Introduction to autonomic pharmacology

Introduction to Autonomic Pharmacology

By

M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Science

Introduction to Autonomic Pharmacology

Introduction Nomenclature Neurochemistry of ANS Cholinergic Transmission Adrenergic Transmission Nonadrenergic, Noncholinergic (NANC) Receptor Subtypes, Mechanisms & Functions Regulation of ANS ANS Interaction (the Eye)

Introduction Autonomic Nervous System (ANS) controls

involuntary body functions. Sympathetic

Parasympathetic

Enteric nervous system (ENS) is a highly organized collection of neurons in the walls of the GI tract.

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Fight or Flight

Rest & Digest

A highly simplified diagram of the intestinal wall and some of the circuitry of the enteric nervous system (ENS). The ENS receives input from both the sympathetic and the parasympathetic systems and sends afferent impulses to sympathetic ganglia and to the central nervous system. Many transmitter or neuromodulator substances have been identified in the ENS.ACh, acetylcholine; AC, absorptive cell; CM, circular muscle layer; EC, enterochromaffin cell; EN, excitatory neuron; EPAN, extrinsic primary afferent neuron; 5HT, serotonin; IN, inhibitory neuron; IPAN, intrinsic primary afferent neuron; LM, longitudinal muscle layer; MP, myenteric plexus; NE, norepinephrine; NP, neuropeptides; SC, secretory cell; SMP, submucosal plexus.

Nomenclature

Synapse is the junction across which a nerve impulse passes from an axon to another neuron.

Nerve fibers carrying the signal into a Synapse are: presynaptic.

Nerve fibers carrying the signal out of a Synapse are: postsynaptic.

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Nomenclature Cont,d

Junction is the connection between a neuron and a non neuronal cell (muscle, gland etc).

Nerve fibers carrying the signal into a junction are prejunctional.

Cells responding to the neuronal signal are postjunctional.

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Nomenclature (Cont,d)

Ganglion is a group of nerve cells forming a nerve center, especially one located outside the brain or spinal cord.

Nerve fibers carrying the signal into a ganglion are: Preganglionic.

Nerve fibers carrying the signal out of a ganglion are: Postganglionic.

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The neurons transmitting the neuronal message out of the CNS to the periphery are efferent fibers.

The neurons transmitting the neuronal message from periphery to the CNS are afferent fibers.

The fibers that control voluntary movements are somatic nerves.

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Parasympathomimetic: Parasympathetic activating Ligand.

Sympathomimetic: Sympathetic activating Ligand.

Parasympatholytic: Parasympathetic inhibiting Ligands.

Sympatholytic: Sympathetic inhibiting Ligand.

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Schematic diagram comparing some anatomic and neurotransmitter features of autonomic and somatic motor nerves. Only the primary transmitter substances are shown. Parasympathetic ganglia are not shown because most are in or near the wall of the organ innervated. Cholinergic nerves are shown in blue; noradrenergic in red; and dopaminergic in green. Note that some sympathetic postganglionic fibers release acetylcholine or dopamine rather than norepinephrine. The adrenal medulla, a modified sympathetic ganglion, receives sympathetic preganglionic fibers and releases epinephrine and norepinephrine into the blood. ACh, acetylcholine; D, dopamine; Epi, epinephrine; M, muscarinic receptors; N, nicotinic receptors; NE, norepinephrine.

Smooth muscle of vessels residing in skeletal muscle

Neurochemistry of ANS

Sympathetic and Parasympathetic are anatomic terms.

They do not depend on the type of transmitter released nor on the kind of effect (excitatory or inhibitory).

A large number of peripheral ANS fibers release acetylcholine; they are Cholinergic fibers.

Almost all efferent fibers leaving the central nervous system are cholinergic.

Most parasympathetic postganglionic and a few sympathetic postganglionic fibers are cholinergic.

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Neurochemistry of ANS Cont,d

Receptors that respond to acetylcholine are Cholinoceptors.

Most postganglionic sympathetic fibers release norepinephrine (noradrenaline); they are noradrenergic or Adrenergic.

Receptors that respond to catecholamines such as norepinephrine are Adrenoceptors.

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Neurochemistry of ANS Cont,d

Dopamine is released by some peripheral sympathetic fibers.

Adrenal medullary cells release a mixture of epinephrine and norepinephrine.

Most autonomic nerves also release several cotransmitters in addition to their primary transmitters.

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Schematic illustration of a generalized cholinergic junction (not to scale). Choline is transported into the presynaptic nerve terminal by a sodium-dependent choline transporter (CHT). This transporter can be inhibited by hemicholinium drugs. In the cytoplasm, acetylcholine is synthesized from choline and acetyl Co-A (AcCoA) by the enzyme choline acetyltransferase (ChAT). Acetylcholine is then transported into the storage vesicle by a second carrier, the vesicle-associated transporter (VAT), which can be inhibited by vesamicol. Peptides (P), adenosine triphosphate (ATP), and proteoglycan are also stored in the vesicle. Release of transmitter occurs when voltage-sensitive calcium channels in the terminal membrane are opened, allowing an influx of calcium. The resulting increase in intracellular calcium causes fusion of vesicles with the surface membrane and exocytotic expulsion of acetylcholine and cotransmitters into the junctional cleft (see text). This step can be blocked by botulinum toxin. Acetylcholine's action is terminated by metabolism by the enzyme acetylcholinesterase. Receptors on the presynaptic nerve ending modulate transmitter release. SNAPs, synaptosome-associated proteins; VAMPs, vesicle-associated membrane proteins.

Cholinergic Transmission

Release of transmitter is dependent on calcium and occurs by the action potential.

The acetylcholine release is blocked by botulinum toxin.

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Cholinergic Transmission Cont,d

Acetylcholinesterase splits acetylcholine into choline and

acetate thereby terminates the action of the transmitter.

The half-life of acetylcholine in the synapse is within

seconds.

Acetylcholinesterase is also found in RBC.

Butyrylcholinesterase (pseudocholinesterase) has a lower

specificity for acetylcholine and is found in blood,

plasma, liver & glia.

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Schematic diagram of a generalized noradrenergic junction (not to scale). Tyrosine is transported into the noradrenergic ending or varicosity by a sodium-dependent carrier (A). Tyrosine is converted to dopamine (see Figure 6–5 for details), and transported into the vesicle by the vesicular monoamine transporter (VMAT), which can be blocked by reserpine. The same carrier transports norepinephrine (NE) and several other amines into these granules. Dopamine is converted to NE in the vesicle by dopamine--hydroxylase. Physiologic release of transmitter occurs when an action potential opens voltage-sensitive calcium channels and increases intracellular calcium. Fusion of vesicles with the surface membrane results in expulsion of norepinephrine, cotransmitters, and dopamine--hydroxylase. Release can be blocked by drugs such as guanethidine and bretylium. After release, norepinephrine diffuses out of the cleft or is transported into the cytoplasm of the terminal by the norepinephrine transporter (NET), which can be blocked by cocaine and tricyclic antidepressants, or into postjunctional or perijunctional cells. Regulatory receptors are present on the presynaptic terminal. SNAPs, synaptosome-associated proteins; VAMPs, vesicle-associated membrane proteins.

Adrenergic Transmission

Metyrosine can inhibit adrenergic transmission.

A carrier for catecholamines located in the vesicle wall (vesicular monoamine transporter, VMAT) is inhibited by the reserpine.

Reserpine causes depletion of transmitter stores.

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Adrenergic Transmission (Cont,d)

Norepinephrine transporter, NET carries norepinephrine back into the cell from the synaptic cleft (uptake 1).

NET is inhibited by cocaine and TCAs, resulting in increased transmitter activity in the synaptic cleft.

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Metabolism of catecholamines by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO).

Adrenergic Transmission (Cont,d)

Tyramine, amphetamines, and ephedrine, can release stored transmitter from noradrenergic nerve endings.

These drugs are poor agonists (some are inactive) at adrenoceptors, but they are excellent substrates for monoamine transporters.

They are taken up into noradrenergic nerve endings by NET where they displace norepinephrine.

Amphetamines also inhibit monoamine oxidase that result in increased norepinephrine activity.

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Nonadrenergic, Noncholinergic (NANC)

Gut, airways, bladder contain nerve fibers which is neither cholinergic nor adrenergic.

Peptides are the most common transmitter found in NANC fibers.

NOS, CGRP, GRP, 5HT, cholecystokinin, VIP, dynorphin, enkephalins, NPY, somatostatin, and substance P is also found.

Some neurons contain as many as five different transmitters

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Major Autonomic Receptor Types

Result of Ligand Binding Receptor Name

CholinoceptorsFormation of IP3 and DAG, increased Ca2+ Muscarinic M1 Opening of potassium channels, inhibition of adenylyl cyclase

Muscarinic M2

Like M1 receptor-ligand binding Muscarinic M3 Like M2 receptor-ligand binding Muscarinic M4 Like M1 receptor-ligand binding Muscarinic M5 Opening of Na+, K+ channels, depolarization Nicotinic NN Opening of Na+, K+ channels, depolarization Nicotinic NM

Result of Ligand Binding Receptor NameAdrenoceptors

Formation of IP3 and DAG, increased Ca2+ Alpha1

Inhibition of adenylyl cyclase, decreased cAMP Alpha2

Stimulation of adenylyl cyclase, increased cAMP Beta1




Result of Ligand Binding Receptor NameDopamine receptors

Stimulation of adenylyl cyclase D 1, D5

Inhibition of adenylyl cyclase; increased potassium conductance

D2

Inhibition of adenylyl cyclase D3

Inhibition of adenylyl cyclase D4


Parasympathetic Sympathetic

Receptor Action Receptor Action Organ

Eye

. . . . . . a1 Contracts Iris radial muscle

M3 Contracts . . . . . . Iris circular muscle

M3 Contracts b [Relaxes] Ciliary muscle

Heart

M2 Decelerates b1, b2 Accelerates Sinoatrial node

. . . . . . b1, b2 Accelerates Ectopic pacemakers

M2Decreases (atria)

b1, b2 Increases Contractility

Blood vessels

. . . . . . a Contracts Skin, splanchnic vessels

. . . . . . b2 Relaxes Skeletal muscle vessels

. . . . . . a [Contracts]

. . . . . . M3 Relaxes

M3,M5 Releases EDRF Endothelium



M3 Contracts b2 Relaxes Bronchiolar smooth muscle

Gastrointestinal tract

Smooth muscle

M3 Contracts a2,b2 Relaxes Walls

M3 Relaxes a1 Contracts Sphincters

M3 Increases . . . . . . Secretion

Genitourinary smooth muscle

M3 Contracts b2 Relaxes Bladder wall

M3 Relaxes a1 Contracts Sphincter

. . . . . . b2 Relaxes Uterus, pregnant

M3 Contracts a Contracts

M Erection a Ejaculation Penis, seminal vesicles



Skin

. . . . . . a Contracts Pilomotor smooth muscle

. . . . . . Sweat glands

. . . . . . M Increases Thermoregulatory

. . . . . . a Increases Apocrine (stress)

Metabolic functions

. . . . . . β2 ,a Gluconeogenesis Liver

. . . . . . β2 ,a Glycogenolysis Liver

. . . . . . b3 Lipolysis Fat cells

. . . . . . b1 Renin release Kidney

Regulation of ANS

The ANS is regulated in three different ways: Presynaptic Regulation

Postsynaptic Regulation

Physiologic reflexes

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Presynaptic Regulation

Some receptors are located on the presynaptic neurons and are activated by the neurotransmitter released from the same neuron.

The presynaptic receptors that respond to their own neurotransmitter are called Autoreceptors.

Autoreceptors are usually (not always) inhibitory.

Somatic motor fibers, have excitatory nicotinic autoreceptors.

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Presynaptic Regulation Cont,d

The α2 receptor is an inhibitory autoreceptor which diminishes further release of norepinephrine.

The presynaptic receptors activated by the transmitters of other neurons are called Heteroreceptors.

Heteroreceptors usually have a modulating effect on neurotransmitter release.

Presynaptic regulation by a variety of endogenous chemicals occurs in all nerve fibers.

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Postsynaptic Regulation

Up- and down-regulation of the receptors occurs in response to decreased or increased activation, respectively.

An extreme form of up-regulation occurs after denervation of some tissues (denervation supersensitivity).

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Physiologic Reflexes

In heart In the absence of reflexes (in a patient with heart transplant) norepinephrine increases heart rate and contractile force.

with intact reflexes, the net effect of norepinephrine is an increase in arterial pressure, and slowing of heart rate.

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Autonomic and hormonal control of cardiovascular function. Note that two feedback loops are present: the autonomic nervous system loop and the hormonal loop. The sympathetic nervous system directly influences four major variables: peripheral vascular resistance, heart rate, force, and venous tone. It also directly modulates renin production (not shown). The parasympathetic nervous system directly influences heart rate. In addition to its role in stimulating aldosterone secretion, angiotensin II directly increases peripheral vascular resistance and facilitates sympathetic effects (not shown). The net feedback effect of each loop is to compensate for changes in arterial blood pressure. Thus, decreased blood pressure due to blood loss would evoke increased sympathetic outflow and renin release. Conversely, elevated pressure due to the administration of a vasoconstrictor drug would cause reduced sympathetic outflow, reduced renin release, and increased parasympathetic (vagal) outflow.

ANS Interaction (the Eye)

Contraction of the ciliary muscle, which occurs with cholinesterase inhibitor is called cyclospasm.

Ciliary muscle contraction also facilitates outflow of the aqueous humor a very useful result in patients with glaucoma.

Alpha adrenoceptors mediate contraction of the dilator muscle fibers in the iris and result in mydriasis.

Beta-adrenoceptors on the ciliary epithelium facilitate the secretion of aqueous humor. Beta blockers provide another therapy for glaucoma.

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Structures of the anterior chamber of the eye. Tissues with significant autonomic functions and the associated ANS receptors are shown in this schematic diagram. Aqueous humor is secreted by the epithelium of the ciliary body, flows into the space in front of the iris, flows through the trabecular meshwork, and exits via the canal of Schlemm (arrow). Blockade of the adrenoceptors associated with the ciliary epithelium causes decreased secretion of aqueous. Blood vessels (not shown) in the sclera are also under autonomic control and influence aqueous drainage.

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Introduction to autonomic pharmacology

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