Transcript PHL 313 practical

PHL. 313
Dr. Khairy M A Zoheir
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Introduction to NS
Pharmacology
&
Dose – Response Curve
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Central Nervous
System
Brain stem
Afferent
Efferent
Cerebrum
Sensory division
Autonomic
Spinal cord
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Peripheral Nervous
System
Somatic
Afferent
It is known as sensory or •
receptor neurons which carry
nerve impulses from receptors
or sense organs toward the
central nervous system.
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Efferent
It is known as motor or effector •
neurons which carry nerve
impulses away from the central
nervous system to effectors
such as muscles or glands
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The Peripheral Nervous System
Efferent nervous system
Somatic nervous system
Autonomic nervous system
(voluntary)
(involuntary)
Skeletal muscle
Heart, blood vessels,
glands, other visceral
organs, smooth muscle
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Anatomic classification
1- sympathetic (fight or flight)
To maintain homeostasis
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2- Parasympathetic (rest and
digest)
Its actions can be summarized •
as "rest and digest", as
opposed to the "fight-or-flight"
effects of the sympathetic
nervous system..
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Neurotransmitter:
A chemical that transmits signals from one neuron to another
or from a neuron to an effector cell.
Chemical
(intracellular
messengers)
Electrical
Chemical
Physiological
Stimulation
(neurotransmitter)
functions
(impulse)
Electrical
(membrane
ion channels)
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Neurotransmitter-based
classification
1- Cholinergic,
2- Adrenergic, and
3- Dopaminergic
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1- Cholinergic transmitter
It means related to the •
neurotransmitter. Acetylcholine.
The parasympathetic nervous system
is entirely cholinergic. Neuromuscular
junctions, preganglionic neurons of
the sympathetic nervous system, and
the sweat glands
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2- Adrenergic
It means "having to do with •
adrenaline (epinephrine) and/or
noradrenaline (norepinephrine)".
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3- Dopaminergic
It means related to the neurotransmitter •
dopamine. For example, certain proteins
such as the dopamine transporter (DAT),
vesicular monoamine transporter 2
(VMAT2)
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Definition of Agonist and Antagonist
Agonist: A structural analog that is capable of stimulating a
biological response.
Antagonist: A receptor-specific blocker
(e.g., enzyme inhibitor) or a physiologic agent (e.g., hormone),
that prevents the action of another molecule.
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Mode of Action
Direct-acting: Molecule that physically binds to the target for its
effect.
Example: carbachol activates cholinergic receptors.
Indirect-acting: Molecule that exerts effect on the target by
interacting with another molecule.
Example:neostigmine blocks AchE, causing Ach accumulation.
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Neurotransmitter Acetylcholine
•Preganglionic synapses of both sympathetic
and parasympathetic ganglia
•Parasympathetic postganglionic
neuroeffector junctions
•All somatic motor end-plates on skeletal
muscle
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Acetylcholine
Acetylcholine is an ester of acetic acid and •
choline with chemical formula
CH3COOCH2CH2N+(CH3)3.
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Muscarinic Autonomic Effects of
Ach
Affect on gatsrtointestinal tract (GIT) as •
follow
1- Motility •
2- Secretion •
3- Sphincters •
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Muscarinic Actions
The “Muscarinic Actions” -- Similar to •
those of parasympathetic stimulation
(M1): CNS, PNS, gastric parietal cells • •
(M2): conducting tissue • •
(M3): exocrine glands; smooth muscle • •
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Practice
Lab. 1
Dose – Response Curve
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Tyroide
Apparatus
Solution
NaCl:
Isotenicity
physiogragh
CaCl2:
H2O
Contraction of
muscle
Glucose:
Energy
NaHCO3:
valve
25 ml
PH
MgCL2:
Intestine part
relaxation
Valve
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Oxygen
supply
(Wash)
Dose – Response Curve
•
It is a relationship between Dose and (Response %)
•
From this curve we can see :
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1.
Potency (a measure of the activity of a drug
in a biological system)
2.
Efficacy (the capacity to produce an effect)
Dose – Response Curve
3- Therapeutic index (dose of a drug for »
50% of the population divided by the
minimum effective dose for 50% of the
population (ED sub 50/sub )
4- ED 50 :dose in pharmacology is the »
amount of drug that produces a therapeutic
response in 50% of the people taking it
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Dose – Response Curve
D+R
DR complex
Response
wash
cm
0.1ml
30
0.2ml
0.4ml
0.8ml
1.6ml
Dose – Response Curve
Dose
(ml)
Response
(cm)
Response
%
(x/ max )*100
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0.1
1
16.6
0.2
3
50
0.4
4
66
0.8
6
100
1.6
6
100
Dose – Response Curve
120
80
60
40
Response % v
(%)
Response
100
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ED 50 = 3.75 ml
0
1
2
3
4
Dose (ml)
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5
6
Lab. 2
Effect of cholinergic drugs on intestine and % of
antagonism.
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The “Muscarinic Actions” -- Similar to those of parasympathetic stimulation
•(M1): CNS, PNS, gastric parietal cells
•(M2): conducting tissue
•(M3): exocrine glands; smooth muscle
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Cholinergics agonist
•Cholinergic agonists (direct acting )
•Bethanechol
•Pilocarpine
•Carbachol
•Anticholinesterases (indirect acting )
• reversible :
Neostigmine, physostigmine, pyridostigmine
•Irreversible : (e.g Organophosphates )
(isoflurophate, echothiophate )
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Cholinergics antagonist
Antimuscarinics
Atropine
Scopolamine
Ipratropium
Ganglionic Blockers (non selective ):
Hexamethonium
Pentamethonium
Neuromuscular Blockers
A. Non-depolarizing : e.g. D-tubocurarine
B. Depolarizing : e.g. suxamethonium
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Depolarization and
Hyperpolarization
• depolarization is a change in a cell's
membrane potential, making it more
positive, or less negative. In neurons and
some other cells, a large enough
depolarization may result in an action
potential. Hyperpolarization is the opposite
of depolarization, and inhibits the rise of
an action potential.
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Effect Of Nicotine & Hexamethonium
% of antagonist
X1 – X2
* 100
X1
X1
Wash
Dil. Nicotine
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No Wash
Hexamethonium
(C6)
x2
Dil. Nicotine
Effect Of Ach & Atropine
% of antagonist
X1 – X2
* 100
X1
X1
Wash
Ach
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No Wash
Atropine
x2
Ach
Effect Of Bacl2 & Atropine
% of antagonist
X1 – X2
* 100
X1
X1
x2
No Wash
Wash
Bacl2
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Hexamethonium (C6)
x2
Wash
Bacl2
No Wash
Atropine
Bacl2
Lab. 3
Effect of adrenergic drugs on intestine and
identification of unknown.
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Adrenergic Receptors
α1 receptor
α2 receptor
• vasoconstriction
• inhibit release of
(nor-epinephrine)
blood pressure
•negative feedback
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Adrenergic Receptors
β1 receptor
β2 receptor
• heart rate
• vasodilatation
• bronchodilatation
• Force of contraction
• glycogenolysis
• release of glucagons
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Catecholamines
• They are sympathetic hormones
• They are released by the adrenal glands in
response to stress
• They are part of sympathetic nervous
system
• They contain a catechol group and amino
acid tyrosin
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Production and degradation
• Catecholamines are produced mainly by the
chromaffin cells of the adrenal medulla and
postsganglionic fibers of sympathetic nervus
system.
• Dopmaine is the first catecholamine to be
synethesied. Ep. And NE are createdand
modified from dopamine.
• Tyrosin is created from phenylalanine by
hydroxylation by enzyme phenylalanine
hydroxylase.
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• Catecholamine synthesis is inhibited by
alpha- methyl-p- tyrosine (AMPT) which
inhibits tyrosine hydroxylase.
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Catecholamines degradation
• Catecholamines have a half- life of a few
minutes when circulating in blood.
• They are degraded by COMT or MAO.
• Amphetamines and MAOIs bind to MAO in
order to inhibit its action of breaking down
catecholamines.
• This is the primary reason why the effects
of amphetamines have a longer lifspan
than cocaine and other substances
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• Amphetamines not only cause a rlease of
dopamine, ep,and NE into blood stream
but also supress re- absorption.
• Two catcholamines,NE and dopamine act
as neuromodulators in CNS and as
hormones in blood circulation.
• High catecholamine level in blood are
associated with stress.
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Receptor type
Agonist
potency order
: α1
norepinephrin
e≥
epinephrine
>>
isoprenaline
smooth
muscle
contraction
Gq:
phospholipas
e C (PLC)
activated, IP3
and calcium
up
norepinephrin
e≥
epinephrine
>>
isoprenaline
smooth muscle
contraction and
neurotransmitte
r inhibition
Gi: adenylate
cyclase
inactivated,
cAMP down
:α2
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Selected
action
of agonist
Mechanism
Agonists
Antagonists
α1 agonists
α1 blockers
Alfuzosin•
Doxazosin•
Phentolamin•
e
Prazosin•
Tamsulosin•
Terazosin•
norepinephrine•
Phenylephrin•
e
Methoxamin•
e
Cirazoline•
α2 agonists
Clonidine•
Lofexidine•
Xylazine•
Tizanidine•
α2 blockers
Yohimbine•
Idazoxan•
Receptor type
Agonist
potency order
β
isoprenaline >
1 epinephrine =
norepinephrin
e
β2
isoprenaline >
epinephrine
>>
norepinephrin
e
Selected
action
of agonist
Mechanism
Agonists
heart muscle
contraction
Gs: adenylate
cyclase
activated,
cAMP up
norepinephrine•
smooth
muscle
relaxation
Gs: adenylate
cyclase
activated,
cAMP up
Short/long)
Salbutamol•
Formoterol •
Isoprenaline •
Salmeterol •
Terbutaline •
Direct Relaxant :
e.g papaverine
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Isoprenaline •
Dobutamine •
Antagonists
(Beta
blockers)
Metoprolol •
Atenolol•
Propranolol•
(Beta
blockers)
Propranolol•
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Identification of unknown
If the unknown produce contraction of the tissue , it may be nicotinic agonist
,muscarinic agonist or direct drug
1- 0.2ml of dil.nicotine , record & wash
2- 0.3ml of C6- blocker, leave 2 min. , add 0.2ml of dil. Nicotine (must block)
without wash add 0.2ml of unk. , block ,,,,, nicotine-like drug .
If response is found the agonist may be muscarinic or direct- like drug.
Agonist on effect muscarinic or direct
3- 0.2ml of Ach. , record & wash
4- 0.3ml of atropine , leave 2 min. , add 0.2ml of Ach. without wash add 0.2ml of
unk. , block ,,,,, muscarin-like drug .
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Lab. 4
Effect of Nm blockers on Frog Rectus Abdomens
Muscle
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Rectus Abdomens Muscle .
Voluntary muscle which receive motor somatic innervations (lack the
ganglia )
Receptor is Nm which is different from receptor in the autonomic
ganglia.
It contains Ach-esterase for destruction if Ach.
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Nm drugs
Cholinergic agonists (direct acting )
• Ach
• Carbachol
• Anticholinesterases (indirect acting )
• reversible :
Neostigmine, physostigmine, pyridostigmine
• Irreversible : (e.g Organophosphates )
(isoflurophate, echothiophate )
Neuromuscular Blockers
A. Non-depolarizing : e.g. D-tubocurarine
B. Depolarizing : e.g. suxamethonium
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Requirements
•Frog-ringer solution
-No Mg+2
(no relaxation)
-(Ca ,K ,PO4, Na ,HCO3 )
-Glucose
-Tension 0.5-4 gm
-Temp. 25 C
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Procedure
1- Add 0.2ml of Ach ,record ,wash .
2- Add 0.2ml of prostigmine , wait 2 min. ,add 0.2ml Ach , record ,wash.
3- Add 0.2ml carbacol ,record ,wash .
4- Add 0,2ml succinylcholine ,record , No wash , add 0.2ml of Ach
5- Add 0.2ml Ach , record ,wash ,Add 0.2ml atracurium
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Lab. 5
Effects of drugs on Isolated Rabbit’s
Heart
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Na for depolarization
K
for repolarization
Glucose for energy
Ca to prevent arrhythmias
HCO3 for adjust PH
Temp. 37
Oxygenation
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Heart rate : Beats/Min
Force of contraction
Coronary Flow Rate: ml/min
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A) Adrenergic Drugs
- Epinephrine ( adrenaline )
Heart Rate
Force of contraction of cardiac Muscle (β- Receptor)
(--) Flow Rate
- Norepinephrine ( noradrenaline )
Heart Rate
less effect on Force of contraction (more on α)
(--) Flow Rate
- Isoproterenol ( Isoprenaline non selective β-Agonist )
Heart Rate
Force of contraction (β - Receptor)
(--) Flow Rate
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B) Cholinergic Drugs :
- Acetylcholine
Heart Rate and cardiac output
(--) Force of contraction of cardiac Muscle (Beta2- Receptor)
(--) Flow Rate
- Atropine (
)
Heart Rate
(--) Flow Rate
C) Calcium channel blockers
- Verapamil
Heart rate
Force of Contraction (--) Flow rate
Heart rate
Force of Contraction (--) Flow rate
- Amlodipine
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D) C.H.F :
- Digoxin
Heart rate
Force of Contraction
- Bretylium ( Adrenergic Neuronal Blocker )
Heart rate
Force of Contraction
- Amiodarone ( Adrenergic Neuronal Blocker )
Heart rate
Force of Contraction
- β1- agonist ( Dobutamine)
Heart rate
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Force of Contraction
Flow rate
E) Vasodilator Drugs :
- Isosorbide (Isordil)
Heart rate
Force of Contraction (--) Flow rate
F) Anti-arrhythmic :
- Procainamide
Heart rate
Force of Contraction (--) Flow rate
Heart rate
Force of Contraction (--) Flow rate
- Lidocaine
- β- blocker ( Propranolol )
Heart rate
Force of Contraction (--) Flow rate
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