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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