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How drugs act: Molecular aspects M.Sc. In Pharm (Pharmacology)
Pharmacodynamics How drugs act: Molecular aspects Pawitra Pulbutr B.Pharm (Hon), M.Sc. In Pharm (Pharmacology)
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Objectives อธิบายถึงเป้าหมายที่ยาออกฤทธิ์ที่สำคัญได้
อธิบายถึงกลไกการออกฤทธิ์ของยาผ่าน Receptor ชนิด Channel-linked receptor, G-protein receptor, Kinase-linked receptor และ Receptor that regulate gene transcription รวมทั้งความแตกต่างของการออกฤทธิ์ผ่านReceptors แต่ละชนิดได้ อธิบายถึงกลไกการออกฤทธิ์ของยาผ่าน Ion channel อธิบายถึงกลไกการออกฤทธิ์ของยาผ่าน Enzymes อธิบายถึงกลไกการออกฤทธิ์ของยาผ่าน Carrier molecules
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Chemotherapy >>> Anticancer, Antimicrobial
Target for drug action Protein Receptors Ion channels Enzymes Carrier molecules Other :- Tubulin, DNA, RNA Chemotherapy >>> Anticancer, Antimicrobial
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ตัวรับสัญญาณของเซลล์ เซลล์ทำงานได้สอดคล้องกัน
Receptors ตัวรับสัญญาณของเซลล์ เซลล์ทำงานได้สอดคล้องกัน การสื่อสารกันระหว่างเซลล์ สาร = Chemical messenger… neurotransmitters, hormones, cytokines, growth factors Chemical messenger Receptor
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Drug (Agonist or Antagonist) Physiological response
Ligand Chemical messenger Drug (Agonist or Antagonist) Receptor Signal transduction Physiological response
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Physiological response No Physiological response
Drugs act at receptor Agonist Antagonist Receptor activation Block receptor No activation Physiological response No Physiological response
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Receptor of chemical messenger in the body
Drugs act at receptor Receptor of chemical messenger in the body Receptor Receptor of specific drug Receptors are mostly named after their ligand.
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Receptor classification by their localization
Cell membrane receptor Nuclear receptor or intracellular receptor Kinase linked receptor Channel linked receptor (Ionotropic receptor) Receptor families G-protein coupled receptor (Metabotropic receptor, 7-transmembrane receptor) Receptor that regulate gene transcription
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Figure 2.1 Types of receptor-effector linkage
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Channel linked receptor
Nicotinic receptor…prototype ACh …natural ligand 5 subunits 2 + 1 + 1 + 1 Ligand binding Channel lining One subunit One receptor
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G-protein coupled receptor
(GPCR) Cell membrane receptor Single polypeptide chain Muscarinic receptor Adrenergic receptor Dopamine receptor 5-HT receptor Opiate receptor GPCR >>> Major drug target
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G-protein coupled receptor
Single peptide Comprised of….. 1. Extracellular N-terminal 2. 7-Transmembrane alpha helices ligand binding Linked with “G-protein” 3. Intracellular C-terminal
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Second messenger production
Role of G-protein Effector molecule G protein “free” Second messenger production GTPase
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Effector molecule or target protein
1. Membrane enzyme Adenylate cyclase Phospholipase C 2. Ion channels
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Enzyme Ion channel G-protein coupled receptor Ligand
Active G protein ( GTP) Enzyme Ion channel Open channel Adenylate cyclase Phospholipase C Increase intracellular calcium IP3 cAMP cAMP dep. Protein kinase DAG Activate protein kinase C phosphorylate enzyme Ion channel
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Tyrosine kinase receptor/ Guanylate cyclase linked receptor
Insulin receptor Cytokine receptor *** Growth factor receptor *** Guanylate cyclase linked receptor Atrial natriuretic peptide receptor
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Kinase linked receptor Catalytic domain (Enzyme activity)
Ligand binding 1. Extracellular domain 2. Transmembrane region 3. Intracellular domain Single helix Catalytic domain (Enzyme activity)
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Ras = membrane protein Ras/ Raf pathway
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Jak/ Stat pathway Jak = cytosolic Tyrosine kinase
Stat = transcriptional factor
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Receptor that regulate gene transcription
Intracellular receptor (Nuclear receptor) Lipophilic ligand Steroid receptor, Thyroid receptor, Vitamin A receptor, Vitamin D receptor
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Receptor Structure Zinc finger Bind with DNA at response element 1. DNA binding domain 2. Ligand binding domain 3. Transcription control domain
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Peroxisome Proliferator Activated Receptor (PPARs)
Nuclear receptor PPAR alpha, PPAR beta, PPAR gamma
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Figure 2.1 Types of receptor-effector linkage
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Receptor dynamics Tolerance
Prolonged agonist activation Desensitization Decrease response (decrease sensitivity) fast occur Phosphorylation of RC >>> Steric hindrance Receptor down regulation Decrease number of receptor slow occur… receptor internalization Decrease Response Tolerance
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Receptor upregulation
Prolonged antagonist blockade Increase number of receptor Over Response -blocker (-adrenergic receptor antagonist) May induce RC upregulation If sudden stop >>> Over response >>> hypertension Should be slowly stop the drugs
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Drugs which directly acting at ion channels
1. Block ion channels Physical properties Local anesthetics Block sodium channels See table 2.2
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2. Bind with accessory site on ion channel
Dihydropyridine Calcium channel blocker Benzodiazepine Chloride channel opening See table 2.2
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Enzymes 1. Enzyme inhibitor 2. False substrate Substrate analog
Reversible Irreversible 2. False substrate Substrate analog Abnormal products See table 2.3
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Carrier molecules
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Inhibit carrier molecule function
Carrier molecules Inhibitors Inhibit carrier molecule function 2. False substrates False uptake See table 2.4
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Chemotherapy >>> Anticancer, Antimicrobial
Target for drug action Protein Receptors Ion channels Enzymes Carrier molecules Other :- Tubulin, DNA, RNA Chemotherapy >>> Anticancer, Antimicrobial
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A, B, C, D, F
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