Pawitra Pulbutr

B.Pharm (Hon),

M.Sc. In Pharm (Pharmacology)

Pharmacodynamics

How drugs act: Molecular aspects

Pharmacodynamics

How drugs act: Molecular aspects

Objectives

อธิ�บายถึ�งเป้�าหมายที่��ยาออกฤที่ธิ��ที่��สำ�าคั�ญได้�อธิ�บายถึ�งกลไกการออกฤที่ธิ��ของยาผ่!าน Receptorชน�ด้ - - Channel linked receptor, G protein

- receptor, Kinase linked receptor และ R eceptor that regulate gene transcripti

on รวมที่�)งคัวามแตกต!างของการออกฤที่ธิ��ผ่!าน Receptors แต!ละชน�ด้ได้�อธิ�บายถึ�งกลไกการออกฤที่ธิ��ของยาผ่!าน Ion channelอธิ�บายถึ�งกลไกการออกฤที่ธิ��ของยาผ่!าน Enzymesอธิ�บายถึ�งกลไกการออกฤที่ธิ��ของยาผ่!าน Carriermolecules

Target for drug action

Protein

• Receptors

• Ion channels

• Enzymes

• Carrier molecules

Other :- Tubulin, DNA, RNA

Chemotherapy >>> Anticancer, Antimicrobial

ReceptorsReceptors

ต�วร�บสำ�ญญาณของเซลล- เซลล-ที่�างานเซลล-ที่�างาน

ได้�ได้�สำอด้คัล�องสำอด้คัล�องก�นก�น

การสำ.�อสำารก�นระหว!างเซลล-

สำาร = Chemical messenger… neurotransmitters, hormones, neurotransmitters, hormones,

cytokines, growth factorscytokines, growth factors

Receptor

Chemical messenger

LigandLigand

• Chemical messenger

• Drug (Agonist or Antagonist)

Receptor

Signal transduction

Physiological response

Drugs act at Drugs act at receptorreceptor

AgonistAgonist AntagonisAntagonistt

Receptor activation

Physiological Physiological responseresponse

Block receptor

No activatio

n

No No Physiological Physiological

responseresponse

Drugs act at Drugs act at receptorreceptor

Receptor

Receptor of chemical messenger in the body

Receptor of specific drug

Receptors are mostly named after their ligand.

Receptor classification by their localization

• Cell membrane receptorCell membrane receptor

• Nuclear receptor or intracellular Nuclear receptor or intracellular receptorreceptor

Receptor familiesReceptor families

Channel linked receptor

(Ionotropic receptor)

G-protein coupled receptor

(Metabotropic receptor, 7-

transmembrane receptor)

Receptor that regulate gene transcription

Kinase linked receptor

Figure 2.1 Types of receptor-effector linkage

Channel linked Channel linked receptorreceptor• Nicotinic receptor Nicotinic receptor…pr…protooto

typetype

• ACh …natural ligandACh …natural ligandLigand binding

Channel

lining One subunit

5 subunits

2 + 1 + 1 + 1

One receptor

G-protein coupled receptorG-protein coupled receptor

(GPCR)(GPCR)

o Cell membrane receptorCell membrane receptor

o Single polypeptide chainSingle polypeptide chain

o Muscarinic receptorMuscarinic receptor

o Adrenergic receptorAdrenergic receptor

o Dopamine receptorDopamine receptor

o 5-HT receptor5-HT receptor

o Opiate receptorOpiate receptor

o GPCR >>> Major drug GPCR >>> Major drug targettarget

G-protein G-protein coupled coupled receptorreceptor

Comprised of…..

1. Extracellular N-terminal

2. 7-Transmembrane alpha helices

3. Intracellular C-terminal

• ligand binding

• Linked with “G-protein”

Single peptid

e

Role of G-protein

G protein

“free”

EffectoEffector r molecumoleculele

GTPase

Second messenger production

Effector molecule or target Effector molecule or target proteinprotein

1. Membrane enzyme1. Membrane enzyme

• Adenylate cyclaseAdenylate cyclase

• Phospholipase CPhospholipase C

2. Ion channels2. Ion channels

LigandLigand

G-protein coupled receptorG-protein coupled receptor

Active G protein ( GTP)

Enzyme Ion channel

Adenylate Adenylate cyclasecyclase

Phospholipase Phospholipase CC

cAMP IP3Increase

intracellular calcium

DAG Activate protein kinase C

cAMP dep. Protein kinase

phosphorylate

enzyme Ion channel

Open channel

Tyrosine kinase receptor/ Tyrosine kinase receptor/ Guanylate cyclase linked receptorGuanylate cyclase linked receptor

• Insulin receptorInsulin receptor

• Cytokine receptor Cytokine receptor ******

• Growth factor receptor Growth factor receptor ******

• Atrial natriuretic peptide Atrial natriuretic peptide receptorreceptor

Tyrosine kinase receptorTyrosine kinase receptor

Guanylate cyclase linked receptorGuanylate cyclase linked receptor

1. Extracellular 1. Extracellular domaindomain

2. Transmembrane 2. Transmembrane regionregion

3. Intracellular 3. Intracellular domain domain

Kinase linked Kinase linked receptorreceptor

Ligand binding

Single helix

Catalytic domain Catalytic domain (Enzyme (Enzyme activity)activity)

Ras/ Raf pathway

Ras = Ras = membrane membrane proteinprotein

Jak/ Stat pathway Jak/ Stat pathway

Jak = cytosolic Tyrosine kinase

Stat = transcriptional factor

Receptor that regulate gene Receptor that regulate gene transcriptiontranscription

• Intracellular receptor (Nuclear Intracellular receptor (Nuclear receptor)receptor)

• Lipophilic ligandLipophilic ligand

• Steroid receptor, Thyroid receptor, Steroid receptor, Thyroid receptor,

• Vitamin A receptor, Vitamin D Vitamin A receptor, Vitamin D receptorreceptor

Receptor Structure

1. DNA binding 1. DNA binding domaindomain

2. Ligand 2. Ligand binding domainbinding domain

3. Transcription 3. Transcription control domaincontrol domain

Zinc fingerZinc finger

Bind with DNA Bind with DNA at at response response elementelement

Peroxisome Proliferator Peroxisome Proliferator Activated ReceptorActivated Receptor (PPARs)(PPARs)

• Nuclear receptor

• PPAR alpha, PPAR beta, PPAR gamma

Figure 2.1 Types of receptor-effector linkage

Receptor dynamics

DesensitizatiDesensitizationon• Decrease response (decrease sensitivity)

• fast occur

• Phosphorylation of RC >>> Steric hindranceReceptor down Receptor down

regulationregulation• Decrease number of receptor

• slow occur… receptor internalization

Prolonged agonist activationProlonged agonist activation

Decrease Response ToleranceTolerance

Receptor Receptor upregulationupregulation

• Increase number of receptor

Prolonged antagonistantagonist blockade

Over Response

-blocker (-adrenergic receptor antagonist)

•May induce RC upregulation

•If sudden stop >>> Over response >>> hypertension

•Should be slowly stop the drugs

Ion channels

Drugs which directly acting at ion channels

1. Block ion channels

• Physical properties

• Local anesthetics

•Block sodium channels

See table 2.2

2. Bind with accessory site on ion channel

• Dihydropyridine Calcium channel blocker

• Benzodiazepine Chloride channel opening

See table 2.2

Enzymes

1. Enzyme inhibitor1. Enzyme inhibitor

• Substrate analog

• Reversible

• Irreversible

2. False substrate2. False substrate

• Substrate analog

• Abnormal products

See table 2.3

Carrier molecules

Carrier moleculesCarrier molecules

1.1. InhibitorsInhibitors

• Inhibit carrier molecule function

2. False substrates2. False substrates

• False uptake

See table 2.4

Target for drug actionTarget for drug action

ProteinProtein

• ReceptorsReceptors

• Ion channelsIon channels

• EnzymesEnzymes

• Carrier moleculesCarrier molecules

Other :- Other :- Tubulin, Tubulin, DNA, RNADNA, RNA

Chemotherapy >>> Chemotherapy >>> Anticancer, Anticancer,

AntimicrobialAntimicrobial

A, B, C, D, F