New Advances in Receptor Pharmacology
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Revista Mexicana de Anestesiología Volumen Suplemento Volume 27 Supplement 1 2004 Artículo: New advances in receptor pharmacology Derechos reservados, Copyright © 2004: Colegio Mexicano de Anestesiología, AC Otras secciones de Others sections in este sitio: this web site: ☞ Índice de este número ☞ Contents of this number ☞ Más revistas ☞ More journals ☞ Búsqueda ☞ Search edigraphic.com DE AN NO EST A ES MG Schwinn DA et al. New advances in receptor pharmacologyIC IO Mexicana de EX L M O G O Í I A G A E L . C C O . C AnestesiologíaRevista A N A T Í E S G S O O L C IO I S ED TE A ES D M AN AUTORES EXTRANJEROS EXICANA DE Vol. 27. Supl. 1 2004 pp 83-87 New advances in receptor pharmacology Debra A. Schwinn, M.D., James B Duke Objective: The goal of this review is to give the clinician a stabilizes specific receptor conformations ranging from in- broad perspective on recent updates in cardiovascular phar- active to active states; the active conformation can then in- macology. Specifically, this review discusses new drugs, old teract with second messenger (effector) systems directly or drugs used in new ways, and a glimpse into the future of via intermediary guanine nucleotide (G) proteins. Nine AR cardiovascular pharmacogenetics. subtypes have been described using molecular cloning tech- α α α α α α β β β niques ( 1a, 1b, 1d, 2a, 2b, 2c, 1, 2, 3), although thus 1. INTRODUCTION AND REVIEW OF CURRENT far cardiovascular pharmacology tends to be based on only α α β β CARDIOVASCULAR MEDICATIONS four “classic” AR subtypes ( 1, 2, 1, 2). Continuous acti- 1.A. Cardiovascular system vation of adrenergic receptors by stress, long term catechola- mine therapy, or selected disease states results in a dampen- The cardiovascular system consists of a complex array of ing of AR response; this process is called desensitization. pipes (vessels), flexible tubing (smooth muscle capable of Desensitization is important in congestive heart failure β constriction and relaxation), flow restrictors (venous and (CHF), where 1AR number and function decreases by 75%, β cardiac valves), and mechanical pump (myocardium). Due with relative sparing of 2AR number and function. to its many functions, chemical modulation of the cardio- vascular system by neurotransmitters, hormones, and drugs 1.C. Standard adrenergic inotropic drugs is distributed over vast physical locations and spans numer- ous receptor systems. Ultimately, distinct receptors bind drugs Most inotropic agents (drugs which mediate increases in (both agonists and antagonists) to mediate clinical respons- myocardial contractility) available for clinical use today are es. In order to rationally administer cardiovascular drugs, it catecholamines, either endogenous (epinephrine, norepineph- is imperative to understand interactions between the sympa- rine, dopamine) or synthetic catecholamine derivatives (iso- thetic nervous system, endogenous neurotransmitters, recep- proterenol, dobutamine, dopexamine, arbutamine). Cate- tors, and drugs, as well as the resultant impact on cholamine structure is distinctive and includes a catechol ring modulation(s) of cardiovascular physiology. moiety, catechol hydroxyl groups, and side chains of vary- ing length and composition. Naturally occurring catechola- 1.B. Receptors mines such as epinephrine, norepinephrine, and dopamine, tend to bind all adrenergic receptor subtypes, but have rela- Distinct individual receptor sites bind drugs, both activating tive selectivity depending on the dose used. At low doses, agonists and inhibiting antagonists. Receptor sites can take dopamine binds to dopamine receptors, while epinephrine the form of cell membrane receptors (as is the case for most and norepinephrine bind to predominantly βARs. At moder- water soluble drugs and hormones), ion channels, ligand- ate doses, both dopamine and epinephrine bind predominant- gated receptor complexes, enzyme systems, and other cyto- ly to βARs, while norepinephrine already binds αARs; this plasmic and nuclear proteins. Since most cardiovascular dose range mediates increases in inotropy via stimulation of drugs used in anesthesia still rely on adrenergicedigraphic.com receptor myocardial βARs. At high doses, all three endogenous cate- (AR)-mediated pathways, these receptors will be used as a cholamines bind to αARs and vasoconstrictive effects pre- model system for this review. ARs are membrane bound re- dominate. Epinephrine is commonly used for cardiac resus- ceptors which bind catecholamines (endogenous hormones citation, but new data suggests that epinephrine may epinephrine and norepinephrine, and other synthetic drugs). significantly increase the severity of post-resuscitation my- Binding of agonist drugs on the extracellular surface of ARs ocardial dysfunction. Hence an α1AR agonist, or epineph- Volumen 27, Suplemento 1, 2004 S83 Schwinn DA et al. New advances in receptor pharmacology MG rine combined with a β1AR antagonist, may reduce post- Therefore, over time, very little endogenous epinephrine is resuscitation myocardial impairment and prolong survival. available to act and the clinical picture is sympatholysis; in Subtle changes in catecholamine side-chain groups can terms of the cardiovascular system, BP decreases. In addi- alter AR subtype selectivity, hence synthetic catecholamines tion to effects on BP, dexmedetomidine has potentially ben- tend to be more subtype selective. AR subtype selectivity eficial anxiolytic and anesthetic sparing properties. Use of for synthetic catecholamines includes the following: isopro- dexmedetomidine during heart surgery, albeit in lower dos- β β β β terenol ( 1AR, 2AR), dobutamine ( 1AR, 2AR), dopex- es than originally proposed, has shown effect in limiting the β β β α amine ( 2AR), and arbutamine ( 1AR, 2AR, 1AR). The use of other anesthetic drugs as well as helping in transition- physiologic effects of synthetic catecholamines can be pre- ing patients through the intensive care unit. dicted based on their adrenergic receptor selectivity. For ex- β ample, drugs binding predominantly to 2ARs will produce 1.F. Phosphodiesterase inhibitors positive inotropy, chronotropy, vasodilation, and bronchod- β ilation. Agents which bind to only 1ARs produce inotropy In order to understand inotropic properties of phosphodi- and chronotropy. Sometimes synthetic catecholamines are esterase inhibitors, it is important to review βAR signal trans- β β developed for a specific clinical purpose. Arbutamine (a 1AR duction. Stimulation of ARs by catecholamines results in selective agonist) was developed primarily for use in stress activation of the G protein subtype Gs, which in turns acti- echocardiography because of its tachycardia properties with- vates the enzyme adenylyl cyclase, ultimately resulting in out vasodilation (especially since it results in fewer arrhyth- the production of cAMP in the cell. Phosphodiesterase in- mias than isoproterenol). hibitors (such as amrinone and milrinone) act indirectly through the βAR system by inhibiting phosphodiesterase 1.D. Sympathomimetics enzymes responsible for the breakdown of cAMP generated with βAR stimulation; the net result is enhanced cAMP lev- Sympathomimetics have many of the same properties as cat- els in the cell. Since tonic stimulation of βARs occurs from echolamines, but do not contain the catechol ring moiety in nanomolar concentrations of circulating catecholamines, their structure. Phenylisopropylamines such as ephedrine and enough cAMP is being generated in the myocyte at baseline denopamine are the only sympathomimetics which have sig- for phosphodiesterase inhibitors to have inotropic proper- nificant βAR properties. Ephedrine has both direct (receptor ties on their own. However, when combined with other βAR binding) and indirect (release of norepinephrine at the nerve agonist drugs, phosphodiesterase inhibitors provide additive terminal) actions; stimulation of both αAR and βARs re- (and sometimes synergistic) effects. Several classes of phos- sults, however βAR stimulation predominates. Hence ephe- phodiesterase inhibitors have been described, with some sub- drine is frequently used in obstetrical settings to raise mater- types demonstrating upregulation in the presence of βAR nal blood pressure without exaggerated vasoconstrictor agonists. It is important to note that phosphodiesterase in- β effects. Denopamine has selective 1AR agonist properties hibitors have vasodilating properties, and often this effect is α combined with 1AR antagonists properties. Thus denopam- seen 15 minutes prior to the onset of clinically significant ine provides positive inotropic effects while simultaneously inotropic effects; hence these agents are frequently refereed reducing afterload. to as “inodilators.” 1.E. Sympatholytics 1.G. Calcium chloride α Dexmedetomidine is a non-subtype selective 2AR agonist. Calcium is important in myocardial excitation-contraction Technically this drug is a sympathomimetic due to its ago- coupling, hence intravenous calcium can be of short term α nist properties at 2ARs, while clinically it acts as a sym- benefit as an inotropic agent in the setting of cardiopulmo- α patholytic agent. A brief review of 2AR pharmacology clar- nary bypass. However, caution should be exercised when α α ifies this paradox. 2ARs reside both presynaptically ( 2A using calcium since ischemic myocardial cells are “leaky” sympathetic nerve terminals and brain) and post-synaptical- to calcium and calcium overload can cause myocardial cell α α ly ( 2B vessels, 2C brain). An intravenous bolus of dexme- death.