- mechanism of drug action&introduction to receptor pharmacology-05mars2012

7/29/2019 - Mechanism of Drug Action&Introduction to Receptor Pharmacology-05mars2012

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Mechanism of Drug Action&

Introduction to receptor

pharmacology

Dr V.N NDIKUM

8-Mar-12

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Resorption

Distribution

Excretion

Receptor

Signal transduction

Cellular reaction

PHARMACODYNAMICSPHARMACOKINETICS


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Definition of Pharmacodynamics (PD)

De

finition of Pharmacodynamics Study of the biochemical and physiologic

processes underlying drug action Mechanism of drug action

Drug-receptor interaction

Efficacy

Safety profile

OR What the drug does to the body

Cellular level

General

OR Quantitative relationship between drug binding to

a receptor and the pharmacological effect Biochemical and physiological effects of drugs and their mechanisms

of action

Relationship between drug concentration and effect


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How do drugs work on the body?

Targets for drug action: Protein Targets

Enzyme inhibition

Receptor binding

Non-protein Targets

Nucleic acid

Cell membrane

others


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How do drugs work.

Protein targets - enzymes many drugs inhibitenzymes

Enzymes control a number of metabolic processes

A very common mode of action of many drugs in the patient (angiotensin converting enzymes inhibitors)

in microbes (sulfas, penicillins)

in cancer cells (5-Fluoro-uracil)

Protein Targets- receptors some drugs bind to protein receptors (in patient,

or microbes)

Non-protein targets


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How do drugs work

Non-protein drug target sites DNA:Mainly cytotoxic agents used in cancer

therapy

DNA / RNA:Antisense oligonucleotides

(experimental)

Membranes :Inhalation anaesthetics (?)

Fluid compartments:Osmotically active solutes

Plasma volume expanders (dextran)

Osmotically acting diuretic agents (mannitol)

Laxatives (Lactulose)


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Drug Receptors and Drug Action

Most drugs bind to cellular receptors Initiate biochemical reactions Pharmacological effect is due to the alteration of

an intrinsic physiologic process and not thecreation of a new process

Definition of a receptor Cellular macromolecule that specifically

(chemically) recognizes a ligand and carries out afunction in response to ligand binding.

Receptors provide means to "amplify" drug

Some Drugs not acting through receptors general anesthetics antacids osmotic diuretics


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Drug Receptors and Drug Action..

Drug receptors are Proteins orglycoproteins

Present on cell surface, on an organellewithin the cell, or in the cytoplasm

Finite number of receptors in a given cell

Receptor mediated responses plateau upon saturation of

all receptors


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Types of receptors

Types of receptors Trans membrane ion channels:

conduct ions across membrane in response to ligand binding, voltage

gradient or second messenger; e.g., H+/K+-ATPase

Transmembrane linked to intracellular G protein; e.g., adrenergic receptors

Transmembrane with enzymatic cytosolic domain; e.g., receptor tyrosine kinases

Intracellular: cytoplasm or nucleus; e.g., DNA, estrogen receptor


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Types of receptors.


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Classification of drug receptors

Classes of receptors are: Enzymes

Ion channels

Ligand-gated channels: Ion channels that open upon

binding of a mediator

Voltage-gated channels: Ion channels that are not

normally controlled by ligand binding but by changes in

the membrane potential

Metabolic receptors

hormone and neurotransmitter receptors that are

coupled to biochemical secondary messenger / effector

mechanisms


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Classes of receptors

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Characteristics of a Receptors Specificity

Receptor interacts with one type of ligand or a structurallyrelated family of ligands

Competition between related ligands Example: glucose transporter binds D-glucose specifically

Affinity

Energetics of ligand receptor interactions Energetics of binding determine specificity

Intrinsic activity A measure of the ability of a bound drug to activate the

receptor Distinguishes agonist from antagonist

Saturability Finite number of binding sites on a receptor, along with

specificity of interactions, implies that binding sites canbecome fully occupied with ligand molecules

Additional ligand leads to non-specific binding

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Interaction between DihydrofolateReductase with Methotrexate


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Molecular Level of Drug-receptor interaction

Drug must fitreceptor (lock andkey concept

Result: change in

cell function


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How do drugs affect receptors?

Action occurs when drug binds toreceptor and this action may be:

Ion channel is opened or closed

Second messenger is activated

cAMP, cGMP, Ca++, inositol phosphates, etc.

Initiates a series of chemical reactions

Normal cellular function is physically

inhibited Cellular function is turned on


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Drug Receptors and Drug Action..

The concept of Second messenger

Second Messenger


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Drug interactions with enzymes

Properties of Enzymes Enzymes = Biological catalysts

Speed chemical reactions

Are not changed themselves

How drugs affect enzymes?

Drugs altering enzyme activity alterprocesses catalyzed by the enzymes

Examples Cholinesterase inhibitors

Monoamine oxidase inhibitors


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Types of Drug interaction with non-receptor targets

Changing Physical Properties Mannitol

Changes osmotic balance acrossmembranes

Causes urine production (osmoticdiuresis)

Changing Cell Membrane Permeability Lidocaine

Blocks sodium channels

Verapamil, nefidipine Block calcium channels


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Types of Drug interaction with non-receptor targets..

Combining or interacting With OtherChemicals Antacids

Antiseptic effects of alcohol, phenol

Chelation of heavy metals

Anti-metabolites Enter biochemical reactions in place of normal

substrate competitors

Result in biologically inactive product

Examples Some anti-neoplastics

Some anti-infectives


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Types of Drug interaction with non-receptor targets

Blocking the activity of a transporterprotein


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- mechanism of drug action&introduction to receptor pharmacology-05mars2012

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