Category:Antianginals

An antianginal is a medicine that relieves or prevents angina pectoris, the chest pain that arises when the oxygen demand of the heart muscle exceeds the supply that the coronary circulation can deliver. The category includes three mechanistically distinct first-line classes (the organic nitrates, the beta-adrenergic blockers, and the calcium channel blockers), and a small number of second-line agents that act on cardiac metabolism or on the sinus-node pacemaker current.

The clinical description came before any treatment. In a lecture to the Royal College of Physicians in London in 1768, the physician William Heberden described a syndrome of strangling chest pain on exertion, particularly after a meal or in cold weather, which he named angina pectoris from the Latin angere (to strangle) and the place where it was felt.^[1] The Scottish anatomist Allan Burns in 1809 proposed that the pain originated in obstruction of the coronary arteries and the resulting ischaemia of the heart muscle. The pharmacological era opened with a medical student. In 1857 Thomas Lauder Brunton, working under John Hughes Bennett at the Royal Infirmary in Edinburgh, observed that his anginal patients improved during bloodletting and concluded that the pain was relieved by lowering blood pressure. Looking for a less aggressive way of doing so, he tried inhaled amyl nitrite, recently described by Antoine-Jérôme Balard as a smooth-muscle relaxant; the report he published in the Lancet in 1867 described almost instant relief of the anginal attack within seconds of inhalation.^[2]

Twelve years later William Murrell of London substituted glyceryl trinitrate, the explosive nitroglycerin synthesized in 1847 by Ascanio Sobrero and brought to industrial use by Alfred Nobel in dynamite, taken sublingually in a tiny dose dissolved on the tongue.^[3] The medicine acted in under two minutes, lasted twenty, and required no inhaler. Within a decade glyceryl trinitrate sublingual tablets had become the standard immediate treatment of an anginal attack, and they remain so a century and a half later. Alfred Nobel, when he developed angina in his sixties, was offered nitroglycerin for it by his Paris physician and is reported to have refused, regarding the proposal as a black-humour confusion of the explosive he had spent his life making safer with the medicine that was now being made from it.

The mechanism by which the organic nitrates relieve angina was elucidated only after a hundred years of empirical use. The American pharmacologist Ferid Murad showed in 1977 that nitroglycerin and the other organic nitrates release nitric oxide in vascular smooth muscle, and the work of Robert Furchgott on endothelium-derived relaxing factor and Louis Ignarro on the identity of EDRF with nitric oxide completed the picture. Furchgott, Ignarro, and Murad shared the Nobel Prize in 1998. Nitric oxide activates guanylate cyclase in smooth muscle, producing cyclic GMP, and the resulting venodilation lowers ventricular preload and so cardiac wall stress and oxygen demand; modest coronary arterial dilation, although less prominent than the venous effect, contributes to the supply side of the same equation. Long-acting nitrates (isosorbide dinitrate and mononitrate, transdermal nitroglycerin) entered clinical use in the 1960s and 1970s; their utility is limited by tachyphylaxis, the rapid development of pharmacological tolerance on continuous exposure, which is managed clinically by a nightly nitrate-free interval.

The second mechanistic addition to antianginal pharmacology was the beta-adrenergic blocker. James Black at Imperial Chemical Industries had developed propranolol in 1964 specifically as an antianginal, on the reasoning that blocking the beta-1 receptor would reduce heart rate, contractility, and so myocardial oxygen demand;^[4] his work was recognised with the 1988 Nobel Prize. The beta-blocker indication for angina has since broadened into routine post-myocardial-infarction and heart-failure use, and the medicines are now considered antianginal as one of several effects rather than as their primary indication. The third class, the calcium channel blockers, arrived through the work of the German pharmacologist Albrecht Fleckenstein on the slow inward calcium current of cardiac and vascular smooth muscle; verapamil (1962), nifedipine (Bayer, 1972), and diltiazem (Tanabe, 1971) lowered coronary vascular resistance and, for the non-dihydropyridines, heart rate and contractility as well. The long-acting dihydropyridine amlodipine (Pfizer, 1992), with its slow onset and 24-hour half-life, became the most widely prescribed antianginal of the contemporary outpatient pharmacopoeia.

The newer antianginal agents address the small fraction of patients whose pain persists despite optimal nitrate, beta-blocker, and calcium-blocker therapy. The selective sinus-node I-f current inhibitor ivabradine (Servier, 2005) lowers heart rate without affecting contractility or blood pressure and is indicated in stable angina at heart rates above 70 beats per minute. The late sodium-current inhibitor ranolazine (CV Therapeutics, 2006) acts intracellularly to reduce calcium overload and diastolic ventricular stiffness without affecting heart rate or blood pressure. The fatty-acid-oxidation inhibitor trimetazidine (Servier, 1978), available in Europe but not in the United States, shifts cardiac metabolism toward glucose utilisation and has shown modest antianginal effect.

The contemporary management of angina is no longer pharmacological alone. Percutaneous coronary intervention (introduced in 1977 by Andreas Grüntzig in Zurich) and surgical coronary artery bypass grafting (first performed in 1960 by Robert Goetz at the Bronx VA and routinely from 1968 by René Favaloro at the Cleveland Clinic) re-established the coronary supply mechanically rather than reducing the cardiac demand pharmacologically, and the optimal balance between medical therapy and revascularisation is the subject of a continuing series of large outcome trials. The COURAGE trial in 2007 and the ISCHEMIA trial in 2020 both demonstrated that, in patients with stable angina, an initial strategy of optimal medical therapy alone was non-inferior to early revascularisation for the major cardiovascular outcomes.^[5]

By mechanism:

• Organic nitrates and other nitric-oxide donors: nitroglycerin (glyceryl trinitrate) (sublingual, lingual spray, intravenous, transdermal), isosorbide dinitrate and mononitrate
• Calcium channel blockers: the dihydropyridines amlodipine and nifedipine; the non-dihydropyridines verapamil and diltiazem
• Beta-adrenergic blockers (cross-indexed; their principal indication is broader): propranolol, atenolol, metoprolol, bisoprolol, carvedilol
• Sinus-node I-f current inhibitors: ivabradine
• Late sodium current inhibitors: ranolazine
• Fatty-acid oxidation inhibitors: trimetazidine (not available in the United States)

The boundary of this category is "medicine prescribed for the symptomatic treatment or prevention of myocardial ischaemic pain." Medicines whose principal indication is the modification of cardiovascular outcome rather than symptom (the statins, the antiplatelet agents, the ACE inhibitors post-infarction) are not collected here, even when their long-term effect includes a reduction in anginal events. The medicines used in the acute coronary syndromes (intravenous heparin, the glycoprotein IIb/IIIa inhibitors, thrombolytics) belong to an adjacent category and are listed under anticoagulants and antiplatelet agents respectively. The phosphodiesterase-5 inhibitors, although they act on the same nitric-oxide / cyclic-GMP pathway as the nitrates, are not antianginals and are mentioned here only because their concurrent use with organic nitrates produces severe and prolonged hypotension; that interaction is documented on the respective medicine pages.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.