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Adrenoceptor Agonists & Sympathomimetic Drugs Overview Adrenergic neurons release norepinephrine as the primary neurotransmitter These neurons are found in the CNS and also in the sympathetic nervous system, where they serve as links between ganglia and the effector organs The adrenergic neurons and receptors, located either presynaptically on the neuron or postsynaptically on the effector organ, are the sites of action of the adrenergic drugs Sympathatic innervation of adrenal medulla Sympathatic Parasympathatic Somatic Ganglionic transmittion NN receptor Adrenal medulla NN receptor NN receptor Neuroeffector transmittion Acetylcholine Norepinephrine Effector organ Effector organ α or β Adrenergic receptor M receptor Neuromuscular junction NM receptor Neurotransmission at adrenergic neurons Presynaptic neuron Tyrosine Na+ Dopamine Tyrosine Action Potential H+ DA NE NE Uptake NE NE a1 NE Effector organ NE b Adrenergic receptors (adrenoceptors) All the adrenoceptors receptors (GPCRs) There are two main groups of adrenergic receptors, α and β, with several subtypes Adrenoceptors were initially identified on the basis of their responses to the adrenergic agonists epinephrine, norepinephrine, and isoproterenol are G-protein coupled α Adrecoceptros Epinephrine Norepinephrine Isoprotenol β Adrecoceptros Isoprotenol High affinity Epinephrine Norepinephrine Low affinity Adrenergic receptors (adrenoceptors) Alpha receptors The α-adrenoceptors are subdivided into two subgroups, α1 and α2, based on their affinities for α agonists and blocking drugs α1 receptors (GPCR-Gq) are present on the postsynaptic membrane of the effector organs and mediate many of the classic involving contraction of smooth muscle Adrenergic receptors (adrenoceptors) Alpha receptors α2 receptors (GPCR-Gi) are located primarily on presynaptic nerve endings and function their as autoreceptor The are located on other cells (e.g β cell of the pancreas) Adrenergic receptors (adrenoceptors) Beta receptors The β-adrenoceptors can be subdivided into three major subgroups, β1, β2, and β3, based on their affinities for adrenergic agonists and antagonists β1 Receptors have approximately equal affinities for epinephrine and norepinephrine, whereas β2 receptors have a higher affinity for epinephrine than for norepinephrine The β-adrenoceptors are coupled via G proteins in the Gs family to adenylyl cyclase Adrenergic receptors (adrenoceptors) Beta receptors β1 Receptors are found on most notably on the heart, where they increase heart rate and cardiac contractility β2 receptors are found in a variety of bronchial and vascular smooth muscles, where stimulation triggers muscle relaxation β3 Receptors may mediate responses to catecholamine at sites with "atypical" pharmacological characteristics (e.g., adipose tissue) β3 receptors are expressed in the detrusor muscle of the bladder and induce its relaxation (e.g.Mirabegron) Distribution of adrenoceptor subtypes Type α1 α2 β1 β2 β3 Tissue Most vascular smooth muscle (innervated) Pupillary dilator muscle Actions Pilomotor smooth muscle Prostate Heart Erects hair Contraction Increases force of contraction Postsynaptic CNS neurons Platelets Adrenergic and cholinergic nerve terminals Some vascular smooth muscle Fat cells Probably multiple Aggregation Heart, juxtaglomerular cells Respiratory, uterine, and vascular smooth muscle Skeletal muscle Human liver Bladder Fat cells Contraction Contraction (dilates pupil) Inhibits transmitter release Contraction Inhibits lipolysis Increases force and rate of contraction; increases renin release Promotes smooth muscle relaxation Promotes potassium uptake Activates glycogenolysis Relaxes detrusor muscle Activates lipolysis Sympathomimetic Drugs I. Direct acting sympathomimetics: Act directly on one or more of the adrenergic receptors These agents may be: a) Selective: for a specific receptor subtype (e.g., phenylephrine for α1, terbutaline for β2) b) None selective: have no or minimal selectivity and act on several receptor types (e.g., epinephrine for α1, α2, β1, β2, and β3 receptors) Sympathomimetic Drugs II. Indirect acting sympathomimetics: Increase the availability of norepinephrine or epinephrine to stimulate adrenergic receptors This can be accomplished in several ways : 1) Displacement of stored catecholamines from the adrenergic nerve ending (amphetamine-like or “displacers” ) 2) Inhibition of reuptake of catecholamines already released (e.g. cocaine & tricyclic antidepressants) From: Adrenoceptor Agonists & Sympathomimetic Drugs Basic & Clinical Pharmacology, 13e, 2015 Legend: Pharmacologic targeting of monoamine transporters. Commonly used drugs such as antidepressants, amphetamines, and cocaine target monoamine (norepinephrine, dopamine, and serotonin) transporters with different potencies. A shows the mechanism of reuptake of norepinephrine (NE) back into the noradrenergic neuron via the norepinephrine transporter (NET), where a proportion is sequestered in presynaptic vesicles through the vesicular monoamine transporter (VMAT). B and C show the effects of amphetamine and cocaine on these pathways. See text for details. Date of download: 3/12/2015 Copyright © 2015 McGraw-Hill Education. All rights reserved. Sympathomimetic Drugs III. Mixed acting sympathomimetics: Indirectly induce the release of norepinephrine from the presynaptic terminal and directly activate receptors (e.g. Ephedrine) Organ System Effects of Sympathomimetic Drugs The response of any cell or organ to sympathomimetics is the density and proportion of α and β adrenergic receptors Adrenergically innervated organs and tissues tend to have a predominance of one type of receptor: tissues such as the vasculature to skeletal muscle have both α1 and β2 receptors, but the β2 receptors predominate Organ System Effects of Sympathomimetic Drugs a. Cardiovascular system Effects of Alpha1-Receptor Activation: α1 receptor activation constrict skin, mucous membranes, and splanchnic blood vessels and causes a rise in peripheral resistance due to vasoconstriction of most vascular beds The enhanced arterial resistance usually leads to a dose-dependent rise in blood pressure In the presence of normal CV reflexes, the rise in blood pressure elicits a compensatory reflex bradycardia Cardiac output may not diminish in proportion to this reduction in rate, since increased venous return may increase stroke volume Organ System Effects of Sympathomimetic Drugs a. Cardiovascular system Effects of Beta-Receptor Activation β1 receptors: direct effects on the heart are determined largely by β1 receptors. Both the heart rate (chronotropic effect) and the force of contraction (inotropic effect) are increased, resulting in a markedly increased cardiac output and cardiac oxygen consumption β2 receptors: activating β2 receptors, leading to vasodilation in vasculature of skeletal muscles Organ System Effects of Sympathomimetic Drugs b. Respiratory system Activation of β2 receptors in bronchial smooth muscle leads to bronchodilation and also inhibits the release of allergy mediator such as histamines from mast cells Organ System Effects of Sympathomimetic Drugs c. The Eye Activation of α1 receptors mediates contraction of the radial pupillary dilator muscle of the iris and results in mydriasis Activiation of Alpha 2 receptors reduces intraocular pressure Activiation of β2 receptors on the ciliary epithelium facilitate the secretion of aqueous humor Organ System Effects of Sympathomimetic Drugs Genitourinary tact The bladder: Stimulation of α1A receptors mediate the contraction of the trigone and sphincter Stimulation of β2 receptors cause the relaxation of the detrusor muscle This can result in hesitancy in urination and may contribute to retention of urine in the bladder d. Organ System Effects of Sympathomimetic Drugs Genitourinary tact Uterus (female): Stimulation of β2 receptors mediate relaxation which may cause significant uterine relaxation d. Genitile (male): α1 receptor activation mediates the contraction of smooth muscles in the ductus deferens, seminal vesicles, and prostate resulting in normal ejaculation Organ System Effects of Sympathomimetic Drugs e. Gastrointestinal tract Activation of both α1 and β2 receptors, located both on smooth muscles and on neurons of the enteric nervous system leads to relaxation of GIT Stimulation of α2 receptors decrease muscle activity indirectly by presynaptically reducing the release of acetylcholine and may also decrease salt and water flux into the lumen of the intestine Organ System Effects of Sympathomimetic Drugs f. Metabolism 1. Lipolysis: enhanced by stimulating β3 receptors in adipocytes 2. Glycogenolysis: β2 receptors in the liver and muscles 3. Insulin secretion: is inhibited by α2 receptors activation and is enhanced by activation of β2 receptors Organ System Effects of Sympathomimetic Drugs h. Hormones secretion Renin secretion is stimulated by β1 and inhibited by α2 receptors Direct acting adrenergic agonists Catecholamine a. Epinephrine (adrenaline) It is an agonist at both α and β adrenergic receptors Respiratory: bronchodilation and inhibiting the release of allergy mediators such as histamines from mast cells (β2 action) Hyperglycemia: because of increased glycogenolysis in the liver (β2 effect), increased release of glucagon (β2 effect), and a decreased release of insulin (α2 effect) Lipolysis: epinephrine initiates lipolysis through its agonist activity on the β receptors of adipose tissue Direct acting adrenergic agonists Catecholamine a. Epinephrine (adrenaline) Cardiovascular effect: Epinephrine is a very potent cardiac stimulant (predominantly β1 receptors): cardiac output increases and myocardial oxygen demand is increased Epinephrine causes a decrease in total peripheral resistance that results from the predominance of vasodilation in the skeletal muscle vascular bed Therefore, the cumulative effect is an increase in systolic blood pressure, coupled with a slight decrease in diastolic pressure Direct acting adrenergic agonists catecholamine b. Norepinephrine (noradrenaline) Activates both α-adrenergic receptor (α1 & α2) and β1 receptors, but has relatively no effect on β2 receptors Norepinephrine increases peripheral resistance and both diastolic and systolic blood pressure Compensatory baroreflex activation tends to overcome the direct positive chronotropic effects of norepinephrine; however, the positive inotropic effects on the heart are maintained Direct acting adrenergic agonists Catecholamine c. Isoproterenol (isoprenaline) Predominantly stimulates both β1- and β2adrenergic receptors. It has little effect on αreceptors It produces intense stimulation of the heart to increase its rate and force of contraction, causing increased cardiac output It also dilates the arterioles of skeletal muscle (β2 effect), resulting in decreased peripheral resistance: these actions lead to a marked fall in diastolic and mean arterial pressure Cardiovascular effects of sympathomimetics Norepinephrine PULSE RATE (min) Isoproterenol Epinephrine 100 50 BLOOD PRESSURE (mm Hg) 180 120 80 PERIPHERAL RESISTANCE 0 15 0 15 TIME (min) 0 15 Direct acting adrenergic agonists Direct acting sympathomimetics a. Phenylphrine It binds primarily to α receptors and favours α1 receptors over α2 receptors It has no effect on the heart itself but rather induces reflex bradycardia when given parenterally It is often used topically on the nasal mucous membranes as a decongestant and in ophthalmic solutions for mydriasis Direct acting adrenergic agonists Direct acting sympathomimetics b. Midodrine Is a selective α1-receptor agonist Primarily indicated for the treatment of orthostatic hypotension, typically due to impaired autonomic nervous system function The drug may cause hypertension when the subject is supine. This can be minimized by avoiding dosing prior to bedtime and elevating the head of the bed Direct acting adrenergic agonists Direct acting sympathomimetics c. Oxymetazoline Is a direct-acting α-adrenoceptor agonists It is used as topical decongestants (nasal spray) because of their ability to promote constriction of the nasal mucosa When taken in large doses, oxymetazoline may cause hypotension, presumably because of a central clonidine-like effect (α2A receptors) Direct acting adrenergic agonists Direct acting sympathomimetics d. Alpha2-selective agonists Agents: clonidine, guanfacine, guanabenz These agents are used primarily for the treatment of systemic hypertension due to their ability to decrease blood pressure through actions in the CNs methyldopa, Direct acting adrenergic agonists Direct acting sympathomimetics g. Beta-selective agonists β1-selective agents: Dobutamine: it increases cardiac output (positive inotropic action) with little change in heart rate, and it does not significantly elevate oxygen demands of the myocardium—a major advantage over other sympathomimetic drugs Direct acting adrenergic agonists Direct acting sympathomimetics g. Beta-selective agonists β2-selective agents: Albuterol, pributerol, terbutaline, salmeterol and formoterol : used primarily as bronchodilator the treatment of asthma Ritodrine is used clinically to achieve uterine relaxation in premature labour (arrest premature labour) Therapeutic Uses of Sympathomimetic Drugs a. Cardiovascular applications 1) Hypotensive emergency to preserve cerebral and coronary blood flow: direct acting α agonists such as: norepinephrine, phenylephrine, and methoxamine is used for short duration 2) Chronic orthostatic hypotension: increasing peripheral resistance is one of the strategies to treat chronic orthostatic hypotension using midodrine (α1 agonist Midodrane ) or droxidopa 3) Emergency treatment of cardiac arrest: isoproterenol and epinephrine Therapeutic Uses of Sympathomimetic Drugs a. Cardiovascular applications 4) Cardiogenic and septic shock: Dopamine is the drug of choice b/c it is a β receptor agonists increase heart rate and force of contraction, α receptor agonists increase peripheral vascular resistance, and it enhances perfusion to the kidney and splanchnic areas (D1 receptors) 5) Acute heart failure: Dobutamine is a β1 agonists useful in this situation because it increases cardiac output and, cause relatively little peripheral vasoconstriction. It does not significantly elevate oxygen demands of the myocardium Therapeutic Uses of Sympathomimetic Drugs b. Inducing Local Vasoconstriction Reduction of local or regional blood flow through α-receptor activation is desirable for: 1) Achieving hemostasis in surgery, for reducing diffusion of local anesthetics away from the site of administration: 1:200,000 parts epinephrine 2) Reducing mucous membrane congestion (decongestant): phenylephrine, xylometazoline, and oxymetazoline (nasal spray) Therapeutic Uses of Sympathomimetic Drugs c. Pulmonary applications Epinephrine is the primary drug used in the emergency treatment of bronchoconstriction Short-acting β2-selective agents (albuterol, metaproterenol, terbutaline) are used in the treatment of acute asthmatic bronchoconstriction Longer-acting β2-selective agonists (salmeterol and formoterol) are used in combination with corticosteroids for chronic asthma treatment in adult Ultra-long acting β2 agonists (Indacaterol, olodaterol, and vilanterol) are approved for oncea-day use in COPD Therapeutic Uses of Sympathomimetic Drugs d. Anaphylaxis Epinephrine (IM) is the DOC for the immediate treatment of anaphylactic shock It can relief bronchospasm, mucous membrane congestion, angioedema, and severe hypotension associated with anaphylactic shock, and can inhibit the release of allergy mediators such as histamine from mast cells Therapeutic Uses of Sympathomimetic Drugs e. Ophthalmic Applications The α- agonists phenylephrine is an effective mydriatic agent frequently used to facilitate examination of the retina and are useful decongestant for minor allergic hyperemia and itching of the conjunctival membranes Sympathomimetics administered as ophthalmic drops are also useful in localizing the lesion in Horner's syndrome Apraclonidine and brimonidine (α2-selective agonists) that lower intraocular pressure and are approved for use in glaucoma Right Horner's syndrome Therapeutic Uses of Sympathomimetic Drugs f. Genitourinary Applications Ritodrine & terbutaline (selective β2 agonist) have been used to suppress premature labor β-agonist therapy may have no significant benefit on perinatal infant mortality and may increase maternal morbidity