Neuropharmacology

Department of Biomedical Sciences

College of Vet. Medicine & Agriculture

Addis Ababa University

 Basic Anatomy and Physiology of NS
 Two parts of the nervous system (NS)
 CNS (central): brain and spinal cord
 PNS (Peripheral):
 Afferent (sensory) neurons (SN)
 Efferent (motor) neurons (MN) = Somatic NS and
Autonomic Ns
 Basic unit of the nervous system = neuron
 Sensory, Associative, Motor
 Parts of the neuron
 Cell body, Dendrite, Axon
 Afferent neurons, which carry nerve impulses into the CNS from
sensory end organs in peripheral tissues, and
 Efferent neurons, which carry nerve impulses from the CNS to effector
cells
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in peripheral tissues.
Topics to be covered

 Pharmacology of Autonomic &

Somatic Nervous System
 Drugs acting on Central Nervous
System
 General and Local Anesthetics (techniques and types)

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Pharmacology of Autonomic and
Somatic Nervous System

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Learning Objectives

Anatomy and functions of the ANS

Neurotransmitters in ANS

Cholinergics and Anticholinergics

Adrenergics and Antiadrenergics

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Introduction to ANS

 ANS also called the visceral, vegetative, or

involuntary nervous system
 distributed widely throughout the body and regulates
autonomic functions
 consists of nerves, ganglia, and plexuses
 innervate the heart, blood vessels, glands, other
visceral organs, and smooth muscle in various tissues.

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Visceral Afferent Fibers

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Visceral Afferent Fibers….cont’d
• Two main sensory systems:
– Cranial (parasympathetic) visceral sensory system
and
– spinal (sympathetic) visceral afferent system

 Cranial visceral sensory system carries

mechanoreceptor & chemosensory information

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Central Autonomic Connections
 Highly integrated patterns of response generally are organized at a
hypothalamic level.

 More limited patterned responses are organized at other levels- basal

forebrain, brainstem, and spinal cord.
 Hypothalamus generally are regarded as principal loci of integration of
ANS functions, which include regulation of:
 Body temperature
 Water balance
 Carbohydrate and fat metabolism
 Blood pressure
 Emotions
 Sleep
 Respiration, and
 Reproduction
 Signals are received through ascending spinobulbar pathways,
the limbic system, neostriatum, cortex, and to a lesser extent
9other higher brain centers
Peripheral Autonomic System (PAS)

 Two large divisions:

(1) the sympathetic or thoracolumbar outflow and
(2) the parasympathetic or craniosacral outflow

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Divisions of the PAS…cont’d

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 Autonomic Nervous System(ANS)
 Sympathetic (Adrenergic): “fight or flight”
 Increases heart rate, respiration rate, and blood flow to muscles;
 decreases GI function;
 causes pupillary dilation
 Preganglionic synapse: ACh;
 postganglionic synapse: epi or norepiniphrine

 Parasympathetic (Cholinergic): “homeostatic”

 Brings heart rate, respiration rate, and blood flow to muscles
back to normal levels;
 returns GI function to normal;
 constricts pupils to normal size
 Pre- and postganglionic synapse: ACh

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 Antagonistic
Control
• Most internal organs are
innervated by both branches of
the ANS which exhibit
antagonistic control

A great example is heart rate.

An increase in sympathetic
stimulation causes HR to
increase whereas an increase in
parasympathetic stimulation
causes HR to decrease
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Exception to the dual innervation rule:
Sweat glands and blood vessel smooth muscle are
only innervated by sympathetic and rely strictly on
up-down control.

Exception to the antagonism rule:

Sympathetic and parasympathetic work cooperatively

to achieve male sexual function.
Parasympathetic is responsible for erection while
sympathetic is responsible to ejaculation.

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NEUROTRANSMISSION

 Conduction- reserved for the passage of an impulse

along an axon or muscle fiber;

 Transmission- the passage of an impulse across a

synaptic or neuro-effector junction.

 Very few drugs (Local anesthetics) modify axonal

conduction in the doses employed therapeutically.

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Cholinergic transmission

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Adrenergic Transmission

20 in the enzymatic synthesis of dopamine, norepinephrine, and epinephrine

Steps
Divisions of the PAS
 Acetylcholine is neurotransmitter:-
 All preganglionic autonomic fibers,
 All postganglionic parasympathetic fibers, and
 A few postganglionic sympathetic fibers
 Cholinergic fibers use Ach

 Adrenergic fibers comprise

 majority of postganglionic sympathetic fibers;
 transmitter is norepinephrine (noradrenaline)

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Skeletal Muscle
 Stimulation of a motor nerve results in the release of ACh
 The combination of ACh with nicotinic ACh receptors induces
an immediate, marked increase in cation permeability
 About 50,000 Na+ ions traverse the channel
 The channel-opening process is the basis for the localized
depolarizing
 which triggers the muscle AP leads to contraction

Autonomic Effectors
 Stimulation of autonomic effector cells occurs on activation
of muscarinic acetylcholine receptors.

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Autonomic Nervous System Drugs
 Autonomic nervous system drugs work either by:
 acting like neurotransmitters or
 by interfering with neurotransmitter release

 Twogroups of drugs affect the parasympathetic

nervous system
 Cholinergic
 Anticholinergic
 Muscarinic antagonists
 Nicotinic antagonists

 Two groups of drugs affect the sympathetic nervous

system:
 Adrenergic and antiadrenergics
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 I. Cholinergic Drugs
/Parasympathomimetics/

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 Cholinergic Drugs
 Mimic the action of the parasympathetic nervous system

A. Muscarinic Agonists /Direct Acting Cholinomimetics

 Cholinomimetic alkaloids:
Muscarine, Pilocarpine
 Ach and Choline esters
Acetylcholine, Methacholine, Carbachol,
Bethanechol

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B. Acetylcholinesterase Inhibitors
/ indirect acting cholinergic agonists/

2.1. Reversible AChE Inhibitors

 Carbamates: Neostigmine, Physostigmine, Rivastigmine,
 Ambenonium, Galatamine, Edrophonium,Tacrine, Donepezil

2.2. Irreversible AChE Inhibitors

 Organophosphates:
 Malathion, parathion, Echothiophate, Isoflurophate

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 Malathion and Parathion

Pralidoxime (2-PAM) is a mechanism based antidote for poisoning

Anticholinestrase poisoning is reversed by
 Atropine- counteract the muscarinic action and
 Pralidoxime- reactivate AChE

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Summary of cholinergics

Cholinergics Acetylcholine
Bethanechol
Direct acting Carbachol
Cevimeline
Pilocarpine
Ambenomium
Donepezil
Indirect acting Edrophonium
(reversible) Galantamine
Neostigmine
Physostigmine
Pyridostigmine
Rivastigmine
Tacrine
Indirect acting
(irreversible) Echothiophate
Isoflurophate

(according to Lippincott´s Pharmacology, 2006)

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 II. Anticholinergic Drugs
/Parasympatholytics/

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Anticholinergic Drugs
 Inhibit the actions of ACh by occupying the acetylcholine
receptors
 Competitive (reversible) antagonists of Ach

 Pharmacologic effects opposite of the muscarinic

agonists

 Antagonistic responses include:

 decreased contraction of GI and urinary tract smooth muscles,
 dilation of pupils,
 reduced gastric secretion,
 decreased saliva secretion.
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Anticholinergic Drugs
Examples include:
 Solanaceous Alkaloids
 Atropine and Scopolamine
 Semi-synthetics
 Homatropine,metscopolamine
 Synthetic congeners
 Clidinium,Telenzepine, Propantheline, Ipratropium
 Benztropine, etc

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Indications Antimuscarinics

 Preanesthetics= Used preoperatively

 Atropine, hyoscine
 GIT
 Relax smooth m/s-
 propantheline, hyoscine, clindinium, dicycloamine
 Facilitate endoscopy-
 Hyoscine
 Irritable bowel syndrome-
 dicycloamine
 Peptic ulcer-
 pirenzepine, telenzepine
 Ophthalmic- to dilate the pupil
 Atropine, scopolamine,tropicamide
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 III. NICOTINIC ANTAGONISTS

Two subclasses:

1. Skeletal neuromuscular blocking agents and

2. Ganglionic blocking agents.

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1. Skeletal neuromuscular blocking
agents
A. Depolarizing Agent
 Succinylcholine/ suxamethonium
 Decamethonium
 Initially depolarizes like Ach but persistent depolarization of
nicotinic receptors at NMJ leads to repolarization
 Decrease Ach release
 m/s relaxation
 Concurrent use of AChE inhibitors aggravate it
 Toxicity is not reversed by use of AChE inhibitors to increase of
Ach
 Action is terminated by plasma cholinesterase

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Skeletal neuromuscular blocking agents

B. Non-depolarizing agent= stabilizing= competitive

blocking agents
 Short acting:
 Mivacurarium
 Intermediate Acting:
 Vecuronium, Rocuronium, Atracurarium,
 Long acting:
 Tubocororium, pancuronium, gallamine

 Competitively displace Ach and prevent depolarization of the

endplate.

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 Tubocurarine and derivatives

 Plant alkaloid from Chondodendron tomentosum.

 Causes muscle paralysis (arrow poison).
 Rapid onset of action

Metocurine is a semi-synthetic analog of tubocurarine.

 More potent than the parent compound.

 Therapeutic Use:
 As a muscle relaxant in various surgical procedures.

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Botulinum Toxin (Botox)

 Toxin produced by the bacterium Clostridium botulinum

 Causes food poisoning; Large doses can be fatal
 Prevents Acetylcholine release from the nerve terminal
 Produces flaccid paralysis of skeletal muscle
 Inhibition lasts from several weeks to 3 to 4 months.

Therapeutic Uses:
 Administered locally, via im or intradermal injections, to
control muscle spasms and to facilitate muscle relaxation
(eye; face; neck etc.)
 Dermatological / Cosmetic Uses in human:
 To treat facial wrinkles (forehead; under the eyes etc.)
 Prevent excessive sweating (palm; armpit etc)
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2. Ganglionic blocking agents
A. Nicotine
 at low dose Stimulate ganglia initially like Ach by
depolarizing the excitatory postsynaptic membranes.
 At high dose, block the ganglia b/c of persistent
depolarization

B. Hexamethonium, Trimethaphan, Mecamylamine

 Impair transmission
 Compete with Ach for nicotinic receptor
 Trimethaphan
 Block the channel after it opens
 Hexamethonium
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Adrenergic Drugs
 Stimulate the action of the sympathetic nervous system
 Examples include:
 epinephrine, norepinephrine, isoproterenol, dopamine,
dobutamine, phenylpropanolamine, isoetharine, albuterol,
terbutaline, ephedrine, and xylazine

 Adrenergic receptors are divided into two major types according

to drug potency on the receptors

 Alpha-(α-) adrenergic receptors

 E > NE >> isoproterenol

 Beta-(β-) adrenergic receptors

 isoproterenol > E > NE
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 -Adrenergic Receptors

α1 α2
Type “Vascular” “Presynaptic”
Distribution Blood vessels, GIT, sphincters, Autonomic nerve terminals, blood
iris radial, liver vessels, pancreatic islets, platelets
Receptor - GqPCR, linked to activation of GiPCR, linked to inhibition of
Transduction PLC-DAG-IP3 adenyl cyclase-c.AMP
Agonist E=NE>>>ISOP E=NE>>> ISOP
Profile
Selective Phenylephrine & methoxamine Clonidine, α-MeDOPA
Agonists
Selective Prazocin Yohimbine
Antagonists
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 -Adrenergic Receptors

β1 β2 β3
Type “Heart” “Smooth M” “Fat”
Distribution Heart, salivary glands Blood vessel, GIT, Fat tissues
uterus, Skeletal
muscle, Liver,
Receptor - Gs-PCR, linked to activation of adenyl cyclase-c.AMP-PKA cascade
Transduction
Agonist ISOP >E=NE ISOP>E>>NE ISOP=NE>E
Profile
Selective Dobutamine Salbutamol, BRL 37344
Agonists terbutaline
Selective Atenolol Butoxamine
Antagonists

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Classification of Adrenergic Receptors

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Classification of Adrenergic Receptors
(2)

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Adrenergic Blocking Agents
 Block the effects of the adrenergic neurotransmitters

 Examples of alpha-blockers include:

 phenoxybenzamine, prazosin, and yohimbine

 Examples of beta-blockers include:

 propranolol, metoprolol, and timolol

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 Sites of Actions of
Anti-adrenergic Drugs
VMC (α2 )
Adrenergic Nerve
terminal
Heart
Ganglia BV

Effectors cell
( α & )

1. Central blockers
2. Ganglionic blockers
3. Adrenergic Nerve
terminal Blockers
4. Adrenergic Receptor
Blockers
• Alpha Blockers
45 45 • Beta Blockers
 Summary

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Summary of ANS

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