Antihypertensive drug

Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction.

The antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure).^[1] Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease.^[2] There are many classes of antihypertensives, which lower blood pressure by different means; among the most important and most widely used are the thiazide diuretics, the ACE inhibitors, the calcium channel blockers, the beta blockers, and the angiotensin II receptor antagonists or ARBs.

Which type of medication to use initially for hypertension has been the subject of several large studies and resulting national guidelines. The fundamental goal of treatment should be the prevention of the important endpoints of hypertension, such as heart attack, stroke and heart failure. Patient age, associated clinical conditions and end-organ damage also play a part in determining dosage and type of medication administered..^[3] The several classes of antihypertensives differ in side effect profiles, ability to prevent endpoints, and cost. The choice of more expensive agents, where cheaper ones would be equally effective, may have negative impacts on national healthcare budgets.^[4] As of 2009, the best available evidence favors the thiazide diuretics as the first-line treatment of choice for high blood pressure when drugs are necessary.^[5]

Available agents

Diuretics

Hydrochlorothiazide, a popular thiazide diuretic

Diuretics help the kidneys eliminate excess salt and water from the body's tissues and blood.

• Loop diuretics:
  • bumetanide
  • ethacrynic acid
  • furosemide
  • torsemide
• Thiazide diuretics:
  • epitizide
  • hydrochlorothiazide and chlorothiazide
  • bendroflumethiazide
• Thiazide-like diuretics:
  • indapamide
  • chlorthalidone
  • metolazone
• Potassium-sparing diuretics:
  • amiloride
  • triamterene
  • spironolactone

Only the thiazide and thiazide-like diuretics have good evidence of beneficial effects on important endpoints of hypertension, and hence, should usually be the first choice when selecting a diuretic to treat hypertension. The reason why thiazide-type diuretics are better than the others is (at least in part) thought to be because of their vasodilating properties. Although the diuretic effect of thiazides may be apparent shortly after administration, it takes longer (weeks of treatment) for the full anti-hypertensive effect to develop. In the United States, the JNC7 (The Seventh Report of the Joint National Committee on Prevention of Detection, Evaluation and Treatment of High Blood Pressure) recommends starting with a thiazide diuretic if single therapy is being initiated and another medication is not indicated.^[6] This is based on a slightly better outcome for chlortalidone in the ALLHAT study versus other anti-hypertensives and because thiazide diuretics are relatively cheap.^[7] A subsequent smaller study (ANBP2) published after the JNC7 did not show this small difference in outcome and actually showed a slightly better outcome for ACE-inhibitors in older male patients.^[8]

Despite thiazides being 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. This is because they have been associated with increased risk of new-onset diabetes and as such are recommended for use in patients over 65 where the risk of new-onset diabetes is outweighed by the benefits of controlling systolic blood pressure ^[9]

Another theory is that they are off-patent and thus rarely promoted by the drug industry.^[10]

Adrenergic receptor antagonists

Propranolol, the first beta-blocker to be successfully developed

• Beta blockers
  • atenolol
  • metoprolol
  • nadolol
  • oxprenolol
  • pindolol
  • propranolol
  • timolol
• Alpha blockers:
  • doxazosin
  • phentolamine
  • indoramin
  • phenoxybenzamine
  • prazosin
  • terazosin
  • tolazoline
• Mixed Alpha + Beta blockers:
  • bucindolol
  • carvedilol
  • labetalol

Although beta blockers lower blood pressure, they do not have a positive benefit on endpoints as some other antihypertensives.^[11] In particular, beta-blockers are no longer recommended as first-line treatment due to relative adverse risk of stroke and new-onset diabetes when compared to other medications^[3], while certain specific beta-blockers such asatenolol appear to be less useful in overall treatment of hypertension than several other agents.^[12] They do, however, have an important role in the prevention of heart attacks in people who have already had a heart attack.^[13] In the United Kingdom, the June 2006 "Hypertension: Management of Hypertension in Adults in Primary Care"^[14] guideline of the National Institute for Health and Clinical Excellence, downgraded the role of beta-blockers due to their risk of provoking type 2 diabetes.^[15]

Despite lowering blood pressure, alpha blockers have significantly poorer endpoint outcomes than other antihypertensives, and are no longer recommended as a first-line choice in the treatment of hypertension.^[16] However, they may be useful for some men with symptoms of prostate disease.

Adrenergic receptor agonists

• Alpha-2 agonists:
  • clonidine
  • methyldopa
  • Guanfacine

Calcium channel blockers

Calcium channel blockers block the entry of calcium into muscle cells in artery walls.

• dihydropyridines:
  • amlodipine
  • felodipine
  • isradipine
  • lercanidipine
  • nicardipine
  • nifedipine
  • nimodipine
  • nitrendipine
• non-dihydropyridines:
  • diltiazem
  • verapamil

ACE inhibitors

Captopril, the prototypical ACE inhibitor

ACE inhibitors inhibit the activity of Angiotensin-converting enzyme (ACE), an enzyme responsible for the conversion of angiotensin I into angiotensin II, a potent vasoconstrictor.

• captopril
• enalapril
• fosinopril
• lisinopril
• perindopril
• quinapril
• ramipril
• trandolapril
• benazepril

Angiotensin II receptor antagonists

Valsartan, an angiotensin II receptor antagonist

Angiotensin II receptor antagonists work by antagonizing the activation of angiotensin receptors.

• candesartan
• eprosartan
• irbesartan
• losartan
• olmesartan
• telmisartan
• valsartan

Aldosterone antagonists

Aldosterone receptor antagonists:

• eplerenone
• spironolactone

Aldosterone antagonists are not recommended as first-line agents for blood pressure,^[6] but spironolactone and eplerenone are both used in the treatment of heart failure.

Vasodilators

Vasodilators act directly on the smooth muscle of arteries to relax their walls so blood can move more easily through them; they are only used in hypertensive emergencies or when other drugs have failed, and even so are rarely given alone.

Sodium nitroprusside, a very potent, short-acting vasodilator, is most commonly used for the quick, temporary reduction of blood pressure in emergencies (such as malignant hypertension or aortic dissection).^[17][18] Hydralazine and its derivatives are also used in the treatment of severe hypertension, although they should be avoided in emergencies.^[18] They are no longer indicated as first-line therapy for high blood pressure due to side effects and safety concerns, but hydralazine remains a drug of choice in gestational hypertension.^[17]

Centrally acting adrenergic drugs

Central alpha agonists lower blood pressure by stimulating alpha-receptors in the brain which open peripheral arteries easing blood flow. Central alpha agonists, such as clonidine, are usually prescribed when all other anti-hypertensive medications have failed. For treating hypertension, these drugs are usually administered in combination with a diuretic.

• Clonidine
• Guanabenz
• Methyldopa
• Moxonidine

Adverse effects of this class of drugs include sedation, drying of the nasal mucosa and rebound hypertension.

Some adrenergic neuron blockers are used for the most resistant forms of hypertension:

• Guanethidine
• Reserpine

Future treatment options

Blood pressure vaccine

Blood pressure vaccinations are being trialed and may become a treatment option for high blood pressure in the future. Research on the vaccine CYT006-AngQb published in The Lancet on the 8 March 2008 titled, “Vaccination against high blood pressure: a new strategy” showed patients experienced a drop in systolic and diastolic blood pressure after taking the vaccine. Effective blood pressure vaccines would assist those people who forget to take their medication. It would also help those who stop taking their medication due to side effects or falsely believing they don't need them anymore once their blood pressure is lowered.^[19]

Choice of initial medication

For mild blood pressure elevation, consensus guidelines call for medically-supervised lifestyle changes and observation before recommending initiation of drug therapy. However, according to the American Hypertension Association, evidence of sustained damage to the body may be present even prior to observed elevation of blood pressure. Therefore the use of hypertensive medications may be started in individuals with apparent normal blood pressures but who show evidence of hypertension related nephropathy, proteinuria, atherosclerotic vascular disease, as well as other evidence of hypertension related organ damage.

If lifestyle changes are ineffective, then drug therapy is initiated, often requiring more than one agent to effectively lower hypertension. Which type of many medications should be used initially for hypertension has been the subject of several large studies and various national guidelines.

The largest study, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), concluded that thiazide-type diuretics are better and cheaper than other major classes of drugs at preventing cardiovascular disease, and should be preferred as the starting drug. ALLHAT used the thiazide diuretic chlorthalidone.^[7] (ALLHAT showed that doxazosin, an alpha-adrenergic receptor blocker, had a higher incidence of heart failure events, and the doxazosin arm of the study was stopped.)

A subsequent smaller study (ANBP2) did not show the slight advantages in thiazide diuretic outcomes observed in the ALLHAT study, and actually showed slightly better outcomes for ACE-inhibitors in older white male patients.^[8]

Thiazide diuretics are effective, recommended as the best first-line drug for hypertension by many experts, and are much more affordable than other therapies, yet they are not prescribed as often as some newer drugs. Hydrochlorothiazide is perhaps the safest and most inexpensive agent commonly used in this class and is very frequently combined with other agents in a single pill. Doses in excess of 25 milligrams per day of this agent incur an unacceptable risk of low potassium or Hypokalemia. Patients with an exaggerated hypokalemic response to a low dose of a thiazide diuretic should be suspected to have Hyperaldosteronism, a common cause of secondary hypertension.

Other drugs have a role in treating hypertension. Adverse effects of thiazide diuretics include hypercholesterolemia, and impaired glucose tolerance with increased risk of developing Diabetes mellitus type 2. The thiazide diuretics also deplete circulating potassium unless combined with a potassium-sparing diuretic or supplemental potassium. Some authors have challenged thiazides as first line treatment.^[20][21][22] However as the Merck Manual of Geriatrics notes, "thiazide-type diuretics are especially safe and effective in the elderly."^[23]

Current UK guidelines suggest starting patients over the age of 55 years and all those of African/Afrocaribbean ethnicity firstly on calcium channel blockers or thiazide diuretics, whilst younger patients of other ethnic groups should be started on ACE-inhibitors. Subsequently if dual therapy is required to use ACE-inhibitor in combination with either a calcium channel blocker or a (thiazide) diuretic. Triple therapy is then of all three groups and should the need arise then to add in a fourth agent, to consider either a further diuretic (e.g. spironolactone or furosemide), an alpha-blocker or a beta-blocker.^[24] Prior to the demotion of beta-blockers as first line agents, the UK sequence of combination therapy used the first letter of the drug classes and was known as the "ABCD rule".^[24][25]

The choice between the drugs is to a large degree determined by the characteristics of the patient being prescribed for, the drugs' side-effects, and cost. For example, asthmatics have been reported to have worsening symptoms when using beta blockers. Most drugs have other uses; sometimes the presence of other symptoms can warrant the use of one particular antihypertensive (such as beta blockers in case of tremor and nervousness, and alpha blockers in case of benign prostatic hyperplasia). The JNC 7 report outlines compelling reasons to choose one drug over the others for certain individual patients.^[6]

Non-drug treatment options

Several studies have found that hibiscus tea has a substantial antihypertensive effect attributable to the flower's ACE-inhibiting anthocyanin content, and possibly to a diuretic effect. One study found that hibiscus conferred an antihypertensive effect comparable to 50 mg./day of the drug captopril.^{[26][27][28][29][30]}

Another potential treatment is Coenzyme Q10^[31], which a meta analysis of 12 studies found reductions in systolic pressure of 10-17 points and a reduction in diastolic pressure of 8-10 points^[32] with doses of roughly 200mg/day.

See also

• Prehypertension
• Pulse pressure

References