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Flashcards in ANS Pharmacology Deck (26):
1

Preganglionic NT and Receptors

Preganglionic neurons
Acetylcholine (ACh) is the neurotransmitter for both the sympathetic and the parasympathetic systems (i.e. at autonomic ganglia) and at the adrenal medulla
ACh binds to neuronal type nicotinic cholinoceptors (Nn) in autonomic ganglia

2

Postganglionic NT and Receptors

Postganglionic neurons
Norepinephrine (NE) is the neurotransmitter for the sympathetic branch (ACh in a few cases)
ACh is the neurotransmitter for the parasympathetic branch
NE binds to alpha and beta adrenoceptors on target tissues
ACh binds to muscarinic cholinoceptors on target tissues

3

Adrenal Medulla NTs

Adrenal medulla
Releases epinephrine (80%) and norepinephrine (20%)
ACh binds to Nn nicotinic receptors (same as for autonomic ganglia)

4

Nicotinic vs. Muscarinic Receptors

Nicotinic receptors only affects autonomic ganglia and skeletal muscle tissues but not effector tissues

Muscarinic receptors only affects effector tissues and not autonomic ganglia or skeletal muscle

5

Parasympathetic, Sympathetic, and Adrenal Medulla Receptors and Effector Tissues

Parasympathetic: ACh to muscarinic receptors for heart, smooth muscle, and gland cells

Sympathetic: ACh to muscarinic receptors for sweat glands and some vessels
NE to alpha, beta receptors for heart, smooth muscle, and gland cells

Adrenal Medulla: E and NE on alpha, beta receptors for heart and blood vessels; ACh on Nm for skeletal muscle

6

Parasympathetic: Receptor Subtypes and CV Responses

ACh effects in heart mediated largely via M2 muscarinic receptors; found in heart muscle (both nodal and non-nodal)

In some blood vessels (salivary and skeletal muscle) muscarinic receptors are present and receive innervation
On endothelial cells of most blood vessels, muscarinic receptors are present but not innervated; M3 important in blood vessels

At least five subtypes of muscarinic receptors (M1-M5) have been identified

7

Sympathetic: Receptor Subtypes and CV Responses

NE effects mediated largely via b1, b2, a1, and a2 adrenoceptors

Adrenoceptors found in heart muscle (both nodal & non-nodal) include b1, b2, and a1; b1 most important in cardiac regulation

Important adrenoceptors in blood vessels are b2, a1, and a2

8

Noradrenergic Synapse: Synthesis and Storage of NE

Synthesis begins with conversion of tyrosine to DOPA by tyrosine hydroxylase (rate-limiting step)

DOPA is converted to dopamine by DOPA decarboxylase (DDC)

Dopamine is converted to NE within storage vesicles by dopamine-b-hydroxylase

9

Noradrenergic Synapse: Release of NE

An action potential arrives causing an influx of calcium thus promoting exocytotic release of NE

10

Noradrenergic Synapse: Receptor Binding

NE binds postjunctionally to alpha or beta adrenoceptors OR prejunctionally to alpha-2 receptors (negative-feedback regulation of NE release)

Binding to alpha1 receptors activates phospholipase C via a Gq-coupling protein; leads to release of IP3 (inositol 1,4,5-trisphosphate) & DAG (diacylglycerol); increases cytosolic calcium

Binding to beta receptors results in stimulation of adenylyl cyclase via Gs and increases cyclic AMP synthesis; in heart, cyclic AMP increases calcium influx and calcium storage inside of the cell

11

Noradrenergic Synapse: NE Removal and Metabolism

Primary mechanism for termination of NE’s effects is reuptake into presynaptic nerve by a transport pump

After reuptake, NE is either restored inside vesicles or oxidized (deaminated) by monoamine oxidase (MAO); catechol-O-methyltransferase (COMT) located extraneuronally contributes further to NE metabolism; vanillyl mandelic acid (VMA) is major end- product

12

CV Effects of Autonomic Receptor Stimulation

Postjunctional Receptors:

M: depreses HR and dilates blood vessels

Alpha 1: weak stimulation of the heart and constricts blood vessels

Alpha 2: constriction of blood vessels

Beta 1: stimulates HR and causes renin release from the JG cells within the kidney

Beta 2: weak stimulation of HR and dilation of blood vessels

13

Parasympathetic Responses and Tone in the Heart and Blood Vessels

The SA and AV nodes are richly innervated by vagal efferent nerves and have a high density of muscarinic (M) receptors; atria (but not ventricles) also receive significant vagal input

Parasympathetic nerve activation:
Decreases heart rate (negative chronotropic effect) via actions on the SA node
Decreases AV nodal conduction (negative dromotropic effect)
Decreases force of contraction in atria (negative inotropic effect)

14

Sympathetic Responses and Tone in the Heart and Blood Vessels

The SA and AV nodes and atrial and ventricular myocardium are richly innervated by sympathetic noradrenergic nerves

Arterial and venous blood vessels are innervated primarily by sympathetic noradrenergic nerves

Sympathetic nerve activation:
Increases heart rate, AV nodal conduction, and force of contraction (positive chronotropic, dromotropic and inotropic effects, respectively)
Results in vasoconstriction

15

Vagal Tone and Sympathetic Tone at Rest

At rest, vagal tone predominantly affects heart rate, whereas sympathetic tone predominantly influences blood vessels

Vagal tone is responsible for low resting heart rates

Sympathetic tone is responsible for maintaining normal arterial blood pressure

Tone can be manipulated pharmacologically. For example, giving a drug that blocks muscarinic receptors (e.g. atropine) in the SA node of the heart will disrupt the vagal tone resulting in increased heart rate.

16

Adrenergic Receptor Agonists and Antagonists

Adrenergic receptor (adrenoceptor) agonists generally mimic the actions of the natural receptor ligand (neurotransmitter), whereas receptor antagonists block those actions

Agonists called sympathomimetics (upregulate sympathetics)
Direct-acting bind to receptor directly to produce effects; indirect-acting induce the release of NE from nerve terminals and/or may block reuptake; mixed-acting act in both ways

Antagonists called sympatholytics (downregulate sympathetics)
Bind to receptors to block them; some are reversible & some are irreversible

17

B-adrenergic Receptor Agonists (Direct-Acting)

Nonselective agonists stimulate b1 and b2 adrenergic receptors, causing cardiac stimulation (ISO, EPI & NE) and systemic vasodilation (e.g. ISO & EPI)

Selective agonists preferentially stimulate b2 adrenergic receptors (e.g. albuterol)
For b1 receptors, the rank order of potency is Isoproterenol (ISO) > EPI > NE

NE is less potent at b2 receptors (rank order of potency is ISO>EPI>>>NE)

18

A-adrenergic Receptor Agonists (Direct-Acting)

Selective agonists at a1 receptors increase arterial pressure by constricting blood vessels (e.g. phenylephrine)

Nonselective agonists EPI & NE also stimulate a1 receptors

For a1 receptors, the rank order of potency is EPI > NE >>> ISO

The synthetic drug ISO [or isoproterenol] is a good b receptor agonist, but not a good a receptor agonist

19

E, NE, and ISO with Arterial, Bronchial Smooth Muscle, and Heart Tissue

The catecholamines epinephrine (E), norepinephrine (NE), and isoproterenol (ISO) were added in increasing concentrations to arterial, bronchial smooth muscle, and heart tissue hung in experimental organ baths. Changes in force of contraction or relaxation were measured.

Arterial Smooth Muscle: contraction via alpha 1; E>NE>>>ISOBronchial

Smooth Muscle: relaxation via beta 2; ISO>E>>>NE

Heart Muscle: positive inotropic effect via beta 1; ISO>E>/=NE

20

Agonists at Both Beta and Alpha Receptors (Direct-Acting)

These agonists cause cardiac stimulation (via beta receptors) and constrict blood vessels thus increasing blood pressure (via alpha receptors), and one agent (epinephrine) may dilate certain blood vessels (via b2 receptors) thus decreasing peripheral resistance

Examples: norepinephrine, epinephrine, and dobutamine

21

Adrenergic Receptor Agonists (Indirect Acting)

Drugs that act by causing the release of NE from nerve terminals (indirect-acting) and/or may block reuptake; no direct binding to receptors

These agents also cause cardiac stimulation and constriction of blood vessels (e.g. amphetamine)

22

Adrenergic Receptor Agonists (Mixed Acting)

Drugs that act by both causing the release of norepinephrine from nerve terminals and by directly activating a and b receptors (mixed-acting)

As for the direct- and indirect-acting drugs, these agents can also produce cardiac stimulation and constriction of blood vessels to raise blood pressure (e.g. ephedrine)

23

B-adrenergic Receptor (Adrenoceptor) Antagonists

Depress cardiac function by preventing the binding of agonists (depress both SA and AV nodes; produce negative chronotropic and inotropic effects)

Lower arterial blood pressure due to decreased cardiac output (offset acutely by unopposed alpha receptor-mediated vasoconstriction and possible reflex increases in sympathetic discharge); chronic use in hypertensive patients reduces blood pressure

24

B-adrenergic Receptor (Adrenoceptor) Nonselective and Selective Antagonists

Nonselective – block both b1 and b2 receptors reversibly (e.g. propranolol, nadolol)

Selective – block b1 receptors reversibly and preferentially (e.g. metoprolol, atenolol); used for patients that need b2 for dilation of vessels including asthma and Raynaud's syndrome

25

A-adrenergic Receptor Antagonists

Dilate systemic vessels and reduce arterial blood pressure (decrease peripheral vascular resistance)

Nonselective, reversible block of both a1 and a2 receptors (e.g. phentolamine)

Nonselective, irreversible block of both a1 and a2 receptors (e.g. phenoxybenzamine)

Selective, reversible block of a1 receptors preferentially (e.g. prazosin)

26

Antagonists that Block Both A and B Adrenergic Receptors

Depress cardiac function as other b receptor antagonists (nonselective, reversible block)

Dilation of systemic vessels and reduce arterial pressure (a1 selective, reversible block)

Examples include labetalol and carvedilol