Sympathetic Nervous System Nervous System CNS Brain Spinal

Sympathetic Nervous System

Nervous System CNS Brain Spinal Cord PNS Autonomic NS Somatic NS Sympathetic Parasympathetic

CNS ACh C ACh M N T ACh NE N L S 1 NE 1 ACh SM N 2

CNS ACh C ACh M N T ACh NE N L N S ACh 1 NE 1 EPI ACh SM N 2

CNS ACh C ACh M N T ACh NE N L N ACh S 1 ACh M SG ACh SM N NE 1 2

(-) CNS Sympathetic Nervous System 2 C M T ACh NE N L N S ACh 1 EPI NE 1 2

Dual Innervation Exceptions - blood vessels (only sympathetic) (only parasympathetic) - bronchioles - ciliary muscles (only parasympathetic) Predominant Tone Primarily parasympathetic NS Exceptions - blood vessels (sympathetic) - sweat glands (sympathetic cholinergic)

Denervation Supersensitivity + Effect NT Before Denervation +++ Effect NT After Denervation

Catecholamines NE EPI DA

PRESYNAPTIC POSTSYNAPTIC NE - predominately removed from synapse via ‘re-uptake 1’ Metabolic Removal Re-uptake 2 Re-uptake 1 NE synthesis COMT MAO NE NE MAO (-) 2 Receptor Binding / Action

Drug actions at presynaptic autonomic nerve terminals

Adrenergic Receptors NE 1, 2, 1 EPI 1, 2, 1, 2

Adrenergic Receptors NE 1, 2, 1 EPI 1, 2, 1, 2 DA 1, DA 1

EFFECTS OF STIMULATING ADRENERGIC RECEPTORS SITE HEART VASCULATURE EFFECT TACHYCARDIA and INCREASED CONTRACTILITY ( 1) VASODILATION ( 2) VASOCONSTRICTION ( 1, 2) AIRWAYS BRONCHORELAXATION ( 2) IRIS MYDRIASIS ( 1) BLADDER DECREASED URINATION ( 2) GI TRACT DECREASED GI MOTILITY and SECRETIONS ( 2) UTERUS RELAXATION ( 2)

1 contractile force heart rate renin release 2 1, 2 vasodilation, TPR vasoconstriction TPR

Drugs and Adrenergic Synapses

Adrenergic Agonists CNS ACh C ACh M N T ACh NE N L N S 1 NE 1 EPI ACh SM N 2

MIXED ADRENERGIC AGONISTS Norepinephrine 1, 2, 1 Epinephrine 1, 2, 1, 2 Dopamine DA 1, 1

HR BP TPR

MIXED ADRENERGIC AGONISTS Norepinephrine Epinephrine ( 1, 2, 1) ( 1, 2, 1, 2) Tx: ● Asthma (but there are better drugs) ● Anaphylactic shock ● Cardiogenic shock ● Prolong action of local anesthetics ● Topical hemostatic agent Dopamine Tx: ● CHF (DA, 1)

ALPHA AGONISTS - Phenylephrine - Methoxamine ( 1) ( 1) - Oxymetazoline ( 1 and 2 in periphery) - Tetrahydrozoline ( 1) - Naphazoline ( 1) - Ephedrine/Pseudoephedrine - Clonidine ( 1) ( 2, Tx site of action is CNS)

Tx uses for ALPHA AGONISTS Alpha-1 agonists Tx: ● Nasal decongestion ● Used in eye drops to ‘get the red out’ ● Hypotensive states Alpha-2 agonists Tx: ● Hypertension

BETA AGONISTS and Tx uses Non-selective 1/2 Selective 2 - Isoproterenol - Albuterol - Metaproterenol Tx: Cardiac stimulant Selective 1 - Dobutamine Tx: Inotropic agent Tx: COPD, Asthma - Terbutaline - Isoetharine - Bitolterol Tx: Uterine relaxation Ritodrine

NE HR BP TPR EPI ISO

Dose-response effects produced by dopamine at different receptors

CNS ADRENERGIC AGENTS CNS : Tx antihypertensive effect - Clonidine ( 2 agonist) - Guanabenz ( 2 agonist) - Guanfacine ( 2 agonist) - Methyldopa Converted in CNS to methylnorepinephrine (low efficacy 2 agonist)

Sympathetic Nervous System CNS (-) C 2 M T L (-) ACh S NE N (-) N 1 NE EPI ACh 2 2 1

Adrenergic Antagonists CNS ACh C ACh M N T ACh X NE N L N S 1 X NE 1 EPI X ACh SM N 2

ALPHA ANTAGONISTS and Tx uses Nonselective 1 and 2 receptor antagonists - Phenoxybenzamine Non-competitive action - Phentolamine Competitive action Tx: - DOC for overdose of alpha agonists - Management of pheochromocytoma - Dental use for reversal of local anesthetic action Selective 1 receptor antagonists - Prazosin - Terazosin (water soluble) Tx: Antihypertensive agents, Management of benign prostatic hypertrophy

Adrenergic Influence on Vascular Smooth Muscle Tone VSMC 2 NE NE (-) 2 1 Vasoconstriction

Adrenergic Influence on Vascular Smooth Muscle Tone EPI VSMC 2 Vasoconstriction NE NE (-) 2 1 Vasoconstriction

Marked hypotensive response produced by dual 1 and 2 - Receptor Blockade on VSMC EPI X VSMC 2 NE NE (-) X 2 Phentolamine - 1 and 2 blockade X 1 Vasodilation

Moderate hypotensive response produced by dual 1 and 2 - Receptor Blockade 0 n VSMC EPI VSMC 2 Vasoconstriction NE NE (-) X 2 Prazosin - selective 1 blockade 1 Vasodilation

BETA ANTAGONISTS ● Non-selective 1, 2 ● ‘Cardio’- Selective 1 Propranolol Atenolol Nadolol Metropolol Esmolol Timolol Acebutolol (ISA) Pindolol Carteolol Intrinsic Sympathomimetic Activity ● Non-selective 1, 2, 1 Labetalol Carvedilol

Beta Blocker Tx Uses: ● Hypertension Angina ● Migrane ● Anxiety ● Congestive heart failure ● Myocardial infarction ● ● Arrhythmias ● Stage fright

INDIRECT ACTING ADRENERGIC AGONISTS Tyramine (dietary substance) Ephedrine Pseudoephedrine Amphetamine

Amphetamine PRESYNAPTIC POSTSYNAPTIC Re-uptake 1 NE NE / Receptor Binding Action

Amphetamine PRESYNAPTIC Re-uptake 1 POSTSYNAPTIC amphetamine NE (+) NE / Receptor Binding Action

Uptake Blockers • Cocaine • Tricyclic Antidepressants

Cocaine PRESYNAPTIC POSTSYNAPTIC Re-uptake 1 NE NE / Receptor Binding Action

Cocaine PRESYNAPTIC POSTSYNAPTIC Re-uptake 1 NE X cocaine NE / Receptor Binding Action

Neuronal Blockers • Reserpine Depletes NE stores by inhibiting vesicular uptake of NE; NE then metabolized by intra-neuronal MAO • Guanethadine Inhibits NE release, also causes NE depletion, and can damage NE neurons

Monoamine Oxidase (MAO) Inhibitors • Pargyline • Tranylcypromine Tyramine (or other drugs that promote NE release) may cause markedly increased blood pressure in patients taking MAO inhibitors