降圧薬

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Antihypertensive drug/ja
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降圧薬は、高血圧の治療に用いられる薬物の一種である。降圧療法は、脳卒中、心不全、腎不全、心筋梗塞などの高血圧の合併症を予防しようとするものである。血圧を5 mmHg下げると、脳卒中のリスクが34％、虚血性心疾患のリスクが21％減少し、認知症、心不全、心血管系疾患による死亡率が減少するというエビデンスがある。抗高血圧薬には多くの種類があり、さまざまな方法で血圧を下げる。最も重要で最も広く使用されている医薬品は、サイアザイド系利尿薬、カルシウム拮抗薬、ACE阻害薬、アンジオテンシンII受容体拮抗薬（ARB）、β遮断薬である。

高血圧に対してどの種類の医薬品を最初に使用するかは、いくつかの大規模な研究によって検討され、その結果、国のガイドラインが作成されている。治療の基本的な目標は、心筋梗塞、脳卒中、心不全などの高血圧の重要なエンドポイントを予防することである。投与する医薬品の量や種類を決定する際には、患者の年齢、関連する臨床症状、末端臓器障害も関係する。いくつかのクラスの抗高血圧薬は，副作用のプロファイル，エンドポイントを予防する能力，そしてコストにおいて異なっている。より安価な薬剤でも同等の効果があるにもかかわらず、より高価な薬剤を選択することは、国の医療予算に悪影響を及ぼす可能性がある。2018年現在、入手可能な最良のエビデンスは、薬物が必要な場合の高血圧治療の第一選択薬として低用量サイアザイド系利尿薬を支持している。臨床エビデンスによれば、カルシウム拮抗薬とサイアザイド系利尿薬が、ほとんどの人にとって（有効性とコストの両面から）望ましい第一選択薬であるが、英国では55歳未満にはACE阻害薬がNICEによって推奨されている。

利尿薬

一般的なサイアザイド系利尿薬であるヒドロクロロチアジド

利尿薬は、腎臓が体内の組織や血液から余分な塩分や水分を排出するのを助ける。

米国では、JNC8（第8回高血圧の予防、検出、評価および治療に関する合同委員会）は、カルシウム拮抗薬、ACE阻害薬、またはアンジオテンシンII受容体拮抗薬との単独療法または併用療法として、サイアザイド系利尿薬を高血圧の第一選択薬として推奨している。ACE阻害薬とサイアザイドの合剤のような配合薬もある。サイアザイド系薬剤は安価で効果的であるにもかかわらず、新しい薬物ほど頻繁に処方されることはない。これは、サイアザイド系薬剤が新規糖尿病発症リスクの増加と関連しているためであり、新規糖尿病発症リスクが収縮期血圧をコントロールするメリットよりも大きい65歳以上の患者への使用が推奨されている。もう一つの説は、これらの薬が特許切れであるため、薬物業界がほとんど宣伝していないということである。

アミロリドやトリアムテレンなどの上皮性ナトリウムチャネル（ENaC）を遮断するカリウム温存利尿薬に分類される医薬品は、単剤療法として処方されることはほとんどない。ENaC遮断薬は、その血圧降下効果について、より強力な公的エビデンスが必要である。

カルシウム拮抗薬

カルシウム拮抗薬は、動脈壁の筋肉細胞へのカルシウムの侵入を阻害する。

第8回米国合同委員会（JNC-8）は、年齢や人種に関係なく、すべての患者に対してカルシウム拮抗薬を単剤またはサイアザイド系利尿薬、ACE阻害薬、アンジオテンシンII受容体拮抗薬との併用で第一選択薬とすることを推奨している。

CCBの抗蛋白尿効果の非ジヒドロピリジン系とジヒドロピリジン系の比率は30対-2であった。

ACE阻害薬

カプトプリル、代表的なACE阻害薬

ACE阻害薬は、アンジオテンシンIから強力な血管収縮物質であるアンジオテンシンIIへの変換を担う酵素であるアンジオテンシン変換酵素（ACE）の活性を阻害する。

35,000人以上が参加した63の試験のシステマティックレビューでは、ACE阻害薬は他の薬物（ARB、α遮断薬、β遮断薬など）に比べて血清クレアチニン値の倍加を有意に抑制することが示され、著者らはこれを第一選択薬として推奨している。AASK試験では、ACE阻害薬はカルシウム拮抗薬やβ遮断薬に比べて腎機能の低下を遅らせる効果があることが示された。そのため、ACE阻害薬は人種や糖尿病の有無にかかわらず、慢性腎臓病患者に選択されるべき薬物治療である。

しかし、ACE阻害薬（およびアンジオテンシンII受容体拮抗薬）は慢性腎臓病のない黒人の高血圧患者には第一選択薬とすべきではない。ALLHAT試験の結果では、このサブグループではACE阻害薬よりもサイアザイド系利尿薬とカルシウム拮抗薬の単剤療法の方が心血管予後の改善に有効であった。さらに、ACE阻害薬はカルシウム拮抗薬と比較して、初回治療として使用した場合、黒人の高血圧患者では血圧降下効果が低く、脳卒中のリスクが51％高かった。ACE阻害薬とサイアザイド系薬剤の合剤のような配合薬もある。

ACE阻害薬の注目すべき副作用には、空咳、カリウムの高血中濃度、疲労、めまい、頭痛、味覚障害、血管浮腫のリスクなどがある。

Angiotensin II receptor antagonists

Valsartan, an angiotensin II receptor antagonist

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

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.Template:Citation needed

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

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.Template:Cn

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:Template:Cn

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.

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:

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 effective, recommended as the best first-line drug for hypertension, and are much more affordable than other therapies, yet they are not prescribed as often as some newer drugs. Chlorthalidone is the thiazide drug that is most strongly supported by the evidence as providing a mortality benefit; in the ALLHAT study, a chlorthalidone dose of 12.5 mg was used, with titration up to 25 mg for those subjects who did not achieve blood pressure control at 12.5 mg. Chlorthalidone has repeatedly been found to have a stronger effect on lowering blood pressure than hydrochlorothiazide, and hydrochlorothiazide and chlorthalidone have a similar risk of hypokalemia and other adverse effects at the usual doses prescribed in routine clinical practice. 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 medications 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.

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. 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".

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.
  • Anxiety may be improved with the use of beta blockers.
  • Asthmatics have been reported to have worsening symptoms when using beta blockers.
  • 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.
  • Late-stage Dementia should consider Deprescribing antihypertensives, according to the Medication Appropriateness Tool for Comorbid Health Conditions in Dementia (MATCH-D)
  • Diabetes mellitus. The ACE inhibitors and angiotensin receptor blockers have been shown to prevent the kidney and retinal complications of diabetes mellitus.
  • Gout may be worsened by thiazide diuretics, while losartan reduces serum urate.
  • Kidney stones may be improved with the use of thiazide-type diuretics
  • 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
  • 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.
  • 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.
  • Periodontal disease could mitigate the efficacy of antihypertensive drugs.
  • 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.
  • Tremor may warrant the use of beta blockers.

The JNC8 guidelines indicate reasons to choose one drug over the others for certain individual patients.

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. 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.

History

Chlorothiazide was discovered in 1957, but the first known instance of an effective antihypertensive treatment was in 1947 using Primaquine, an antimalarial.

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.

Withdrawal of 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. 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.

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