1 phl. 313 dr. khairy m a zoheir. 2 introduction to ns pharmacology & dose – response curve
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PHL. 313
Dr. Khairy M A Zoheir
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Introduction to NS Pharmacology
&Dose – Response Curve
Introduction to NS Pharmacology
&Dose – Response Curve
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Central Nervous System
Brain stem
Cerebrum
Spinal cord
Peripheral Nervous System
Afferent Efferent Sensory division Autonomic
Somatic
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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
Somatic nervous system
(voluntary)
Skeletal muscle
Autonomic nervous system
(involuntary)
Heart, blood vessels,
glands, other visceral
organs, smooth muscle
Efferent nervous system
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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.
Electrical
Stimulation
(impulse)
Chemical
(neurotransmitter)
Chemical
(intracellular
messengers)
Electrical
(membrane
ion channels)
Physiological
functions
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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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Lab. 1
Dose – Response Curve
Practice Practice
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ApparatusApparatus
Valve
(Wash)
valve
H2O
physiogragh
Tyroide
Solution
Intestine part
25 ml
Oxygen supply
NaCl:
Isotenicity
CaCl2:
Contraction of muscle
Glucose:
Energy
NaHCO3:
PH
MgCL2:
relaxation
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Dose – Response Curve
• It is a relationship between Dose and (Response %)
• From this curve we can see :
1. Potency (a measure of the activity of a drug in a biological system)
2. Efficacy (the capacity to produce an effect)
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»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
Dose – Response Curve
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Dose – Response Curve
D + R DR complex Response
cm
0.1ml 0.2ml 0.4ml 0.8ml 1.6ml
wash
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Dose – Response Curve
Dose
)ml(
Response (cm)
Response %
)x/ max*( 100
0.1116.6
0.2350
0.4466
0.86100
1.66100
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Dose – Response Curve
0
20
40
60
80
100
120
1 2 3 4 5 6
Dose )ml(
Resp
onse
)%(
Response % v
ED 50 = 3.75 ml
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Effect of cholinergic drugs on intestine and % of Effect of cholinergic drugs on intestine and % of antagonism.antagonism.
Effect of cholinergic drugs on intestine and % of Effect of cholinergic drugs on intestine and % of antagonism.antagonism.
Lab. 2
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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
AtropineScopolamineIpratropium
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
Dil. Nicotine Hexamethonium (C6)
Dil. Nicotine
Wash No Wash
X1
x2
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Effect Of Ach & Atropine
%of antagonist
X1 – X2 * 100
X1
Ach Atropine Ach
Wash No Wash
X1
x2
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Effect Of Bacl2 & Atropine
%of antagonist
X1 – X2 * 100
X1
Bacl2 Hexamethonium (C6) Bacl2
Wash No Wash X1 x2
Wash
Atropine
No Wash
Bacl2
x2
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Effect of adrenergic drugs on intestine and Effect of adrenergic drugs on intestine and identification of unknown.identification of unknown.
Effect of adrenergic drugs on intestine and Effect of adrenergic drugs on intestine and identification of unknown.identification of unknown.
Lab. 3
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Adrenergic Receptors
α1 receptor
• vasoconstriction
blood pressure
α2 receptor
• inhibit release of (nor-epinephrine)
•negative feed-back
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β1 receptor
• heart rate
• Force of contraction
Adrenergic Receptors
β2 receptor
• vasodilatation
• bronchodilatation
• 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 typeAgonist potency order
Selected action
of agonist
MechanismAgonistsAntagonists
α1:norepinephrine ≥
epinephrine >>
isoprenaline
smooth muscle
contraction
Gq:
phospholipase C (PLC)
activated, IP3
and calcium up
α1 agonists•norepinephrine
•Phenylephrine •Methoxamine •Cirazoline
α1 blockers•Alfuzosin •Doxazosin •Phentolamine •Prazosin •Tamsulosin •Terazosin
α2:norepinephrine ≥
epinephrine >>
isoprenaline
smooth muscle contraction and neurotransmitte
r inhibition
Gi: adenylate cyclase
inactivated, cAMP down
α2 agonists•Clonidine •Lofexidine •Xylazine •Tizanidine
α2 blockers•Yohimbine •Idazoxan
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Receptor typeAgonist potency order
Selected action
of agonist
MechanismAgonistsAntagonists
β1isoprenaline > epinephrine = norepinephrin
e
heart muscle contraction
Gs: adenylate
cyclase activated, cAMP up
•norepinephrine
•Isoprenaline •Dobutamine
(Beta blockers)
•Metoprolol •Atenolol•Propranolol
β2isoprenaline > epinephrine
>> norepinephrin
e
smooth muscle
relaxation
Gs: adenylate
cyclase activated, cAMP up
Short/long) •Salbutamol•Formoterol •Isoprenaline •Salmeterol •Terbutaline
(Beta blockers)
•Propranolol
Direct Relaxant :
e.g papaverine
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Identification of unknownIdentification 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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Effect of Nm blockers on Frog Rectus Abdomens Effect of Nm blockers on Frog Rectus Abdomens Muscle Muscle
Effect of Nm blockers on Frog Rectus Abdomens Effect of Nm blockers on Frog Rectus Abdomens Muscle Muscle
Lab. 4
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Rectus Abdomens Muscle .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
-(Ca ,K ,PO4, Na ,HCO3 )
-Glucose
-Tension 0.5-4 gm
-Temp. 25 C
(no relaxation)
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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
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
- Amlodipine Heart rate Force of Contraction (--) Flow rate
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D) C.H.F :
- Digoxin
Heart rate Force of Contraction Flow rate
- Bretylium ( Adrenergic Neuronal Blocker )
Heart rate Force of Contraction
- Amiodarone ( Adrenergic Neuronal Blocker )
Heart rate Force of Contraction
- β1- agonist ( Dobutamine)
Heart rate Force of Contraction
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E) Vasodilator Drugs :
- Isosorbide (Isordil)
Heart rate Force of Contraction (--) Flow rate
F) Anti-arrhythmic :
- Procainamide Heart rate Force of Contraction (--) Flow rate
- Lidocaine Heart rate Force of Contraction (--) Flow rate
- β- blocker ( Propranolol ) Heart rate Force of Contraction (--) Flow rate