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ANS & Autonomic Drugs Handouts SY 2007-2008

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DEPARTMENT OF PHARMACOLOGYFACULTY OF MEDICINE AND SURGERY

UNIVERSITY OF SANTO TOMAS

The NS and UTONOMIC DRUGS

Prof. Maria Minerva P. Calimag, MD, DPBA, FPSECP, MSc

Objectives of the lecture

The lecture consists of a general overview of the anatomy, physiology and neurochem-

istry of the sympathetic and parasympathetic subdivisions of the autonomic nervous sys-

tem. An overview of the steps in autonomic neurotransmission that can be affected by vari-ous pharmacological agents, with specific examples, is also provided.

At the end of the Course, with 75% accuracy, the student should be able to: 1) discuss

the synthesis, fate and action of the neurotransmitters as the possible target of action of

autonomic drugs, and 2) name, classify and differentiate the autonomic drugs according to

their mechanism of action and spectrum of pharmacologic effects.

Suggested Reading

v Chapter 6, Neurotransmission The autonomic and somatic motor nervous systems.

In: Goodman & Gilmans The Pharmacological Basis of Therapeutics

SUBDIVISIONS OF THE PERIPHERAL NERVOUS SYSTEM

Somatic nervous system

Motor and sensory divisions

Autonomic nervous system

Sympathetic and parasympathetic divisions


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SOMATIC NERVOUS SYSTEM

The somatic nervous system consists of the motor and the sensory divisions, i.e.,

Anatomical considerations

Somatic innervations consist of a single neuron (final common motor neuron

arising in spinal cord and extending via the ventral root to the skeletal muscles.

Releases acetylcholine (Ach) at neuromuscular junctions

Functional considerations

Innervation of skeletal muscles (movement) with CNS control via the corticospinal

or pyramid tracts comprise the motor division

Innervation of organs that send afferent impulses centrally, comprise the sensory di-

vision

Functions in these systems occur under conscious, voluntary control

AUTONOMIC NERVOUS SYSTEM

The autonomic nervous system consists of the sympathetic and parasympathetic di-visions

Anatomical considerations

v in contrast to somatic efferents, autonomic innervations consist of 2 sequen-

tial neurons

v these sequential neurons are the preganglionic and postganglionic neurons

which synapse at autonomic ganglia

Functional considerations:

mediates control of vegetative or involuntary functions

innervation of cardiac muscle, vascular and non-vascular smooth muscle and exo-

crine glands

v functions in these systems often occur without conscious control


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Sympathetic nervous system

Preganglionic neuronsexit the spinal cord at the thoraco-lumbarlevel to synapse

with postganglionic nerves at para vertebral ganglia (22 pairs on each side

of spinal cord) or prevertebral ganglia (celiac, mesenteric) in the abdomen.

The adrenal medulla is considered to be a modified sympathetic ganglion; the

medulla is embryonically and anatomically homologous to the sympathetic

ganglia

Sympathetic innervations usually consist of one short preganglionic fiber synaps-

ing with several (one or more) long postganglionic fibers in the sympatheric

ganglia

There is a greater ramification of sympathetic fibers compared to the parasympa-

thetic system (the ratio of pre to postganglionic fibers = 1:20)

Diffuse action; fight or flight responses (i.e., stress)

Not essential for life

This system is normally active with the degree of activity varying from moment

to moment and organ to organ

This system constantly adjusts to a changing environment, especially during rage

or fright

Typical sympathetic responses include:

Increase in heart rate

Shift of blood flow in muscles

Increase in blood glucose levels

Dilation of the pupils

Parasympathetic Nervous System

Preganglonic neuronsoriginate in the cranial nervesof the brain stem and the

sacral portion of the spinal cord

These neurons synapse with post-ganglionic neurons in ganglia very close or in

the organs innervated


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Parasympathetic innervations typically consist of one long preganglionic fiber

synapsing with one short post-ganglionic fiber in the parasympathetic gan-

glia.

This system is more circumscribed than the sympathetic system, although a 1:1

ratio of pre to postganglonic fibers is not always the case

Discrete action; conservation and restoration of energy, localized control of dis-

crete functions

Essential for life

Typical parasympathetic responses include:

Slowing the heart rate

Lowering blood pressureProtecting the retina from light

Emptying the bladder

Physiological antagonism

The sympathetic and parasympathetic systems usually do not function independ-

ently; i.e., they are physiological antagonists.

Often when one system inhibits a process, the other system will augment the

level of activity so that the total response depends on the influence of both

systems, although this is not always the case.

The integration of these system regulates functions below the level of conscious-

ness

Potential ways to affect autonomic neurotransmission

Synthesis

availability of precursors for the NT

availability of synthesis enzymesStorage vesicles)

Protects the NT from degradation

Release of the neurotransmitter

Release (Ca2+ dependent exocytosis)

Agents could interfere with or enhance the release of the NT


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Reuptake of neurotransmitter

Binding to and activation of receptor

Agonist high affinity and high intrinsic activity

Antagonist high affinity but NO intrinsic activity

Breakdown of neurotransmitter with termination of effect

Acetylcholine metabolism in synaptic cleft via acetylcholine esterase

Norepinephrine reuptake into presynaptic neuron

Neurochemical classification of Peripheral Nervous System

Acetylcholine (Ach or Cholinergic) synapses include:

All preganglionic fibers outside CNS (sympathetic & parasympathetic)

All parasympathetic postganglionic nerve endings (ACh is the transmitter)

Exception: sympathetic postganglionic nerve endings of sweat glands

Somatic motor neurons innervating skeletal muscle

Noradrenergic (NE) synapses

All postganglionic sympathetic fibers (except those to sweat glands)

Adrenal medulla (norepinephrine & epinephrine)

Acetylcholine

Chemistry

Acetylcholine is synthesized from acetyl co-enzyme A and choline using the enzyme cho-

line acetyl transferase

The major means of inactivation of acetylcholine is degradation in the synapse using the

enzyme acetylcholine esterase

Acetylcholine cholinergic) Receptors

Muscarinic receptors

Postganglionic parasympathetic fibers innervating heart, smooth muscle and exo-

crine glands


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Exception: postganglionic sympathetic fibers innervating sweat glands

Blocked by antimuscarinic agents (e.g., atropine)

Nicotinic receptors

Classically a biphasic response is observed with stimulation at low doses and

inhibition at high doses

Sympathetic and parasympathetic autonomic ganglia, the adrenal medulla and

the neuromuscular junction of skeletal muscle

Effects blocked with ganglionic blockers (e.g., trimethapahan, hexamethonium)

and neuromuscular blockers (e.g., curare)

Norepinephrine

Chemistry

Norepineprine is ultimately synthesized from tyrosine using the enzyme tyrosine hy-

droxylase which converts tyrosine to DOPA

Aromatic L-amino acid decarboxylase converts DOPA to dopamine

Dopamine b-hydroxylase converts dopamine to norepinephrine

Phenylethanolamine N-methyl-transferase converts norepinephrine to epinephrine

The major means of inactivation of norepinephrine is reuptake back into the presynaptic

neuron from which it was released

Norepineprine noradrenergic) receptors

1 alpha 1)

vascular smooth muscle, genitourinary smooth muscle, liver (contraction)

intestinal smooth muscle (hyperpolarization and relaxation)

heart (increased contractile force, arrhythmias)

2 alpha 2)

pancreatic islets (b cells, decreased insulin secretion)

platelets (aggregation)

vascular smooth muscle (contratin)


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1 beta 1)

heart (increased force and rate of contraction, AV nodal conduction velocity)

juxtraglomerular cells (increased renin secretion)

2 beta 2)

smooth muscle (vascular, bronchial, gastrointestinal, genitourinary) {relaxation}

skeletal muscle (glycogenolysis; uptake of K+)

liver (glycogenolysis; gluconeogenesis)

Cellular Mechanisms of Drug Action

Receptors

Receptorsare large proteins that bind specific molecules (ligands) stereoselectively

Plasma membrane receptors

Intracellular receptors

Ligandsmay be either agonists, antagonists or inverse agonists

Ion Channels

Membrane-spanning proteins with a central porethrough which ions traverse the cell

membrane. Very fast response times (milliseconds)

Two types

Voltage-gated channelsopen and close in response to changes in the membrane

potential

Ligand-gated channelsopen in response to binding of specific ligand. Often

have several ligand-binding sites

Receptors and ion channels

G protein-coupled receptors

The binding of ligands to many receptors leads to an increase in the concentra-

tion of intracellular molecules called second messenger, which trigger changes in the

activity of other intracellular enzymes or proteins thereby producing the final cellular

response. The process is known as intracellular signaling.


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Examples of G protein-coupled receptors are: 1) acetylcholine muscarinic recep-

tors; 2) adrenergic receptors; 3) dopamine receptors; 4) Adenosine receptors; 5) 5-

HT (serotonin) receptors; 6) GABAB receptors.

Acetylcholine receptors

Acetylcholine (ACh) is an example of an endogenous neurotransmitter that

binds to more than one receptor type: the nicotinic (nAChR) which

preferentially binds nicotine and the muscarinic receptor, which binds

muscarine. The latter is a G protein-coupled receptor whereas nAChR is

an excitatory ligand-gated ion channel which transports Na+ ions.

Nicotinic receptors are found in the autonomic ganglia and the neuro-

muscular junction of skeletal muscles.

Adrenergic receptors

The adrenoceptors are G protein-coupled receptors but second messenger

and G protein linkage differ between the subtypes

The alpha1 and beta adrenoceptors are located in postsynaptic junction of

sympathetic nerve terminals innervating smooth muscles and endocrine

glands or cardiac cells (beta1)

Most vasoconstrictor responses to sympathetic stimulation are mediated by

alpha1

In general alpha2 and beta2 are prejunctional adrenergic neuronal mem-

branes and inhibit and facilitate, respectively the release of norepineph-

rine

Prejunctional alpha2 adrenoceptors also exist on cholinergic neurons and

inhibit the release of acetylcholine

The beta1 receptor is present mainly in the heart

The beta2 adrenoceptors is found in skeletal muscle, the uterus and in the

bronchial smooth muscle, where beta2 agonists act as bronchodilators

The main location of the beta3 is the adipose tissue where it seems to regu-

late norepinephrine-induced changes in energy metabolism and ther-

mogenesis


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Dopamine receptors

Dopamine is a major neurotransmitter which acts on multiple receptors. It

can activate both alpha and beta receptors in addition to acting on spe-

cific dopamine receptors

Six CNS and 2 peripheral dopamine receptors have been identified

The antiemetic metoclopramide is a dopamine antagonist whose central ef-

fects are mediated via D2 receptors in the CTZ in the area postrema

The effect of low concentrations of dopamine in enhancing urine output is

due to its action on DA1 receptors in the renal vasculature

Dopexamine is a DA1 agonist with beta2 adrenoceptor agonist activity

Ligand-gated ion channels

Acetylcholine nicotinic receptors

GABAA receptors

NMDA receptors

5-HT3 receptors

Receptors with intrinsic enzyme activity

Protein kinases

Guanylyl cyclase

Receptors: Affinity and Efficacy

Agonists

-binding to receptors triggers a pharmacologic response 9 with affinity and

intrinsic efficacy)

Full agonist produces maximum response(intrinsic activity = 1)

Partial agonist cannot produce maximum response (intrinsic activity


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Inverse agonist ligand binding produces opposite effects to those of an agonist. They

are no the same as antagonistis, which block the effects of both Agonists and inverse

agonists

The Sympathetic receptors and subtypes

Alpha receptorsare found in smooth muscles and glands

v Alpha1 are postsynaptic receptors which are excitatory

v Alpha2 are presynaptic receptors that cause feedback inhibition on the re-

lease of NE

Beta receptors

v Beta1 are excitatory to the heart and fat cells

v Beta2 are inhibitory to smooth muscles and glands

The Parasympathetic receptors and subtypes

Nicotinic receptors are ligand-gated ion channels

v Nicotinic muscle-subtypefound in the NM junction

v Nicotinic neuronal-subtypein the autonomic ganglia

Muscarinic receptorsare part of the transmembrane G protein coupled receptors

(5 subtypes)

v M1 - found in the autonomic ganglia and CNS

v M2 - supraventricular parts of the heart

v M3 smooth muscles and glands, and on endothelial cells in the vascula-

ture.

v M1 and M3 receptors generally mediate excitatory responses in effector

cells.

v M1 receptorspromote depolarization of postganglionic autonomic

nerves, and


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v M3 receptorsmediate contraction of all smooth muscles and increased

secretion in glands, except for the effect of ACh on blood vessels. Ach

causes vasodilation and decreased blood pressure. This is mediated by an

effect of ACh on the endothelial cells of the vasculature.

Effect of Acetylcholine on Blood Vessels

Activation of M3 receptors on the surface of the endothelial cells in-

creases intracellular Ca++ and causes activation of the enzyme nitric oxide

synthetase (NOS)increases synthesis of the highly diffusable free radical,

nitric oxide (NO) NO diffuses from endothelialcells into the adja-

cent smooth muscle cells of the vasculature NO activates the cytoplas-

mic enzyme, guanylate cyclase causing an increase in intracellular cyclic

GMP or cGMP, which promotes relaxation of the vascular smooth mus-cle cells.

Note:The relaxation of vascular smooth muscle by ACh is an indirect effect

that is utterly dependent on the presence of intact endothelial cells. If the

endothelium is removed, ACh exerts a stimulatory effect on vascular smooth

muscle cells, as it does on other smooth muscle cells. The interaction be-

tween endothelial and vascular smooth muscle cells was demonstrated by

Robert Furchgott who was recently awarded the Nobel Prize.

v M2 muscarinic receptors, in contrast to M1 and M3 receptors, tend to me-

diate inhibition of cellular activity

v They do so through G proteins that inhibit adenylyl cyclase (opposite of

the activation of adenylyl by beta adrenergic receptors) and by activation

of K channels in the plasma membrane


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The NS Drugs

The Sympathetic Drugs

Adrenergic Agonists Sympathomimetic)

v Direct acting

v Mixed alpha and beta (NE, EPI)

v Alpha2 selective (clonidine)

v Beta2 selective (terbutaline, isoproterenol)

v Indirect acting (amphetamine, cocaine)

v Dual-acting (ephedrine)

Adrenergic Antagonists Sympatholytic)

v Alpha blockers

v Nonselective (phenoxybenzamine, phentolamine)

v Selective alpha1 (prazosin)

v Beta blockers

v Nonselective (propanolol)

v Selective beta1 (metoprolol)

Structure-Activity Relationships of Sympathetic Drugs

Substitution of the benzene ring

v Substitution of hydroxyl groups at the 3- and 4-positions of the benzene

ringconverts benzene to catechol, and thus the dihydroxylated phenylethyl-

amine compounds are known as catecholamines with maximal and ef-

fects.

v Absence of one or the other substituent particularly at the 3-position causes

marked diminution in potency. effect is decreased a 100-fold and effect

is negligible.

v Substitution of hydroxyl groups at the 3- and 5-positions of the benzene

ringimparts2 selectivity


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Unsubstituted benzene ring

v The catecholamines are primarily metabolized by COMT. Loss either of thetwo hydroxyl groups enhances oral effectiveness and duration of action be-

cause the drug is no longer metabolized by COMT. It also causes increased

CNS effects.

v Noncatecholamines are primarily metabolized by MAO.

Substitution at the carbon

v Noncatecholamines that have a substituted -carbon have a longer duration

of action because they are not metabolized by either COMT or MAO.

Substitution at the carbon

v Typical of direct acting agonists, important for storage of sympathomimetic

amines in neural vesicles

Substitution at the amine side chain

v Substitution of bulky structuresto the catecholamine amino group increases2-selectivity, decreases affinity for-receptors, and protects against me-

tabolism by COMT. Examples are 1) epinephrine with 1 methyl substitu-

ent; 2) Isoproterenol with 2 methyl substituents and 3) Terbutaline with 3

methyl substituents


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Adrenergic Agonists Sympathomimetic Drugs)

Drug

Mechanism of Ac-

tion

Indications

Epinephrine Act directly on bothalpha and beta receptors

Used in asthma and other allergicdiseases it relaxes airways and re-duces swelling

Pseudo

ephedrine

Causes release ofnoradrenaline

Used as treatment for rhinitis andcolds as a decongestant

Phenylephrine Acts directly on alphareceptors. Selective al-pha 1 agonist

Used as decongestant in rhinitisand colds

Amphetamines Causes accumulation ofnoradrenaline at the syn-apses

No longer used clinically exceptfor treatment of narcolepsy andattention deficiency hyperkinesis

Ephedrine Acts indirectly on bothalpha and beta receptors.Causes release of en-

dogenous catechola-mines

Used as vasopressor

Terbutaline Selective beta 2 agonist Used as a bronchodilator inasthma and as a tocolytic agent inpremature labor.

Clonide Selective alpha2 agonist Used for the treatment of hyper-tension.


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Adrenergic Antagonists Sympatholytic Drugs)

Drug Mechanism of Action Indications

Reserpine Blocks the synthesis andstorage of noradrenaline

Used in the management of sometypes of hypertension. Sedation is aside effect.

Phenoxy-

benzamine

Noncompetitively blocksalpha receptors

Used in the management of malignanthypertension secondary to pheochro-mocytoma.

Phento-

lamine

Competitively blocks alphareceptors

Used for the management of malig-nant hypertension during operations

for pheochromocytoma .

Prazosin Selectively blocks alpha 1receptors

Used in the management of sometypes of hypertension. No reflextachycardia and postural hypotension.

Propanolol Nonselectively blocks betareceptors

Used in hypertension, angina, mi-graine headaches and mitral valveprolapse.

Metoprolol Selectively blocks beta 1receptors.

Predominant effects are cardiac


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The Parasympathetic Drugs

Cholinergic Agonists parasympathomimetic)

v Direct-acting muscarinic

v Naturally occurring alkaloids (muscarine, arecoline, pilocarpine)

v Synthetic alkaloids (carbachol betanechol)

v Indirect-acting muscarinic AchE inhibitors)

v Short Acting (edrophonium)

v Medium Acting (neostigmine, physostigmine)

v Long Acting (organophosphates)

v Direct-acting nicotinic depolarizing NMB

Cholinergic Antagonists parasympatholytic)

v Antimuscarinic belladona alkaloids

v Antinicotinic nondepolarizing NMB and ganglionic blockers

Cholinergic Agonists Parasympathomimetic Dugs)

At Muscarinic Sites

Drug

Mechanism of

Action

Indications

Acetylcholine Acts directly on mus-carinic receptors

Used a eye drops in Ophthalmologyto constrict the Iris of the eye.

Pilocarpine Acts directly on mus-carinic receptors

Used as eye drops in ophthalmology

to constrict the iris of the eye. Usedin the treatment of acute angle clo-sure glaucoma

Betanechol Acts directly on mus-carinic receptors

Used for the treatment of GI andbladder atony.


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At Nicotinic Sites

Cholinergic Antagonists Parasympatholytic Drugs)

At Muscarinic Sites

Drug

Mechanism of

Action

Indications

Succinylcholine Acts directly onnicotinic NMJ receptors Depolarizing NMJ blocker. Causesnoncompetitive inhibition on nicon-tinic NMJ receptors. Faciculationsfollowed by paralysis is a hallmark.

Acetylcholi-

nesterase Inhibi-

tors

Acts indirectly on nico-tinic receptors

Quaternary am-

monium com-

pounds

edrophonium)

Short-acting reversible Used as a diagnostic aid in the diag-nosis of myasthenia gravis.

Carbamates

neostigmine,

physostigmine

Moderately reversible Used to reverse nondepolarizingNMJ blockers.

Organophos-

phates

Irreversible Used as insecticides. Poisoning withorganophosphates is treated withanticholinergic drugs.

Drug

Mechanism of

Action

Indications

Atropine Acts directly on mus-carinic receptors

Used as anticholinergic agent to reducesalivation, increase heart rate, decreasegastric motility, cause mild bronchodila-

tation, and in the treatment of organo-phosphate poisoning.

Scopolamine Acts directly on mus-carinic receptors

Same as atropine, but with more centraleffect, may cause mild sedation.


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At Nicotinc Sites

Drug

Mechanism of

Action

Indications

Nondepolarizig

NMJ blockers

gallamine, pan-

curonium, atra-

curium,

vecuronium, ro-

curonium)

Competitively inhib-its acetylcholine atnicotinic NMJ sites

Causes nondepolarizing block of theNMJ. Block can b reversed by increasingthe amount of acetylcholine at the NMJ

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