Մասնակից:Nare Hovakimyan 21/Ավազարկղ2

Վիքիպեդիայից՝ ազատ հանրագիտարանից

Chemistry[խմբագրել | խմբագրել կոդը]

The minimum requirement for adrenergic agents is a primary or secondary amine separated from a substituted benzene ring by one or two carbons.[1] 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.[1] 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.[2]

Labetalol has two chiral carbons and consequently exists as four stereoisomers.[3] Two of these isomers, the (S,S)- and (R,S)- forms are inactive. The third, the (S,R)-isomer, is a powerful α1 blocker. The fourth isomer, the (R,R)-isomer which is also known as dilevalol, is a mixed nonselective β blocker and selective α1 blocker.[2] Labetalol is typically given as a racemic mixture to achieve both alpha and beta receptor blocking activity.[4]

Stereoisomers of labetalol

(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

Labetalol acts by blocking alpha and beta adrenergic receptors, resulting in decreased peripheral vascular resistance without significant alteration of heart rate or cardiac output.

The β:α antagonism of labetalol is approximately 3:1.[5][6]

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.[4][7]

Pharmacology[խմբագրել | խմբագրել կոդը]

Mechanism of action[խմբագրել | խմբագրել կոդը]

Labetalol's dual alpha and beta 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.[8] During long-term use, labetalol can reduce heart rate during exercise while maintaining cardiac output by an increase in stroke volume.[9]

Labetalol is a dual alpha (α1) and beta (β1/β2) adrenergic receptor blocker and competes with other Catecholamines for binding to these sites.[10] Its action on these receptors are potent and reversible.[11] Labetalol is highly selective for postsynaptic alpha1- adrenergic, and non-selective for beta-adrenergic receptors. It is about equipotent in blocking beta1- and beta2- receptors.[2]

The amount of alpha to beta blockade depends on whether labetalol is administered orally or intravenously (IV). Orally, the ratio of alpha to β blockade is 1:3. Intravenously, alpha to β blockade ratio is 1:7.[2][11] Thus, the labetalol can be thought to be a beta-blocker with some alpha-blocking effects.[11][10][12] By comparison, labetalol is a weaker β-blocker than propranolol, and has a weaker affinity for alpha-receptors compared to Phentolamine.[2][10]

Labetalol possesses intrinsic sympathomimetic activity.[12] In particular, it is a partial agonist at beta2- receptors located in the vascular smooth muscle. Labetalol relaxes vascular smooth muscle by a combination of this partial beta2- agonism and through alpha1- blockade.[12][13] Overall, this vasodilatory effect can decrease blood pressure.[14]

Similar to local anesthetics and sodium channel blocking antiarrhythmics, labetalol also has membrane stabilizing activity.[12][15] By decreasing sodium entry, labetalol decreases action potential firing and thus has local anesthetic activity.[16]

Physiological action[խմբագրել | խմբագրել կոդը]

The physiological effects of labetalol when administered acutely (intravenously) are not predictable solely by their receptor blocking effect, i.e. blocking beta1- 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 alpha1-, beta1- and beta2- blocking mechanism.[8][9] These effects are mainly seen when the person is in the upright position.[14]

Long term labetalol use also has different effects from other beta-blocking drugs. 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.[9]

Pharmacokinetics[խմբագրել | խմբագրել կոդը]

Labetalol, in animal models, was found to cross the blood-brain-barrier in only negligible amounts.[17]

History[խմբագրել | խմբագրել կոդը]

Labetalol was the first drug created that combined both alpha- and beta- 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 beta-receptors or tachycardia after blocking alpha 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 alpha- and beta- receptors could work together to decrease blood pressure.[2][9]

  1. ↑ 1,0 1,1 «Medicinal Chemistry of Adrenergics and Cholinergics». Արխիվացված է օրիգինալից 2010-11-04-ին. Վերցված է 2010-10-16-ին.
  2. ↑ 2,0 2,1 2,2 2,3 2,4 2,5 Louis, W.J.; McNeill, JJ; Drummer, OH (1988). Doyle, AE (ed.). Labetalol and other vasodilator/Beta-blocking drugs. IN: Handbook of Hypertension. Amsterdam, Netherlands: Elsevier Sciences Publishing Co. էջեր 246–273. ISBN 978-0-444-90469-0.
  3. ↑ Riva E, Mennini T, Latini R (December 1991). «The alpha- and beta-adrenoceptor blocking activities of labetalol and its RR-SR (50:50) stereoisomers». Br. J. Pharmacol. 104 (4): 823–8. doi:10.1111/j.1476-5381.1991.tb12513.x. PMC 1908821. PMID 1687367.
  4. ↑ 4,0 4,1 Robertson D, Biaggioni, I. Adrenoceptor Antagonist Drugs. In: Katzung BG, Masters SB, Trevor AJ, eds. Basic & Clinical Pharmacology. 12th ed. San Francisco, CA: McGraw Hill Lange Medical; 2012: 151-168. 978-0-07-176401-8.
  5. ↑ Katzung, Bertram G. (2006). Basic and clinical pharmacology. New York: McGraw-Hill Medical. էջ 170. ISBN 978-0-07-145153-6.
  6. ↑ D A Richards; J Tuckman; B N Prichard (October 1976). «Assessment of alpha- and beta-adrenoceptor blocking actions of labetalol». Br J Clin Pharmacol. 3 (5): 849–855. doi:10.1111/j.1365-2125.1976.tb00637.x. PMC 1428931. PMID 9968.
  7. ↑ «labetalol | C19H24N2O3 - PubChem». pubchem.ncbi.nlm.nih.gov. Վերցված է 2015-11-04-ին.
  8. ↑ 8,0 8,1 MacCarthy, E. P.; Bloomfield, S. S. (1983-08-01). «Labetalol: a review of its pharmacology, pharmacokinetics, clinical uses and adverse effects». Pharmacotherapy. 3 (4): 193–219. doi:10.1002/j.1875-9114.1983.tb03252.x. ISSN 0277-0008. PMID 6310529. S2CID 20410587.
  9. ↑ 9,0 9,1 9,2 9,3 Louis, W. J.; McNeil, J. J.; Drummer, O. H. (1984-01-01). «Pharmacology of combined alpha-beta-blockade. I». Drugs. 28 Suppl 2: 16–34. doi:10.2165/00003495-198400282-00003. ISSN 0012-6667. PMID 6151889. S2CID 46974416.
  10. ↑ 10,0 10,1 10,2 Robertson, D; Biaggioni, I (2012). Katzung, BG (ed.). Adrenoceptor Antagonist Drugs IN: Basic & Clinical Pharmacology (12 ed.). San Francisco: McGraw Hill Lange Medical. էջեր 151–168. ISBN 978-0-07-176401-8.
  11. ↑ 11,0 11,1 11,2 «Labetalol [package insert]. Spring Valley, NY: Par Pharmaceutical; 2011» (PDF). Արխիվացված է օրիգինալից (PDF) 2015-12-10-ին. Վերցված է 2015-11-03-ին.
  12. ↑ 12,0 12,1 12,2 12,3 Westfall, David P (2004). Craig, Charles R (ed.). Adrenoreceptor Antagonists IN: Modern Pharmacology with Clinical Applications (6th ed.). Baltimore, MD: Lippincott Williams & Wilkins. էջեր 109–117. ISBN 978-0781737623.
  13. ↑ Lund-Johansen, P. (1988-01-01). «Hemodynamic effects of beta-blocking compounds possessing vasodilating activity: a review of labetalol, prizidilol, and dilevalol». Journal of Cardiovascular Pharmacology. 11 Suppl 2: S12–17. doi:10.1097/00005344-198800000-00004. ISSN 0160-2446. PMID 2464093.
  14. ↑ 14,0 14,1 Lund-Johansen, P. (1984-01-01). «Pharmacology of combined alpha-beta-blockade. II. Haemodynamic effects of labetalol». Drugs. 28 Suppl 2: 35–50. doi:10.2165/00003495-198400282-00004. ISSN 0012-6667. PMID 6151890. S2CID 46986875.
  15. ↑ Mottram, Allan R.; Erickson, Timothy B. (2009). Field, John (ed.). Toxicology in Emergency Cardiovascular Care IN: The Textbook of Emergency Cardiovascular Care and CPR. Philadelphia, PA: Lippincott Williams & Wilkins. էջեր 443–452. ISBN 978-0-7817-8899-1.
  16. ↑ Exam Zone (1 January 2009). Elsevier Comprehensive Guide. Elsevier India. էջեր 449–. ISBN 978-81-312-1620-0.
  17. ↑ Detlev Ganten; Patrick J. Mulrow (6 December 2012). Pharmacology of Antihypertensive Therapeutics. Springer Science & Business Media. էջեր 147–. ISBN 978-3-642-74209-5.
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