Sympathetic Nervous System

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

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

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

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

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

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

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

Catecholamines NE EPI DA

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

Drug actions at presynaptic autonomic nerve terminals

Adrenergic Receptors 1, 2, 1 NE 1, 2, 1, 2 EPI

Adrenergic Receptors 1, 2, 1 NE 1, 2, 1, 2 EPI 1, 1, DA1 DA

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

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

Drugs and Adrenergic Synapses

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

MIXED ADRENERGIC AGONISTS Norepinephrine 1, 2, 1 Epinephrine 1, 2, 1, 2 Dopamine DA1, 1, 1

HR BP TPR

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

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

Tx uses for ALPHA AGONISTS Alpha-1 agonists Alpha-2 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 - Isoproterenol Selective 1 - Dobutamine Selective 2 - Albuterol Tx: Cardiac stimulant - Metaproterenol Tx: COPD, Asthma - Terbutaline - Isoetharine - Bitolterol Tx: Inotropic agent Tx: Uterine relaxation - Ritodrine

NE EPI ISO HR BP TPR

Dose-response effects produced by dopamine at different receptors

CNS : Tx antihypertensive effect 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 (-) 2 C M T ACh 1 (-) NE N (-) L NE N 1 EPI ACh 2 S 2

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

 Nonselective 1 and 2 receptor antagonists 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 1 Vasoconstriction (-) 2

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

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

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

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

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

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

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

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

Tricyclic Antidepressants Uptake Blockers Cocaine Tricyclic Antidepressants

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

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

Neuronal Blockers Reserpine Guanethadine 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