Diseases

Hypertension

Hypertension is high blood pressure. If untreated, it can lead to a heart attack, stroke, heart failure or kidney damage. Many people who develop hypertension do not get treatment. Over the years, the pharmaceutical industry has developed many medicines to treat hypertension. Further research aims to reduce the toll of the condition called the 'silent killer'.

What is hypertension? Top

Hypertension, or high blood pressure, is often called the “silent killer”, because most people with hypertension feel well and have no clinical symptoms. During each heartbeat, there is a fluctuation in the pressure exerted on the inside of the arteries.

The normal maximum, or systolic pressure is between 110-140mm mercury (Hg) and the minimum, or diastolic pressure is 70-90mm. There is much individual variation, depending on time of day, activity, age, general condition of health; however, a consistent reading of greater than 140mmHg for systolic pressure and/or 90mmHg for diastolic pressure is considered to indicate hypertension, irrespective of age.

Hypertension can be classified as essential or secondary. It is said to be essential if no specific cause can be found for it. If untreated, it much increases the risk of stroke, heart attack, heart failure, kidney problems and diabetes. Secondary hypertension follows from an underlying pathology which may need separate treatment, e.g. kidney disease.

Only essential hypertension is considered further here, as it represents more than 95 per cent of cases of high blood pressure. Hypertension in the circulation through the lung (pulmonary arterial hypertension) is seen in chronic obstructive pulmonary disease (COPD) and has a poor prognosis if untreated.

Who does hypertension affect? Top

By the current definition, more than 50 per cent of people aged over 55 are estimated to have raised blood pressure. For adults as a whole, 40 per cent of men and 33 per cent of women have hypertension. Strikingly, above the age of 65, about 15 per cent of men and 25 per cent of women are being treated for hypertension but still have blood pressure levels above the normal range, and almost half of both men and women in this age group have hypertension but are not being treated for it.

 

Computer graphic model of the molecular structure of a treatment in use for high blood pressure

Present treatments Top

Anti-hypertensives fall into eight main classes. Each has strengths, weaknesses and specific applications, and it is not possible here to list more than the main classes.

The medicines currently recommended for initial treatment are:

• angiotensin converting enzyme (ACE) inhibitors - they prevent the formation of angiotensin 2 (A-2), a powerful vasoconstrictor that raises peripheral resistance;

• angiotensin 2 receptor blockers (ARBs) – these molecules stop A-2 binding to its receptor site and are recommended if ACE inhibitors are not tolerated;

• diuretics – these act by dilating arterial vessels and increasing sodium excretion and urine output, which in turn lowers blood volume and pressure;

• calcium channel-blockers – these compounds inhibit the movement of calcium into smooth muscles in the walls of blood vessels and the heart, causing relaxation of blood vessels´ walls.

ACE inhibitors and ARBs are first-line treatments for hypertensive target organ damage and progressive kidney disease. Their effects are greater than could be expected of their ability to lower blood pressure alone. ARBs have been shown to reduce the frequency of atrial fibrillation and stroke. Renin-angiotensin system blockade delays or avoids the onset of type 2 diabetes and prevents cardiovascular and renal events in diabetic patients. Thus, blockade of this system will remain a cornerstone of therapeutic strategies to reduce cardiovascular risk in general.

No longer recommended for initial treatment, because some evidence suggests that they lower blood pressure less well than the medicines above are the beta-blockers, which are mainly divided into medicines that are heart-selective, those that are non heart-selective and those that combine beta-blockade with dilating peripheral blood vessels. Beta-blockers slow the heart rate and decrease blood output. They are still of value in the management of heart failure and for those who, for example, do not tolerate ACE inhibitors.

Three other types of antihypertensive medicines are used less frequently:

• alpha1 antagonists block nerve impulses that trigger blood vessel constriction

• imidazoline agonists act on receptors in the brain

• central alpha agonists also act in the brain.

Secondary effects can occur with any antihypertensive medicine, but differ according to the type of medication and the individual. A doctor will take account of a person’s age and general condition, and medication may be changed if it is not well tolerated.

What’s in the development pipeline? Top

Currently available medicines give satisfactory control of blood pressure in many cases and, with over 40 chemically distinct compounds in the first five classes of antihypertensives listed above, there is a wide choice. However, surveys show that many patients do not achieve target blood pressure levels with existing therapies, perhaps in part due to the need to take several medicines each day.

The medical considerations driving further development are (i) to find the best agent or combination of agents for a particular situation, and (ii) to quantify the benefits of the different classes of medicine in terms of outcomes other than just hypertension, especially in the elderly, who are most in need of blood pressure lowering treatment.

New approaches to treatment are less easy to find in such an intensively studied field, but they are possible. After more than 30 years of basic research, scientists have finally found an orally active non-peptide renin inhibitor which has shown encouraging antihypertensive efficacy in trials, both on its own and in combination with other antihypertensive medicines. The molecule acts on the same biological system as ACE inhibitors and ARBs, but it acts at its starting point – the generation of renin. It was approved by the US FDA in 2007 and should soon be available in the EU. Further compounds with improved oral bioavailability, specificity, and efficacy are now in preclinical development.

Other research groups are studying the effects of selective endothelin-A receptor antagonists. Endothelin-A binds to receptors in smooth muscle cells and causes the narrowing of blood vessels. Another new pathway consists of an oral compound that stimulates an enzyme to release nitric oxide in the cells of the inner lining of blood vessels, making surrounding smooth muscle relax and reducing blood pressure.

Particular approaches are compounds that break the glucose-protein cross-links that accumulate with age in the arteries, especially in people with diabetes. Preliminary studies show this compound to reduce arterial pulse pressure significantly, restoring arterial flexibility. Also a new class of anti-hypertensive treatments are vasopeptidase inhibitors.

An interesting model is the development of a vaccine against angiotensin 2. Instead of blocking the formation of A-2 (as ACE inhibitors do) or its action on specific receptors (as ARBs do), this vaccine stimulates the production of antibodies that bind to it, preventing it acting, and remove it from circulation.

Last, but not least, development of existing classes of antihypertensive medicines has not stopped. Several fixed-dose combinations of ARBs or ACE inhibitors with calcium channel-blockers are being tested.

The longer-term future Top

Hypertension is such an important health problem that research into new treatments will continue to be lively. Inhibitors of the production or action of endothelin and other peptides and enzymes that may be involved in vasoconstriction are among the new compounds being tested.

Research into better ways of using the various classes of antihypertensive medicines is also important, with attention paid to outcomes other than blood pressure control, such as protection of kidney function and prevention of heart attacks and strokes being a key focus. Large long-term trials in these areas are underway