Antihypertensive drug
Antihypertensives are a class of
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
Diuretics
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:
- Thiazide-like diuretics:
- indapamide
- chlorthalidone
- metolazone
- xipamide
- clopamide
- Potassium-sparing diuretics:
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
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.[10]
Calcium channel blockers
Calcium channel blockers block the entry of calcium into muscle cells in artery walls, resulting in the relaxation of muscle cells and vasodilation.[11][12]
- dihydropyridines:
- non-dihydropyridines:
The 8th Joint National Committee (JNC-8) recommends calcium channel blockers to be a first-line treatment either as monotherapy or in combination with
The ratio of CCBs' anti-proteinuria effect, non-dihydropyridine to dihydropyridine was 30 to −2.[13] 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.[14]
Notable side effects of CCBs include edema, flushing in the face, headache, drowsiness, and dizziness.[14]
ACE inhibitors
- 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.
However, ACE inhibitors (and angiotensin II receptor antagonists) should not be a first-line treatment for black hypertensives without
Notable side effects of ACE inhibitors include
Angiotensin II receptor antagonists
In 2004, an article in the
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.[26]
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.[27]
As a consequence of AT1 blockade, ARBs increase angiotensin II levels several-fold above baseline by uncoupling a
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.[31][32][33]
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 (such as epinephrine and norepinephrine), 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. [34]
Alpha-blockers can block alpha-1 adrenergic receptors and/or alpha-2 adrenergic receptors.[35] Those that block alpha-1-adrenergic receptors on vascular smooth muscle cells prevent vasoconstriction.[35] Blockade of alpha-2-adrenergic receptors prevents the negative feedback mechanism of norepinephrine (NE).[35] Non-selective alpha-blockers generate a balance whereby alpha-2-blockers release NE to reduce the vasodilation effects induced by alpha-1-blockers.[35]
- Beta blockers
- Alpha blockers:
- Mixed Alpha + Beta blockers:
- bucindolol
- carvedilol
- labetalol
- clonidine (indirectly)
Although
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.[41] However, they may be useful for some men with symptoms of prostate disease.
Vasodilators
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.[45]
Aldosterone receptor antagonist
Aldosterone receptor antagonists, also known as mineralocorticoid receptor antagonist (MRA) can lower blood pressure by blocking the binding of aldosterone to the mineralocorticoid receptor. Spironolactone and eplerenone are MRAs that causes a block in the reabsorption of sodium, resulting in a decrease in blood pressure.[46][47]
Aldosterone receptor antagonists are not recommended as first-line agents for blood pressure,[48] 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
Adverse effects of this class of drugs include sedation, drying of the nasal mucosa and rebound hypertension upon discontinuation.[49]
Some indirect anti-adrenergics are rarely used in treatment-resistant hypertension:
- guanethidine – replaces norepinephrine in vesicles, decreasing its tonic release
- antinicotinicand ganglion blocker
- VMATinhibition
For the most resistant and severe disease, oral minoxidil (Loniten) in combination with a diuretic and β-blocker or other sympathetic nervous system suppressants may be used.[medical citation needed]
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.[50]
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.
The first large study to show a mortality benefit from antihypertensive treatment was the VA-NHLBI study, which found that chlorthalidone was effective.[51] 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).[18] (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.[52]
Thiazide diuretics are effective, recommended as the best first-line drug for hypertension,
Other medications have a role in treating hypertension. Adverse effects of thiazide diuretics include
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
Patient factors
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. Most drugs have other uses; sometimes the presence of other symptoms can warrant the use of one particular antihypertensive. Examples include:
- Age can affect the choice of medications. Current UK guidelines suggest starting patients over the age of 55 years first on calcium channel blockers or thiazide diuretics.
- Age and multi-morbidity can affect the choice of medication, the target blood pressure and even whether to treat or not.[62]
- Anxiety may be improved with the use of beta blockers.
- Asthmatics have been reported to have worsening symptoms when using beta blockers.
- Beta blockers can trigger or worsen psoriasis, psoriatic arthritis, and rheumatoid arthritis.[63]
- Benign prostatic hyperplasia may be improved with the use of an alpha blocker.
- Chronic kidney disease. ACE inhibitors or ARBs should be included in the treatment plan to improve kidney outcomes regardless of race or diabetic status.[7][17]
- Medication Appropriateness Tool for Comorbid Health Conditions in Dementia (MATCH-D).[64]
- complications of diabetes mellitus.
- Gout may be worsened by thiazide diuretics, while losartan reduces serum urate.[65]
- Kidney stones may be improved with the use of thiazide-type diuretics [66]
- Heart block. β-blockers and nondihydropyridine calcium channel blockers should not be used in patients with heart block greater than first degree. JNC8 does not recommend β-blockers as initial therapy for hypertension.[67]
- Heart failure may be worsened with nondihydropyridine calcium channel blockers, the alpha blocker doxazosin, and the alpha-2 agonists moxonidine and clonidine. On the other hand, β-blockers, diuretics, ACE inhibitors, angiotensin receptor blockers, and aldosterone receptor antagonists have been shown to improve outcome.[68]
- Pregnancy. Although α-methyldopa is generally regarded as a first-line agent, labetalol and metoprolol are also acceptable. Atenolol has been associated with intrauterine growth retardation, as well as decreased placental growth and weight when prescribed during pregnancy. ACE inhibitors and angiotensin II receptor blockers (ARBs) are contraindicated in women who are or who intend to become pregnant.[48]
- Periodontal disease could mitigate the efficacy of antihypertensive drugs.[69]
- Race. JNC8 guidelines particularly point out that when used as monotherapy, thiazide diuretics, and calcium channel blockers have been found to be more effective in reducing blood pressure in black hypertensives than β-blockers, ACE inhibitors, or ARBs.[7]
- Tremor may warrant the use of beta blockers.
The JNC8 guidelines indicate reasons to choose one drug over the others for certain individual patients.[7]
Antihypertensive Medication during the First Trimester of Pregnancy
Hypertensive disorders during pregnancy constitute a significant risk factor for maternal and fetal outcomes, necessitating antihypertensive treatment. However, current data concerning the safety of in utero exposure to antihypertensive medication are controversial. While some studies recommend the administration of certain agents, others underline the possible adverse effects on fetal development. In general, a-methyldopa, β-blockers and calcium channel blockers are the first or second treatment line for hypertension during pregnancy. However, ACEIs, ARBs and diuretics are mostly contraindicated, as the potential risk outweighs the benefits of their administration. Additionally, several drugs should be avoided, due to the lack of data regarding their safety.[70] Women are often concerned about the safety of antihypertensives and as a result, many do not take their treatment as prescribed. Shared decision-making aids have been shown to reduce women's uncertainty about taking antihypertensives and increase the number of women taking them as prescribed.[71][72]
History
History of Thiazides
Chlorothiazide was discovered in 1957, but the first known instance of an effective antihypertensive treatment was in 1947 using primaquine, an antimalarial.[73]
History of Calcium Channel Blockers
In 1883, Ringer discovered the involvement of calcium for cellular activity on isolated heart.[74] Later in 1901, Stiles reported the same activity in muscle contraction.[74] In the early 1940s, Kamada (from Japan) and Heilbrunn (from the United States) noted how calcium was involved with muscle contractions.[74] In 1964, calcium channel blockers were discovered in Godfraind’s laboratory through the screening of coronary dilators, which showed how calcium was blocked from entering artery cells, resulting in vasorelaxation.[74]
Research
Blood pressure vaccines
Vaccinations are being trialed and may become a treatment option for high blood pressure in the future. CYT006-AngQb was only moderately successful in studies, but similar vaccines are being investigated.[75]
Anti-hypertensive drugs in older people
The latest evidence does not have evidence of an effect due to discontinuing vs continuing medications used for treating elevated blood pressure or prevention of heart disease in older adults on all-case mortality and incidence of heart attack.[76] The findings are based on low quality evidence suggesting it may be safe to stop anti-hypertensive medications. However, older adults should not stop any of their medications without talking to a healthcare professional.[76]
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