mechanism of drug action

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very systamatic

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Mechanisms of drug action:

Mechanisms of drug action

Overview:

Overview Introduction Aims and objectives History Receptor mediated & Non receptor mediated Receptor regulation Receptor and diseases Recent advances

Aims and objectives:

Aims and objectives Molecular aspects of mechanisms of drug action Receptor mediated Non receptor mediated

Slide 4:

Atropine in pilocarpine induced salivation…… “ Receptive substances” (1878) John Newport Langley

Slide 5:

Coined the term Receptor in 1909 ‘A drug will not work unless it is bound’. Paul Ehrlich

Drug targets:

Drug targets Drug targets :- cellular macromolecule or macromolecular complex with which the drug interact to elicit a cellular response Primary drug targets are:- Receptors Ion channels Enzymes Carrier molecules (transporters)

Mechanism of drug action :

Mechanism of drug action Receptor mediated Non receptor mediated

Receptor mediated :

Receptor mediated Receptor :- Protein macromolecule which combine with and mediate the action of signal molecule . Majority of drug targets are physiological receptors Two major domain within the receptor Ligand binding domain Effector domain

Receptor superfamilies :

Receptor superfamilies Ligand gated ion channels (ionotrophic receptors) G Protein coupled receptors (metabotropic receptors) Kinase linked receptors Nuclear receptors

GPCR:

GPCR

Function of G Protein:

Function of G Protein

Bidirectional control of target enzyme:

Bidirectional control of target enzyme

Main effector pathways of GPCR:

Main effector pathways of GPCR Adenylyl cyclase pathway / cAMP pathway Phospholipase C / inositol pathway ion channel Rho A / Rho kinase

Adenylyl cyclase and cAMP pathway:

Adenylyl cyclase and cAMP pathway Increased lipolysis Reduced glycogen synthesis Increased glycogen breakdown

Slide 17:

β -Adr receptor G S AC ATP Ca 2+ Pk a Troponin Better excitation-contraction coupling Cardiac Contractility cAMP GDP GTP Drug action Intermittent steps (transducer) Drug effect ACTION-EFFECT SEQUENCE OF A G-PROTEIN COUPLED RECEPTOR

Phospho inositol pathway:

Phospho inositol pathway

Slide 19:

Gq PIP 2 DAG IP 3 PK C PLc Ca 2+ Other effectors CCPK MLCK Ca 2+ CAM CAM PUMP Ca 2+ GDP GTP CYTOSOL MEMBRANE ca +2 channel

Ion channels :

Ion channels Activated G protein can open or close ion channels. G α s open ca 2+ in myocardium and skeletal muscle G i open K + channel in heart, smooth muscles and close neuronal ca channel opiate analgesics open K + channels through β ϒ

Rho/Rho kinase system:

Rho/Rho kinase system G 12/13. G α interacts with guanine nucleotide exchange factors. Angiogenesis, smooth muscle contraction and prolifertion.

GPCR families:

GPCR families Family Receptors Rhodopsin family Largest group. Neurotransmittter,neuropeptides,cannabinoid Secretin family Receptors for peptide hormones secretin, glucagon and calcitonin Metabotropic glutamate receptor/calcium channel family GABA B , calcium sensing receptors, Glutamate

Slide 25:

Functional family Ligands Transducers and effectors Example drugs β adrenergic receptor NE,Epi,DA G S, Ac Dobutamine, propanolol Muscuranic cholinergic Ach G i , and Gq , AC,ion channels, PLC Atropine Eicosanoid PG S , LXT S , TX S G s , G i , G q Misoprostol, Montelukast Thrombin (protease activated) Receptor peptide G 12/13, GEF (in dev)

Slide 26:

Ligand gated ion channel

Ligand gated ion channel:

Ligand gated ion channel

Kinase linked receptor:

Kinase linked receptor Main types Receptor tyrosine kinases Serine/theonine kinases Cytokine receptors Guanylyl cyclase linked receptors

Slide 32:

Functional family Physiological ligand Effectors and transducer Example drugs Receptor for tyrosine kinase Insulin,PDGF,EGF, VEGF SH2 domain Herceptin,imatinib Cytokine receptors Interleukins and other cytokines Jak / STAT Guanylyl cyclase Natriuretic peptides cGMP Nesiritide

Structure of nuclear receptor:

Structure of nuclear receptor

Nuclear receptor:

Nuclear receptor

Types of nuclear receptor:

Types of nuclear receptor Class I Hybrid class Class II Cytoplasm Homodimers Ex:- MR,ER,PR Heterodimers with RXR TR,VDR Nucleus Heterodimers Except RXR PPAR,LXR,FXR,RXR induce drug metabolising enzymes

Desensitization:

Desensitization

Receptor regulation:

Receptor regulation D Down regulation u UP regulation

Non receptor mediated:

Non receptor mediated Ion channels Enzymes Transporters

Voltage gated sodium channel:

Voltage gated sodium channel

Ion channels:

Ion channels

Slide 43:

K + channels :- voltage gated K + channel :- aminopyridine Inward rectifying K + channel :- sulfonylureas nicorandil Two pore domain K + channel

Slide 44:

Ca + channels :- voltage gated L type : nifedipine,diltiazam T type : ethosuximide, flunarazine N type : ω conotoxin TRP Channels : role in many sensory function mutation cause hypomagnesemia,hypocalcaemia

Enzymes as drug target:

Enzymes as drug target

Transporters as drug target:

Transporters as drug target Neurotransmitter transporters 2 superfamilies: SLC 1 and SLC 6 NET : Tricyclic antidepressant DAT : Cocaine SERT: Fluoxetine GAT : Tiagabine Nonneuronal transporter Cholesterol transporter Nucleoside transporter Glucose transporter Na + H + antiporter

Receptor and diseases:

Receptor and diseases Deficiency of receptor:- Androgen receptor Autoimmune depletion of receptor Loss of receptor Activation of effector mechanism in absence of agonist Mutation in GPCR(G α ) and G βϒ :- hypoparathyroidiam and hypertension respectively

Recent advances:

Recent advances GPCR oligomerization:- new targets for drug development. Signaling by internalized GPCR.

References:

References Pharmacology :-Rang and dale sixth edition Goodman & Gillman 12 th edition Oligomeriazation of GPCR : A reality. current opinion in pharmacology 2009 Signaling by internalized GPCR. Trends in Pharmacology Sciences vol 31 march 2010 The role of Rho kinase A/ rho kinase pathway in pulmonary hypertension.Current drug discovery technologies 2009

Slide 52:

THANK YOU