Antihypertensive


Antihypertensives are a class of drugs that are used to treat hypertension. Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infarction. Evidence suggests that a reduction of blood pressure by 5 mmHg can decrease the risk of stroke by 34% and of ischaemic heart disease by 21%. It can reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. There are many classes of antihypertensives, which lower blood pressure by different means. Among the most important and most widely used medications are thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers or antagonists, and beta blockers.
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. 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. As of 2018, the best available evidence favors low-dose thiazide diuretics as the first-line treatment of choice for high blood pressure when drugs are necessary. Although clinical evidence shows calcium channel blockers and thiazide-type diuretics are preferred first-line treatments for most people, an ACEi is recommended by NICE in the UK for those under 55 years old.

Diuretics

s help the kidneys eliminate excess salt and water from the body's tissues and blood.
In the United States, the JNC8 recommends thiazide-type diuretics to be one of the first-line drug treatments for hypertension, either as monotherapy or in combination with calcium channel blockers, ACEis, or ARBs. There are fixed-dose combination drugs, such as ACE inhibitor and thiazide combinations. Despite thiazides being cheap and effective, 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, for whom the risk of new-onset diabetes is outweighed by the benefits of controlling systolic blood pressure. Another theory is that they are off-patent and thus rarely promoted by the drug industry.
Medications that are classified as potassium-sparing diuretics which block the epithelial sodium channel, such as amiloride and triamterene, are seldom prescribed as monotherapy. ENaC blocker medications need stronger public evidence for their blood pressure reducing effect.

Calcium channel blockers

s block the entry of calcium into muscle cells in artery walls, resulting in the relaxation of muscle cells and vasodilation.
The 8th Joint National Committee recommends calcium channel blockers to be a first-line treatment either as monotherapy or in combination with thiazide-type diuretics, ACEis, or ARBs for all patients regardless of age or race.
The ratio of CCBs' anti-proteinuria effect, non-dihydropyridine to dihydropyridine was 30 to −2. The anti-proteinuria effect of non-dihydropyridine is due to better selectivity during glomerular filtration and/or a lower perfusion rate through the renal system.
Notable side effects of CCBs include edema, flushing in the face, headache, drowsiness, and dizziness.

ACEis

ACEis inhibit the activity of angiotensin-converting enzyme, an enzyme responsible for the conversion of angiotensin I into angiotensin II, a potent vasoconstrictor.
A systematic review of 63 trials with over 35,000 participants indicated ACEis significantly reduced doubling of serum creatinine levels compared to other drugs, and the authors suggested this as a first line of defense. The AASK trial showed that ACEis are more effective at slowing down the decline of kidney function compared to calcium channel blockers and beta blockers. As such, ACEis should be the drug treatment of choice for patients with chronic kidney disease regardless of race or diabetic status.
However, ACEis should not be a first-line treatment for black hypertensives without chronic kidney disease. Results from the ALLHAT trial showed that thiazide-type diuretics and calcium channel blockers were both more effective as monotherapy in improving cardiovascular outcomes compared to ACEis for this subgroup. Furthermore, ACEis were less effective in reducing blood pressure and had a 51% higher risk of stroke in black hypertensives when used as initial therapy compared to a calcium channel blocker. There are fixed-dose combination drugs, such as ACE inhibitor and thiazide combinations.
Notable side effects of ACEis include dry cough, high blood levels of potassium, fatigue, dizziness, headaches, loss of taste and a risk for angioedema.

ARBs

ARBs work by antagonizing the activation of angiotensin receptors.
In 2004, an article in the BMJ examined the evidence for and against the suggestion that ARBs may increase the risk of myocardial infarction. The matter was debated in 2006 in the medical journal of the American Heart Association. There is no consensus on whether ARBs have a tendency to increase MI, but there is also no substantive evidence to indicate that ARBs are able to reduce MI.
In the VALUE trial, the ARB valsartan produced a statistically significant 19% relative increase in the prespecified secondary end point of myocardial infarction compared with amlodipine.
The CHARM-alternative trial showed a significant +52% increase in myocardial infarction with candesartan despite a reduction in blood pressure.
As a consequence of AT1 blockade, ARBs increase angiotensin II levels several-fold above baseline by uncoupling a negative-feedback loop. Increased levels of circulating angiotensin II result in unopposed stimulation of the AT2 receptors, which are, in addition upregulated. Recent data suggest that AT2 receptor stimulation may be less beneficial than previously proposed and may even be harmful under certain circumstances through mediation of growth promotion, fibrosis, and hypertrophy, as well as proatherogenic and proinflammatory effects.
An ARB happens to be the favorable alternative to an ACEi if a hypertensive patient with the heart-failure type of reduced ejection fraction treated with an ACEi was intolerant of cough, angioedema other than hyperkalemia or chronic kidney disease.

Adrenergic receptor antagonists

Beta-blockers can block beta-1 adrenergic receptors and/or beta-2 adrenergic receptors. Those that block beta-1-adrenergic receptors prevent the binding of endogenous catecholamines, which ultimately reduces blood pressure through decreasing renin and cardiac output release. Those that block beta-2-adrenergic receptors reduce blood pressure through increased relaxation of smooth muscle.
Alpha-blockers can block alpha-1 adrenergic receptors and/or alpha-2 adrenergic receptors. Those that block alpha-1-adrenergic receptors on vascular smooth muscle cells prevent vasoconstriction. Blockade of alpha-2-adrenergic receptors prevents the negative feedback mechanism of norepinephrine. Non-selective alpha-blockers generate a balance whereby alpha-2-blockers release NE to reduce the vasodilation effects induced by alpha-1-blockers.
Although beta blockers lower blood pressure, they do not have a positive benefit on endpoints as some other antihypertensives do. In particular, beta-blockers are no longer recommended as first-line treatment due to relative adverse risk of stroke and new-onset of type 2 diabetes when compared to other medications, while certain specific beta-blockers such as atenolol appear to be less useful in overall treatment of hypertension than several other agents. A systematic review of 63 trials with over 35,000 participants indicated β-blockers increased the risk of mortality, compared to other antihypertensive therapies. They do, however, have an important role in the prevention of heart attacks in people who have already had a heart attack. In the United Kingdom, the June 2006 "Hypertension: Management of Hypertension in Adults in Primary Care" 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.
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.
However, they may be useful for some men with symptoms of prostate disease.