ADRENERGIC AGONISTS • Course: Integrated Therapeutics 1 • Lecturer: Dr. E. Konorev • Date: September 16, 2010 • Materials on: Exam #2 • Required reading: Katzung, Chapter 9 1 ADRENERGIC NEUROTRANSMISSION Pre-Synaptic Neuron Synapse Post-Synaptic Neuron Tyrosine Reuptake Tyrosine Hydroxylase NE -receptors NE -receptors MAO 2-autoreceptors NE = norepinephrine 2 REGULATION OF ADRENERGIC TRANSMISSION BY PRESYNAPTIC RECEPTORS • Autoreceptors (2) • Heteroreceptors 3 CATECHOLAMINES AS ADRENERGIC NEUROTRANSMITTERS Sympathetic Neurotransmitters 4 TYPES OF ADRENERGIC RECEPTORS • -AR defined by the following potency norepinephrine > epinephrine >> isoproterenol – Subtypes of were originally identified by selective antagonists • 1 blocked by prazosin • 2 blocked by yohimbine – Further subtypes are now known – Selective 1 and 2 agonists are now known Dr. Raymond Ahlquist (1914-1989), suggested that CA act via two principal types of AR, and (1948) 5 TYPES OF ADRENERGIC RECEPTORS • -AR defined by the following potency isoproterenol >> epinephrine > norepinephrine – 1 and 2 subtypes of determined by affinity • 1 affinity – epinephrine = norepinephrine • 2 affinity – epinephrine >> norepinephrine – 3-AR subtype has now been described • Dopamine (D) receptors – Distinct from and receptors – Important in brain, splanchnic and renal vasculature 6 TYPES OF ADRENERGIC RECEPTORS Gene on Receptor Agonist Antagonist Effects Chromosome 1 type Phenylephrine Prazosin ↑ IP3, DAG common to all 1A C5 1B C8 1D C20 2 type Clonidine Yohimbine cAMP common to all 2A Oxymetazoline C10 2B C2 2C C4 type Isoproterenol Propranolol ↑ cAMP common to all 1 Dobutamine Betaxolol C10 2 Albuterol Butoxamine C5 3 C8 Dopamine Dopamine type D1 Fenoldopam ↑ cAMP C5 D2 Bromocriptine cAMP C11 D3 cAMP C3 D4 Clozapine cAMP C11 7 D5 ↑ cAMP C4 SIGNAL TRANSDUCTION BY ADRENOCEPTORS 1 receptor activation IP3 – increase in cytosolic Ca DAG – activation of PKC Activation of mitogen- activated kinases (MAPK) and polyphosphoinositol-3- kinase (PI-3 kinase) regulate gene expression, lead to stimulation of cell growth and proliferation 8 SIGNAL TRANSDUCTION BY ADRENOCEPTORS -receptor activation -agonist -agonist •Accumulation of 2 cAMP •Activation of protein kinase A (PKA) by cAMP 2-receptor activation •Decrease in cAMP levels •Inhibition of PKA PKA 9 DOWNREGULATION OF ADRENERGIC TRANSMISSION • Desensitization of adrenergic receptors • GRK, G-protein coupled receptor kinase 10 DOWNREGULATION OF ADRENERGIC TRANSMISSION • Receptor internalization and lysosomal degradation 11 The Sympathetic Nervous System “fight or flight” EYES: Dilates pupil: mydriasis SALIVARY : Decreased salivation GLANDS Increases heart rate HEART Speeds up conduction through AV node Increased cardiac output Increases force of contraction LUNGS: Relaxation of bronchial smooth muscle GI TRACT : Decreased motility (relaxes smooth muscle, contracts sphincters) LIVER: increased glucose production (stimulates gluconeogenesis and glycogenolysis) ADRENAL : Releases norepinephrine and epinephrine MEDULLA (via circulating norepinephrine and epinephrine) BLADDER: relaxation (urinary retention) PROSTATE GLAND: smooth muscle VASCULAR SMOOTH MUSCLE: contraction (urinary SWEAT Arteries supplying skeletal muscle and liver: : Increased sweating obstruction) GLANDS relaxation (vasodilation) 12 Most other vessels: contraction (vasoconstriction) SOME IMPORTANT SYMPATHETIC RECEPTORS 2 Receptors EYES: Dilates pupil Inhibit sympathetic n.s. SALIVARY : DecreasedReceptors salivation GLANDS 1 Increases heart rate Speeds up conduction through AV node HEART Increased cardiac output Increases force of contraction LUNGS: Relaxation of bronchial smooth muscle GI TRACT : Decreased motility2 Receptors (relaxes smooth muscle, contracts sphincters) LIVER: increased glucose production VASCULAR SMOOTH MUSCLE: (stimulates gluconeogenesis and Arteries supplying skeletal muscle and liver: glycogenolysis) relaxation (vasodilation) ADRENAL : Releases norepinephrine and epinephrine MEDULLA (via circulating norepinephrine and epinephrine) BLADDER: relaxation (urinary retention) PROSTATE GLAND: smooth muscle M Receptors contraction (urinary obstruction)PROSTATE GLAND: smooth muscle contraction (urinary SWEATSWEAT : Increased: Increased sweating sweating obstruction) VASCULAR SMOOTH MUSCLE: GLANDSGLANDS 1 Receptors Most other vessels: contraction (vasoconstriction)13 DISTRIBUTION OF ADRENOCEPTORS Type Tissue Actions Most vascular smooth muscle Contraction 1 (innervated) Pupillary dilator muscle Contraction (dilates pupil) Prostate Contraction 2 Platelets Aggregation Adrenergic and cholinergic Inhibition of transmitter release nerve terminals Some vascular smooth muscle Contraction Fat cells Inhibition of lipolysis Increases force and rate of Heart 1 contraction Respiratory, uterine, and Promotes smooth muscle relaxation 2 vascular smooth muscle Human liver Activates glycogenolysis 3 Fat cells Activates lipolysis D1 Smooth muscle Dilates renal blood vessels 14 D2 Nerve endings Modulates transmitter release ORGAN SYSTEM EFFECTS • Overall effect of adrenergic drugs on organs and tissues is determined by – The type of receptor(s) the tissue is expressing – Selectivity of the drug for receptor subtypes – Intrinsic activity of the drug at receptor – Compensatory reflexes – Development of tolerance and tachyphylaxis 15 DIRECT vs. INDIRECT SYMPATHOMIMETIC DRUGS Pre-Synaptic Neuron Synapse Post-Synaptic Neuron Reuptake Blockers Adrenergic Cocaine Reuptake Receptor Agonists INDIRECT ACTING DIRECT ACTING NE -receptors -receptors MAO Monoamine Oxidase Releasing agents (MAO) Inhibitors Amphetamines, Phenelzine Ephedrine INDIRECT ACTING 16 NE - Norepinephrine INDIRECT ACTING TYPES OF SYMPATHOMIMETIC DRUGS • Direct sympathomimetics – Alpha agonists • Phenylephrine • Methoxamine • Clonidine – Mixed alpha and beta agonists • Norepinephrine • Epinephrine – Beta agonists • Dobutamine • Isoproterenol • Terbutaline • Albuterol • Ritodrine – Dopamine agonists • Dopamine • Fenoldopam • Indirect sympathomimetics 17 SELECTIVITY OF ADRENERGIC AGONISTS 18 ORGAN SYSTEMS EFFECTS • Cardiovascular system – Blood vessels • 1 causes contraction and increase in vascular resistance • 2 causes smooth muscle relaxation • D1 causes smooth muscle relaxation • Significant differences in receptor types found in vascular beds –Skin vessels and mucous membranes – mostly 1 –Splanchnic – mostly 1 and D1 –Skeletal muscle – 1 and 2 –Renal, cerebral – D1 and 1 19 ORGAN SYSTEM EFFECTS • Cardiovascular system – Heart – mostly 1 • Increase calcium influx –Positive chronotropic – increase pacemaker rate –Increase in conduction velocity at AV node –Refractory period decreased –Positive inotropic effects • Presence of normal reflexes – heart rate response may be dominated by reflex response to blood pressure changes 20 ORGAN SYSTEM EFFECTS Cardiovascular system • Blood Pressure = Cardiac Output x Vascular Resistance • Epinephrine = agonists at ALL adrenergic receptors; little change in blood pressure • Norepinephrine = low affinity towards beta-2 adrenergic receptors; large increase in blood pressure Norepinephrine Epinephrine 1 1 2 Vasoconstriction = Increased Cardiac Vasodilation = Increased Blood Output = Increased Decreased Blood Pressure Blood Pressure Pressure 21 ORGAN SYSTEM EFFECTS 22 Effect of adrenomimetics on heart rate (HR) and blood pressure (BP) ORGAN SYSTEM EFFECTS • Cardiovascular system – Alpha agonist – phenylephrine • Increases peripheral arterial resistance • Decreases venous capacitance • Increase blood pressure but a reflex decrease in heart rate • CO may not change - increase venous return may increase stroke volume – Beta agonist – isoproterenol • Increases cardiac function and cardiac output • Relaxes vascular smooth muscle and decreases blood pressure 23 ORGAN SYSTEMS EFFECTS • Eye – 1 agonist – contracts pupil dilator muscle - mydriasis • Respiratory tract – 2 agonist – bronchodilation – 1 agonist – decrease in mucus secretion in the upper respiratory tract – decongestant action – is due to the contraction of vascular smooth muscle 24 ORGAN SYSTEMS EFFECTS • Genitourinary system – Human uterus contains both and 2 • 2 – mediates relaxation – useful in pregnancy – Bladder base, urethral sphincter and prostate • 1 promotes contraction urinary retention • 2 mediates relaxation – Ejaculation – proper receptor activation – Detumescence of erectile tissue – via 1 25 ORGAN SYSTEM EFFECTS • Metabolic effects – 3 activation – fat cells – lipolysis, enhance the release of free fatty acids into plasma – 2 in lipocytes – inhibits lipolysis by decreasing intracellular cAMP – 2 agonists – increase glycogenolysis and gluconeogenesis in the liver • Endocrine effects – 2 receptor activation – stimulates insulin secretion – 2 agonists – inhibit insulin secretion – Stimulationof renin release by 1 (inhibited by 2) • One mechanism by which -receptor antagonists are effective for the treatment of hypertension 26 ORGAN SYSTEM EFFECTS • Central nervous system – Vary significantly with the ability to pass BBB – Catecholamines – do not pass – Non-catecholamines (such as amphetamine) will pass BBB and have following effects • Mild alerting effects • Improved attention to boring tasks • Insomnia • Euphoria • Anorexia • Psychotic behavior 27 ALPHA ADRENERGIC AGONISTS • Phenylephrine – direct acting agonist - 1 > 2 >>>>> – Not a catechol – not inactivated by COMT – longer duration of action – Effective mydriatic and decongestant – Can be used to raise blood pressure • Methoxamine – direct acting