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