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1. Neuropharmacology
By
Takele Beyene
Department of Biomedical Sciences
College of V t Medicine & Agriculture
C ll f Vet. M di i A i lt
Addis Ababa University
y

2. Basic Anatomy and Physiology of NS
Two parts of the nervous system (NS)
CNS (central): brain and spinal cord
( ) p
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 b d Dendrite, Axon
body, Dendrite A n
Afferent neurons, which carry nerve impulses into the CNS from
sensory end organs in peripheral tissues, and
y g p p ,
Efferent neurons, which carry nerve impulses from the CNS to
effector cells in peripheral tissues.
2

3. Topics to be covered
I. Pharmacology of Autonomic & Somatic Nervous
System
II. Drugs acting on Central Nervous System
General and Local Anesthetics (techniques and
types)
3

4. I. Pharmacology of Autonomic and Somatic
Nervous System
Learning Objectives
Anatomy and functions of the ANS
Neurotransmitters in ANS
Cholinergics and Anticholinergics
Adrenergics and Antiadrenergics
4

5. Introduction to ANS
ANS also called the visceral, vegetative, or
, g ,
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
heart, vessels, glands,
visceral organs, and smooth muscle in various tissues.
5

6. Visceral Afferent Fibers
6

7. 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
7

8. Central Autonomic Connections
Hypothalamus generally are regarded as principal loci of
integration of ANS functions, which include regulation of:
Body t
B d temperaturet
Water balance
Carbohydrate and fat metabolism
Blood pressure
Emotions
Sleep
Respiration, and
Reproduction
8

9. Peripheral Autonomic System (PAS)
Two l
T large di i i
divisions:
(1) the sympathetic or thoracolumbar outflow and
(2) the parasympathetic or craniosacral outflow
9

10. Divisions of the PAS…cont’d
10

11. Autonomic Nervous System(ANS)
Sympathetic (Adrenergic): “fight or flight”
Increases heart rate, respiration rate, and blood flow to
p
muscles;
decreases GI function;
causes pupillary dilation
p p y
Preganglionic synapse: ACh;
postganglionic synapse: epi or norepi
Parasympathetic (Cholinergic): “homeostatic”
Brings heart rate, respiration rate, and blood flow to
muscles back to normal levels;
l b k ll l
returns GI function to normal;
constricts pupils to normal size
Pre- and postganglionic synapse: ACh
11

12. 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
th ti stimulation
ti l ti
causes HR to decrease
12

13. Exception to the dual innervation rule:
Sweat glands and blood vessel smooth muscle are
only innervated by sympathetic and rely strictly on
.
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.
13

14. NEUROTRANSMISSION
Conduction-
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
therapeutically.
14

15. Cholinergic transmission
15

16. Adrenergic Transmission
Steps in the enzymatic synthesis of dopamine, norepinephrine, and epinephrine
16

17. Divisions o t e PAS
s o s of the S
Acetylcholine is neurotransmitter:-
All preganglionic autonomic fibers
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)
17

18. 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
ff
Stimulation of autonomic effector cells occurs on
activation of muscarinic acetylcholine receptors.
18

19. Autonomic Nervous System Drugs
Autonomic nervous system drugs work either by:
acting like neurotransmitters or
by interfering with neurotransmitter release
Two groups of drugs affect the parasympathetic
nervous system
Cholinergic
Anticholinergic
Muscarinic antagonists
Nicotinic t
Ni ti i antagonists
it
Two groups of drugs affect the sympathetic nervous
system:
Adrenergic and antiadrenergics
19

20. I. Cholinergic Drugs
/Parasympathomimetics/
/P th i ti /
20

21. Cholinergic Drugs
Mimic the action of the parasympathetic nervous system
A. Muscarinic Agonists /Direct Acting
Direct
Cholinomimetics
Cholinomimetic alkaloids:
Muscarine, Pilocarpine
, p
Ach and Choline esters
Acetylcholine, Methacholine, Carbachol,
Bethanechol
B h h l
21

22. B. Acetylcholinesterase Inhibitors
/ indirect acting cholinergic agonists/
2.1.
2 1 Reversible ACE Inhibitors
Carbamates: Neostigmine, Physostigmine, Rivastigmine,
Ambenonium, galatamine, Edrophonium,Tacrine,
donepezil
2.2. I
2 2 Irreversible ACE Inhibitors
ibl I hibit
Organophosphates:
Malathion, parathion, Echothiophate, Isoflurophate
22

23. Malathion and Parathion
Pralidoxime (2 PAM) is a mechanism based antidote for poisoning
(2-PAM)
Anticholinestrase poisoning is reversed by
Atropine- counteract the muscarinic action and
Pralidoxime- reactivate AChE
23

24. Summary of cholinergics
Cholinergics Acetylcholine
Bethanechol
Direct acting Carbachol
Cevimeline
C
Pilocarpine
Ambenomium
Donepezil
p
Indirect acting Edrophonium
(reversible) Galantamine
Neostigmine
Physostigmine
Pyridostigmine
P id i i
Rivastigmine
Tacrine
Indirect acting
g
(irreversible) Echothiophate
Isoflurophate
(according to Lippincott´s Pharmacology, 2006)
24

25. II. Anticholinergic Drugs
/Parasympatholytics/
/P h l i /
25

26. 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 i
i i include:
decreased contraction of GI and urinary tract smooth muscles,
dilation of pupils,
p p ,
reduced gastric secretion,
decreased saliva secretion.
26

27. Anticholinergic Drugs
Examples include:
Solanaceous Alkaloids
Atropine and Scopolamine
Semi-synthetics
Homatropine, metscopolamine
Synthetic congeners
Clidinium,Telenzepine, P
Clidi i Tl i Propantheline, I
h li Ipratropium
i
Benztropine, etc
27

28. Indications Antimuscarinics
Preanesthetics= Used preoperatively
Atropine, hyoscine
GIT
Relax smooth m/s-
propantheline, hyoscine, clindinium, dicycloamine
Facilitate endoscopy-
Hyoscine
Irritable bowel syndrome-
syndrome
dicycloamine
Peptic ulcer-
p
pirenzepine, telenzepine
p p
Ophthalmic- to dilate the pupil
Atropine, scopolamine,tropicamide
28

29. III. NICOTINIC ANTAGONISTS
III
Two b l
T subclasses:
1.
1 Skeletal neuromuscular blocking agents and
2. Ganglionic blocking agents.
29

30. 1. Skeletal neuromuscular blocking
agents
A. Depolarizing Agent
Succinylcholine/ suxamethonium
Decamethonium
Initially depolarizes like Ach but persistent depolarization of
y p p p
nicotinic receptors at NMJ leads to repolarization
Decrease Ach release
m/s relaxation
/ l
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
yp
30

31. Skeletal neuromuscular blocking agents
B. Non-depolarizing agent= stabilizing=
co pet t ve blocking age ts
competitive b oc g agents
Short acting:
Mivacurarium
Intermediate Acting:
I di A i
Vecuronium, Rocuronium, Atracurarium,
Long acting:
Tubocororium, pancuronium, gallamine
Competitively displace Ach and prevent depolarization of the
C i i l di l A h d d l i i f h
endplate.
31

32. Tubocurarine and derivatives
Plant alkaloid from Chondodendron tomentosum
tomentosum.
Causes muscle paralysis (arrow poison).
Rapid onset of action
Metocurine is a semi-synthetic analog of tubocurarine.
semi synthetic
More potent than the parent compound.
Therapeutic Use:
As a muscle relaxant in various surgical procedures.
32

33. 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
p y
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 (
l i (eye; f
face; neck etc.)
k )
Dermatological / Cosmetic Uses in human:
To treat facial wrinkles (forehead; under the eyes etc.)
( ; y )
Prevent excessive sweating (palm; armpit etc)
33

34. 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
d l i i
B. Hexamethonium Trimethaphan, Mecamylamine
B Hexamethonium,Trimethaphan
Impair transmission
Compete with Ach for nicotinic receptor
Trimethaphan
Block the channel after it opens
Hexamethonium
34

35. Adrenergic Drugs
Simulate the action of the sympathetic nervous system
Examples include:
p
epinephrine, norepinephrine, isoproterenol, dopamine,
dobutamine, phenylpropanolamine, isoetharine, albuterol,
terbutaline, ephedrine, and xylazine
, p , y
Adrenergic receptors are divided into two major types
according to drug potency on the receptors
g gp y p
Alpha-(α-) adrenergic receptors
E > NE >> isoproterenol
p
Beta-(β-) adrenergic receptors
isoproterenol > E > NE
35

36. α-Adrenergic Receptors
α1 α2
Type “Vascular” “Presynaptic”
D istribution Blood vessels, G sphincters,
IT, A utonom nerve term
ic inals, blood
iris radial, liver vessels, pancreatic islets, platelets
R eceptor
eceptor- GPCR, linked to activation of
q GPCR, linked to inhibition of
i
Transduction PLC-DA -IP3G adenyl cyclase-c.A P
M
A gonist E=N E>>>ISO P E=N E>>>ISO P
Profile
Selective Phenylephrine &m ethoxamine Clonidine, α-M O
eD PA
A gonists
Selective Prazocin Y bine
ohim
Antagonists
36

37. β-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
37

38. Classification of Adrenergic Receptors
38

39. Classification of Adrenergic Receptors (2)
39

40. Adrenergic Blocking Agents
Block the effects of the adrenergic neurotransmitters
Examples of alpha-blockers include:
phenoxybenzamine, prazosin,
phenoxybenzamine prazosin and yohimbine
Examples of beta-blockers include:
beta blockers
propranolol, metoprolol, and timolol
40

41. Sites of Actions of
Anti adrenergic
Anti-adrenergic Drugs
VMC (α2 )
Adrenergic Nerve
terminal
Heart
Ganglia BV
Effectors cell
( α & β)
1. Central blockers
2. Ganglionic blockers
3. Adrenergic Nerve terminal
Blockers
4. Adrenergic Receptor
g
Blockers
41 • Alpha Blockers
41
• Beta Blockers

42. Summary of ANS
42