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Pronunciation | /ləˈbɛtəlɔːl/ |
Trade names | Normodyne, Trandate, others |
Other names | Ibidomide; AH-5158; SCH-19927 |
AHFS/Drugs.com | Monograph |
MedlinePlus | a685034 |
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Routes of administration | By mouth, intravenous |
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Pharmacokinetic data | |
Bioavailability | 25% (11–86%) [1] [2] [3] |
Protein binding | 50% [1] [3] |
Metabolism | Mainly conjugation via glucuronidation [1] [2] [3] |
Metabolites | • Glucuronide conjugates [2] |
Elimination half-life | Oral: 6–8 hours [1] [2] [3] IV : 5.52 hours [2] |
Duration of action | 8–12 hours [1] |
Excretion | Urine (55–60% as conjugates or unchanged within 24 hours) [1] |
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ECHA InfoCard | 100.048.401 |
Chemical and physical data | |
Formula | C19H24N2O3 |
Molar mass | 328.412 g·mol−1 |
3D model (JSmol) | |
Chirality | Racemic mixture |
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Labetalol is a medication used to treat high blood pressure and in long term management of angina. [4] [5] This includes essential hypertension, hypertensive emergencies, and hypertension of pregnancy. [5] In essential hypertension it is generally less preferred than a number of other blood pressure medications. [4] It can be given by mouth or by injection into a vein. [4]
Common side effects include low blood pressure with standing, dizziness, feeling tired, and nausea. [4] Serious side effects may include low blood pressure, liver problems, heart failure, and bronchospasm. [4] Use appears safe in the latter part of pregnancy and it is not expected to cause problems during breastfeeding. [5] [6] It works by blocking the activation of β- and α-adrenergic receptors. [4]
Labetalol was patented in 1966 and came into medical use in 1977. [7] It is available as a generic medication. [5] In 2021, it was the 213th most commonly prescribed medication in the United States, with more than 2 million prescriptions. [8] [9]
Labetalol is effective in the management of hypertensive emergencies, postoperative hypertension, pheochromocytoma-associated hypertension, and rebound hypertension from beta blocker withdrawal. [10]
It has a particular indication in the treatment of pregnancy-induced hypertension which is commonly associated with pre-eclampsia. [11]
It is also used as an alternative in the treatment of severe hypertension. [10]
Labetalol is useful in the treatment of acute cardiovascular toxicity (e.g. in overdose) caused by sympathomimetics like amphetamine, methamphetamine, cocaine, ephedrine, and pseudoephedrine. [12] [13] Other beta blockers are also used. [12] [13] However, the controversial yet possible phenomenon of "unopposed α-stimulation" with administration of selective beta blockers to block non-selective sympathomimetics potentially makes dual alpha-1 and beta blockers like labetalol and carvedilol more favorable for such purposes. [12] [13] The rate of unopposed α-stimulation with selective beta blockers has been reported to be 0.4%, [12] whereas no cases of unopposed α-stimulation have been reported with dual alpha and beta blockers like labetalol. [13]
Pregnancy: studies in lab animals showed no harm to the baby. However, a comparable well-controlled study has not been performed in pregnant women. [1]
Nursing: breast milk has been shown to contain small amounts of labetalol (0.004% original dose). Prescribers should be cautious in the use of labetalol for nursing mothers. [1]
Pediatric: no studies have established safety or usefulness in this population. [1]
Geriatric: the elderly are more likely to experience dizziness when taking labetalol. Labetalol should be dosed with caution in the elderly and counseled on this side effect. [1]
Low blood pressure with standing is more severe and more common with IV formulation (58% vs 1% [1] ) and is often the reason larger doses of the oral formulation cannot be used. [14]
Labetalol is contraindicated in people with overt cardiac failure, greater-than-first-degree heart block, severe bradycardia, cardiogenic shock, severe hypotension, anyone with a history of obstructive airway disease including asthma, and those with hypersensitivity to the drug. [16]
Labetalol is a beta blocker, or an antagonist of the β-adrenergic receptors. It is specifically a non-selective antagonist of the β1- and β2-adrenergic receptors. [17] Labetalol has intrinsic sympathomimetic activity. [17] It is also an antagonist of the α1-adrenergic receptor, and hence is additionally an alpha blocker. The antagonism of the adrenergic receptors by labetalol is competitive against other catecholamines [18] and its actions on the receptors are potent and reversible. [16] Labetalol acts by blocking α- and β-adrenergic receptors, resulting in decreased peripheral vascular resistance without significant alteration of heart rate or cardiac output.
Labetalol is about equipotent in blocking β1- and β2-adrenergic receptors. [19] The amount of α to β blockade depends on whether labetalol is administered orally or intravenously (IV). Orally, the ratio of α to β blockade is 1:3. [20] [21] Intravenously, α to β blockade ratio is 1:7. [19] [16] Thus, the labetalol can be thought to be a beta blocker with some α-blocking effects. [16] [18] [22] By comparison, labetalol is a weaker β-adrenergic receptor blocker than propranolol, and has a weaker affinity for α-adrenergic receptors compared to phentolamine. [19] [18]
Labetalol's dual α- and β-adrenergic antagonism has different physiological effects in short- and long-term situations. In short-term, acute situations, labetalol decreases blood pressure by decreasing systemic vascular resistance with little effect on stroke volume, heart rate and cardiac output. [23] During long-term use, labetalol can reduce heart rate during exercise while maintaining cardiac output by an increase in stroke volume. [24]
Labetalol possesses significant intrinsic sympathomimetic activity (ISA). [2] [22] In particular, it is a partial agonist at β2-adrenergic receptors located in the vascular smooth muscle. Labetalol relaxes vascular smooth muscle by a combination of this partial β2-adrenergic receptor agonism and through α1-adrenergic receptor blockade. [22] [25] Overall, this vasodilatory effect can decrease blood pressure. [26] It was originally reported to lack ISA, but a slight degree of activity was subsequently characterized. [2]
Similar to local anesthetics and sodium channel blocking antiarrhythmics, labetalol also has membrane stabilizing activity. [2] [22] [27] By decreasing sodium entry, labetalol decreases action potential firing and thus has local anesthetic activity. [28]
The physiological effects of labetalol when administered acutely (intravenously) are not predictable solely by their receptor blocking effect, i.e. blocking β1-adrenergic receptors should decrease heart rate, but labetalol does not. When labetalol is given in acute situations, it decreases the peripheral vascular resistance and systemic blood pressure while having little effect on the heart rate, cardiac output and stroke volume, despite its α1-, β1- and β2-adrenergic receptor blocking mechanism. [23] [24] These effects are mainly seen when the person is in the upright position. [26]
Long term labetalol use also has different effects from other beta blockers. Other beta blockers, such as propranolol, persistently reduce cardiac output during exercise. The peripheral vascular resistance decreases when labetalol is first administered. Continuous labetalol use further decreases peripheral vascular resistance. However, during exercise, cardiac output remains the same due to a compensatory mechanism that increases stroke volume. Thus, labetalol is able to reduce heart rate during exercise while maintaining cardiac output by the increase in stroke volume. [24]
Labetalol is often classified as a beta blocker with low lipophilicity and hence lower potential for crossing the blood–brain barrier and blood–placenta barrier. [17] [29] [30] This in turn may result in fewer effects in the central nervous system as well as a lower risk of neuropsychiatric side effects. [17] Paradoxically however, labetalol actually shows high lipophilicity. [31] [3] [32] [33] [34] [2] In any case, labetalol, in animals including rats, rabbits, and dogs, was found to cross into the brain in negligible amounts, probably for reasons other than low lipophilicity. [1] [2] [35] On the other hand, the drug has been shown to cross the blood–placenta barrier in humans. [1]
The minimum requirement for adrenergic agents is a primary or secondary amine separated from a substituted benzene ring by one or two carbons. [36] This configuration results in strong agonist activity. As the size of the substituent attached to the amine becomes greater, particularly with respect to a t-butyl group, then the molecule typically is found to have receptor affinity without intrinsic activity, and is, therefore, an antagonist. [36] Labetalol, with its 1-methyl-3-phenylpropyl substituted amine, is greater in size relative to a t-butyl group and therefore acts predominantly as an antagonist. The overall structure of labetalol is very polar. This was created by substituting the isopropyl group in the standard beta blocker structure with an aralkyl group, including a carboxamide group on the meta position, and by adding a hydroxyl group on the para position. [19]
Labetalol has two chiral carbons and consequently exists as four stereoisomers. [37] Two of these isomers, the (S,S)- and (R,S)- forms are inactive. The third, the (S,R)-isomer, is a powerful α1-adrenergic receptor blocker. The fourth isomer, the (R,R)-isomer which is also known as dilevalol, is a mixed non-selective β-adrenergic receptor blocker and selective α1 blocker. [19] Labetalol is typically given as a racemic mixture to achieve both α- and β-adrenergic receptor blocking activity. [38]
Stereoisomers of labetalol | |
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(R,R)-Labetalol CAS number: 75659-07-3 | (S,S)-Labetalol CAS number: 83167-24-2 |
(R,S)-Labetalol CAS number: 83167-32-2 | (S,R)-Labetalol CAS number: 83167-31-1 |
It is chemically designated in International Union of Pure and Applied Chemistry (IUPAC) nomenclature as 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzamide monohydrochloride. [38] [39]
The experimental log P of labetalol is 2.7 to 3.1 and its predicted log P ranges from 1.73 to 3.1. [31] [3] [32] [33] Hence, it has relatively high lipophilicity. [31] [3] [32] [33] [34]
Labetalol was the first drug created that combined both α- and β-adrenergic receptor blocking properties. It was created to potentially fix the compensatory reflex issue that occurred when blocking a single receptor subtype, i.e. vasoconstriction after blocking β-adrenergic receptors or tachycardia after blocking α-adrenergic receptors. Because the reflex from blocking the single receptor subtypes acted to prevent the lowering of blood pressure, it was postulated that weak blocking of both α- and β-adrenergic receptors could work together to decrease blood pressure. [19] [24]
Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms (arrhythmia), and to protect the heart from a second heart attack after a first heart attack. They are also widely used to treat high blood pressure, although they are no longer the first choice for initial treatment of most patients.
Propranolol, sold under the brand name Inderal among others, is a medication of the beta blocker class. It is used to treat high blood pressure, a number of types of irregular heart rate, thyrotoxicosis, capillary hemangiomas, performance anxiety, and essential tremors, as well to prevent migraine headaches, and to prevent further heart problems in those with angina or previous heart attacks. It can be taken orally or by intravenous injection. The formulation that is taken orally comes in short-acting and long-acting versions. Propranolol appears in the blood after 30 minutes and has a maximum effect between 60 and 90 minutes when taken orally.
The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta blockers, beta-2 (β2) agonists and alpha-2 (α2) agonists, which are used to treat high blood pressure and asthma, for example.
Antihypertensives are a class of drugs that are used to treat hypertension. 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.
Atenolol is a beta blocker medication primarily used to treat high blood pressure and heart-associated chest pain. Although used to treat high blood pressure, it does not seem to improve mortality in those with the condition. Other uses include the prevention of migraines and treatment of certain irregular heart beats. It is taken orally or by intravenous injection. It can also be used with other blood pressure medications.
Isoprenaline, also known as isoproterenol and sold under the brand name Isuprel among others, is a sympathomimetic medication which is used in the treatment of acute bradycardia, heart block, and rarely for asthma, among other indications. It is used by injection into a vein, muscle, fat, or the heart, by inhalation, and in the past under the tongue or into the rectum.
Dobutamine is a medication used in the treatment of cardiogenic shock and severe heart failure. It may also be used in certain types of cardiac stress tests. It is given by IV only, as an injection into a vein or intraosseous as a continuous infusion. The amount of medication needs to be adjusted to the desired effect. Onset of effects is generally seen within 2 minutes. It has a half-life of two minutes. This drug is generally only administered short term, although it may be used for longer periods to relieve symptoms of heart failure in patients awaiting heart transplantation.
Phentolamine, sold under the brand name Regitine among others, is a reversible nonselective α-adrenergic antagonist.
Bisoprolol, sold under the brand name Zebeta among others, is a beta blocker which is selective for the beta-1 receptor and used for cardiovascular diseases, including tachyarrhythmias, high blood pressure, angina, and heart failure. It is taken by mouth.
Carvedilol, sold under the brand name Coreg among others, is a beta blocker medication, that may be prescribed for the treatment of high blood pressure (hypertension) and chronic heart failure with reduced ejection fraction. Beta-blockers as a collective medication class are not recommended as routine first-line treatment of high blood pressure for all patients, due to evidence demonstrating less effective cardiovascular protection and a less favourable safety profile when compared to other classes of blood pressure-lowering medications.
Fenoldopam mesylate (Corlopam) is a drug and synthetic benzazepine derivative which acts as a selective D1 receptor partial agonist. Fenoldopam is used as an antihypertensive agent. It was approved by the Food and Drug Administration (FDA) in September 1997.
Penbutolol is a medication in the class of beta blockers, used in the treatment of high blood pressure. Penbutolol is able to bind to both beta-1 adrenergic receptors and beta-2 adrenergic receptors, thus making it a non-selective β blocker. Penbutolol is a sympathomimetic drug with properties allowing it to act as a partial agonist at β adrenergic receptors.
The alpha-2 (α2) adrenergic receptor is a G protein-coupled receptor (GPCR) associated with the Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-, α2B-, and α2C-adrenergic. Some species other than humans express a fourth α2D-adrenergic receptor as well. Catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) signal through the α2-adrenergic receptor in the central and peripheral nervous systems.
Nebivolol is a beta blocker used to treat high blood pressure and heart failure. As with other β-blockers, it is generally a less preferred treatment for high blood pressure. It may be used by itself or with other blood pressure medication. It is taken by mouth.
An adrenergic antagonist is a drug that inhibits the function of adrenergic receptors. There are five adrenergic receptors, which are divided into two groups. The first group of receptors are the beta (β) adrenergic receptors. There are β1, β2, and β3 receptors. The second group contains the alpha (α) adrenoreceptors. There are only α1 and α2 receptors. Adrenergic receptors are located near the heart, kidneys, lungs, and gastrointestinal tract. There are also α-adreno receptors that are located on vascular smooth muscle.
Alpha-blockers, also known as α-blockers or α-adrenoreceptor antagonists, are a class of pharmacological agents that act as antagonists on α-adrenergic receptors (α-adrenoceptors).
Beta adrenergic agonists or beta agonists are medications that relax muscles of the airways, causing widening of the airways and resulting in easier breathing. They are a class of sympathomimetic agents, each acting upon the beta adrenoceptors. In general, pure beta-adrenergic agonists have the opposite function of beta blockers: beta-adrenoreceptor agonist ligands mimic the actions of both epinephrine- and norepinephrine- signaling, in the heart and lungs, and in smooth muscle tissue; epinephrine expresses the higher affinity. The activation of β1, β2 and β3 activates the enzyme, adenylate cyclase. This, in turn, leads to the activation of the secondary messenger cyclic adenosine monophosphate (cAMP); cAMP then activates protein kinase A (PKA) which phosphorylates target proteins, ultimately inducing smooth muscle relaxation and contraction of the cardiac tissue.
Landiolol (INN) is an ultra short-acting, β1-superselective intravenous adrenergic antagonist, which decreases the heart rate effectively with less negative effect on blood pressure or myocardial contractility. In comparison to other beta blockers, landiolol has the shortest elimination half-life, ultra-rapid onset of effect, and predictable effectiveness with inactive metabolites. The pure S-enantiomer structure of landiolol is believed to develop less hypotensive side effects in comparison to other β-blockers. This has a positive impact on the treatment of patients when reduction of heart rate without decrease in arterial blood pressure is desired. It is used as landiolol hydrochloride.
β adrenergic receptor antagonists were initially developed in the 1960s, for the treatment of angina pectoris but are now also used for hypertension, congestive heart failure and certain arrhythmias. In the 1950s, dichloroisoproterenol (DCI) was discovered to be a β-antagonist that blocked the effects of sympathomimetic amines on bronchodilation, uterine relaxation and heart stimulation. Although DCI had no clinical utility, a change in the compound did provide a clinical candidate, pronethalol, which was introduced in 1962.
Peripherally selective drugs have their primary mechanism of action outside of the central nervous system (CNS), usually because they are excluded from the CNS by the blood–brain barrier. By being excluded from the CNS, drugs may act on the rest of the body without producing side-effects related to their effects on the brain or spinal cord. For example, most opioids cause sedation when given at a sufficiently high dose, but peripherally selective opioids can act on the rest of the body without entering the brain and are less likely to cause sedation. These peripherally selective opioids can be used as antidiarrheals, for instance loperamide (Imodium).