Lecture 2 - Gen-principles - 2 Sep 2006
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PROF. CHARLES EZEAMUZIE .PhD (London), MIBiol., C.Biol Professor of Immunopharmacology
DEFINITIONS Pharmacology: A study of the interaction of drugs with living tissues/organisms Toxicology: Aspect of Pharmacology dealing with undesirable effects of drugs Drug: Any chemical substance that alters the body’s function Pharmacodynamics: What the drug does to the body (drug actions) Pharmacokinetics: What the body does to the drug (absorption, metabolism, excretion)
NATURE OF DRUGS Drugs vary widely with respect to: a. Molecular size b. Structure and configuration (including isomers) c. Chemical nature (reactive/inert; weak acid/base) d. Sources (synthetic, natural products)
CLASSIFICATION OF DRUG EFFECTS Therapeutic Effect: Side Effect:
Any effect other than desired one
Adverse Effect: Toxic Effect:
Desired Effect
Side effect that is harmful
Adverse effect resulting from high (toxic) dose Idiosyncrasy: Abnormal response to a drug occurring only in a minority of individuals
DRUG RECEPTORS Definition: A receptor is a specific binding site for a drug on or within the cell, which when activated leads to a biological response. Why do receptors exist? To serve endogenous chemical mediators ( neurotransmitters, hormones etc). (Note: Exogenous drugs merely fit receptors by chance or are custom-designed to fit)
CHARACTERISTICS OF CLASSICAL RECEPTORS Structural specificity: Drug interacts with receptor in lock and key manner (Basis for structure-activity relationship) Optical specificity: Optical isomers of active drug may be inactive Saturability: High concentrations of a drug saturates the receptors. Receptor number finite. Dynamic expression: Receptors can be up - or down - regulated Response: Activation of a receptor result in biological response
Drug-Receptor Interaction ))Lock and key Agonist
Antagonist
Receptor Response
No Response Drug X
Receptor
No fit, no response
TYPES OF RECEPTOR COUPLING
As part of ion channel (eg nicotinic Rec.)
Connected via G-proteins (e.g. adrenoceptors)
Have direct enzyme activity (e.g. insulin receptor)
Directly activates enzymes (kinases) (e.g. cytokines)
Directly controls DNA transcription
RECEPTOR COUPLING MECHANISMS
Do all drugs have to act through ?receptors
DRUGS THAT DEPEND ON NON-SPECIFIC PHYSICOCHEMICAL MECHANISMS PROPERTY
DRUG EXAMPLES
Possession of osmotic properties
Osmotic laxatives
Neutralization of acid
Antacids
Precipitation of proteins
Silver compounds
Formation of protective barriers
Glycerol
Adsorptive Properties
Natural fibers, Kaolin
Radioactivity
Radioactive iodine
MEASUREMENT OF DRUG EFFECT Graded Response Small increment in dose causing corresponding increase in effect. Quantal Response (Yes or No Response) Drug effect measured on all or none basis (eg sleep, death, convulsion) in a population.
Information Obtainable From A Dose-Response Curve
ED50: The dose of a drug that produces 50% of the desired effect. LD50: The dose that results in the death of 50% of the test organism. Therapeutic index (TI): Ratio of LD50 to ED50. It is a measure of safety margin of a drug (compare penicillin with digoxin). Emax: Maximum effect produced by the drug on a given tissue - a measure of efficacy of a drug.
Quantal Dose-Response Curves
SPECIFIC LEARNING OBJECTIVES 1. Appreciate the molecular nature of drugs and receptors. 2. Define and differentiate therapeutic effect, side effect, adverse effect, toxic effect and idiosyncrasy. 3. Classify the different binding sites for drugs. 4. Describe the different types of receptor coupling, with examples. 5. Understand the meaning and significance of ED50, LD50 and therapeutic index.
THE DOSE-RESPONSE CURVE
Sigmoid curve
Hyperbolic curve 125 Emax
100
% Response
% Response
125
75 50 25 0
ED50 0
25
50
75
100
Concentration
125
Emax
100 75 50 25 0
ED50 -9
-8
-7
-6
-5
-4
Log Concentration
-3
TARGETS OF DRUG ACTION Typical Receptors Acetylcholine receptor Insulin receptor
Bethanechol Insulin
Ion Channels Voltage-gated sodium channel Calcium channels
Local anaesthetics Nifedipine
Enzymes Acetylcholinesterase Xanthine oxidase
Neostigmine Allopurinol
Carriers (Transport systems) Noradrenaline uptake 1 Weak acid carrier
Cocaine Probenecid
DEFINITIONS Pharmacology: A study of the interaction of drugs with living tissues/organisms Toxicology: Aspect of Pharmacology dealing with undesirable effects of drugs Drug: Any chemical substance that alters the body’s function Pharmacodynamics: What the drug does to the body (drug actions) Pharmacokinetics: What the body does to the drug (absorption, metabolism, excretion)
NATURE OF DRUGS Drugs vary widely with respect to: a. Molecular size b. Structure and configuration (including isomers) c. Chemical nature (reactive/inert; weak acid/base) d. Sources (synthetic, natural products)
CLASSIFICATION OF DRUG EFFECTS Therapeutic Effect: Side Effect:
Any effect other than desired one
Adverse Effect: Toxic Effect:
Desired Effect
Side effect that is harmful
Adverse effect resulting from high (toxic) dose Idiosyncrasy: Abnormal response to a drug occurring only in a minority of individuals
DRUG RECEPTORS Definition: A receptor is a specific binding site for a drug on or within the cell, which when activated leads to a biological response. Why do receptors exist? To serve endogenous chemical mediators ( neurotransmitters, hormones etc). (Note: Exogenous drugs merely fit receptors by chance or are custom-designed to fit)
CHARACTERISTICS OF CLASSICAL RECEPTORS Structural specificity: Drug interacts with receptor in lock and key manner (Basis for structure-activity relationship) Optical specificity: Optical isomers of active drug may be inactive Saturability: High concentrations of a drug saturates the receptors. Receptor number finite. Dynamic expression: Receptors can be up - or down - regulated Response: Activation of a receptor result in biological response
Drug-Receptor Interaction ))Lock and key Agonist
Antagonist
Receptor Response
No Response Drug X
Receptor
No fit, no response
TYPES OF RECEPTOR COUPLING
As part of ion channel (eg nicotinic Rec.)
Connected via G-proteins (e.g. adrenoceptors)
Have direct enzyme activity (e.g. insulin receptor)
Directly activates enzymes (kinases) (e.g. cytokines)
Directly controls DNA transcription
RECEPTOR COUPLING MECHANISMS
Do all drugs have to act through ?receptors
DRUGS THAT DEPEND ON NON-SPECIFIC PHYSICOCHEMICAL MECHANISMS PROPERTY
DRUG EXAMPLES
Possession of osmotic properties
Osmotic laxatives
Neutralization of acid
Antacids
Precipitation of proteins
Silver compounds
Formation of protective barriers
Glycerol
Adsorptive Properties
Natural fibers, Kaolin
Radioactivity
Radioactive iodine
MEASUREMENT OF DRUG EFFECT Graded Response Small increment in dose causing corresponding increase in effect. Quantal Response (Yes or No Response) Drug effect measured on all or none basis (eg sleep, death, convulsion) in a population.
Information Obtainable From A Dose-Response Curve
ED50: The dose of a drug that produces 50% of the desired effect. LD50: The dose that results in the death of 50% of the test organism. Therapeutic index (TI): Ratio of LD50 to ED50. It is a measure of safety margin of a drug (compare penicillin with digoxin). Emax: Maximum effect produced by the drug on a given tissue - a measure of efficacy of a drug.
Quantal Dose-Response Curves
SPECIFIC LEARNING OBJECTIVES 1. Appreciate the molecular nature of drugs and receptors. 2. Define and differentiate therapeutic effect, side effect, adverse effect, toxic effect and idiosyncrasy. 3. Classify the different binding sites for drugs. 4. Describe the different types of receptor coupling, with examples. 5. Understand the meaning and significance of ED50, LD50 and therapeutic index.
THE DOSE-RESPONSE CURVE
Sigmoid curve
Hyperbolic curve 125 Emax
100
% Response
% Response
125
75 50 25 0
ED50 0
25
50
75
100
Concentration
125
Emax
100 75 50 25 0
ED50 -9
-8
-7
-6
-5
-4
Log Concentration
-3
TARGETS OF DRUG ACTION Typical Receptors Acetylcholine receptor Insulin receptor
Bethanechol Insulin
Ion Channels Voltage-gated sodium channel Calcium channels
Local anaesthetics Nifedipine
Enzymes Acetylcholinesterase Xanthine oxidase
Neostigmine Allopurinol
Carriers (Transport systems) Noradrenaline uptake 1 Weak acid carrier
Cocaine Probenecid
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