pharma2 وقت الحاجه

8/4/2019 pharma2 وقت الحاجه

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A continuous response

BP, HR, FBG, Cholesterol,…

GRADED DOSE RESPONSE CURVE



% of Maximal

Effect

0

20

40

60

80

100

0 200 400 600 800

Max effect = Emax Effect when all the R are occupied by D

C that gives the half-maximal effect

E= -----------

Emax xC

C+ EC50

As C ↑ response

increment ↓

0

20

40

60

80

100

1 10 100 1000

% of Maximal

Effect

EC50

Graded dose-response curves are used to determine:

1.The max efficacy (E max) → highest limit of dose-response relationship on response axis.

2.The potency = The concentration of drug required to produce a specified response

The smaller the EC50 , the greater the potency of the agonist, the lower C needed to

elicit the maximum biological response.

3. Compare the relative potency and efficacy of drugs that produce the same effect.

EC50

[C]

[C]




A > e f f i c a c y t h a n

B

B P a r t i a l A g o n i s

t

E F F I C A C Y

POTENCY

A > potent B



X > potent than Y & Z

X & Z > e f f i c

a c y t h a n Y

X & Z a r e e q u a l e f f i c a c y

Y> potent than Z


Y > potent but

< efficacious than Z



QANTAL DOSE RESPONSE CURVE

All-non responses

% s u b j e c t s

r e s p o n

d i n g

Dose-frequency relationship



QANTAL DOSE RESPONSE CURVE: used to determine

at which 50% of individuals exhibit the specified therapeutic response

Therapeutic Index The relation between dose to induce a desired

effect versus that producing the unwanted effect.

TD50

ED50

When low → the drug has a narrow margin of safety digoxin

When high → the drug has a safe profile diazepam

0

20

40

60

80

100

1 10 100 1000

[Dose]

ED50

%

s u b j e c t s r e s p o n d i n g

TD50 LD50 Median toxic dose

Median lethal dose

Median EffectiveDose

Therapeutic EffectToxic Effect

Lethal Effect



Types

Physiological

Chemical

Pharmacokinetic

Non-Competitive

It is the diminution or the complete abolishment of the effect of one drug in the presence of another.

Receptor Blockade (Competitive )

Two drugs react chemically resulting in loss of activity of activedrug

Dimercaprol reduces heavy metal toxicity [ lead, cadmium ….]

Two drugs possess opposing actions in the body, so tend to

cancel each other’s effect

The antagonist effectively reduces the concentrationof the active drug at the site of action

Phenobarbitone induces an accelerated hepatic metabolism warfarine

Nor adrenaline & histamine Omeprozole & histamine

ANTAGONISM



Receptor

Blockade

Competitive

Non-

Competitive

Antagonist prevents binding of agonist to the

receptor at the same binding site ( = competes withit at same occupancy site )

Antagonist block at some point

the chain of events that ignite

the response of agonist

Agonist and Antagonist can be bound simultaneously

Agonist and Antagonist compete ( only one is bound)

ANTAGONISM

Irreversible

Reversible



Reversible

Antagonist readily dissociate from binding site of

agonist to the receptor

Antagonist form stable, permanent / near permanent chemical

bond with receptor.

Inactivation lasts for duration of receptor turnover or its de-novo synthesis → explains its longevity of action

Antagonism can be overcomed by increasing

concentration of agonist = Surmountable

Naloxone vs morphine

Phenoxybenzamine & Noradrenaline

Atropine vs Ach

Irreversible

COMPETATIVE ANTAGONISM



Parallel shift to the right, without any change in slope or maximum

No parallel shift

But both a decrease in slope and a reduced maximum are obtained.

Competitive Antagonism

Irreversible

Reversible



Agonist

Agonist + irreversible competitiveantagonist

Agonist + non-competitiveantagonist

0

20

40

60

80

100

1 10 100 1000

% of Maximal

Effect

[C]

Antagonism cannot be overcomed by increasing concentration of agonist = NON-

SURMOUNTABLE

Agonist + reversible competitiveantagonist

Competitive vs Noncompetative Antagonism

Depression of maximal

response +/- rightward

shifts ( if some R are spare )

Antagonism can be overcomed by increasing concentration of agonist = SURMOUNTABLE

Verapamil vs noradrenaline





By the end of this lecture you will be able to :

Classify receptors into their main superfamilies

Identify the nature & time frame of their response

Recognize their different transduction mechanism

ilos



1.Recognition

2.Reception

3.Transduction

4.Response

A RECEPTOR

Coupler

Transduction

Direct

Its Structure:

1

2 3 4



Location

Structure

Transduction Mechanism

Classified according to their

Time scale of Response 4 Main SUPERFAMILIES

Channel-Linked Receptor

G-Protein Coupled Receptors

Nuclear Receptors

Enzyme-Linked Receptors

Nature of Response



Conductance Cell Signal Transcription& Translation

Cell Signal

Hours /Days

Minutes / Hours

1 2 3 4

Channel-Linked G-Protein Coupled Enzyme-Linked Nuclear



Channel-Linked Receptor1

Ionotropic Receptor

Ligand-Gated-Ion Channel

Different from Voltage-Gated Ion Channel

Is activated by a change in action potential not by occupancy of a ligand

Involved in fast synaptic neurotransmission occurring

over millisecondsIt is activated directly when a ligand binds to the

receptor to open the channel that is incorporated as

part of its structure. Examples;

Nicotinic Ach receptor activated by AchGABA A receptor activated by benzodiazipines

NMDA receptor inhibited by glycine



G-

Protein

G-Protein-Coupled Receptor

Metabotropic Receptor

PHOSPHORYLATION OF TARGET PROTEINS

Involved in less rapid transmission of mAch R, amine transmitters, Adr R, Dopa-minergic R, histamine R, 5-HT R…Neuropeptide R, prostanoid R, purine R,… Hormones; glycogen

Adenyl cyclase (AC) cAMP PKAPhospholipase C (PLC)IP3 Ca++ intacellular

Ca2+ /CaMCAMPKDAG PKC

An enzyme 2nd messenger

RESPONSE

Go-between proteins

Coupler

Agonist

2Composed of 3 subunits

[ g] + GDP



g

ATP ATPATPATP

G-Protein

R

E

PKA


Adenyle cyclase

g ATP ATPATPATP

R

E

cAMP

P

Channels

P

P Phosphorylate

Proteins

P

Not activated

Ligand binding activates it



g

E

Phospholypase C

PIP2 DAG

Phosphatidic aInositol

↑


IP3

Ca++

PKC

+CaM

Enzymes

Cytoskeletal Proteins

P

Channels

P

P

P



RESPONSE



mAch; m1, m2, m3, m4,

Adrenergic receptors; 1 & 2 / 1 & 25-HT1; 5-HT1A – 1D receptor


Different Classes of Receptors

Different Receptors Subtypes

Ach R m Adrenergic R & Dopaminergic R D1 & D2 5-HT 5-HT1-2 / 5-HT 4-7

Different in G-Protein Classes

Are the Most Abundant Type

Divided according to their α

-subunits into Gs, Gi and Gq Gs and Gi produce, respective, stimulation and inhibition of AC

Gq is linked to activation of PLC-IP3 -Ca++ CaM & PKC

Show selectivity to receptors & effectors with which they couple

The a 1 Adrenoceptors couple to Gq to stimulate PLC.



++

PLC GqGq

Bronchi Blood Vessel

PLC


+

AC

Adrenoceptor 2 Adrenoceptor

Inhibitory Receptor Stimulatory Receptor

Adr

GsGi

↑cAMP cAMP

1 Adrenoceptor M1 Ach receptor

Stimulatory Receptor Stimulatory Receptor

↑Ca ++

Adr Ach

↑Ca ++



1, 2 & AdrenoceptorsDiffer from each other both in ligand selectivity amongdrugs and in coupling to G proteins (Gq, Gi, and Gs,

respectively)M1 and M3 Ach receptors activate the Gq-PLC-IP3-Ca2+ pathwayM2 and M4 Ach receptors activate Gi to reduce the

activity of AC

http://www.cnsforum.com/content/pictures/imagebank/hirespng/rcpt_sys_N2_antag.png

http://www.cnsforum.com/content/pictures/imagebank/hirespng/Rcpt_sys_mus_ag.png



Enzyme-Linked Receptors3

Involved in slow action of; hormones (insulin), growth factors, cytokines, …..

Their cytosolic domain either:

Associate directly with an enzyme (guanyl cyclase)

Possess intrisic kinase activity (as tyrosine or serine/threonine kinase) thatcan phosphorylate itself & / or other proteins that they dock.

They control many cellular

functions as motility, growth,differentiation, division &morphogenesis.

This usually require manyintracellular signaling steps

that take time to process.

Tyrosine Kinase-Linked Receptors



Phosphorylate other

proteins that it docks

Activated Receptor

autophosphorylates

Ligands cross link or

dimerize receptors

Tyrosine Kinase-Linked Receptors


Phosphory

lateddockedproteins

Phosphorylates

other targets

RESPONSE

Examples

Insulin receptors

Growth factors

receptors




Guanyle cyclase-Linked Receptors

Atrial Natriueretic Peptide [ANP] RECEPTORS

They that have a single transmembrane spanning element.

These have integral intrinic guanylate cyclase activity .

Their 2nd messenger is cGMP

→ activates PKG → phosphorylate down stream

protein signaling molecules.

↑cGMP



Nuclear Receptors4Are intra-cellularly located whether in cytosol or the nucleus.

Their ligands are usually either:

Extracellular lipophylic hormones; steroids, thyroids, …etc Intracellular 2nd messenger developed along signalingcascade of cell membrane receptors.

They possess a conserved areathat recognizes specific DNA

sequence in the nucleus→ once bound to their ligandsthey react as

TRANSCRIPTION FACTORSexpressing or repressing

target genes.

By this they are involved in

regulation of PROTEIN SYNTHESIS

→so are the most slowest in action.

Protein

Transcription

Translation



Nuclear Receptors4

The activated GR complex

Up-regulates expression of anti-inflammatory proteins

Represses expression of pro-inflammatory

proteins in cytosol ( preventing the translocation

of other transcription factors from the cytosol

into the nucleus).

GLUCOCORTICOIDRECEPTOR

proteins

In Cytosol



THYROID HORMONE

RECEPTOR

Nuclear Receptors4

Intra nuclear



Quiz?

• An example of an agent thatexerts much of its effectsthrough intracellular receptors

that in complex form binds toDNA response elements:

• A) acetylcholineB) dopamineC) corticosteroidsD) diltiazemE) atropine



Quiz?

• Example(s) of endogenousligands that interact withmembrane-integrated ionchannels and affect(s) ionconductance.

• A) acetylcholineB) GABAC) glutamateD) aspartate

E) glycine



Quiz?

• Example(s) of anintracellular receptor:

–

? beta-adrenergic receptor – ? muscarinic cholinergic

receptor

– ? steroid receptor



Quiz?

• Example(s) of agents thataffect ion conductance --affecting cellular membranepotentials

– ? acetylcholine

– ? gamma-aminobutyric

acid (GABA)

– ? aspartate

– ? glutamate



Quiz?

• Regulatory moleculesinfluenced by G proteinsystems:

– ? adenylyl cyclase

– ? phospholipase A2,C,D

– ? calcium, potassium,

sodium ion channels

– ? transport proteins



Quiz?

• Longer-lastingphysiological responseto drug:

• A) increase in heart ratefollowing epinephrineinfusionB) changes in geneproduct productionfollowing corticosteroid

injection.



Quiz?

• Signal transductioninvolves G proteincoupled receptorsystems:

• A) biogenic aminesB) peptide hormonesC) steroid hormones

• D) insulin



Quiz?

• Growth factors and insulinexert their signalling effectvia:-

A. Calcium channels

B. G-protein

C. Tyrosine kinase

D. DNA transcription

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pharma2 وقت الحاجه