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ACE inhibitor

Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of high blood pressure and heart failure. This class of medicine works by causing relaxation of blood vessels as well as a decrease in blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart.

ACE inhibitors inhibit the activity of angiotensin-converting enzyme, an important component of the renin–angiotensin system which converts angiotensin I to angiotensin II, and hydrolyses bradykinin. Therefore, ACE inhibitors decrease the formation of angiotensin II, a vasoconstrictor, and increase the level of bradykinin, a peptide vasodilator. This combination is synergistic in lowering blood pressure.

As a result of inhibiting the ACE enzyme in the bradykinin system, the ACE inhibitor drugs allow for increased levels of bradykinin which would normally be degraded. Bradykinin produces prostaglandin. This mechanism can explain the two most common side effects seen with ACE Inhibitors: angioedema and cough.

Frequently prescribed ACE inhibitors include benazepril, zofenopril, perindopril, trandolapril, captopril, enalapril, lisinopril, and ramipril.

Medical use
ACE inhibitors were initially approved for the treatment of hypertension and can be used alone or in combination with other anti-hypertensive medications. Later, they were found useful for other cardiovascular and kidney diseases including:
 * Acute myocardial infarction (heart attack)
 * Heart failure (left ventricular systolic dysfunction)
 * Kidney complications of diabetes mellitus (diabetic nephropathy) by means of decreasing the blood pressure and preventing glomerular hyperfiltration injury

In treating high blood pressure, ACE inhibitors are often the first drug choice, particularly when diabetes is present, but age can lead to different choices and it is common to need more than one drug to obtain the desired improvement. There are fixed-dose combination drugs, such as ACE inhibitor and thiazide combinations. ACE inhibitors have also been used in chronic kidney failure and kidney involvement in systemic sclerosis (hardening of tissues, as scleroderma renal crisis). In those with stable coronary artery disease, but no heart failure, benefits are similar to other usual treatments.

In 2012, a meta-analysis published in the BMJ described the protective role of ACE inhibitors in reducing the risk of pneumonia when compared to angiotensin II receptor blocker (ARBs). The authors found a decreased risk in patients with previous stroke (54% risk reduction), with heart failure (37% risk reduction), and of Asian descent (43% risk reduction vs 54% risk reduction in non-Asian population). However, no reduced pneumonia-related mortality was observed.

Other
ACE inhibitors may also be used to help decrease excessive water consumption in people with schizophrenia resulting in psychogenic polydipsia. A double-blind, placebo-controlled trial showed that when used for this purpose, enalapril led to decreased consumption (determined by urine output and osmolality) in 60% of people; the same effect has been demonstrated in other ACE inhibitors.

Additionally ACE-I are commonly used after renal transplant to manage post-transplant erythrocytosis, a condition characterised by a persistently high hematocrit greater than 51% which often develops 8–24 months after successful transplantation, as ACE-I have been shown to decrease erythropoietin production.

Adverse effects
Common side effects include: low blood pressure, cough, hyperkalemia, headache, dizziness, fatigue, nausea, and kidney impairment.

The main adverse effects of ACE inhibition can be understood from their pharmacological action. The other reported adverse effects are liver problems and effects on the fetus. Kidney problems may occur with all ACE inhibitors that directly follows from their mechanism of action. Patients starting on an ACE inhibitor usually have a modest reduction in glomerular filtration rate (GFR). However, the decrease may be significant in conditions of pre-existing decreased renal perfusions, such as renal artery stenosis, heart failure, polycystic kidney disease, or volume depletion. In these patients, the maintenance of GFR depends on angiotensin-II-dependent efferent vasomotor tone. Therefore, renal function should be closely monitored over the first few days after initiation of treatment with ACE inhibitor in patients with decreased renal perfusion. A moderate reduction in renal function, no greater than 30% rise in serum creatinine, that is stabilized after a week of treatment is deemed acceptable as part of the therapeutic effect, providing the residual renal function is sufficient.

Reduced GFR is especially a problem if the patient is concomitantly taking an NSAID and a diuretic. When the three drugs are taken together, the risk of developing renal failure is significantly increased.

High blood potassium is another possible complication of treatment with an ACE inhibitor due to its effect on aldosterone. Suppression of angiotensin II leads to a decrease in aldosterone levels. Since aldosterone is responsible for increasing the excretion of potassium, ACE inhibitors can cause retention of potassium. Some people, however, can continue to lose potassium while on an ACE inhibitor. Hyperkalemia may decrease the velocity of impulse conduction in the nerves and muscles, including cardiac tissues. This leads to cardiac dysfunction and neuromuscular consequences, such as muscle weakness, paresthesia, nausea, diarrhea, and others. Close monitoring of potassium levels is required in patients receiving treatment with ACE inhibitors who are at risk of hyperkalemia.

Another possible adverse effect specific for ACE inhibitors, but not for other RAAS blockers, is an increase in bradykinin level.

A persistent dry cough is a relatively common adverse effect believed to be associated with the increases in bradykinin levels produced by ACE inhibitors, although the role of bradykinin in producing these symptoms has been disputed. Many cases of cough in people on ACE inhibitors may not be from the medication itself, however. People who experience this cough are often switched to angiotensin II receptor antagonists.

Some (0.7%) develop angioedema due to increased bradykinin levels. A genetic predisposition may exist.

A severe rare allergic reaction can affect the bowel wall and secondarily cause abdominal pain.

Blood
Hematologic effects, such as neutropenia, agranulocytosis and other blood dyscrasias, have occurred during therapy with ACE inhibitors, especially in people with additional risk factors.

Pregnancy
In pregnant women, ACE inhibitors taken during all the trimesters have been reported to cause congenital malformations, stillbirths, and neonatal deaths. Commonly reported fetal abnormalities include hypotension, renal dysplasia, anuria/oliguria, oligohydramnios, intrauterine growth retardation, pulmonary hypoplasia, patent ductus arteriosus, and incomplete ossification of the skull. Overall, about half of newborns exposed to ACE inhibitors are adversely affected, leading to birth defects.

ACE inhibitors are ADEC pregnancy category D and should be avoided in women who are likely to become pregnant. In the U.S., ACE inhibitors must be labeled with a boxed warning concerning the risk of birth defects when taken during the second and third trimester. Their use in the first trimester is also associated with a risk of major congenital malformations, particularly affecting the cardiovascular and central nervous systems.

Overdose
Symptoms and Treatment: There are few reports of ACE inhibitor overdose in the literature. The most likely manifestations are hypotension, which may be severe, hyperkalemia, hyponatremia and renal impairment with metabolic acidosis. Treatment should be mainly symptomatic and supportive, with volume expansion using normal saline to correct hypotension and improve renal function, and gastric lavage followed by activated charcoal and a cathartic to prevent further absorption of the drug. Captopril, enalapril, lisinopril and perindopril are known to be removable by hemodialysis.

Contraindications and precautions
The ACE inhibitors are contraindicated in people with:
 * Pregnancy or breastfeeding
 * Previous angioedema associated with ACE inhibitor therapy
 * Bilateral renal artery stenosis
 * Hypersensitivity to ACE inhibitors

ACE inhibitors should be used with caution in people with:
 * Impaired renal function
 * Aortic valve stenosis or cardiac outflow obstruction
 * Hypovolemia or dehydration
 * Hemodialysis with high-flux polyacrylonitrile membranes

A combination of ACE inhibitor with other drugs may increase effects of these drugs, but also the risk of adverse effects. The commonly reported adverse effects of drug combination with ACE inhibitor are acute renal failure, hypotension, and hyperkalemia. The drugs interacting with ACE inhibitor should be prescribed with caution. Special attention should be given to combinations of ACE inhibitor with other RAAS blockers, diuretics (especially potassium-sparing diuretics), NSAIDs, anticoagulants, cyclosporine, DPP-4 inhibitors, and potassium supplements.

Potassium supplementation should be used with caution and under medical supervision owing to the hyperkalemic effect of ACE inhibitors.

Concomitant use with cyclooxygenase inhibitors tends to decrease ACE inhibitor's hypotensive effect.

Mechanism of action
ACE inhibitors reduce the activity of the renin–angiotensin–aldosterone system (RAAS) as the primary etiologic (causal) event in the development of hypertension in people with diabetes mellitus, as part of the insulin-resistance syndrome or as a manifestation of renal disease.

Renin–angiotensin–aldosterone system
The renin–angiotensin–aldosterone system is a major blood pressure regulating mechanism. Markers of electrolyte and water imbalance in the body such as hypotension, low distal tubule sodium concentration, decreased blood volume and high sympathetic tone trigger the release of the enzyme renin from the cells of juxtaglomerular apparatus in the kidney.

Renin activates a circulating liver derived prohormone angiotensinogen by proteolytic cleavage of all but its first ten amino acid residues known as angiotensin I. ACE (angiotensin converting enzyme) then removes a further two residues, converting angiotensin I into angiotensin II. ACE is found in the pulmonary circulation and in the endothelium of many blood vessels. The system increases blood pressure by increasing the amount of salt and water the body retains, although angiotensin II is also a potent vasoconstrictor.

Effects
ACE inhibitors block the conversion of angiotensin I (ATI) to angiotensin II (ATII). They thereby lower arteriolar resistance and increase venous capacity; decrease cardiac output, cardiac index, stroke work, and volume; lower resistance in blood vessels in the kidneys; and lead to increased natriuresis (excretion of sodium in the urine). Renin increases in concentration in the blood as a result of negative feedback of conversion of ATI to ATII. ATI increases for the same reason; ATII and aldosterone decrease. Bradykinin increases because of less inactivation by ACE.

Under normal conditions, angiotensin II has these effects:
 * Vasoconstriction (narrowing of blood vessels) and vascular smooth muscle hypertrophy (enlargement) induced by ATII may lead to increased blood pressure and hypertension. Further, constriction of the efferent arterioles of the kidney leads to increased perfusion pressure in the glomeruli.
 * It contributes to ventricular remodeling and ventricular hypertrophy of the heart through stimulation of the proto-oncogenes c-fos, c-jun, c-myc, transforming growth factor beta (TGF-B), through fibrogenesis and apoptosis (programmed cell death).
 * Stimulation by ATII of the adrenal cortex to release aldosterone, a hormone that acts on kidney tubules, causes sodium and chloride ions retention and potassium excretion. Sodium is a "water-holding" ion, so water is also retained, which leads to increased blood volume, hence an increase in blood pressure.
 * Stimulation of the posterior pituitary to release vasopressin (antidiuretic hormone, ADH) also acts on the kidneys to increase water retention. If ADH production is excessive in heart failure, Na+ level in the plasma may fall (hyponatremia), and this is a sign of increased risk of death in heart failure patients.
 * A decrease renal protein kinase C

During the course of ACE inhibitor use, the production of ATII is decreased, which prevents aldosterone release from the adrenal cortex. This allows the kidney to excrete sodium ions along with obligate water, and retain potassium ions. This decreases blood volume, leading to decreased blood pressure.

Epidemiological and clinical studies have shown ACE inhibitors reduce the progress of diabetic nephropathy independently from their blood pressure-lowering effect. This action of ACE inhibitors is used in the prevention of diabetic renal failure.

ACE inhibitors have been shown to be effective for indications other than hypertension even in patients with normal blood pressure. The use of a maximum dose of ACE inhibitors in such patients (including for prevention of diabetic nephropathy, congestive heart failure, and prophylaxis of cardiovascular events) is justified, because it improves clinical outcomes independently of the blood pressure-lowering effect of ACE inhibitors. Such therapy, of course, requires careful and gradual titration of the dose to prevent the effects of rapidly decreasing blood pressure (dizziness, fainting, etc.).

ACE inhibitors have also been shown to cause a central enhancement of parasympathetic nervous system activity in healthy volunteers and patients with heart failure. This action may reduce the prevalence of malignant cardiac arrhythmias, and the reduction in sudden death reported in large clinical trials. ACE Inhibitors also reduce plasma norepinephrine levels, and its resulting vasoconstriction effects, in heart failure patients, thus breaking the vicious circles of sympathetic and renin angiotensin system activation, which sustains the downward spiral in cardiac function in congestive heart failure

The ACE inhibitor enalapril has also been shown to reduce cardiac cachexia in patients with chronic heart failure. Cachexia is a poor prognostic sign in patients with chronic heart failure. ACE inhibitors are under early investigation for the treatment of frailty and muscle wasting (sarcopenia) in elderly patients without heart failure.

Examples
Currently, there are 10 ACE inhibitors approved for use in the United States by the FDA: captopril (1981), enalapril (1985), lisinopril (1987), benazepril (1991), fosinopril (1991), quinapril (1991), ramipril (1991), perindopril (1993), moexipril (1995) and trandolapril (1996).

ACE inhibitors are easily identifiable by their common suffix, '-pril'. ACE inhibitors can be divided into three groups based on their molecular structure of the enzyme binding sites (sulfhydryl, phosphinyl, carboxyl) to the active center of ACE:

Sulfhydryl-containing agents

 * Alacepril
 * Captopril (trade name Capoten), the first ACE inhibitor.
 * Zofenopril

These agents appear to show antioxidative properties but may be involved in adverse events such as skin eruptions.

Dicarboxylate-containing agents
This is the largest group, including:
 * Enalapril (Vasotec/Renitec/Berlipril/Enap/Enalapril Profarma)
 * Ramipril (Altace/Prilace/Ramace/Ramiwin/Triatec/Tritace/Ramitac)
 * Quinapril (Accupril)
 * Perindopril (Coversyl/Aceon/Perindo)
 * Lisinopril (Listril/Lopril/Novatec/Prinivil/Zestril, Lisidigal)
 * Benazepril (Lotensin)
 * Imidapril (Tanatril)
 * Trandolapril (Mavik/Odrik/Gopten)
 * Cilazapril (Inhibace)

Phosphonate-containing agents

 * Ceronapril (never marketed)
 * Fosinopril (Fositen/Monopril)

Naturally occurring

 * A comprehensive resource on anti-hypertensive peptides is available in form of a database. It contains around 1700 unique antihypertensive peptides
 * Arfalasin (HOE 409) is angiotensin antagonist.

Dairy products

 * Casokinins and lactokinins, breakdown products of casein and whey, occur naturally after ingestion of milk products, especially cultured milk. Their role in blood pressure control is uncertain.
 * The lactotripeptides Val-Pro-Pro and Ile-Pro-Pro produced by the probiotic Lactobacillus helveticus or derived from casein have been shown to have ACE-inhibiting and antihypertensive functions. In one study, L. helveticus PR4 was isolated from Italian cheeses.

Comparative information
All ACE inhibitors have similar antihypertensive efficacy when equivalent doses are administered. The main differences lie with captopril, the first ACE inhibitor. Captopril has a shorter duration of action and an increased incidence of adverse effects. It is also the only ACE inhibitor capable of passing through the blood–brain barrier, although the significance of this characteristic has not been shown to have any positive clinical effects.

In a large clinical study, one of the agents in the ACE inhibitor class, ramipril (Altace), demonstrated an ability to reduce the mortality rates of patients with a myocardial infarction and to slow the subsequent development of heart failure. This finding was made after it was discovered that regular use of ramipril reduced mortality rates even in test subjects who did not have hypertension.

Some believe ramipril's additional benefits may be shared by some or all drugs in the ACE-inhibitor class. However, ramipril currently remains the only ACE inhibitor for which such effects are actually evidence-based.

A meta-analysis confirmed that ACE inhibitors are effective and certainly the first-line choice in hypertension treatment. This meta-analysis was based on 20 trials and a cohort of 158,998 patients, of whom 91% were hypertensive. ACE inhibitors were used as the active treatment in seven trials (n=76,615) and angiotensin receptor blocker (ARB) in 13 trials (n=82,383). ACE inhibitors were associated with a statistically significant 10% mortality reduction: (HR 0.90; 95% CI, 0.84–0.97; P=0.004). In contrast, no significant mortality reduction was observed with ARB treatment (HR 0.99; 95% CI, 0.94–1.04; P=0.683). Analysis of mortality reduction by different ACE inhibitors showed that perindopril-based regimens are associated with a statistically significant 13% all-cause mortality reduction. Taking into account the broad spectrum of the hypertensive population, one might expect that an effective treatment with ACE inhibitors, in particular with perindopril, would result in an important gain of lives saved.

Equivalent doses in hypertension
The ACE inhibitors have different strengths with different starting dosages. Dosage should be adjusted according to the clinical response.

Combination with angiotensin II receptor antagonists
ACE inhibitors possess many common characteristics with another class of cardiovascular drugs, angiotensin II receptor antagonists, which are often used when patients are intolerant of the adverse effects produced by ACE inhibitors. ACE inhibitors do not completely prevent the formation of angiotensin II, as blockage is dose-dependent, so angiotensin II receptor antagonists may be useful because they act to prevent the action of angiotensin II at the AT1 receptor, leaving AT2 receptor unblocked; the latter may have consequences needing further study.

The combination therapy of angiotensin II receptor antagonists with ACE inhibitors may be superior to either agent alone. This combination may increase levels of bradykinin while blocking the generation of angiotensin II and its activity at the AT1 receptor. This 'dual blockade' may be more effective than using an ACE inhibitor alone, because angiotensin II can be generated via non-ACE-dependent pathways. Preliminary studies suggest this combination of pharmacologic agents may be advantageous in the treatment of essential hypertension, chronic heart failure, and nephropathy. However, the more recent ONTARGET study showed no benefit of combining the agents and more adverse events. While statistically significant results have been obtained for its role in treating hypertension, clinical significance may be lacking. There are warnings about the combination of ACE inhibitors with ARBs.

Patients with heart failure may benefit from the combination in terms of reducing morbidity and ventricular remodeling.

The most compelling evidence for the treatment of nephropathy has been found: This combination therapy partially reversed the proteinuria and also exhibited a renoprotective effect in patients with diabetic nephropathy, and pediatric IgA nephropathy.

History
Leonard T. Skeggs and his colleagues (including Norman Shumway) discovered ACE in plasma in 1956. It was also noted that those who worked in banana plantations in South-western Brazil collapsed after being bitten by a pit viper, leading to a search for a blood pressure lowering component in its venom. Brazilian scientist Sérgio Henrique Ferreira reported a bradykinin-potentiating factor (BPF) present in the venom of Bothrops jararaca, a South American pit viper, in 1965. Ferreira then went to John Vane's laboratory as a postdoctoral fellow with his already-isolated BPF. The conversion of the inactive angiotensin I to the potent angiotensin II was thought to take place in the plasma. However, in 1967, Kevin K. F. Ng and John R. Vane showed plasma ACE is too slow to account for the conversion of angiotensin I to angiotensin II in vivo. Subsequent investigation showed rapid conversion occurs during its passage through the pulmonary circulation.

Bradykinin is rapidly inactivated in the circulating blood, and it disappears completely in a single pass through the pulmonary circulation. Angiotensin I also disappears in the pulmonary circulation because of its conversion to angiotensin II. Furthermore, angiotensin II passes through the lungs without any loss. The inactivation of bradykinin and the conversion of angiotensin I to angiotensin II in the lungs was thought to be caused by the same enzyme. In 1970, Ng and Vane, using BPF provided by Ferreira, showed the conversion is inhibited during its passage through the pulmonary circulation.

BPFs are members of a family of peptides whose potentiating action is linked to inhibition of bradykinin by ACE. Molecular analysis of BPF yielded a nonapeptide BPF teprotide (SQ 20,881), which showed the greatest ACE inhibition potency and hypotensive effect in vivo. Teprotide had limited clinical value as a result of its peptide nature and lack of activity when given orally. In the early 1970s, knowledge of the structure-activity relationship required for inhibition of ACE was growing. David Cushman, Miguel Ondetti and colleagues used peptide analogues to study the structure of ACE, using carboxypeptidase A as a model. Their discoveries led to the development of captopril, the first orally-active ACE inhibitor, in 1975.

Captopril was approved by the United States Food and Drug Administration in 1981. The first nonsulfhydryl-containing ACE inhibitor, enalapril, was approved four years later. At least 8 other ACE inhibitors have since been marketed.

In 1991, Japanese scientists created the first milk-based ACE inhibitor, in the form of a fermented milk drink, using specific cultures to liberate the tripeptide isoleucine-proline-proline (IPP) from the dairy protein. Valine-proline-proline (VPP) is also liberated in this process—another milk tripeptide with a very similar chemical structure to IPP. Together, these peptides are now often referred to as lactotripeptides. In 1996, the first human study confirmed the blood pressure-lowering effect of IPP in fermented milk. Although twice the amount of VPP is needed to achieve the same ACE-inhibiting activity as the originally discovered IPP, VPP also is assumed to add to the total blood pressure lowering effect. Since the first lactotripeptides discovery, more than 20 human clinical trials have been conducted in many different countries.

title: ACE inhibitor


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Antianginal

An antianginal is a drug used in the treatment of angina pectoris, a symptom of ischaemic heart disease.

Myocardial ischemia arises from the dysfunction of coronary macrovascular or microvascular components, leading to a compromised supply of oxygen and nutrients to the myocardium. The underlying pathophysiological mechanisms encompass a range of factors, including atherosclerosis in epicardial coronary arteries, vasospasm in large or small vessels, and microvascular dysfunction—whose clinical significance is increasingly acknowledged. The diverse clinical presentations of myocardial ischemia collectively fall under the term chronic coronary syndromes.

Addressing these conditions involves a multifaceted approach, where the most common antianginal medications alleviate symptoms by inducing coronary vasodilation and modifying the determinants of myocardial oxygen consumption, such as heart rate, myocardial wall stress, and ventricular contractility. Additionally, these medications can alter cardiac substrate metabolism to alleviate ischemia by enhancing the efficiency of myocardial oxygen utilization. While there is consensus on the prognostic importance of lifestyle interventions and preventive measures like aspirin and statin therapy, determining the optimal antianginal treatment for chronic coronary syndrome patients remains less defined.

The majority of individuals experiencing stable angina can effectively address their condition through lifestyle modifications, particularly by embracing smoking cessation and incorporating regular exercise into their routine. Alongside these lifestyle changes, the use of antianginal drugs is a common approach. However, findings from randomized controlled trials reveal that the efficacy of various antianginal drugs is comparable, with none demonstrating a significant reduction in mortality or the risk of myocardial infarction (MI). Despite this, prevailing guidelines lean towards recommending beta-blockers and calcium channel blockers as the preferred first-line treatment.

The European Society of Cardiology (ESC) guidelines for managing stable coronary artery disease provide well-defined classes of recommendation with corresponding levels of evidence. In a parallel vein, the National Institute for Health and Care Excellence (NICE) guidelines for stable angina management consider cost-effectiveness in their recommendations, designating terms such as first-line and second-line therapy. Notably, both sets of guidelines advocate for the use of low-dose aspirin and statins as disease-modifying agents.

This article aims to critically examine and evaluate the pharmacological recommendations outlined in these guidelines for the management of patients with stable angina. By delving into the nuances of these recommendations, we seek to provide a comprehensive understanding of the rationale behind the suggested pharmacological interventions for stable angina, shedding light on their respective strengths and considerations in clinical practice.

Political Considerations
The 2019 guidelines from the European Society of Cardiology (ESC) advocate for a personalized approach in which antianginal medications are tailored to an individual patient's comorbidities and hemodynamic profile. It's noteworthy that, although antianginal medications do not improve survival, their effectiveness in symptom reduction significantly depends on the underlying mechanism of angina.

Key considerations in antianginal therapies involve enhancing coronary vascular oxygen supply to the ischemic myocardium, reducing heart rate, myocardial work, and oxygen consumption, as well as optimizing the energetic efficiency of cardiomyocytes. Despite current guidelines recommending β-blockers and calcium-channel blockers as first-line therapy, there is a lack of evidence demonstrating their superiority over second-line therapies.

In this comprehensive review, it is crucial to emphasize that, thus far, neither drugs nor interventions that reduce ischemia have been shown to prolong survival in patients with chronic coronary syndromes.

Examples
Drugs used are nitrates, beta blockers, or calcium channel blockers.

Nitrates
Nitrates cause vasodilation of the venous capacitance vessels by stimulating the endothelium-derived relaxing factor (EDRF). Used to relieve both exertional and vasospastic angina by allowing venous pooling, reducing the pressure in the ventricles and so reducing wall tension and oxygen requirements in, the heart. Short-acting nitrates are used to abort angina attacks that have occurred, while longer-acting nitrates are used in the prophylactic management of the condition.

Agents include glyceryl trinitrate (GTN), pentaerythritol tetranitrate, isosorbide dinitrate and isosorbide mononitrate.

Beta blockers
Beta blockers are used in the prophylaxis of exertional angina by reducing the myocardial oxygen demand below the level that would provoke an angina attack.

They are contraindicated in variant angina and can precipitate heart failure. They are also contraindicated in severe asthmatics due to bronchoconstriction, and should be used cautiously in diabetics as they can mask symptoms of hypoglycemia.

Agents include either cardioselectives such as acebutolol or metoprolol, or non-cardioselectives such as oxprenolol or sotalol.

Calcium channel blockers
Calcium ion (Ca++) antagonists (Calcium channel blockers) are used in the treatment of chronic stable angina, and most effectively in the treatment of variant angina (directly preventing coronary artery vasospasm). They are not used in the treatment of unstable angina.

In vitro, they dilate the coronary and peripheral arteries and have negative inotropic and chronotropic effects - decreasing afterload, improving myocardial efficiency, reducing heart rate and improving coronary blood flow. In vivo, the vasodilation and hypotension trigger the baroreceptor reflex. Therefore, the net effect is the interplay of direct and reflex actions.

 * Class I agents have the most potent negative inotropic effect and may cause heart failure.
 * Class II agents do not depress conduction or contractility.
 * Class III agent has negligible inotropic effect and causes almost no reflex tachycardia.

Examples include Class I agents (e.g., verapamil), Class II agents (e.g., amlodipine, nifedipine), or the Class III agent diltiazem.

Nifedipine is more a potent vasodilator and more effective in angina. It is in the class of dihydropyridines and does not affect refractory period on SA node conduction.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Antianginal


text:
Anatomical Therapeutic Chemical Classification System

The Anatomical Therapeutic Chemical (ATC) Classification System is a drug classification system that classifies the active ingredients of drugs according to the organ or system on which they act and their therapeutic, pharmacological and chemical properties. Its purpose is an aid to monitor drug use and for research to improve quality medication use. It does not imply drug recommendation or efficacy. It is controlled by the World Health Organization Collaborating Centre for Drug Statistics Methodology (WHOCC), and was first published in 1976.

Coding system
This pharmaceutical coding system divides drugs into different groups according to the organ or system on which they act, their therapeutic intent or nature, and the drug's chemical characteristics. Different brands share the same code if they have the same active substance and indications. Each bottom-level ATC code stands for a pharmaceutically used substance, or a combination of substances, in a single indication (or use). This means that one drug can have more than one code, for example acetylsalicylic acid (aspirin) has as a drug for local oral treatment,  as a platelet inhibitor, and  as an analgesic and antipyretic; as well as one code can represent more than one active ingredient, for example  is the combination of perindopril with amlodipine, two active ingredients that have their own codes ( and  respectively) when prescribed alone.

The ATC classification system is a strict hierarchy, meaning that each code necessarily has one and only one parent code, except for the 14 codes at the topmost level which have no parents. The codes are semantic identifiers, meaning they depict information by themselves beyond serving as identifiers (namely, the codes depict themselves the complete lineage of parenthood). As of 7 May 2020, there are 6,331 codes in ATC; the table below gives the count per level.

History
The ATC system is based on the earlier Anatomical Classification System, which is intended as a tool for the pharmaceutical industry to classify pharmaceutical products (as opposed to their active ingredients). This system, confusingly also called ATC, was initiated in 1971 by the European Pharmaceutical Market Research Association (EphMRA) and is being maintained by the EphMRA and Intellus. Its codes are organised into four levels. The WHO's system, having five levels, is an extension and modification of the EphMRA's. It was first published in 1976.

Classification
In this system, drugs are classified into groups at five different levels:

First level
The first level of the code indicates the anatomical main group and consists of one letter. There are 14 main groups:

Example: C Cardiovascular system

Second level
The second level of the code indicates the therapeutic subgroup and consists of two digits.

Example: C03 Diuretics

Third level
The third level of the code indicates the therapeutic/pharmacological subgroup and consists of one letter.

Example: C03C High-ceiling diuretics

Fourth level
The fourth level of the code indicates the chemical/therapeutic/pharmacological subgroup and consists of one letter.

Example: C03CA Sulfonamides

Fifth level
The fifth level of the code indicates the chemical substance and consists of two digits.

Example: C03CA01 furosemide

ATCvet
The Anatomical Therapeutic Chemical Classification System for veterinary medicinal products (ATCvet) is used to classify veterinary drugs. ATCvet codes can be created by placing the letter Q in front of the ATC code of most human medications. For example, furosemide for veterinary use has the code QC03CA01.

Some codes are used exclusively for veterinary drugs, such as QI Immunologicals, QJ51 Antibacterials for intramammary use or QN05AX90 amperozide.

Herbal ATC (HATC)
The Herbal ATC system (HATC) is an ATC classification of herbal substances; it differs from the regular ATC system by using 4 digits instead of 2 at the 5th level group.

The herbal classification is not adopted by WHO. The Uppsala Monitoring Centre is responsible for the Herbal ATC classification, and it is part of the WHODrug Global portfolio available by subscription.

Defined daily dose
The ATC system also includes defined daily doses (DDDs) for many drugs. This is a measurement of drug consumption based on the usual daily dose for a given drug. According to the definition, "[t]he DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults."

Adaptations and updates
National issues of the ATC classification, such as the German Anatomisch-therapeutisch-chemische Klassifikation mit Tagesdosen, may include additional codes and DDDs not present in the WHO version.

ATC follows guidelines in creating new codes for newly approved drugs. An application is submitted to WHO for ATC classification and DDD assignment. A preliminary or temporary code is assigned and published on the website and in the WHO Drug Information for comment or objection. New ATC/DDD codes are discussed at the semi-annual Working Group meeting. If accepted it becomes a final decision and published semi-annually on the website and WHO Drug Information and implemented in the annual print/on-line ACT/DDD Index on January 1.

Changes to existing ATC/DDD follow a similar process to become temporary codes and if accepted become a final decision as ATC/DDD alterations. ATC and DDD alterations are only valid and implemented in the coming annual updates; the original codes must continue until the end of the year. An updated version of the complete on-line/print ATC index with DDDs is published annually on January 1.