antihypertensive drug antihypertensive drug antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infarction. evidence suggests that reduction of the blood pressure by 5 mmhg can decrease the risk of stroke by 34% and of ischaemic heart disease by 21%, and 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, ace inhibitors, angiotensin ii receptor antagonists (arbs), 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 (from both efficacy and cost points of view), an ace inhibitor is recommended by nice in the uk for those under 55 years old. 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 methyclothiazide polythiazide thiazide-like diuretics: indapamide chlorthalidone metolazone xipamide clopamide potassium-sparing diuretics: amiloride triamterene spironolactone eplerenone in the united states, the jnc8 (eighth joint national committee on the prevention, detection, evaluation, and treatment of high blood pressure) 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, ace inhibitors, or angiotensin ii receptor antagonists. 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 (enac), 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 calcium channel blockers block the entry of calcium into muscle cells in artery walls. dihydropyridines: amlodipine barnidipine cilnidipine clevidipine felodipine isradipine lercanidipine levamlodipine nicardipine nifedipine nimodipine nisoldipine nitrendipine non-dihydropyridines: diltiazem verapamil the 8th joint national committee (jnc-8) recommends calcium channel blockers to be a first-line treatment either as monotherapy or in combination with thiazide-type diuretics, ace inhibitors, or angiotensin ii receptor antagonists for all patients regardless of age or race. the ratio of ccbs' anti-proteinuria effect, non-dihydropyridine to dihydropyridine was 30 to -2. 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 moexipril perindopril quinapril ramipril trandolapril benazepril a systematic review of 63 trials with over 35,000 participants indicated ace inhibitors significantly reduced doubling of serum creatinine levels compared to other drugs (arbs, α blockers, β blockers, etc.), and the authors suggested this as a first line of defense. the aask trial showed that ace inhibitors are more effective at slowing down the decline of kidney function compared to calcium channel blockers and beta blockers. as such, ace inhibitors should be the drug treatment of choice for patients with chronic kidney disease regardless of race or diabetic status. however, ace inhibitors (and angiotensin ii receptor antagonists) 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 ace inhibitors for this subgroup. furthermore, ace inhibitors 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 ace inhibitors include dry cough, high blood levels of potassium, fatigue, dizziness, headaches, loss of taste and a risk for angioedema. angiotensin ii receptor antagonists valsartan, an angiotensin ii receptor antagonist angiotensin ii receptor antagonists work by antagonizing the activation of angiotensin receptors. azilsartan candesartan eprosartan irbesartan losartan olmesartan telmisartan valsartan fimasartan in 2004, an article in the bmj examined the evidence for and against the suggestion that angiotensin receptor blockers may increase the risk of myocardial infarction (heart attack). 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 angiotensin ii receptor blocker valsartan produced a statistically significant 19% (p=0.02) relative increase in the prespecified secondary end point of myocardial infarction (fatal and non-fatal) compared with amlodipine. the charm-alternative trial showed a significant +52% (p=0.025) increase in myocardial infarction with candesartan (versus placebo) 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. arbs happens to be the favorable alternative to ace inhibitors if the hypertensive patients with the heart failure type of reduced ejection fraction treated with aceis was intolerant of cough, angioedema other than hyperkalemia or chronic kidney disease. adrenergic receptor antagonists propranolol, the first beta-blocker to be successfully developed beta blockers acebutolol atenolol bisoprolol betaxolol carteolol carvedilol labetalol metoprolol nadolol nebivolol oxprenolol penbutolol pindolol propranolol timolol alpha blockers: doxazosin chlorpromazine phentolamine indoramin phenoxybenzamine prazosin terazosin tolazoline urapidil mixed alpha + beta blockers: bucindolol carvedilol labetalol clonidine (indirectly) although beta blockers lower blood pressure, they do not have a positive benefit on endpoints as some other antihypertensives. 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. 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). hydralazine and its derivatives are also used in the treatment of severe hypertension, although they should be avoided in emergencies. 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. renin inhibitors renin comes one level higher than angiotensin converting enzyme (ace) in the renin–angiotensin system. renin inhibitors can therefore effectively reduce hypertension. aliskiren (developed by novartis) is a renin inhibitor which has been approved by the u.s. fda for the treatment of hypertension. aldosterone receptor antagonist aldosterone receptor antagonists: eplerenone spironolactone aldosterone receptor antagonists are not recommended as first-line agents for blood pressure, but spironolactone and eplerenone are both used in the treatment of heart failure and resistant hypertension. alpha-2 adrenergic receptor agonists central alpha agonists lower blood pressure by stimulating alpha-receptors in the brain which open peripheral arteries easing blood flow. these alpha 2 receptors are known as autoreceptors which provide negative feedback in neurotransmission (in this case, the vasoconstriction effects of adrenaline). 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 guanfacine methyldopa moxonidine adverse effects of this class of drugs include sedation, drying of the nasal mucosa and rebound hypertension. some indirect anti-adrenergics are rarely used in treatment-resistant hypertension: guanethidine - replaces norepinephrine in vesicles, decreasing its tonic release mecamylamine - antinicotinic and ganglion blocker reserpine - indirect via irreversible vmat inhibition for the most resistant and severe disease, oral minoxidil (loniten) in combination with diuretic and β-blocker or other sympathetic nervous system suppressants may be used. endothelium receptor blockers bosentan belongs to a new class of drugs and works by blocking endothelin receptors. it is specifically indicated only for the treatment of pulmonary artery hypertension in patients with moderate to severe heart failure. 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. considerations include factors such as age, race, and other medical conditions. in the united states, jnc8 (2014) recommends any drug from one of the four following classes to be a good choice as either initial therapy or as an add-on treatment: thiazide-type diuretics, calcium channel blockers, ace inhibitors, or angiotensin ii receptor antagonists. the first large study to show a mortality benefit from antihypertensive treatment was the va-nhlbi study, which found that chlorthalidone was effective. the largest study, antihypertensive and lipid-lowering treatment to prevent heart attack trial (allhat) in 2002, concluded that chlorthalidone, (a thiazide-like diuretic) was as effective as lisinopril (an angiotensin converting enzyme inhibitor) or amlodipine (a calcium channel blocker). (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. thiazide diuretics are