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Pharmacodynamics How drugs act: Molecular aspects Pawitra Pulbutr B.Pharm (Hon), M.Sc. In Pharm (Pharmacology) Objectives อธิบายถึงเป้ าหมายที่ยาออกฤทธิ์ท่สี าคัญได้ อธิบายถึงกลไกการออกฤทธิ์ของยาผ่าน Receptor ชนิ ด Channellinked receptor, G-protein receptor, Kinase-linked receptor และ Receptor that regulate gene transcription รวมทัง้ ความแตกต่างของการ ออกฤทธิ์ผ่านReceptors แต่ละชนิ ดได้ อธิบายถึงกลไกการออกฤทธิ์ของยาผ่าน Ion channel อธิบายถึงกลไกการออกฤทธิ์ของยาผ่าน Enzymes อธิบายถึงกลไกการออกฤทธิ์ของยาผ่าน Carrier molecules Target for drug action Protein • Receptors • Ion channels • Enzymes • Carrier molecules Other :Tubulin, DNA, RNA Chemotherapy >>> Anticancer, Antimicrobial Receptors ตัวรับสัญญาณของเซลล์ การสือ่ สารกันระหว่างเซลล์ เซลล์ทางานได้ สอดคล้องกัน สาร = Chemical messenger… neurotransmitters, hormones, cytokines, growth factors Chemical messenger Receptor Ligand • Chemical messenger • Drug (Agonist or Antagonist) Receptor Signal transduction Physiological response Drugs act at receptor Agonist Antagonist Receptor activation Block receptor Physiological response No activation No Physiological response Drugs act at receptor Receptor of chemical messenger in the body Receptor Receptor of specific drug Receptors are mostly named after their ligand. Receptor classification by their localization • Cell membrane receptor • Nuclear receptor or intracellular receptor Kinase linked receptor Channel linked receptor (Ionotropic receptor) Receptor families Receptor that regulate gene transcription G-protein coupled receptor (Metabotropic receptor, 7transmembrane receptor) Figure 2.1 Types of receptor-effector linkage Channel linked receptor • Nicotinic receptor…prototype ACh …natural ligand 5 •subunits Ligand binding 2 + 1 + 1 + 1 Channel lining One subunit One receptor G-protein coupled receptor (GPCR) o Cell membrane receptor o Single polypeptide chain o Muscarinic receptor o Adrenergic receptor o Dopamine receptor o 5-HT receptor o Opiate receptor o GPCR >>> Major drug target G-protein coupled receptor Comprised of….. Single peptide 1. Extracellular N-terminal 2. 7-Transmembrane alpha helices • ligand 3. Intracellular C-terminal • Linked with “G-protein” binding Role of G-protein G protein “free” GTPase Effector molecule Second messenger production Effector molecule or target protein 1. Membrane enzyme • Adenylate cyclase • Phospholipase C 2. Ion channels Ligand G-protein coupled receptor Active G protein ( GTP) Enzyme Adenylate cyclase Phospholipase C IP3 cAMP cAMP dep. Protein kinase phosphorylate enzyme Ion channel Ion channel DAG Open channel Increase intracellular calcium Activate protein kinase C Tyrosine kinase receptor/ Guanylate cyclase linked receptor Tyrosine kinase receptor • Insulin receptor • Cytokine receptor *** • Growth factor receptor *** Guanylate cyclase linked receptor • Atrial natriuretic peptide receptor Kinase linked receptor 1. Extracellular domain Ligand binding 2. Transmembrane region Single helix 3. Intracellular domain Catalytic domain (Enzyme activity) Ras = membrane protein Ras/ Raf pathway Jak/ Stat pathway Jak = cytosolic Tyrosine kinase Stat = transcriptional factor Receptor that regulate gene transcription • Intracellular receptor (Nuclear receptor) • Lipophilic ligand • Steroid receptor, Thyroid receptor, • Vitamin A receptor, Vitamin D receptor Receptor Structure 1. DNA binding domain 2. Ligand binding domain 3. Transcription control domain Zinc finger Bind with DNA at response element Peroxisome Proliferator Activated Receptor (PPARs) • Nuclear receptor • PPAR alpha, PPAR beta, PPAR gamma Figure 2.1 Types of receptor-effector linkage Receptor dynamics 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 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 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 inhibitor • Substrate analog • Reversible • Irreversible 2. False substrate • Substrate analog • Abnormal products See table 2.3 Carrier molecules Carrier molecules 1. Inhibitors • Inhibit carrier molecule function 2. False substrates • False uptake See table 2.4 Target for drug action Protein • Receptors • Ion channels • Enzymes • Carrier molecules Other :Tubulin, DNA, RNA Chemotherapy >>> Anticancer, Antimicrobial A, B, C, D, F
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