Mechanism of Drug Action & Introduction to receptor pharmacology

Dr V.N NDIKUM
8-Mar-12

PHARMACOKINETICS

PHARMACODYNAMICS

Resorption

Distribution

Receptor

Excretion

Signal transduction

Cellular reaction

Definition of Pharmacodynamics (PD)

Definition of Pharmacodynamics
processes underlying drug action
Mechanism of drug action
Drug-receptor interaction

Study of the biochemical and physiologic

Efficacy Safety profile

What the drug does to the body

Cellular level General

OR

Quantitative relationship between drug binding to

OR

a receptor and the pharmacological effect

Biochemical and physiological effects of drugs and their mechanisms of action Relationship between drug concentration and effect

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

How do drugs work.

Protein targets - enzymes
many drugs inhibit enzymes 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

Definition of a receptor

an intrinsic physiologic process and not the creation of a new process

Cellular macromolecule that specifically

Receptors provide means to "amplify" drug

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

Some Drugs not acting through receptors

general anesthetics antacids osmotic diuretics

Drug Receptors and Drug Action..

Drug receptors are Proteins or glycoproteins
Present on cell surface, on an organelle

within the cell, or in the cytoplasm Finite number of receptors in a given cell
Receptor mediated responses plateau upon saturation of all receptors

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

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

Classes of receptors

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Characteristics of a Receptors
Specificity Receptor interacts with one type of ligand or a structurally related 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 can become fully occupied with ligand molecules Additional ligand leads to non-specific binding
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Interaction between Dihydrofolate Reductase with Methotrexate

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Molecular Level of Drug-receptor interaction Drug must fit receptor (lock and key concept Result: change in cell function

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How do drugs affect receptors?

Action occurs when drug binds to receptor 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 alter
Examples
Cholinesterase inhibitors Monoamine oxidase inhibitors

processes catalyzed by the enzymes

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Types of Drug interaction with non-receptor targets

Changing Physical Properties

Mannitol Changes osmotic balance across

membranes Causes urine production (osmotic diuresis)

Changing Cell Membrane Permeability

Lidocaine

Blocks sodium channels

Block calcium channels
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Verapamil, nefidipine

Types of Drug interaction with non-receptor targets..

Combining or interacting With Other Chemicals

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 transporter protein

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