 mg, 20 mg/12.5 mg, 20 mg/25 mg)

Captopril and hydrochlorothiazide (25 mg/15 mg, 25 mg/25 mg, 50 mg/15 mg, 50 mg/25 mg)

Enalapril and hydrochlorothiazide (5 mg/12.5 mg, 10 mg/25 mg)

Lisinopril and hydrochlorothiazide (10 mg/12.5 mg, 20 mg/12.5 mg, 20 mg/25 mg)

Moexipril and hydrochlorothiazide (7.5 mg/12.5 mg, 15 mg/25 mg)

Angiotensin-II receptor antagonists and diuretics

Losartan and hydrochlorothiazide (50 mg/12.5 mg, 100 mg/25 mg)

Valsartan and hydrochlorothiazide (80 mg/12.5 mg, 160 mg/12.5 mg)

ACE inhibitors and diuretics

Benazepril and hydrochlorothiazide (5 mg/6.25 mg, 10 mg/12.5 mg, 20 mg/12.5 mg, 20 mg/25 mg)

Captopril and hydrochlorothiazide (25 mg/15 mg, 25 mg/25 mg, 50 mg/15 mg, 50 mg/25 mg)

Enalapril and hydrochlorothiazide (5 mg/12.5 mg, 10 mg/25 mg)

Lisinopril and hydrochlorothiazide (10 mg/12.5 mg, 20 mg/12.5 mg, 20 mg/25 mg)

Moexipril and hydrochlorothiazide (7.5 mg/12.5 mg, 15 mg/25 mg)

Angiotensin-II receptor antagonists and diuretics

Losartan and hydrochlorothiazide (50 mg/12.5 mg, 100 mg/25 mg)

Valsartan and hydrochlorothiazide (80 mg/12.5 mg, 160 mg/12.5 mg)

Calcium channel blockers and ACE inhibitors

Amlodipine and benazepril (2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg)

Diltiazem and enalapril (180 mg/5 mg)

Felodipine and enalapril (5 mg/5 mg)

Verapamil and trandolapril (180 mg/2 mg, 240 mg/1 mg, 240 mg/2 mg, 240 mg/4 mg)

Miscellaneous combinations

Clonidine and chlorthalidone (0.1 mg/15 mg, 0.2 mg/15 mg, 0.3 mg/15 mg)

Hydralazine and hydrochlorothiazide (25 mg/25 mg, 50 mg/50 mg, 100 mg/50 mg)

Methyldopa and hydrochlorothiazide (250 mg/15 mg, 250 mg/25 mg, 500 mg/30 mg, 500 mg/50 mg)

Prazosin and polythiazide (1 mg/0.5 mg, 2 mg/0.5 mg, 5 mg/0.5 mg)

ACE = angiotensin-converting enzyme

Diuretics in Combination Antihypertensive Therapy

Diuretics are effective antihypertensive drugs. Treatment with a diuretic such as hydrochlorothiazide results in a dose-dependent blood pressure reduction that levels off with higher dosages. In long-term trials, diuretics have been shown to reduce the incidence of stroke, congestive heart failure, coronary artery disease and total mortality from cardiovascular disease.

Unfortunately, the degree of improvement in cardiovascular mortality is less than would have been expected based on epidemiologic data. One postulated but not yet proven explanation is that the higher diuretic dosages used in the large trials cause relative hypokalemia, as well as increased serum lipid levels, insulin resistance and uric acid levels. These adverse metabolic effects counteract the positive cardiovascular benefits of blood pressure reduction. Such effects do not occur when diuretics are administered in a low dosage, such as 6.25 or 12.5 mg per day of hydrochlorothiazide.

Because diuretics blunt the sodium- and water-retaining effects of many other antihypertensive drugs, they are the most commonly used medication in combination antihypertensive agents. The JNC VI states clearly, "If a diuretic is not chosen as the first drug, it is usually indicated as a second-step agent because its addition will enhance the effects of other agents."

Potassium-Sparingand Thiazide Diuretics

The discrepancy between the JNC VI recommendations for first-line use of thiazide diuretics and the actual use of these agents in clinical practice may be attributable to physicians' concerns about the development of hypokalemia and hypomagnesemia, as well as the marketing of newer agents by pharmaceutical companies. Combination therapy with a potassium-sparing diuretic and a thiazide diuretic attempts to reduce the risk of adverse metabolic effects. Combination therapy does not obviate the need for serial monitoring of serum electrolyte levels, but it does decrease the incidence of thiazide-induced hypokalemia without an increased risk of hyperkalemia.

Fixed-dose potassium-sparingthiazide diuretic combinations have been in use for more than 20 years. Current combinations include spironolactone-hydrochlorothiazide (Aldactazide), triamterene-hydrochlorothiazide (Dyazide, Maxzide) and amiloride-hydrochlorothiazide (Moduretic). These combination drugs do not appear to differ significantly in efficacy or adverse effects.¹³ The described improvement in the bioavailability of Maxzide over Dyazide has not been shown to yield improved blood pressure control.

All potassium-sparingthiazide diuretic combinations seem to reduce blood pressure to the same degree as thiazide diuretics alone. In one large postmarketing surveillance study of patients treated with triamterene-hydrochlorothiazide, the incidence of hypokalemia was approximately one half to one third that expected in hydrochlorothiazide monotherapy. In addition, the amiloride-hydrochlorothiazide combination caused significantly less alteration of serum potassium levels than did hydrochlorothiazide given alone in dosages of 25 to 100 mg per day. The clinical applicability of the findings may be questionable because the studies used hydrochlorothiazide dosages that were significantly higher than those currently recommended.

The low dosages of hydrochlorothiazide (12.5 to 25 mg per day) advocated in the JNC VI provide significant blood pressure reduction while minimizing electrolyte abnormalities. It remains unclear whether the addition of a potassium-sparing agent confers additional benefit compared with a low dosage of hydrochlorothiazide alone.

Diuretics interaction

Thiazide diuretics are a family of drugs that remove water from the body. They are referred to as potassium-depleting because they cause the body to lose potassium as well as water. Potassium-depleting diuretics also cause the body to lose magnesium. Thiazide diuretics are used to lower blood pressure in people with high blood pressure. Diuretics are also used to reduce water accumulation caused by other diseases.

Thiazide diuretics are also combined with other drugs to treat various conditions.

The information in this article pertains to thiazide diuretics in general. The interactions reported here may not apply to all the Also Indexed As terms. Talk to your doctor or pharmacist if you are taking any of these drugs.

Thiazide Diuretics Interactions with Dietary Supplements

Calcium

Thiazide diuretics decrease calcium loss in the urine due to actions on the kidneys. As a result, it may be less important for some people taking thiazide diuretics to supplement calcium than it is for other people.

Folic acid

One study showed that people taking diuretics for more than six months had dramatically lower blood levels of folic acid and higher levels of homocysteine compared with individuals not taking diuretics. Homocysteine, a toxic amino acid byproduct, has been associated with atherosclerosis. Until further information is available, people taking diuretics for longer than six months should probably supplement with folic acid.

Magnesium and Potassium

Potassium-depleting diuretics, including thiazide diuretics, cause the body to lose potassium; they may also cause cellular magnesium depletion, although this deficiency may not be reflected by a low blood level of magnesium. Magnesium loss induced by potassium-depleting diuretics can cause additional potassium loss. Until more is known, it has been suggested that people taking potassium-depleting diuretics, including thiazide diuretics, should supplement both potassium and magnesium.

Magnesium supplementation for people taking thiazide diuretics is typically 300–600 mg per day, though higher amounts (over 800 mg per day) have been reported in a controlled study to reduce side effects of thiazides. Combining supplementation of both potassium and magnesium has been reported to correct abnormally low blood levels of potassium and also to protect against excessive loss of magnesium.

Vitamin D

The reduction in urinary calcium loss resulting from treatment with thiazide diuretics is due primarily to changes in kidney function and may also be due, in part, to changes in vitamin D metabolism. However, there is no evidence to suggest that people taking diuretics have different requirements for vitamin D.

Sodium

Diuretics, including thiazide diuretics, cause increased loss of sodium in the urine. By removing sodium from the body, diuretics also cause water to leave the body. This reduction of body water is the purpose of taking diuretics. Therefore, there is usually no reason to replace lost sodium, although strict limitation of salt intake in combination with the actions of diuretics can sometimes cause excessive sodium depletion. On the other hand, people who restrict sodium intake, and in the process reduce blood pressure, may need to have their dose of diuretics lowered.

Interaction of angiotensin antagonists

Interaction between the nonpeptide angiotensin antagonist SKF-108,566 and histidine 256 (HisVI:16) of the angiotensin type 1 receptor

His256 (HisVI:16) of transmembrane segment (TM)-VI of the rat angiotensintype 1 (AT1) receptor was targeted for mutagenesis to investigate itspotential involvement in ligand binding. Substitution of His256 withalanine, phenylalanine, glutamine, or isoleucine did not affect the bindingof either angiotensin II or nine different biphenylimidazole AT1antagonists. In contrast, the binding affinity of the prototypeimidazoleacrylic acid antagonist SKF-108,566 was reduced 15-fold by theexchange of His256 with alanine. Substitution of His256 with eitherisoleucine or phenylalanine yielded similar results, whereas a glutamineresidue was able to substitute for His256, suggesting that theepsilon-nitrogen of His256 could be involved in the interaction with theimidazoleacrylic acid. To identify the chemical groups on SKF-108,566 thatinteract with His256 and with Asn295, a previously identified interactionpoint for nonpeptide antagonists located in TM-VII, we tested the bindingof 15 analogs of SKF-108,566 in which different chemical moieties weresystematically exchanged. The results indicated that the carboxyphenylgroup of SKF-108,566 interacts with the imidazole side chain of His256. Thedata did not point to any particular contact group on the antagonist forAsn295. It is concluded that the imidazoleacrylic acid antagonists sharesome interactions in TM-VII of the AT1 receptor with the biphenylimidazoleantagonists, but the binding of the imidazoleacrylic acid compounds isuniquely dependent on His256 in TM-VI, possibly through the carboxyphenylmoiety.

[beta]-Blockers

These drugs are not used alone in case of Hypertension but can use in the combination with diuretics.

[beta]-Blockers decrease myocardial oxygen demand through reductions in heart rate, blood pressure, and myocardial contractility. The American College of Cardiology/American Heart Association guidelines endorse [beta]-blockers as first-line therapy for chronic stable angina, advocating calcium channel blockers only when [beta]-blockers are contraindicated, poorly tolerated, or unsuccessful (all class I recommendations) .The guidance extrapolates from three bodies of evidence: early, small, short-term studies in stable angina; robust postinfarct reductions in hard endpoints; and purported benefits in hypertension .The former greatly underrepresents the newer long-acting calcium channel blockers, as exemplified by amlodipine. The latter is highly questionable .Even the postinfarct evidence may lack relevance in the modern era. What of the low-risk patient with a minimal troponin rise, preserved systolic function, and stable occasional exertional angina? No antianginal agents, including [beta]-blockers, reduce cardiovascular death or myocardial infarction in patients with stable angina. All decrease frequency of angina and prolong exercise duration before onset of symptoms or ST segment depression .None has proven superiority.

Meta-analysis of 90 randomized controlled trials comparing antianginal agents revealed similar reductions in cardiac events, anginal symptoms, and time to ischaemia. Only a handful of studies, however, used newer drugs such as amlodipine (n = 1), bisoprolol (n = 2), or carvedilol (n = 2), limiting applicability to modern practice. The International Verapamil-Trandolapril Study (INVEST) ,the only trial to recruit patients with both hypertension and CAD, confirmed the equivalence of verapamil–trandolapril and atenolol–hydrochlorothiazide based strategies in preventing death, myocardial infarction, or stroke (adjusted hazards ratio 0.98 [0.91–1.07], P = 0.69). Though the study sought to compare multidrug regimens, open blinding and use of ACE inhibitors and diuretics in both arms served to attenuate differences between the two strategies. In the respective groups, 81.5% of patients received verapamil vs. 77.5% atenolol, 82.0 vs. 71.6% received an ACE inhibitor, and 63.0 vs. 81.4% a diuretic at 24 months. Conclusions regarding the contribution of any single agent are not possible. Both groups achieved similar blood pressure reduction (18.7/10.0 vs. 19.0/10.2 mmHg) and number of patients reaching Joint National Committee on Hypertension VI blood pressure targets (71.7 vs. 70.7%, P = 0.18). This corresponded with marked decreases in the prevalence of angina in both verapamil-based and atenolol-based groups, from 66.2 and 67.0% to 27.3 and 28.3%, respectively. The message is clear. Blood pressure reduction is the key, with no evidence of [beta]-blocker superiority.

In the Anglo-Scandinavian Cardiac Outcomes Trial – Blood Pressure Lowering Arm (ASCOT-BPLA) ,the amlodipine–perindopril strategy reduced cardiovascular mortality and major cardiovascular events, particularly stroke, compared with the atenolol–bendroflumethiazide regimen. Subsequent meta-analysis suggested that [beta]-blockers reduce risk of stroke in primary hypertension by about half that expected (only 19%), the risk being 16% higher than for other drugs. Patients with coexistent CAD are unlikely to differ. Despite this, [beta]-blockers have one undeniable advantage as first-line agents over rate-limiting calcium antagonists in these patients. They may be combined with newer non-rate-limiting calcium antagonists, notably amlodipine, to provide dual antianginal and antihypertensive therapy.

In a meta-analysis of 31 randomized trials involving nearly 25 000 patients, long-term [beta]-blockade following myocardial infarction significantly reduced mortality and reinfarction by about 25%, with no such benefits observed in short-term trials. The recent Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) in more than 45 000 patients, 43% with known hypertension, reinforces this evidence and guides the timing of initiation. Immediate intravenous then oral metoprolol until discharge failed to reduce overall risk of death, reinfarction, or cardiac arrest following acute myocardial infarction. Early increased risk of cardiogenic shock (days 0–1) counterbalanced reduced risk of reinfarction and ventricular fibrillation (significant from day 2 onwards). Consequently the effect of metoprolol on the combined efficacy and safety outcome of death, reinfarction, arrest, or shock was adverse initially and beneficial thereafter (P = 0.0003 for trend in odds ratio). Systolic blood pressure lower than 120 mmHg, and to a lesser extent 160 mmHg or higher, increased the risk of cardiogenic shock with metoprolol. Conservative blood pressure reduction that avoids coronary hypoperfusion is critical in the acute situation. [beta]-Blockers should be commenced only once a patient's haemodynamic condition has stabilized, even in those with hypertension or tachycardia.

Beta Blockers and Diuretics

Beta blockers cause retention of sodium and water. Diuretics can cause mild volume reduction that leads to an increase in renin secretion by the kidney. The rationale for combining beta blockers with diuretics is twofold: beta blockers blunt the increase in the plasma renin level that is induced by diuretics, and diuretics decrease the sodium and water retention that is caused by beta blockers. The combination of a beta blocker and a diuretic produces additive effects compared with monotherapy using either agent alone. A recent study assessed the safety and efficacy of antihypertensive therapy using the cardioselective beta blocker bisoprolol alone and in combination with low dosages of hydrochlorothiazide. The dosages of bisoprolol were 2.5, 5 and 10 mg per day. The hydrochlorothiazide dosages were 6.25 and 25 mg per day. The study showed that monotherapy with either agent was more effective than placebo, but that when combination therapy was used, the beneficial effects were greater than when either agent was used alone .In the same study, combination therapy was associated with a low incidence of adverse effects. Side effects for combined hydrochlorothiazide in a dosage of 6.5 mg per day and bisoprolol in all dosages included fatigue (9 percent of recipients), dizziness (6 percent), somnolence (3 percent), impotence (2 percent) and diarrhea (4 percent). When used in combination with bisoprolol, hydrochlorothiazide (6.25 mg) did not cause hypokalemia or any adverse effects on the lipid profile. Side effects increased with the use of higher dosages of bisoprolol or hydrochlorothiazide. The incidence of hypokalemia and hyperuricemia was greater for 25 mg per day of hydrochlorothiazide than for 6.25 mg per day. With higher bisoprolol dosages, the frequency and severity of asthenia, diarrhea, dyspepsia and somnolence increased significantly.

Angiotensin-converting enzyme inhibitors

In animal models, angiotensin-converting enzyme (ACE) inhibitors modulate atherosclerotic pathways by inhibition of angiotensin II formation, bradykinin potentiation, and increased nitric oxide production .Whether this translates into clinical benefits, providing vasculoprotective effects beyond blood pressure reduction, is unclear .Even the renoprotective effects are now under debate .The Heart Outcomes Prevention Evaluation (HOPE), study demonstrated that ramipril reduced morbidity and mortality in high-risk patients with cardiovascular disease or diabetes plus one additional risk factor. Risk reduction was about three times greater than predicted for the modest reduction in blood pressure (3.3/1.4 mmHg) ,the difference being attributed to antiatherogenic effects. The HOPE protocol uniquely administered study medication at bedtime, however. Blood pressure measurement approximately 10–18 hours later therefore missed the peak effect after 3–6 hours. A substudy revealed far greater 24-hour ambulatory blood pressure reduction (10/4 mmHg), particularly marked overnight (17/8 mmHg).

The European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) studied the effect of perindopril in a low-risk population with predominantly asymptomatic stable CAD. Risk of the composite primary outcome was significantly reduced, largely powered by a reduction in myocardial infarction. No significant difference was observed in cardiovascular or total mortality, however. The results suggested that 50 patients need to be treated for 4 years to prevent one major cardiovascular event.

In contrast to HOPE and EUROPA, addition of an ACE inhibitor to modern conventional therapy provided no further benefit in the recent Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial ,despite reducing blood pressure by 3.0/he 1.2 mmHg relative to placebo. There are several reasons for these surprising results..

cardiovascular event rate was substantially lower than in previous trials due to exclusion of significant left ventricular systolic dysfunction, prior coronary revascularization, and more intensive medical therapy. Though nearly half of patients had a history of hypertension, mean baseline systolic blood pressure was 133 mmHg, the level achieved using an ACE inhibitor in both HOPE and EUROPA. The higher prevalence of lipid-lowering therapy compared with previous trials, and consequently lower serum cholesterol levels, may also lessen the potential antiatherogenic benefits of ACE inhibition .Finally, significantly fewer patients were receiving maximum-dose ACE inhibitor after 3 years (57.8%) [12•] than in HOPE and EUROPA (70.9 and 74%, respectively). The routine use of ACE inhibitors in patients with hypertension and CAD is therefore no longer advocated, provided blood pressure, cardiovascular risk factors, and symptoms are controlled.

Ace Inhibitors and Diuretics

Angiotensin-converting enzyme (ACE) inhibitors are among the best tolerated antihypertensive drugs and have been used extensively as initial agents in the treatment of hypertension. The JNC VI¹ recommends ACE inhibitors as second-line agents in most patients with hypertension and as first-line choices only in selected patients, including those with left ventricular systolic dysfunction and those with diabetes and microalbuminuria or proteinuria.

The renin-angiotensin-aldosterone axis is important in the maintenance of systemic blood pressure. By causing volume and sodium depletion, thiazide diuretics stimulate the production of renin and angiotensin. This leads to a relative increase in blood pressure and sodium retention, which counteracts some of the other antihypertensive effects of the thiazide diuretics. ACE inhibitors interfere with the conversion of angiotensin I to angiotensin II and thereby decrease angiotensin II levels. These effects lead to decreased sodium retention and an enhanced antihypertensive effect.

Synergism between ACE inhibitors and diuretics is especially prominent in black patients, a population in whom monotherapy with ACE inhibitors has been shown to be less effective than it is in white patients. One small study of black patients with hypertension (N = 38) compared monotherapy using 20 mg per day of enalapril with combination therapy consisting of 20 mg of enalapril plus 12.5 mg of hydrochlorothiazide per day. Combination therapy significantly reduced systolic, diastolic and 24-hour ambulatory blood pressure measurements compared with monotherapy. Combination therapy controlled blood pressure to a level of less than 140/90 mm Hg in 74 percent of patients.

Studies have shown that ACE inhibitor diuretic combinations achieve blood pressure control in approximately 80 percent of patients. Typical results were obtained in one of the larger double-blind, placebo-controlled trials.

In this study, 505 patients with diastolic blood pressures of 100 to 114 mm Hg received placebo, lisinopril (10 mg per day), hydrochlorothiazide (12.5 or 25 mg per day) or the combination of lisinopril (10 mg per day) and hydrochlorothiazide (12.5 or 25 mg per day). All drug therapies were more effective than placebo in lowering blood pressure, but the combination antihypertensive therapies produced the greatest effect .

No significant differences in blood pressure reduction were observed for the two dosages of hydrochlorothiazide, whether the drug was used alone or in a combination. Adverse metabolic effects were observed only for regimens containing hydrochlorothiazide in a dosage of 25 mg per day. Serum potassium levels were significantly lower only for monotherapy with 25 mg per day of hydrochlorothiazide. Serum glucose measurements increased with the 25-mg dosage used as monotherapy or in combination with lisinopril.

The study found that the combination consisting of 10 mg per day of lisinopril and 12.5 mg per day of hydrochlorothiazide was well tolerated. The most commonly observed side effects were pharyngitis (14 percent of recipients), increased cough (6 percent), dizziness (2 percent), headache (12 percent) and asthenia (4 percent). Cough was the only side effect that was more prevalent in this group than in the placebo group.

Based on this large study, antihypertensive drug combinations containing an ACE inhibitor and a lower dose of hydrochlorothiazide are more desirable. It is important to be aware that the doses of ACE inhibitor in the antihypertensive drug combinations do not reach the target doses of ACE inhibitors recommended for the treatment of congestive heart failure, which may be a limitation in these patients.

Angiotensin-II Antagonists and Diuretics

In patients for whom ACE inhibitor diuretic combinations are indicated but not tolerated because of cough, angiotensin-II receptor antagonistdiuretic combinations are available. Angiotensin-II receptor antagonists work by blocking specific angiotensin II subtype I, thereby selectively inhibiting the vasoactive properties of angiotensin II.

Calcium channel blockers

Two recent studies support the use of dihydropyridine (non-rate-limiting) calcium channel blockers in CAD. ACTION (A Coronary Disease Trial Investigating Outcome with Nifedipine GITS [gastrointestinal therapeutic system]) studied the effects of nifedipine in 7665 patients with treated stable angina pectoris, finding no reduction in the primary composite endpoint. In the prespecified hypertensive subgroup (52%) with blood pressure above 140/90 mmHg, however, nifedipine improved major cardiovascular event-free survival by 13% (P < 0.05), principally due to reductions in coronary angiography, stroke, and new overt heart failure .The concurrent blood pressure reduction (6.6/3.5 mmHg) highlights the importance of improving control in patients with established CAD.

The Comparison of Amlodipine Versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) compared the effects of amlodipine, enalapril, and placebo in 1991 patients with angiographic CAD. Although 60.5% of patients had documented hypertension, mean baseline blood pressure was normal (129/78 mmHg) due to exclusion of patients with diastolic pressure above 100 mmHg. Amlodipine significantly reduced the primary composite endpoint of major cardiovascular events relative to placebo (0.69 [0.54–0.88], P = 0.003), largely due to fewer hospitalizations for angina and coronary revascularization procedures. Despite almost identical blood pressure reductions, enalapril failed to significantly reduce the primary or secondary outcomes. An intravascular ultrasound substudy demonstrated a trend toward less progression of atherosclerosis in the amlodipine group, which was significant in those with systolic blood pressures above the mean (P = 0.02). The CAMELOT study provides two important insights. Firstly, ACE inhibition offered no specific vasculoprotective effects beyond an active comparator. Secondly, though the two cannot be directly linked, fewer cardiovascular events occurred alongside lowering of blood pressure already considered within normal limits. In the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial ,nearly half of patients had verified coronary disease. Compared with valsartan, amlodipine reduced blood pressure more effectively and significantly reduced risk of myocardial infarction and frequency of angina. Together these studies form a compelling argument for including amlodipine in treating patients with both hypertension and CAD.

Calcium Channel Blockers and ACE Inhibitors

The combination of a calcium channel blocker and an ACE inhibitor is appealing on theoretic grounds. Although calcium antagonists exert much of their antihypertensive effect through a vasodilatory action, they also have diuretic and natriuretic properties. ACE inhibitors blunt the stimulation of the renin-angiotensin-aldosterone axis that may result from this diuretic effect. These agents also inhibit the central sympathetic stimulation that may result from calcium antagonistassociated vasodilatation, although both classes of drugs are potent vasodilators. ACE inhibitors and calcium channel blockers work effectively in combination to lower blood pressure. In one representative study, diastolic blood pressures were reduced by 3.6 mm Hg more with a trandolapril-verapamil combination than with monotherapy using either agent. No increase in side effects was observed for treatment with combined trandolapril and verapamil.

Calcium antagonists and ACE inhibitors may also work together to favorably influence target-organ disease independent of their effect on blood pressure. Together they appear to have a renal-protective effect, to promote reduction of left ventricular mass and to decrease mediators of vascular disease. The relatively low dose of ACE inhibitor in some combinations may not confer the same degree of renal or cardiac protection that has been demonstrated for higher doses.

Calcium channel blockerACE inhibitor combinations may result in fewer or milder side effects than occur with either agent alone. The addition of an ACE inhibitor to therapy with a dihydropyridine calcium antagonist significantly reduces the incidence of peripheral edema and reflex tachycardia. Neither class of medications has prominent metabolic side effects, an advantage in patients with diabetes and renal disease.

Four fixed-dose combinations of calcium channel blockers and ACE inhibitors are currently available in the United States. These combinations have yet to be proved more efficacious than antihypertensive combinations containing diuretics.

Miscellaneous Combination Agents

Other combination antihypertensive agents that have existed for many years include diuretics with a direct-acting vasodilator (hydralazine-hydrochlorothiazide [Apresazide]), a central alpha-adrenergic agonist (methyldopa-hydrochlorothiazide [Aldoril] and clonidine-chlorthalidone [Combipres]) or a peripheral alpha-adrenergic blocker (prazosin-polythiazide [Minizide]). No trials have indicated survival benefit with their use.

The JNC VI specifically mentioned that the three nondiuretic classes represented in these combinations "are not well suited for initial monotherapy because they produce annoying adverse effects in many patients.No studies have provided conclusive evidence of increased tolerance when these agents are taken orally in combination with a diuretic. Therefore, these combinations are not indicated for first-line therapy.

Final Comment

The JNC VI¹ continues to recommend monotherapy with a diuretic or beta blocker as initial treatment for the undifferentiated patient with hypertension. At the same time, it is recognized that monotherapy will not provide adequate blood pressure control in a large proportion of patients, and that many patients will experience unacceptable side effects with higher dosages of a single agent. Fixed-dose combination antihypertensive medications are a useful and appropriate treatment option in this large group of patients.

Central sympatholytics

OBJECTIVE: To provide a comprehensive review of the pharmacokinetic and

pharmacodynamic interactions between antipsychotics and antihypertensive and to provide recommendations for the selection of antihypertensive in patients receiving antipsychotic therapy. DATA SOURCES: A MEDLINE search of the English-language literature was used to identify pertinent human and animal studies, reviews, and case reports. STUDY SELECTION: All available sources were reviewed. DATA EXTRACTION: Background information was obtained from comprehensive reviews. Individual case reports were assimilated, and pertinent data were extracted. DATA SYNTHESIS: Because hypertension is common in patients with psychiatric illness and antihypertensive agents are used for a multiplicity of indications, significant numbers of patients receive concurrent therapy with antihypertensives and antipsychotics. Many antipsychotics may block the antihypertensive efficacy of guanethidine and related drugs. The interaction between clonidine and antipsychotics is defined less clearly. Limited data suggest possible additive hypotensive effects when chlorpromazine and methyldopa are given in combination. Increased plasma concentrations of thioridazine with a resultant increase in adverse effects have been reported when propranolol or pindolol are added to the regimen. A similar increase in chlorpromazine concentrations has been reported when propranolol was added. Although there are no reports documenting an interaction between a calcium-channel antagonist and an antipsychotic, the possible inhibition of oxidative metabolism of antipsychotics, additive calcium-blocking activity, and additive pharmacodynamic effects are theorized. Hypotension and postural syncope were reported in a patient given therapeutic dosages of chlorpromazine and captopril, and in 2 patients when clozapine was added to enalapril therapy. CONCLUSIONS: No antipsychotic-antihypertensive combination is absolutely contraindicated, but no combination should be considered to be completely without risk. Antihypertensives with no centrally acting activity, such as diuretics, may be the least likely to result in adverse reactions. The combination of the beta-antagonists propranolol or pindolol with thioridazine or

chlorpromazine should be avoided if possible. Scrupulous patient monitoring for attenuated or enhanced activity of either agent is essential whenever antipsychotics and antihypertensives are given concurrently

ACE inhibitor

Captopril, the first ACE inhibitor

ACE inhibitors, or inhibitors of Angiotensin-Converting Enzyme, are a group of pharmaceuticals that are used primarily in treatment of hypertension and congestive heart failure, in most cases as the drugs of first choice.

Clinical use

Indications for ACE inhibitors include:

Prevention of cardiovascular disorders
Congestive heart failure
Hypertension
Left ventricular dysfunction
Prevention of nephropathy in diabetes mellitus

In several of these indications, ACE inhibitors are used first-line as several agents in the class have been clinically shown to be superior to other classes of drugs in the reduction of morbidity and mortality.

ACE inhibitors are often combined with diuretics in the control of hypertension (usually a thiazide), when an ACE inhibitor alone proves insufficient; and in chronic heart failure (usually furosemide) for improved symptomatic control. Thus there exists, on the market, combination products combining an ACE inhibitor with a thiazide (usually hydrochlorothiazide) in a single tablet to allow easy administration by patients.

The Renin-Angiotensin-Aldosterone System

This system is activated in response to hypotension, decreased sodium delivery, decreased blood volume and sympathetic stimulation. In such a situation, the kidneys release renin which cleaves the liver derived angiotensinogen into Angiotensin I. Angiotensin I is then converted to angiotensin II via the angiotensin-converting-enzyme (ACE) in the pulmonary circulation. The system in general aims to increase blood pressure.

Effects of ACE inhibitors

ACE inhibitors lower arteriolar resistance and increase venous capacitance; increase cardiac output and cardiac index, stroke work and volume, lower renovascular resistance, and lead to increased natriuresis (excretion of sodium in the urine).

Normally,angiotensin II will have the following effects:

-Vasoconstriction (narrowing of blood vessels).

-cardiac hypertrophy.

- stimulate the adrenal cortex to release aldosterone, a hormone which acts on kidney tubules to retain sodium and chloride ions and excrete potassium. Sodium is a "water-holding" molecule, so water is also retained. This leads to increased blood volume, hence an increase in blood pressure.

- stimulate the posterior pituitary into releasing vasopressin (also known as anti-diuretic hormone (ADH)) which also acts on the kidneys to increase water retention.

With ACE inhibitor use, the effects of angiotensin II are prevented, leading to decreased blood pressure.

Epidemiological and clinical studies have shown that ACE inhibitors reduce the progress of diabetic nephropathy independently from their blood pressure-lowering effect. This action of ACE inhibitors is utilised in the prevention of diabetic renal failure.

ACE inhibitors have been shown to be effective for indications other than hypertension even in patients with normal blood pressure. The use of a maximum dose of ACE inhibitors in such patients (including for prevention of diabetic nephropathy, congestive heart failure, prophylaxis of cardiovascular events) is justified because it improves clinical outcomes, independent of the blood pressure lowering effect of ACE inhibitors. Such therapy, of course, requires careful and gradual titration of the dose to prevent the patient suffering from the effects of rapidly decreasing their blood pressure (dizziness, fainting, etc).

Adverse effects

Common adverse drug reactions (≥1% of patients) include: hypotension, cough, hyperkalemia, headache, dizziness, fatigue, nausea, renal impairment. A persistent dry cough is a relatively common adverse effect believed to be associated with the increases in bradykinin levels produced by ACE inhibitors, although the role of bradykinin in producing these symptoms remains disputed by some authors. Patients who experience this cough are often switched to angiotensin II receptor antagonists.

Rash and taste disturbances, infrequent with most ACE inhibitors, are more prevalent in captopril and is attributed to its sulfhydryl moiety. This has led to decreased use of captopril in clinical setting, although it is still used in scintigraphy of the kidney.

Renal impairment is a significant adverse effect of all ACE inhibitors, and is associated with their effect on angiotensin II-mediated homeostatic functions such as renal bloodflow. ACE inhibitors can induce or exacerbate renal impairment in patients with renal artery stenosis. This is especially a problem if the patient is also concomitantly taking an NSAID and a diuretic - the so-called "triple whammy" effect - such patients are at very high risk of developing renal failureSome patients develop angioedema due to increased bradykinin levels. There appears to be a genetic predisposition towards this adverse effect in patients who degrade bradykinin slower than average.

Examples of ACE inhibitors

ACE inhibitors can be divided into three groups based on their molecular structure.

Sulfhydryl-containing ACE inhibitors

Captopril

Dicarboxylate-containing ACE inhibitors

This is the largest group, including:

Enalapril Ramipril Quinapril Perindopril Lisinopril Benazepril Phosphonate-containing ACE inhibitors

Fosinopril the only member

Naturally occurring

Casokinins and lactokinins are breakdown products of casein and whey that occur naturally after ingestion of milk products, especially sour milk. Their role in blood pressure control is uncertain.

Comparative information

Comparatively, all ACE inhibitors have similar antihypertensive efficacy when equivalent doses are administered. The main point-of-difference lies with captopril, the first ACE inhibitor, which has a shorter duration of action and increased incidence of certain adverse effects (cf. captopril).

Certain agents in the ACE inhibitor class have been proven, in large clinical studies, to reduce mortality post-myocardial infarction, prevent development of heart failure, etc. While these effects are likely to be class-effects, good evidence-based medicine practice would direct the use of those agents with established clinical efficacy.

Contraindications and precautions

The ACE inhibitors are contraindicated in patients with:

Previous angioedema associated with ACE inhibitor therapy
Renal artery stenosis (bilateral, or unilateral with a solitary functioning kidney)

ACE inhibitors should be used with caution in patients with:

Impaired renal function
Aortic valve stenosis or cardiac outflow obstruction
Hypovolaemia or dehydration
Haemodialysis with high flux polyacrylonitrile membranes

ACE inhibitors are ADEC Pregnancy category D, and should be avoided in women who are likely to become pregnant. In the U.S., ACE inhibitors are required to be labelled with a "black box" warning concerning the risk of birth defects when taking during the second and third trimester. It has also been found that use of ACE inhibitors in the first trimester is also associated with a risk of major congenital malformations, particularly affecting the cardiovascular and central nervous systemsPotassium supplementation should be used with caution and under medical supervision owing to the hyperkalaemic effect of ACE inhibitors.

Angiotensin II receptor antagonists

ACE inhibitors share many common characteristics with another class of cardiovascular drugs called angiotensin II receptor antagonists, which are often used when patients are intolerant of the adverse effects produced by ACE inhibitors. ACE inhibitors do not completely prevent the formation of angiotensin II, as there are other conversion pathways, and so angiotensin II receptor antagonists may be useful because they act to prevent the action of angiotensin II at the AT₁ receptor.

Use in combination with ACE inhibitors

While counterintuitive at first glance, the combination therapy of angiotensin II receptor antagonists with ACE inhibitors may be superior to either agent alone. This combination may increase levels of bradykinin while blocking the generation of angiotensin II and its activity at the AT₁ receptor. This 'dual blockade' may be more effective than using an ACE inhibitor alone, because angiotensin II can be generated via non-ACE-dependent pathways. Preliminary studies suggest that this combination of pharmacologic agents may be advantageous in the treatment of essential hypertension, chronic heart failure, and nephropathy. However, more studies are needed to confirm these highly preliminary results. While statistically significant results have been obtained for its role in treating hypertension, clinical significance may be lacking.

Patients with heart failure may benefit from the combination in terms of reducing morbidity and ventricular remodeling.

The most compelling evidence has been found for the treatment of nephropathy: this combination therapy partially reversed the proteinuria and also exhibited a renoprotective effect in patients afflicted with diabetic nephropathy, and pediatric IgA nephropathy

Ace Inhibitor Interaction

Blockade of the renin-angiotensin system improves morbidity and mortality of patients with cardiovascular diseases, e.g. arterial hypertension, renal failure, following myocardial infarction and in congestive heart failure. The angiotensin II type 1 (AT(1)) receptor antagonists (angiotensin receptor blockers; ARBs), i.e. losartan, eprosartan, irbesartan and valsartan were developed by computer-based molecule design. Early observations already indicate that the ARBs elicit pleiotropic effects developing anti-aggregatory, anti-inflammatory and anti-mitogenic effects independent from their actions at the AT(1) receptor. Losartan metabolism indicates a number of known active intermediates and pointed to further interactions of these derivatives with other receptors and cellular signaling systems. Here we discuss a compilation of detailed pharmacokinetic and pharmacodynamic data of active metabolites of ARBs indicating their mode of action and suggest novel therapeutic implications. The clinical observations that ARBs elicit potencies in patients with cardiovascular diseases via the regulation of inflammatory, growth and homeostatic factors lead us to focus on specific, reactive metabolites, which hold potential for future indications and possible drug interactions in card.

Adrenergic Receptor Antagonists

(Sympatholytic Drugs)

Beta-Adrenoceptor Agonists (α-agonists)

General Pharmacology

Beta-adrenoceptor agonists (α-agonists) bind to α-receptors on cardiac and smooth muscle tissues. They also have important actions in other tissues, especially bronchial smooth muscle (relaxation), the liver (stimulate glycogenolysis) and kidneys. Beta-adrenoceptors normally bind to norepinephrine released by sympathetic adrenergic nerves, and to circulating epinephrine. Therefore, α-agonists mimic the actions of sympathetic adrenergic stimulation acting through α-adrenoceptors. Overall, the effect of α-agonists is cardiac stimulation (increased heart rate, contractility, conduction velocity, relaxation) and systemic vasodilation. Arterial pressure may increase, but not necessarily because the fall in systemic vascular resistance offsets the increase in cardiac output. Therefore, the effect on arterial pressure depends on the relative influence on cardiac versus vascular α-adrenoceptors. α-agonists cause α-receptor down-regulation, which limits their therapeutic efficacy to short-term application. Beta-agonists, because they are catecholamines, have a low bioavailability and therefore must be given by intravenous infusion.

Heart.

Beta-agonists bind to beta-adrenoceptors located in cardiac nodal tissue, the conducting system, and contracting myocytes. The heart has both α1 and α2 adrenoceptors, although the predominant receptor type in number and function is α1. These receptors primarily bind norepinephrine that is released from sympathetic adrenergic nerves. Additionally, they bind norepinephrine and epinephrine that circulate in the blood.

Beta-adrenoceptors are coupled to a Gs-proteins, which activate adenylyl cyclase to form cAMP from ATP. Increased cAMP activates a cAMP-dependent protein kinase (PK-A) that phosphorylates L-type calcium channels, which causes increased calcium entry into the cells. Increased calcium entry during action potentials leads to enhanced release of calcium by the sarcoplasmic reticulum in the heart; these actions increase inotropy (contractility). Gs-protein activation also increases heart rate by opening ion channels responsible for pacemaker currents in the sinoatrial node. PK-A phosphorylates sites on the sarcoplasmic reticulum, which enhances the release of calcium through the ryanodine receptors (ryanodine-sensitive, calcium-release channels) associated with the sarcoplasmic reticulum. This provides more calcium for binding the troponin-C, which enhances inotropy.Finally, PK-A can phosphorylate myosin light chains, which may also contribute to the positive inotropic effect of beta-adrenoceptor stimulation. In summary, the cardiac effects of a α-agonist are increased heart rate, contractility, conduction velocity, and relaxation rate. Blood vessels, Vascular smooth muscle has α2-adrenoceptors that are normally activated by norepinephrine released by sympathetic adrenergic nerves or by circulating epinephrine. These receptors, like those in the heart, are coupled to a Gs-protein, which stimulates the formation of cAMP. Although increased cAMP enhances cardiac myocyte contraction (see above), in vascular smooth muscle an increase in cAMP leads to smooth muscle relaxation. The reason for this is that cAMP inhibits myosin light chain kinase that is responsible for phosphorylating smooth muscle myosin. Therefore, increases in intracellular cAMP caused by α2-agonists inhibits myosin light chain kinase thereby producing less contractile force (i.e., promoting relaxation).

Other tissues, α activation of α2-adrenoceptors in the lungs causes bronchodilation. α2-adrenoceptor activation leads to hepatic glycogenolysis and pancreatic release of glucagon, which increases plasma glucose concentrations. α1-adrenoceptor stimulation in the kidneys causes the release of renin, which stimulates the production of angiotensin II and the subsequent release of aldosterone by the adrenal cortex.

Specific Drugs and Therapeutic Uses

There are several different α-agonists that are used clinically for the treatment of heart failure or circulatory shock, all of which are either natural catecholamines or analogs. Nearly all of these α-agonists, however, have some degree of α-agonist activity. These drugs along with their agonist properties are given in the table below. Note that for some of the drugs the receptor selectivity is highly dose-dependent.Drug	Receptor Selectivity	Clinical Use	Comments
Epinephrine	α₁ α α₂> α₁= α₂	Anaphylactic shock; cardiogenic shock; cardiac arrest	Low doses produce cardiac stimulation and vasodilation, which turns to vasoconstriction at high doses. *At high plasma concentrations, =αselectivity.
Norepinephrine	α₁ α αα_1α α₂=α₂	Severe hypotension; septic shock	Reflex bradycardia masks direct stimulatory effects on sinoatrial node.
Dopamine	α₁αα₂>α₁*	–Acute heart failure, cardiogenic shock and acute renal failure	Biosynthetic precursor of norepinephrine; stimulates norepinephrine release. *At low doses, it stimulates the heart and decreases systemic vascular resistance; at high doses, vasodilation becomes vasoconstriction as lower affinity α -receptors bind to the dopamine α also binds to D1 receptors in kidney, producing vasodilation.
Dobutamine	α₁ α α₂> α₁	Acute heart failure; cardiogenic shock; refractory heart failure	Net effect is cardiac stimulation with modest vasodilation.
Isoproterenol	α₁αα₂	Bradycardia and atrioventricular block	Net effect is cardiac stimulation and vasodilation with little change in pressure.

Side Effects and Contraindications

A major side effect of α-agonists is cardiac arrhythmia. Because these drugs increase myocardial oxygen demand, they can precipitate angina in patients with coronary artery disease. Headache and tremor are also common.

Definition: Drugs that decrease sympathetic neuronal activity

Classification according to mechanism of action:

1. Indirect-acting:

Drugs that interfere with sympathetic neuronal function by inhibiting:

a)Synthesis of NE

b) Storage of NE

c) Release of NE-used mainly to treat hypertension

2. Direct-acting:

Adrenergic Receptor Antagonists: -drugs that bind to adrenergic receptors but don't activate themIncludes:
a) α receptor blocking drugs: treatment of hypertension (limited use)
b) α receptor blocking drugs: treatment of cardiovascular disorders (widely used)

nonselective: block both α₁ & α₂ receptors
selective: block either α₁ or α₂ receptors

Pre- and post-junctional sites of action of sympatholytic drugs

Figure Legend:

1. Inhibition of synthesis of NE

eg. 1a, alpha-methyltyrosine
eg. 1b, carbidopa
eg. 1c, disulfiram

2. Disruption of vesicular storage of NE

eg. reserpine

3. Inhibit release of NE

eg. guanethidine

4. Alpha & beta receptor antagonists

eg. phentolamine
eg. propranolol

Prejunctional autoreceptors: α ₂subtype are activated by NE (or agonists) ----> decrease release of NE

.: inhibitory autoreceptor mechanism regulates neurotransmitter release

1. Drugs that interfere with Sympathetic Neuronal Function

i) Inhibit synthesis of NE

a) Metyrosine

-inhibits tyrosine hydroxylase ----> decreased dopamine, NE & EP.
Used in patients with pheochromocytoma (tumor of the adrenal gland which secretes NE & EP ----> signs of catecholamine excess eg. hypertension, tachycardia & arrhythmias)

b) Carbidopa

-acts like methyldopa & blocks peripheral dopa decarboxylase activity ----> decreased formation of dopamine (no effect on NE)
-doesn't cross blood-brain barrier .: acts only peripherally
----> decreased side effects (motor symptoms) due to dopamine formation in peripheral tissues of patients with Parkinson's disease treated with L-dopa

ii) Prevents storage

c) Reserpine

-decreases storage of NE which leaks from vesicles and is deaminated by MAO

-effects are decreased peripheral resistance, CO and BP

-used in low doses with diuretics to treat mild hypertension

-long duration of action

-not widely used

iii) Inhibit release

d) Guanethidine

-impairs the release of norepinephrine from presynaptic sympathetic neurons

-doesn't cross blood-brain barrier

-taken up by nerve terminals and stored in synaptic vesicles

-decreases release of NE in response to action potentials or indirect acting sympathomimetics

-decreases response of α & α receptors equally
.: decreases sympathetic tone to all organs

Side effects:

Decreased BP, HR, & CO & postural hypotension
Increased gut motility & diarrhea
nasal stuffiness, impaired ejaculation

Use: because of side effects, only used for moderate to severe hypertension

Definition: Postural or Orthostatic hypotension is a fall in blood pressure associated with dizziness, syncope and blurred vission occurring upon standing

e)Bretylium

-accumulates in noradrenergic sympathetic neurons ----> decreased release of NE

-direct and indirect effects on the heart
-used for IV treatment of ventricular dysrhythmias

iv) Reduction of central sympathetic flow

f) Methyldopa (converted to α -methylnorepinephrine) and clonidine

-drugs that decrease sympathetic outflow in the CNS. Both activate α ₂ receptors in the hypothalamus and medulla ----> decrease sympathetic outflow ----> decreased total peripheral resistance, HR, CO ----> decrease BP
-no postural hypotension because they don't interfere with baroreceptor reflexes

1) α Receptor Blocking Drugs

Types of α blockers:

nonselective: eg. phenoxybenzamine and phentolamine (α ₁ & α ₂)
selective: eg. prazosin (α ₁)

Reversible	Irreversible
-may dissociate from receptor -response varies with: T_1/2 of drug rate of dissociation from receptor addition of NE -eg. phentolamine	-don't dissociate from receptor -response varies with: number of receptors occupied rate of synthesis of new receptor -eg. phenoxybenzamine

Clinical Pharmacology:

Mechanism:

- α receptors are present on vascular smooth muscle
----> control arteriolar and venous tone
.: α ₁ blockade ----> vasodilation ----> decreased peripheral resistance and BP
.: reflex sympathetic control of capacitance vessels is blocked
----> postural hypotension & reflex tachycardia
- α ₂ blockade enhances this reflex tachycardia because the inhibitory effect on NE release is blocked
-more NE released to stimulate α₁ receptors in the heart

Major side effects of α blockers:

-related to decreased sympathetic tone at α -receptors (due to α -blocking effect)

postural hypotension
reflex tachycardia
inhibition of ejaculation
nasal stuffiness

A) Nonselective α blockers:

i) Phenoxybenzamine

-irreversible α _1&2receptor blockade

-binds covalently to receptor (14-48 hours duration)

-blocks catecholamine-induced vasoconstriction

-used to diagnose & treat pheochromocytoma (tumor of adrenal gland which secretes NE & EP ----> signs of catecholamine excess eg. hypertension, tachycardia & arrhythmias

-also used to correct severe hypertension and decrease blood volume before patient with pheochromocytoma undergoes surgery

-causes postural hypotension, tachycardia

-also acts centrally to cause nausea, vomiting, sedation & weakness

ii) Phentolamine

-potent competitive reversible α _1&2 receptor blocker

-major clinical use in treatment of pheochromocytoma

-used to treat episodes that occur during surgical removal of tumor

-causes postural hypotension, tachycardia

-also stimulates gastrointestinal tract ----> abdominal pain & diarrhea (not α blocking effect)

B) Selective α blockers:

i) Prazosin (Minipress) - (Antihypertensive)

-potent selective α ₁ receptor antagonist (reversible).

-causes dilation of both arterial & venous smooth muscle

-effective in the management of chronic hypertension

-well absorbed orally but substantial first pass metabolism

-only 50% available (T_1/2=3-4 hrs)

-causes less tachycardia because α ₂ receptors aren't blocked

2)α Receptor Blocking Drugs

-drugs which antagonize the effects of catecholamines at α receptors

General characteristics of α blockers:

-all are pure antagonists (ie. no receptor activation).

-those with higher affinity for α₁ than α₂ are important clinically.

-most resemble isoproterenol ( receptor agonist)

-most are well absorbed but low bioavailability due to extensive hepatic metabolism (limited1/2)
-variable plasma concentration due to individual variations in metabolism
eg. decreased elimination in:

liver disease
decreased blood flow to liver
inhibition of liver enzymes

Effects and Clinical Uses:

predictable from blockade of α adrenergic receptors
important cardiovascular and opthalmic applications

a) Propranolol

-prototype α blocking drug

-potent reversible α₁ and α₂ receptor antagonist

-blocks +ve chronotropic and inotropic effects on heart

-effects more dramatic during exercise

Clinical Use: various cardiovascular diseases (ie. hypertension, angina, dysrhythmia, postmyocardial infarction etc.)

Side Effects:

-few in normal individuals, can occur in disease states

-predictable from α blockade

i) Patients with diabetes:

-propranol blocks metabolic effects of α receptor stimulation (ie. inhibits increase in free fatty acids and glycogenolysis)
.: can increase insulin-induced hypoglycemia

ii) Patients with heart disease:

-contraindicated in patients with sinus bradycardia, partial heart block & congestive heart failure
-CO depends on sympathetic output which is decreased with α blockers
-withdrawal symptoms (ie. angina, tachycardia, dysrhythmias) may develop after withdrawal from long term patients

iii) Patients with asthma:

-α₂ receptor blockade can ----> increase airway resistance
-selective α₁ blockers should be used

b) Timolol

-nonselective α adrenergic blocker used orally for hypertension and angina, and topically for the treatment of glaucoma

c) Selective α₁ adrenergic blockers (acebutolol, metoprolol, esmolol)

-are less likely to increase bronchoconstriction in patients with asthma
-useful in the treatment of hypertension and angina pectoris

Clinical Pharmacology of α Blockers

Used in the treatment of:

a) Hypertension:

-decreased BP mainly due to effects on the heart ie. -ve inotropic and chronotropic effects

b) Ischemic heart disease: eg. angina

-decreased angina and increased exercise tolerance due to decreased cardiac work, decreased HR, & decreased oxygen demand

c) Cardiac arrhythmias

α₁ blockade results in:

decreased rate of spontaneous discharge of SA node
decreased AV conduction
decreased AV node refractory period
decreased ventricular response to atrial flutter
decreased ventricular or ectopic beats

Alpha₁-adrenergic blockers

Definition

Alpha₁-adrenergic blockers are drugs that work by blocking the alpha₁-receptors of vascular smooth muscle, thus preventing the uptake of catecholamines by the smooth muscle cells. This causes vasodilation and allows blood to flow more easily.

Purpose

These drugs, called alpha blockers for short, are used for two main purposes: to treat high blood pressure (hypertension) and to treat benign prostatic hyperplasia (BPH), a condition that affects men and is characterized by an enlarged prostate gland.

High blood pressure

High blood pressure puts a strain on the heart and the arteries. Over time, hypertension can damage the blood vessels to the point of causing stroke, heart failure or kidney failure. People with high blood pressure may also be at higher risk for heart attacks. Controlling high blood pressure makes these problems less likely. Alpha blockers help lower blood pressure by causing vasodilation, meaning an increase in the diameter of the blood vessels, which allows blood to flow more easily.

Description

Commonly prescribed alpha blockers for hypertension and BPH include doxazosin (Cardura, prazosin (Minipress) and terazosin (Hytrin). Prazosin is also used in the treatment of heart failure. All are available only with a physician's prescription and are sold in tablet form.

Examples of alpha blockers

Alpha blockers include:

• Doxazosin

• Prazosin

• Phenoxybenzamine

• Phentolamine

• Tamsulosin

• Alfuzosin

• Terazosin

Tamsulosin is relatively selective for α_1a-adrenergic receptors, which are mainly present in the prostate. Hence, it may have a more selective action in BPH with minimal effects on blood pressure.

Precautions

Alpha blockers may lower blood pressure to a greater extent than desired. This can cause dizziness, lightheadedness, heart palpitations, and fainting. Activities such as driving, using machines, or doing anything else that might be dangerous for 24 hours after taking the first dose should be avoided. Patients should be reminded to be especially careful not to fall when getting up in the middle of the night. The same precautions are recommended if the dosage is increased or if the drug has been stopped and then started again. Anyone whose safety on the job could be affected by taking alpha blockers should inform his or her physician, so that the physician can take this factor into account when increasing dosage.

Some people may feel drowsy or less alert when using these drugs. They should accordingly avoid driving or performing activities that require full attention.

People diagnosed with kidney disease or liver disease may also be more sensitive to alpha blockers. They should inform their physicians about these conditions if alpha blockers are prescribed. Older people may also be more sensitive and may be more likely to have unwanted side effects, such as fainting, dizziness, and lightheadedness.

It should be noted that alpha blockers do not cure high blood pressure. They simply help to keep the condition under control. Similarly, these drugs will not shrink an enlarged prostate gland. Although they will help relieve the symptoms of prostate enlargement, the prostate may continue to grow, and it eventually may be necessary to have prostate surgery.

Alpha blockers may lower blood counts. Patients may need to have their blood checked regularly while taking this medicine.

Anyone who has had unusual reactions to alpha blockers in the past should let his or her physician know before taking the drugs again. The physician should also be told about any allergies to foods, dyes, preservatives, or other substances.

The effects of taking alpha blockers during pregnancy are not fully understood. Women who are pregnant or planning to become pregnant should inform their physicians. Breastfeeding mothers who need to take alpha blockers should also talk to their physicians. These drugs can pass into breast milk and may affect nursing babies. It may be necessary to stop breastfeeding while being treated with alpha blockers.

Side effects

The most common side effects are dizziness, drowsiness, tiredness, headache, nervousness, irritability, stuffy or runny nose, nausea, pain in the arms and legs, and weakness. These problems usually go away as the body adjusts to the drug and do not require medical treatment. If they do not subside or if they interfere with normal activities, the physician should be informed.

If any of the following side effects occur, the prescribing physician should be notified as soon as possible:

· fainting

· shortness of breath or difficulty breathing

· fast, pounding, or irregular heartbeat

· swollen feet, ankles, wrists

Other side effects may occur. Anyone who has unusual symptoms after taking alpha blockers should contact his or her physician.

Interactions

Alpha blocker

These drugs may be used to treat:

benign prostatic hyperplasia (BPH)
high blood pressure (hypertension). This is not typically the drug of choice unless the patient also has BPH.
symptoms of non inflammatory chronic pelvic pain syndrome, a type of prostatitis. As a side effect they may reduce blood pressure and result in lightheadedness.

Adverse effects and interactions

By reducing α₁-adrenergic activity of the blood vessels, these drugs may cause hypotension and interrupt the baroreflex response. In doing so, they may cause dizziness, lightheadedness, or fainting when rising from a lying or sitting posture (known as orthostatic hypotension or postural hypotension). For this reason, it is generally recommended that alpha blockers should be taken at bedtime. Additionally, the risk of orthostatic hypotension may be reduced by starting at a low dose and titrating upwards as needed.

Because these medications may cause orthostatic hypotension, as well as hypotension in general, these agents may interact with other medications that increase risk for hypotension, such as other antihypertensives and vasodilators.

As discussed above, tamsulosin may have less risk for hypotension and orthostatic hypotension due to its selectivity for α_1a-adrenergic receptors. On the other hand, the drug (a) elevates risk for floppy iris syndrome, and (b) might show ADRs characteristic of the sulfa related drugs.

Doxazosin (Cardura) is not known to interact with any other drugs. Terazosin (Hytrin) may interact with nonsteroidal anti-inflammatory drugs, such as ibuprofen (Motrin), and with other blood pressure drugs, such as enalapril (Vasotec), and verapamil (Calan,Verelan). Prazosin (Minipress) may interact with beta adrenergic blocking agents such as propranolol (Inderal) and others, and with verapamil (Calan, Isoptin.) When drugs interact, the effects of one or both of the drugs may change or the risk of side effects may be greater.

• Doxazosin

• Prazosin

• Phenoxybenzamine

• Phentolamine

• Tamsulosin

• Alfuzosin

• Terazosin

Examples of alpha blockers

Alpha blockers include:

Tamsulosin is relatively selective for α_1a-adrenergic receptors, which are mainly present in the prostate. Hence, it may have a more selective action in BPH with minimal effects on blood pressure.

The physiological framework for understanding hypertension: Ventriculo-arterial coupling

SV EaPressure 1 23 4 LVEDP EDPVRESP ESPVR = Emax = Es

LVEDV

Volume

Key: 1 = End diastole, just prior to LV contraction. The pressure at 1 is the left ventricular end diastolic pressure (LVEDP) and the volume is the left ventricular end diastolic volume (LVEDV) (1 to 2 = isovolemic contraction) 2 = Opening of the aortic valve and beginning of ejection into the aorta (2 to 3 is the volume ejected from the LV into the aorta which is the stroke volume (SV)) 3 = End systole. The pressure at 3 is known as the end-systolic pressure (ESP). The aortic valve shuts just after 3. (3 to 4 is isovolumic relaxation) 4 = Beginning of passive diastolic filling. 4 to 1 is diastolic filling along the dotted curve. This dotted curve is the end-diastolic pressure volume relation

(EDPVR). ESPVR = End-systolic pressure volume relation. This also called Emax or Es

which stand for maximal elastance or elastance at end-systole, respectively. This characterizes the strength of the LV irrespective of the systolic load it faces. Ea = Effective arterial elastance. This is characterizes the arterial tree and the load it presents to the LV during systole. Ea is primarily determined by arterial resistance but arterial compliance effects it too. Ea and ESPVR “Couple” to exactly determine the stroke volume. In essence, the volume lost by one chamber is exactly equal to the volume gained by the other. The elastance of each chamber (heart and vascular tree) determines the pressure. The exact systolic and diastolic pressures that obtain are dependent on arterial properties (Ea), ventricular properties (ESPVR) and the filling state (LVEDV).

There are FOUR possible mechanisms for hypertension

1. The volume ejected from the LV can be too high. This could result from an excessive contraction during systole (a very high ESPVR). This mechanism is described in the medical literature but is not typical. A hyperdynamic circulation is thought to play a role in the hypertension seen in some young, otherwise fit African-American males.

2. The intravascular volume may be too high causing an excess of venous return, leading to an elevated LVEDV. The very full heart would then eject a large volume into the arterial tree thus leading to hypertension. The high intravascular volume could be caused by renal dysfunction with subsequent fluid retention, or it could be due to exogenous administration. There does seem to be a subset of patients that has an elevated intravascular volume Nevertheless, the excessive intravascular volume mechanism appears to occur infrequently since many newly diagnosed hypertensive patients actually have a contracted intravascular volume. The excessive intravascular volume mechanism also implies that the cardiac output would be elevated, but it is usually normal.

3. Excess venous return could also occur even with a reduced intravascular volume if the venous tone were significantly elevated. This would cause a rise in the LVEDV even

with a normal or low actual blood volume. Whether this occurs as a regular feature of hypertension is not known.

4. The effective arterial elastance (Ea) can be too high. This can occur either because the resistance is too high or because the compliance is too low. Many forms of hypertension are associated with an elevated arterial resistance. Furthermore, in older humans, the arterial tree becomes stiffer and less compliant. Thus, for a given stroke volume delivered into the arterial tree, the pressure goes up, especially the systolic pressure.

Central Sympatholytics

Centrally Acting Sympatholytics

General Pharmacology

The sympathetic adrenergic nervous system plays a major role in the regulation of arterial pressure. Activation of these nerves to the heart increases the heart rate (positive chronotropy), contractility (positive inotropy) and velocity of electrical impulse conduction (positive dromotropy). The norepinephrine-releasing, sympathetic adrenergic

nerves that innervate the heart and blood vessels are postganglionic efferent nerves whose cell bodies originate in prevertebral and paraveterbral sympathetic ganglia. Preganglionic sympathetic fibers, which travel from the spinal cord to the ganglia, originate in the medulla of the brainstem. Within the medulla are located sympathetic excitatory neurons that have significant basal activity, which generates a level of sympathetic tone to the heart and vasculature even under basal conditions. The sympathetic neurons within the medulla receive input from other neurons within the medulla (e.g., vagal neurons), from the nucleus tractus solitarius (receives input from peripheral baroreceptors and chemoreceptors), and from neurons located in the hypothalamus. Together, these neuronal systems regulate sympathetic (and parasympathetic) outflow to the heart and vasculature.

Sympatholytic drugs can block this sympathetic adrenergic system are three different levels. First, peripheral sympatholytic drugs such as alpha-adrenoceptor and beta-adrenoceptor antagonists block the influence of norepinephrine at the effector organ (heart or blood vessel). Second, there are ganglionic blockers that block impulse transmission at the sympathetic ganglia. Third, there are drugs that block sympathetic activity within the brain. These are called centrally acting sympatholytic drugs.

Centrally acting sympatholytics block sympathetic activity by binding to and activating alpha₂ (α₂)-adrenoceptors. This reduces sympathetic outflow to the heart thereby decreasing cardiac output by decreasing heart rate and contractility. Reduced sympathetic output to the vasculature decreases sympathetic vascular tone, which causes vasodilation and reduced systemic vascular resistance, which decreases arterial pressure.

Therapeutic Indications

Centrally acting α₂-adrenoceptor agonists are used in the treatment of hypertension. However, they are not considered first-line therapy in large part because of side effects that are associated with their actions within the brain. They are usually administered in combination with a diuretic to prevent fluid accumulation, which increases blood volume and compromises the blood pressure lowering effect of the drugs. Fluid accumulation can also lead to edema. Centrally acting α₂-adrenoceptor agonists are effective in hypertensive patients with renal disease because they do not compromise renal function.

Specific Drugs

Several different centrally acting α₂-adrenoceptor agonists are available for clinical use:

· Clonidine

· Guanabenz

· Guanfacine

· α-methyldopa

Clonidine, guanabenz and guanfacine are structurally related compounds and have similar antihypertensive profiles. α-methyldopa is a structural analog of dopa and functions as a prodrug. After administration, α-methyldopa is converted to α-methynorepinephrine, which then serves as the α₂-adrenoceptor agonist in the medulla to decrease sympathetic outflow.

Side Effects and Contraindications

Side effects of centrally acting α₂-adrenoceptor agonists include sedation, dry mouth and nasal mucosa, bradycardia (because of increased vagal stimulation of the SA node as well as sympathetic withdrawal), orthostatic hypotension, and impotence. Constipation, nausea and gastric upset are also associated with the sympatholytic effects of these drugs. Fluid retention and edema is also a problem with chronic therapy; therefore, concurrent therapy with a diuretic is necessary. Sudden discontinuation of clonidine can lead to rebound hypertension, which results from excessive sympathetic activity.

Methyldopa

Systematic (IUPAC) name 2-amino-3-(3,4-dihydroxyphenyl)-2-methyl-propanoic acid Chemical data Formula C10H13NO4

Mol. Mass 211.215 g/mol

Pharmacokinetic data Bioavailability approximately 50%

Metabolism Hepatic

Half life 105 minutes

Excretion Renal for metabolites

Therapeutic considerations Pregnancy cat.

Routes Oral, IV

Methyldopa or alpha-methyldopa is a centrally-acting adrenergic antihypertensive medication. Its use is now deprecated following introduction of alternative safer classes of agents. However it continues to have a role in otherwise difficult to treat hypertension and pregnancy-induced hypertension.

Mechanism of action

Methyldopa has variable absorption from the gut of approximately 50%. It is metabolized in the intestines and liver; its metabolite alpha-methylnorepineprine acts in the brain to stimulate alpha-adrenergic receptors decreasing total peripheral resistance. It is excreted in urine.

Methyldopa, in its active metabolite form, leads to increased alpha-2 receptor-mediated inhibition of SNS (centrally and peripherally), allowing PSNS tone to increase. Such activity leads to a decrease in total peripheral resistance (TPR) and cardiac output.

If methyldopa is abruptly withdrawn, rebound hypertension happens. This results because the long term use of methyldopa lowers the sensitivity of presynaptic alpha 2 receptors: the release of norepinephrine (NE) from sympathetic nerve endings is modulated by NE itself acting on the presynaptic alpha 2 autoreceptors thus inhibiting its own release. The discontinuation of methyldopa removes the inhibition on NE release leading to excessive NE release from the SNS and the rebound hyertension.

Side effects

There are many possible reported side-effects with some, whilst rare, being serious. Side effects are usually fewer if the dose is less than 1 g per day:

• Gastro-intestinal disturbances

• Dry mouth

• Bradycardia (slow pulse rate)

• Worsening of angina

• Orthostatic hypotension (Postural hypotension)

• Sedation, headaches, dizziness

• Myalgia (muscle pain), arthralgia (joint pain) or paraesthesia (numbness)

• Nightmares, mild psychosis, depression

• Parkinsonism, Bell's palsy

• Abnormal liver functions tests and hepatitis

• Pancreatitis

• Haemolytic anaemia

• Bone marrow suppresion leading to thrombocytopenia (low platelets) or leucopenia (low white blood cells)

• Hypersensitivity reactions including lupus erythematosus-like syndrome, myocarditis (heart muscle inflammation), pericarditis and rashes

• Ejaculatory failure, Impotence, decreased libido, gynecomastia (breast enlargement in men), hyperprolactinaemia and amenorrhoea

Central sympatholytics

Interactions

OBJECTIVE: To provide a comprehensive review of the pharmacokinetic and pharmacodynamic interactions between antipsychotics and antihypertensive and to provide recommendations for the selection of antihypertensive in patients receiving antipsychotic therapy

SYNTHESIS: Because hypertension is common in patients with psychiatric illness and antihypertensive agents are used for a multiplicity of indications, significant numbers of patients receive concurrent therapy with antihypertensives and antipsychotics. Many antipsychotics may block the antihypertensive efficacy of guanethidine and related drugs. The interaction between clonidine and antipsychotics is defined less clearly. Limited data suggest possible additive hypotensive effects when chlorpromazine and methyldopa are given in combination. Increased plasma concentrations of thioridazine with a resultant increase in adverse effects have been reported when propranolol or pindolol are added to the regimen. A similar increase in chlorpromazine concentrations has been reported when propranolol was added. Although there are no reports documenting an interaction between a calcium-channel antagonist and an antipsychotic, the possible inhibition of oxidative metabolism of antipsychotics, additive calcium-blocking activity, and additive pharmacodynamic effects are theorized. Hypotension and postural syncope were reported in a patient given therapeutic dosages of chlorpromazine and captopril, and in 2 patients when clozapine was added to enalapril therapy.

CONCLUSIONS: No antipsychotic-antihypertensive combination is absolutely contraindicated, but no combination should be considered to be completely without risk. Antihypertensives with no centrally acting activity, such as diuretics, may be the least likely to result in adverse reactions. The combination of the beta-antagonists propranolol or pindolol with thioridazine or chlorpromazine should be avoided if possible. Scrupulous patient monitoring for attenuated or enhanced activity of either agent is essential whenever antipsychotics and antihypertensives are given concurrently

Clonidine


Clonidine
Systematic (IUPAC) name
N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine
Chemical data
Formula	C₉H₉N₃Cl₂
Mol. mass	230.093 g/mol
Pharmacokinetic data
Bioavailability	75-95%
Protein binding	20-40%
Metabolism	Hepatic to inactive metabolites
Half life	12-16 hours
Excretion	?
Therapeutic considerations


Routes	oral, transdermal

Mechanism of action

Clonidine is a direct-acting adrenergic agonist prescribed historically as an anti-hypertensive agent. It has found new uses, including treatment of some types of neuropathic pain, opioid detoxification, sleep hyperhydrosis, and, off-label, to counter the side effects of stimulant medications such as methylphenidate or Adderall. It is becoming a more accepted treatment for insomnia because clonidine is less addictive than most prescription sleep aids. Clonidine is increasingly used in conjunction with stimulants to treat attention-deficit hyperactivity disorder (ADHD), where it's given in late afternoon and/or evening for sleep, and because it sometimes helps moderate ADHD-associated impulsive and oppositional behavior, and may reduce tics.[1] Clonidine can also be used in the treatment of Tourette syndrome.

Clonidine for opiate withdrawals

Clonidine is a centrally-acting alpha-2 agonist. It selectively stimulates receptors in the brain that monitor catecholamine levels in the blood. These receptors close a negative feedback loop that begins with descending sympathetic nerves from the brain that control the production of catecholamines (epinephrine, also known as adrenaline, and norepinephrine) in the adrenal medulla. By fooling the brain into believing that catecholamine levels are higher than they really are, clonidine causes the brain to reduce its signals to the adrenal medulla, which in turn lowers catecholamine production and blood levels. The result is a lowered heart rate and blood pressure, with side effects of dry mouth and fatigue. If clonidine is suddenly withdrawn the sympathetic nervous system will revert to producing high levels of epinephrine and norepinephrine, higher even than before treatment, causing rebound hypertension. Rebound hypertension can be avoided by slowly withdrawing treatment.

Clonidine is regularly prescribed to opiate addicts to help alleviate their withdrawals. It is mainly used to combat the sympathetic response to opiate withdrawal,(tachycardia and hypertension) in the first couple days of withdrawals. It helps take away the sweating, hot/cold flashes, and general restlessness. The sedation effect is also useful.

Administration

Clonidine is typically available as tablets as a transdermal patch ,or as an injectable form to be given epidurally, directly to the central nervous system.

Reserpine


Reserpine
Systematic (IUPAC) name
methyl-11,17α-dimethoxy-18β-[(3,4,5-trimethoxybenzoyl) oxy]-3β,20α-yohimban-16β-carboxylate
Chemical data
Formula	C₃₃H₄₀N₂O₉
Mol. mass	608.679 g/mol
Pharmacokinetic data
Bioavailability	50%
Metabolism	gut/liver
Half life	phase 1 = 4.5h, phase 2 = 271h, average = 33h
Excretion	62% feces / 8% urine
Therapeutic considerations
Pregnancy cat.	D (fetotoxic)
Legal status	Rx-only (some countries banned/discontinued)
Routes	oral

•Reserpine is an indole alkaloidantipsychotic and antihypertensive drug known to irreversibly bind to storage vesicles of neurotransmitters such as dopamine, norepinephrine, and serotonin.Reserpine depletion of monoamine neurotransmitters in the synapses is often used to bolster the theory that depletion of the neurotransmitters causes subsequent depression in humans. Moreover, reserpine has a peripheral action in many parts of the body, resulting in a preponderance of the cholinergic part of the nervous system (GI-Tract, smooth muscles vessels).Reserpine has been discontinued in the UK for some years due to its vast interactions and side effects.

Uses today

In some countries reserpine is still available as part of combination drugs for the treatment of hypertension, in most cases they contain also a diuretic and/or a vasodilator like hydralazine. These combinations are currently regarded as second choice drugs. The daily dose of reserpine in antihypertensive treatment is as low as 0.1 to 0.25mg. The use of reserpine as an antipsychotic drug has been nearly completely abandoned. Originally, doses of 0.5mg to 40mg daily were used to treat psychotic diseases. Doses in excess of 3mg daily often required use of an anticholinergic drug to combat excessive cholinergic activity in many parts of the body as well as parkinsonism. Reserpine may be used as a sedative for horses.

Side effects

Reserpine has a narrow therapeutic index and a multitude of side-effects, including: Nausea, vomiting, weight gain, gastric intolerance, gastric ulceration (due to increased cholinergic activity in gastric tissue and impaired mucosal quality), stomach cramps and diarrhea are noted. The drug causes hypotension and bradycardia and may worsen asthma. Congested nose is another consequence of alpha-blockade. Depression does occur and may be severe enough to lead to suicide. Other central effects are a high incidence of drowsiness, dizziness, and nightmares. Parkinsonism occurs in a dose dependent manner. General weakness or fatigue is quite often encountered. High dose studies in rodents found reserpine to cause fibroadenoma of the breast and malignant tumors of the semen vesicles among others. Early suggestions that reserpine causes breast cancer in women (risk approximately doubled) were not confirmed.

Vasodilators

Definition

Vasodilators are medicines that act directly on muscles in blood vessel walls to make blood vessels widen (dilate).

Purpose

Vasodilators are used to treat high blood pressure (hypertension). By widening the arteries, these drugs allow blood to flow through more easily, reducing blood pressure. Controlling high blood pressure is important because the condition puts a burden on the heart and the arteries, which can lead to permanent damage over time. If untreated, high blood pressure increases the risk of heart attack, heart failure, stroke, or kidney failure. Vasodilators usually are prescribed with other types of blood pressure drugs and rarely are used alone.

Description

Examples of vasodilators are hydralazine (Apresoline) and minoxidil (Loniten). The vasodilator hydralazine also may be used to control high blood pressure in pregnant women or to bring down extremely high blood pressure in emergency situations. In the forms used for treating high blood pressure (tablets or injections), these drugs are available only with a physician's prescription. A liquid form of minoxidil, used to promote hair growth in people with certain kinds of baldness and is applied directly to the scalp, and is sold without a prescription.

Precautions

Seeing a physician regularly while taking a vasodilator is important, especially during the first few months. The physician will check to make sure the medicine is working as it should and will watch for unwanted side effects. People who have high blood pressure often feel fine. But even when they feel well, patients should keep seeing their physicians and taking their medicine.

Vasodilators will not cure high blood pressure, but will help control the condition. To avoid the serious health problems that high blood pressure can cause, patients may have to take medicine for the rest of their lives. Furthermore, medicine alone may not be enough. People with high blood pressure also may need to avoid certain foods and keep their weight under control. The health care professional who is treating the condition can offer advice on what measures may be necessary.

Some people feel dizzy or have headaches while using this medicine. These problems are especially likely to occur in older people, who are more sensitive than younger people to the medicine's effects. Anyone who takes these drugs should not drive, use machines, or do anything else that might be dangerous until they know how the drugs affect them.

Vasodilators interaction.

Interactions of cAMP-mediated vasodilators with angiotensin II in rat kidney during hypertension

In previous studies reported that vasodilator prostaglandins (PGs) are defective in bufferingthe angiotensin II (ANG II)-induced vasoconstriction in the renalvasculature of spontaneously hypertensive rats (SHR). The purpose of thepresent study was to determine whether this defect in SHR kidneys isspecific to PGs or generalized to the action of vasodilators and to gaininsight into which intracellular signal(s) mediates this abnormality. Renalblood flow (RBF; electromagnetic flowmetry) was measured in 7 wk-oldanesthetized, euvolemic SHR and normotensive Wistar-Kyoto (WKY) ratspretreated with indomethacin to avoid interactions with endogenous PGs. ANGII (2 ng) was injected into the renal artery before and during continuousintrarenal infusion of fenoldopam [DA1 receptor agonist and Gprotein-dependent stimulator of adenosine 3',5'-cyclic monophosphate(cAMP)], forskolin (G protein-independent stimulator of cAMP),dibutyryl-cAMP (soluble cAMP), and acetylcholine (cGMP stimulator). Eachvasodilator was infused at a low dose that did not affect baseline arterialpressure or RBF. In the control period, ANG II reduced RBF by 50% in bothstrains. Infusion of fenoldopam significantly blunted the ANG II-inducedvasoconstriction in WKY, but not in SHR. In contrast, forskolin,dibutyryl-cAMP, and acetylcholine effectively buffered the vasoconstrictiondue to ANG II in both SHR and WKY. These results suggest that renalvasodilators acting through receptor binding to stimulate the cAMPsignaling pathway are ineffective in counteracting the ANG II-inducedvasoconstriction in SHR kidneys.

Statins

Stains are also the drug of choice in the treatment of Hypertension by lowering the blood pressure.

Statin therapy is undoubtedly the single most important risk factor intervention beyond blood pressure reduction. In the ASCOT Lipid Lowering Arm ,reductions in coronary events were apparent at 30 days and significant within 3 months. The National Cholesterol Education Program guidelines introduced a low-density lipoprotein cholesterol (LDL-c) target of 1.8 mmol/l (70 mg/dl) for very high-risk patients, alongside a target of 2.5 mmol/l (100 mg/dl) for high-risk patients. Two recent trials suggest that intensive compared with moderate lipid lowering, and the lower LDL-c target, may be appropriate for all patients with CAD. The Treating to New Targets (TNT) [28••] study randomly assigned 10 000 patients with stable CAD to receive 80 mg or 10 mg of atorvastatin daily, lowering mean LDL-c to 2.0 mmol/l and 2.6 mmol/l, respectively. Major cardiovascular events, the primary outcome, were significantly reduced by 22% (0.78 [0.69–0.89], P < 0.001). Similar benefits occurred in the broader composite outcomes of any cardiovascular or any coronary event. Results were tempered by a nonsignificant increase in noncardiovascular deaths, however, leading to a call for further reassurance as to the safety of atorvastatin 80 mg/day .

Concerns regarding safety were lessened by the recent Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study [30•]. Nearly 9000 patients with a previous myocardial infarction were randomly assigned to receive high-dose atorvastatin 80 mg/day or usual-dose simvastatin 20 mg/day, reducing mean LDL-c to 2.1 mmol/l and 2.7 mmol/l, respectively. The aggressive lipid lowering failed to achieve a significant reduction in the primary outcome, defined as coronary death, myocardial infarction, or resuscitated cardiac arrest (0.89 [0.78–1.01], P = 0.07). Risk of major cardiovascular events including stroke, the primary outcome in the TNT study, however, was significantly reduced by 13% (0.87 [0.77–0.98], P = 0.02). More importantly, no excess of noncardiovascular deaths was observed in the atorvastatin group, In both, serious myopathy and rhabdomyolysis were rare and of similar frequency in each treatment group.

Patients receiving high-dose atorvastatin had more nonserious adverse events resulting in drug discontinuation, including persistent transaminase elevation (about 1.0%).

The importance of LDL-c lowering was highlighted by the Cholesterol Treatment Trialists' (CTT) Collaborators' meta-analysis [31] of 14 trials involving 90 000 patients. Statin therapy reduced coronary mortality, revascularization, myocardial infarction, and stroke by about 20% per 1 mmol/l decrement in LDL-c, with a corresponding 12% proportional reduction in all-cause mortality. Benefits were consistent in all subgroups including patients with hypertension, pretreatment LDL-c less than 2.6 mmol/l, and even LDL-c less than 2.0 mmol/l. Absolute benefit was determined by the absolute risk of events and the absolute reduction in LDL-c achieved. Thus the overall risk reduction of about 20% per mmol/l LDL-c reduction translated into 48 fewer patients having major cardiovascular events per 1000 among those with preexisting CAD, compared with 25

per 1000 among patients with no such history. Rather than achieving specific target levels, the goal should be substantial absolute reductions in LDL-c, irrespective of baseline cholesterol.

Comments

Anonymous22 August 2021 at 02:31
We tried to get pregnant for a few years in a local clinic. There were no results. We've tried everything possible but nothing. We were recommended to use eggs. I know we have to go abroad. I was terrified. I didn't know where to go and where to begin my search. When my friend recommended Dr Itua to me from western Africa I thought she was joking. I knew nothing about that country but I well know they have powerful gifts on herbal medicines and I was afraid because of the language barrier. Anyway she convinced me to give a try. She told me that Dr Itua can also cure my prostate cancer which gives me more motivation to give a try to Dr Itua herbal center medicines. I've done the research and thought that maybe this really is a good idea. Dr Itua has reasonable prices which I ordered two four bottles and I drank it as instructed and everything went well. My prostate cancer is gone. Also it has high rates of successful treatments. Plus it uses natural herbs. Well I should say I was convinced. We contacted Dr Itua and now we can say it was the best decision in our lives. We were trying for so long to have a child and suddenly it all looked so simple. Dr Itua was so confident and hopeful he projected those feelings on me too. I am so happy to be a mother and eternally thankful to Dr Itua herbal Cure . Don’t be afraid and just do it!
Dr Itua can cure the following diseases:Sickle Cell,Hiv,Herpes,Shingles, Hepatitis B,Liver Inflammatory,Diabetes,Fibroid,Parkinson's,Alzheimer’s disease,Bechet’s disease,Crohn’s disease,Lupus,Hpv,Weak Erection,Infertility,fibromyalgia,Chronic Diarrhea,Get Your Ex Back,Als,SYPHILIS,Cancer,Autism,Genetic disease,Epilepsy, Parkinson's disease, Doctor Itua Contact Email: drituaherbalcenter@gmail.com Or Whats-App Chat : +2348149277967

ANTIHYPERTENSIVE DRUG

Thiazide Diuretics Interactions with Dietary Supplements

Interaction between the nonpeptide angiotensin antagonist SKF-108,566 and histidine 256 (HisVI:16) of the angiotensin type 1 receptor

ACE inhibitor

Clinical use

The Renin-Angiotensin-Aldosterone System

Adverse effects

Examples of ACE inhibitors

Sulfhydryl-containing ACE inhibitors

Dicarboxylate-containing ACE inhibitors

Naturally occurring

Comparative information

Contraindications and precautions

Angiotensin II receptor antagonists

Use in combination with ACE inhibitors

Adrenergic Receptor Antagonists

(Sympatholytic Drugs)

Figure Legend:

Clinical Pharmacology:

Examples of alpha blockers

Alpha blocker

Adverse effects and interactions

Examples of alpha blockers

Methyldopa

Mechanism of action

Side effects

Clonidine

Mechanism of action

Clonidine for opiate withdrawals

Reserpine

Uses today

Side effects

Interactions of cAMP-mediated vasodilators with angiotensin II in rat kidney during hypertension

Comments

Post a Comment

Popular posts from this blog

Pepsin

List of Drugs Banned in India

Standard Operating Procedure