Lecture 1 Pharmacodynamics
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Transcript of Lecture 1 Pharmacodynamics
PharmacodynamicsPharmacodynamics
Dr Rizwan Ashraf
Lecture Objectives Lecture Objectives To understand the basic concepts regarding pharmacodynamics To define agonist and antagonists and other terms in relation to pharmacodynamics To explain the mechanism of drug receptor interaction Define spare receptors To differentitate between different tyes of antagonism
WHAT IS PHARMACODYNAMICS ?
Action of a drug on the body receptor interactions, mechanisms of therapeuticdose-response phenomena, toxic action.
RECEPTOR INTERACTION
A drug will not work unless it is bound
AGREED or NOT AGREED
BOUND WITH WHAT ?
PARTICULAR CONSTITUENTS OF
CELLS & TISSUES IN ORDER TO
PRODUCE AN EFFECT
PROTEINS LIPIDS DNA
RECEPTORS ?
ARE THERE DRUGS THAT ACT WITHOUT ARE THERE DRUGS THAT ACT WITHOUT BEING BOUND TO ANY OF THE TISSUE BEING BOUND TO ANY OF THE TISSUE
CONSTITUENTSCONSTITUENTS
YES OR
NO
YESYES
OSMOTIC DIURETICSOSMOTIC PURGATIVESANTACIDSHEAVY METALS CHELATING AGENTS
BUTBUT
PRINCPLES REMAIN TRUE FOR GREAT MAJORITY
THAT IS _____________________
______________________________.
Most drugs act through Most drugs act through ReceptorsReceptors
Receptors Receptors
Drug ReceptorDrug Receptor
A macromolecular component of a cell with which a drug interacts to
produce a response
Usually a protein
Receptors must be biologically important molecules
Receptors must have structural features that permit drug specificity
Receptors must have a drug-binding site and a biologically active site
Characteristics of ReceptorsCharacteristics of Receptors
a. specificity a. specificity
b. selectivity of response b. selectivity of response
c. sensitivity c. sensitivity
Molecules capable of serving Molecules capable of serving as as
ReceptorsReceptors
Enzymes
Membrane proteins
glycoproteins, lipoproteins)
Nucleic acids
Complex polysaccharides
Many drugs inhibit enzymes
in the patient (ACE inhibitors)
in microbes (sulfas, Penicillins)
in cancer cells (5-FU, 6-MP)
Types of ProteinTypes of Protein Receptors Receptors
Regulatory – mediate the action of endogenous chemicals e.g. hormones,
NT,autocoids
Enzymes – may be inhibited or activated e.g. dihydrofolate reductase
receptor for methotrexate
Transport – e.g. Na+ /K+ ATP’ase for digitalis glycosides
Structural – e.g. tubulin,receptor for colchicine
some drugs bind to:
the genome (cyclophosphamide)
microtubules (vincristine)
Non-receptor Mediated EffectsNon-receptor Mediated Effects Interaction with small molecules
(e.g. binding of heavy metals)
Interaction with enzymes (e.g. sulfonamides, digitalis)
Incorporation into a macromolecule (e.g. some anticancer agents - purine and
pyrimidine analogues)
Nonspecific effects (e.g. membrane perturbation by general anesthetics)
Receptor-independent drug actionsReceptor-independent drug actions Chemically reactive agents
Disinfectants
Alkylating anticancer drugs
Physically active agents
Mannitol
Hydrogen peroxide
Counterfeit biochemical constituents
5-bromouracil
Antagonists tend to up regulate receptors
Receptor regulationReceptor regulation
1.1. HomeostasisHomeostasis 2. Up and down regulation 2. Up and down regulation
3. Desensitization 3. Desensitization
4. Tolerance 4. Tolerance
agonists desensitize receptors homologous
(decreased receptor number)
heterologous
(decreased signal transduction
PharmacodynamicsPharmacodynamics
Drug receptor interactionDrug receptor interaction
D + R DR Complex
Drug - Receptor BindingDrug - Receptor Binding
Affinity
Drug Receptor InteractionDrug Receptor Interaction
DR Complex Effect
Theories of the Theories of the relationship between relationship between binding and responsebinding and response
a. Occupation theorya. Occupation theory
D + R D + R DR DR RESPONSE RESPONSE:response is proportional to the fraction of occupied :response is proportional to the fraction of occupied receptors receptors :maximal response occurs when all the receptors are occu:maximal response occurs when all the receptors are occupiedpied
AriensAriens
response is proportional to the fraction of response is proportional to the fraction of occupied receptors occupied receptors ANDAND the the intrinsic activity intrinsic activity
Stephenson Stephenson response is aresponse is a FUNCTION FUNCTION of occupancy of occupancy maximum response can be produced maximum response can be produced WITHOUT 100% occupation, WITHOUT 100% occupation,
i.e. tissues havei.e. tissues have spare receptorsspare receptors
BIOLOGICAL STIMULUSBIOLOGICAL STIMULUS
PERCENT RECEPTOR OCCUPANCYPERCENT RECEPTOR OCCUPANCY
0%0% 100%100%
BIOLOGICAL RESPONSEBIOLOGICAL RESPONSE RECEPTOR RESERVERECEPTOR RESERVETRETHOLDTRETHOLD
0%0% 100%100%
Max EffectMax EffectThreshold EffectThreshold Effect
Schematic representation of the relationship between threshold, receptor Schematic representation of the relationship between threshold, receptor reserve, receptor occupancy, biological stimulus and biological responsereserve, receptor occupancy, biological stimulus and biological response
Receptors are said to be spare
for a given pharmacological response
when the maximal response can be elicited
by an agonist at a concentration that does
not result in occupancy of the full complement
of available receptors
Spare receptors More receptors available than needed
to elicit maximum responseallow maximal response without total receptor occupancy – increase sensitivity of the system
Agonist has to bind only a portion of
receptors for full effect
Some terminologies regarding Some terminologies regarding drug receptor interactiondrug receptor interaction
Affinity
Efficacy
Potency
Ligand
Affinity: measure of propensity of a drug to bind receptor; the attractiveness of drug and
receptor
Efficacy: Potential maximum therapeutic response
that a drug can produce.
Potency: Amount of drug needed to produce an
effect.
POTENCY
OR
EFFICACY
Which one is important while selecting a drug for therapy ?
Ligand:
Molecules that binds to a receptor
Classification of Ligands Classification of Ligands
a.a. agonist agonist
b. partial agonistb. partial agonist
c. antagonist c. antagonist
pharmacological vs. physiological vs. chemical pharmacological vs. physiological vs. chemical
pharmacological antagonistspharmacological antagonists
- - competitive competitive
surmountable surmountable
- - noncompetitive noncompetitive
AGONIST
AgonistsAgonists Drugs that cause a response Drugs that interact with and activate receptors; They possess both affinity and efficacyTypes Full agonists
An agonist with maximal efficacy (response) has affinity plus intrinsic activity Partial agonists
An agonist with less then maximal efficacy has affinity and less intrinsic activity
Agonists differing in potency and maximum efficacy
Response
Dose
Full agonist
Partial agonist
Agonist Dose Response Curves
[D] (concentration units)
% M
axim
al E
ffec
t
0.01 0.10 1.00 10.00 100.00 1000.000.0
0.2
0.4
0.6
0.8
1.0
Partial agonist
Full Agonist
Partial agonist
PARTIAL AGONISTS - EFFICACYEven though drugs may occupy the same # of receptors, the magnitude
of their effects may differ.
AntagonistsAntagonists Interact with the receptor but do NOT change the receptor
Have affinity but NO efficacy
Block the action of other drugs
Effect only observed in presence of agonist
Types of AntagonistsTypes of Antagonists
Competitive
(Surmountable)decrease apparent
Potency
Noncompetitivedecrease
apparent maximum
efficacy
Competitive AntagonistCompetitive Antagonist
competes with ________for receptor
surmountable with increasing agonist concentration
displaces agonist dose response curve to the ___________(dextral shift)
reduces the apparent affinity of the __________.
Noncompetitive AntagonistNoncompetitive Antagonist
drug binds to receptor and stays boundirreversible – does not let go of receptor
produces slight dextral shift in the agonist DR curve in the low concentration range
but, as more and more receptors are bound (and essentially destroyed),
the agonist drug becomes incapable of eliciting a maximal effect
AGONIST VS ANTAGONIST
What happen when you increase agonist concentration even higher
How do non competitive antagonist affect receptor function
Summary (T or F)
Pharmacodynamics is the study of absorption, distribution, metabolism and elimination of drug. Some drugs can act without binding to a receptor spare receptors allow maximum response without full receptor occupancy Efficacy is the amount of drug needed to produce an effect. Affinity is the attractiveness between 2 drug molecules. Agonist are the drugs that block the response. Partial agonist has affinity and maximum efficacy. Antagonist has efficacy but no affinity. Competitive antagonist decreases potency Non competitive antagonist decreases efficacy