drug receptors and pharmacodynamics.pptx
DESCRIPTION
lecture on pharmacodynamicsbased on basic and clinical pharmacology by katzungTRANSCRIPT
DRUG RECEPTORS & PHARMACODYNAMICS
Prepared by:Abraham Daniel C. Cruz, MDInstructor A, Department of Pharmacology, FEU-NRMF Inst. of MedicineMS (Candidate) Pharmacology, UP – Manila College of Medicine(1° Reference – Basic and Clinical Pharmacology by Katzung)
Learning Objectives
By the end of the lecture, the student should be able to:
▪ Understand basic principles of receptor pharmacology and types of drug-receptor interactions (agonist and antagonist)
▪ Correlate drug dose and biologic response using the graded and quantal dose-response curves
▪ Describe the different receptor types and the specific mechanisms of signalling and regulation that result in a biologic response
▪ Describe the different factors that cause variations in drug response
The Receptor Concept
Receptors component of a cell or organism that interacts
with a drug and initiates the chain of events leading to the drug’s observed effects
Focus of drug effects and mechanisms of action Applicable in:
▪ endocrinology, immunology, molecular biology to explain biologic regulation
▪ Drug development and clinical decision making Key to understanding drug action and
clinical uses
The Receptor Concept
largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects affinity for drug binding determines the concentration required to form
a significant number of drug-receptor complexes total number of receptors may limit the maximal effect of a drug
responsible for selectivity of drug action molecular size, shape, and electrical charge of a drug - determine
whether—and with what affinity—it will bind to a particular receptor changes in the chemical structure of a drug – can increase or decrease
a new drug's affinities for different classes of receptors alterations in therapeutic and toxic effects
mediate both pharmacologic agonist and antagonist action Agonists - activate the receptor to signal as a direct result of binding to
it or through indirect means
Direct vs. Indirect Agonists/Antagonists
Direct – bind to receptors directly Indirect
Increase or decrease concentration of endogenous ligands
May bind to:▪ Enzymes (synthesis or metabolism)▪ Transport proteins
The Receptor Concept
Pharmacologic antagonists Bind to receptors but do not activate the
generation of a signal interfere with agonist to activate the receptor▪ Prevent agonist binding▪ Suppress basal signalling (“constitutive”)
activity of receptors
Macromolecular Nature of Drug Receptors
Proteins/polypeptides – diverse; specific shape and electrical charge
Identification process Old – drug binding purify and identify receptors
from tissue extracts New – molecular biology and gene sequencing
predict structure or sequence homology to other known receptors (structure – activity relati0nship) drug development▪ Discoveries
▪ Many drugs bind to receptors other than previously known▪ “orphan” receptors – no known ligands; target of research
Macromolecular Nature of Drug Receptors
Types of drug receptors Regulatory proteins (mediate action of
endogenous chemical signals) Enzymes Transport proteins (ion channels) Structural proteins (tubulin)
Macromolecular Nature of Drug Receptors
Determinants of the quantitative relation between drug concentration and pharmacologic response
Regulatory proteins/components for cell signaling mechanisms drug targets
Determinant of therapeutic and toxic effects in patients
Relation Between Drug Concentration and Response
Concentration-Effect Curves and Receptor Binding of Agonists
Hyperbolic Low dose –
response increment increases in direct proportion to dose (linear)
Increasing doses – response increment diminishes
Very high doses – no further increase in response
E = effect observed at concentration C
Emax = maximal response that can be produced by the drug
EC50 - concentration of drug that produces 50% of maximal effect
Concentration-Effect Curves and Receptor Binding of Agonists
Concentration-Effect Curves and Receptor Binding of Agonists
Hyperbolic action resembles the mass action law (association between two molecules [agonist + receptor] of a given affinity)
B = drug bound to receptors
C = free (unbound) drug
B max = total number of receptor sites; sites bound to the drug at infinitely high drug concentrations
Kd = dissociation constant
Concentration-Effect Curves and Receptor Binding of Agonists
Concentration-Effect Curves and Receptor Binding of Agonists
Concentration-Effect Curves and Receptor Binding of Agonists
HYPERBOLIC CURVE SIGMOID CURVE – AGONIST/DRUG CONCENTRATION IN LOGARITHMIC SCALE
Receptor-Effector Coupling Coupling – transduction process that links
receptor occupancy and pharmacologic response
Determinants of coupling efficiency: Initial conformational change (based on
structure – activity relationship)▪ full agonists – more efficiently coupled compared to
partial agonists Signal transduction
▪ biochemical events that transduce receptor occupancy to a response▪ Re== –relation to number of receptors bound; example Ion
channels▪ Non-linear – biologic response increased disproportionately to
number of receptors bound receptors linked to enzymatic signal transduction cascades
Spare Receptors
One factor for non-linear occupancy-response coupling
Maximal biologic response at agonist concentration that does not result in full occupancy of receptors
“Spareness” Temporal - Ex. G protein-coupled receptors and second
messengers▪ Elicits response AFTER drug is no longer bound to
receptors Number
▪ Affinity of agonist to receptor (Kd, dissociation constant)
▪ Degree of “spareness” total number of receptors present compared to the number required to elicit a maximal biologic response
Spare Receptors
Allows for precise evaluation of the effect of drug dosage without considering the biochemical details of the signaling response
The Kd of the agonist-receptor interaction determines the fraction of total receptors (B/Bmax) that will be occupied at a given concentration (C) of agonist (regardless of receptor concentration)
Spare Receptors
Example One cell, 4 receptors (no spare
receptors), 4 effectors ▪ Half maximal response is elicited when an
agonist binds 2 receptors (50% of receptors) One cell, 40 receptors, 4 effectors
▪ Half maximal response is elicited when an agonist binds 2 receptors (5% of receptors)
▪ Therefore: lower agonist concentration is required to reach half maximal response increased tissue sensitivity
Competitive and Irreversible Antagonists
Receptor Antagonists Pharmacologic antagonists
▪ Bind to receptors but do not activate them▪ Prevent agonists (drugs or endogenous
molecules) from activating receptors “inverse agonists” – reduce receptor
activity below basal levels; (-) bound ligand▪ binds to the same receptor as an agonist but
induces a pharmacological response opposite to that agonist
Reversible vs. irreversible competitive antagonists
Relative Strength of Bonds Between Receptors and Drugs
BOND TYPE
MECHANISM BOND STRENGTH
van der Waals
Shifting electron density in areas of a molecule, or in a molecule as a whole, results in the generation of transient positive or negative charges. These areas interact with transient areas of opposite charge on another molecule.
+
Hydrogen Hydrogen atoms bound to nitrogen or oxygen become more positively polarized, allowing them to bond to more negatively polarized atoms such as oxygen, nitrogen, or sulfur.
++
Ionic Atoms with an excess of electrons (imparting an overall negative charge on the atom) are attracted to atoms with a deficiency of electrons (imparting an overall positive charge on the atom).
+++
Covalent Two bonding atoms share electrons. ++++
Reversible Competitive Antagonists
In the presence of a fixed concentration of agonist increasing antagonist concentration
progressively inhibit the agonist response Effects can be surmounted by sufficiently
high agonist concentrations Emax remains the same for any fixed
concentration of antagonist Increases agonist concentration required
for a given degree of response Shifts concentration-effect curve to the right
Reversible Competitive Antagonists
Schild Equation
Used primarily to determine Ki (dissociation constant)
Reversible Competitive Antagonists
Therapeutic implications degree of inhibition produced by a competitive
antagonist depends on the concentration of antagonist (ex. Interindividual variation in drug clearance)
Clinical response to a competitive antagonist depends on the concentration of agonist that is competing for binding to receptors▪ Ex. Beta-adrenoreceptor blockers vs. norepinephrine
(endogenous) blockade may be overcome in situations that increase NE (exercise, postural changes, stress)
Irreversible Antagonists
(or nearly irreversible)covalent bond or tight binding to
receptor unavailable for agonist binding
Remaining unoccupied receptors are too low to elicit a response despite high agonist levels EXCEPTION: presence of spare receptors
(but requires higher agonist doses)
Irreversible Antagonists
need not be in the unbound form to elicit a response once bound to receptors
Duration of action is dependent on the rate of turnover of receptor molecules and not its elimination rate
Advantage: prevent responses to varying high and low agonist concentrations
Disadvantage: if overdose occurs, a physiologic antagonist must be given (acts on another receptor but elicits the opposite response)
Noncompetitive Antagonists
Bind to a site on the receptor protein separate from the agonist binding site Prevent receptor activation WITHOUT
blocking agonist binding Actions are reversible if anatagonists do
not bind covalently
Allosteric Modulators
Bind on a separate site on the receptor protein and alter receptor function without inactivating receptor
Example: benzodiazepines and GABAA receptor – enhance the net activating effect of GABA on channel conductance
Partial Agonists
produce a lower response at full receptor occupancy produce concentration-effect curves that
resemble those observed with full agonists in the presence of an antagonist that irreversibly blocks some of the receptor sites
Failure to produce a maximal response is not due to decreased affinity for binding to receptors (even at high concentrations that saturate binding to all receptors)
competitively inhibit the responses produced by full agonists (Figure 2–4C)
many drugs used clinically as antagonists are in fact weak partial agonists
Other Mechanisms of Drug Antagonism
Chemical antagonism Does not involve receptors; chemical
interactions between two substances (ionic binding, etc.) that render one of the drugs unavailable for receptor binding (ex. Protamine + Heparin)
Physiologic antagonism Antagonism between endogenous regulatory
pathways mediated by different receptors Effects are less specific and less easy to control Ex. Glucocorticoids hyperglycemia; insulin
hypoglycemia
Signaling Mechanisms and Drug Action
Transmembrane Signaling
Intracellular Receptors for Lipid-Soluble Agents
Ligands – steroids (glucocorticoids, mineralocorticoids, sex steroids, vitamin D) and thyroid hormones
Stimulate transcription of genes by binding to specific target DNA sequences (response elements)
Intracellular Receptors for Lipid-Soluble Agents
Intracellular Receptors for Lipid-Soluble Agents
Therapeutic consequences Effects are produced after a lag period of
30 minutes to several hours (time required for protein synthesis) effects are NOT immediate
Effects persist for hours to days after agonist concentration has been reduced to zero due to slow turnover of newly synthesized proteins
Ligand Regulated Transmembrane Enzymes (including tyrosine kinases)
Ligands - insulin, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), atrial natriuretic peptide (ANP), transforming growth factor-alpha (TGF-alpha ), and many other trophic hormones
Ligand Regulated Transmembrane Enzymes (including tyrosine kinases)down-regulation
Limits intensity and duration of action ligands
Occurs by accelerated endocytosis and eventual degradation of receptors after ligand binding▪ Occurs faster than de novo synthesis of
receptors decreased effector cell responsiveness
Cytokine Receptors
Similar to tyrosine kinasesDifferent phosphorylation system JAK-STAT
Janus kinase family Signal transducers and activators of
transcription
Cytokine Receptors
Ligands – interleukins, luekotrienes, GH, prolactin
Ligand Gated (Ion) Channels
Natural ligands – synaptic neurotransmitters Ach, 5-HT, GABA, Glutamate
Increase transmembrane conductance of a relevant ion alters electrical potential across the membrane
May be: Directly linked G protein coupled 2nd messenger
system Regulated by phosphorylation and
endocytosis
Ligand-Gated (Ion) Channels
G Protein-Coupled Receptors and Second Messengers
For signal amplification Effect is magnified relative to drug-
receptor binding (intensity and duration) Transmembrane signaling system w/ 3
components Cell-surface receptor G-protein
▪ Changes the activity of an effector element
Effector element (enzyme or ion channel)▪ Changes the concentration of
intracellular second messenger
G Protein-Coupled Receptors and Second Messengers
G Protein-Coupled Receptors and Second Messengers
Second messengers cAMP, calcium ion, phosphoinositides
Example receptors beta-adrenoceptors, glucagon receptors,
thyrotropin receptors, and certain subtypes of dopamine and serotonin receptors
G Proteins
G Protein-Coupled Receptors 7-TM receptors seven transmembrane “serpentine”
Receptor polypeptide chain “snakes” across the plasma membrane seven times
Ligands adrenergic amines Serotonin Acetylcholine
▪ (muscarinic but not nicotinic) many peptide hormones, odorants, and even
visual receptors (in retinal rod and cone cells)
G Protein-Coupled Receptors
Regulation of G Protein-Coupled Receptors
Desensitization Β-adrenoreceptor (example) Phosphorylation of the carboxy terminal
(OH residues) after prolonged exposure to agonist▪ By G protein-coupled receptor kinases (GRKs)▪ Results in
▪ Increased binding of β-arrestin prevents receptor from binding to G protein
▪ Increased receptor endocytosis
▪ REVERSED when agonist is removed for a few minutes
Regulation of G Protein-Coupled Receptors
Regulation of G Protein-Coupled Receptors
Regulation of G Protein-Coupled Receptors
Second Messengers
Cyclic Adenosine Monophosphate
Produced by increased activity of adenylyl cyclase
mediates: mobilization of stored energy (β-adrenomimetic
catecholamines) conservation of water by the kidney
(vasopressin) Ca2+ homeostasis (parathyroid hormone) increased rate and contractile force of heart
muscle (β-adrenomimetic catecholamines regulates the production of adrenal and sex
steroids (in response to corticotropin or follicle-stimulating hormone)
relaxation of smooth muscle endocrine and neural processes
Cyclic Adenosine Monophosphate
Cyclic Adenosine Monophosphate
Termination of action After cessation of hormonal
stimulus▪ Dephosphorylation of enzyme
substrates▪ By specific and non-specific phosphatases
▪ Degradation of cAMP to 5'-AMP▪ By several cyclic nucleotide phosphodiesterases (PDE) Competitive inhibition MOA of caffeine, theophylline (methylxanthines)
Calcium and Phosphoinositides
Hormones, NT, growth factorsG protein coupled or through
tyrosine kinasesCrucial step: stimulation of
phospholipase C Splits PIP2 to
▪ DAG▪ Confined to membrane▪ Activates protein kinase C (phospholipid- and
calcium-sensitive)
▪ IP3▪ Water soluble diffuses to the cytoplasm▪ Triggers calcium ion release from storage vesicles
binds to calmodulin regulates calcium-dependent protein kinases
Calcium and Phosphoinositides
Calcium and Phosphoinositides
More complex than cAMP pathwayOne cell may contain multiple
calcium- and calmodulin-dependent kinases
Termination of action IP3 dephosphorylation DAG
▪ Phosphorylation phosphatidic acid converted back to phospholipids
▪ Deacetylation arachidonic acid Calcium actively removed by pumps
Cyclic Guanosine Monophosphate
Ligands stimulate guanylyl cyclase to produce cGMP Stimulate cGMP-dependent protein kinases
Termination of action Enzymatic degradation Dephosphorylation of kinase substrates
Examples Vascular smooth muscle relaxation (thru MLC
dephosphorylation) NO (from nitrates) activates guanylyl cyclase
vasodilation PDE inhibitors (ex. Sidenafil) inhibit cGMP
breakdown
Phosphorylation
Amplification attachment of a phosphoryl group records a
molecular memory that the pathway has been activated
dephosphorylation erases the memory takes a longer time compared ligand dissociation
Flexible regulation branch points in signaling pathways that may
be independently regulated cAMP, Ca2+, or other second messengers can
use the presence or absence of particular kinases or kinase substrates to produce quite different effects in different cell types
Drug Dose and Clinical Response
DOSE-RESPONSE RELATIONSHIPS
The response to a drug is proportional to the concentration of the receptors that are bound (occupied) by the drug
Two major types1. Graded2. Quantal
GRADED DOSE-RESPONSE RELATIONSHIPS
ASSUMPTION: response to a drug is proportional to the concentration of receptors that are bound by the drug
response = [DR] = [D]______
max response [Ro] [D] + Kd
GRADED DOSE-RESPONSE RELATIONSHIPS
Assumption: response is proportional to receptor occupancy
TWO IMPORTANT PARAMETERS: Potency (EC50) – concentration at which
the drug elicits 50% of its maximal response
Efficacy (Emax)- maximal response produced by the drug (also known as maximal efficacy)
GRADED-DOSE RESPONSE CURVES
Shows increasing responses of to increasing doses of a drug
Typical log dose-response curve
Graded Dose Response Curves for Four Drugs
QUANTAL DOSE-RESPONSE GRAPH
Graph of the fraction of a population that shows a specified response to increasing doses of drug
For evaluating an all-or-none response Ex. Prevent seizures, relief of headache,
etc.
QUANTAL DOSE-RESPONSE RELATIONSHIPS
Application – Drug Efficacy and Safety
Characterizing the Quantal-Dose Effect Curve
median effective dose (ED50) dose at which 50% of individuals exhibit the
specified quantal effect median toxic dose (TD50)
dose required to produce a particular toxic effect in 50% of animals
median lethal dose (LD50) - if the toxic effect is death of the animal
*may also give information on the potency between 2 drugs given a specified quantal response
THERAPEUTIC INDEX and THERAPEUTIC WINDOW: Evaluating Margin of Safety
TI= TD50 / ED50
Lower TI, higher probability of toxicity and loss of efficacy
Higher TI, less likely to cause adverse effects
Variations in Drug Responsiveness
Variations in Drug Response
idiosyncratic drug response Unusual, infrequently observed; due to:
▪ genetic differences in metabolism of the drug▪ immunologic mechanisms (allergic reactions)
hyporeactive or hyperreactive intensity of effect of a given dose of drug
is diminished or increased in comparison to the effect seen in most individuals
hypersensitivity allergic or other immunologic responses
to drugs
Variations in Drug Response Tolerance (relative)
intensity of response to a given dose may change during the course of therapy decreased responsiveness due to continued drug administration
Tachyphylaxis Rapid diminution of responsiveness after
administration Other factors that predict direction and
extent of variation in response age, sex, body size, disease state, genetic
factors, and simultaneous administration of other drugs.
Mechanisms of Variation in Drug Response
Alteration of drug concentration that reaches receptors PK changes due to age, sex, disease
state, kidney and liver functionVariation in concentration of
endogenous receptor ligandAlteration in function or number of
receptorsChanges in components of response
distal to the receptor
Drug-Drug Interactions
Pharmacokinetic vs Pharmacodynamic Additive
▪ 1 + 1 = 2 Potentiation
▪ 1 + 0 > 1 Synergism
▪ 1 + 1 > 2 Antagonism – as described above
Clinical Selectivity: Beneficial vs Toxic Effects
No drug causes only a single, specific effect
Drugs are only selective in their actions bind to one or a few types of receptor
more tightly than to others these receptors control discrete
processes that result in distinct effects
Beneficial and Toxic Effects
May be mediated by Same receptor-effector mechanism Same receptor but different tissue or
effector mechanism Different receptor types
Learning Objectives
By the end of the lecture, the student should be able to:
▪ Understand basic principles of receptor pharmacology and types of drug-receptor interactions (agonist and antagonist)
▪ Correlate drug dose and biologic response using the graded and quantal dose-response curves
▪ Describe the different receptor types and the specific mechanisms of signalling and regulation that result in a biologic response
▪ Describe the different factors that cause variations in drug response
SUMMARY OF PHARMACODYNAMIC PRINCIPLES
Receptor Types
Drug receptors can be divided into five groups
These groups have different locations and effects
See table below
Drug-Receptor Interactions
Most agonist (receptor-activating) and antagonist (receptor-blocking) drugs bind to their receptors with weak, reversible bonds
A few antagonists bind with strong, covalent bonds, resulting in irreversible action.
Graded Dose-Response Relationships
When an agonist drug is applied in increasing doses to a responsive system and the increments are recorded, a graded dose-response curve is observed
Binding of drugs to its receptors follows a similar curve
Graded Dose-Response Relationships
Two properties derived from this curve EC50 or ED50
▪ Concentration or dose for half-maximal effect▪ Measure of potency of the drug and its
affinity for its receptor Emax – maximum effect
▪ Measure of the maximum response that can be expected from the drug in this system
Kd and Bmax – corresponding measures for concentration-binding plots
Quantal Dose-Response Relationships
When a specific intensity or drug response is defined and the dose required to produce that intensity of response are measured in a large population of subjects, biologic variation results in a spread of these doses over a range
Quantal Dose-Response Relationships
The defined response may be a therapeutic or a toxic effect. Comparison of the median dose to produce a toxic effect versus the median dose to produce a therapeutic effect may be carried out to determine a therapeutic index (TI) TI = TD50/ED50
The therapeutic index is sometimes usedin research to compare the safety of different members of a family of drugs
Drug-Drug Antagonism
A drug that binds to a drug receptor without activating it acts as an antagonist
A drug that binds to any portion of a receptor molecule and inactivates it through a chemical action will antagonize the action of agonists
Drug-Drug Antagonism
Competitive pharmacologic antagonism Reversible binding to the receptor site
that can be surmounted by an agonist will increase the measured EC50 of the agonist drug but have no effect on the Emax (see panel A below)
Drug-Drug Antagonism
Irreversible pharmacologic antagonism Irreversible binding that cannot be
surmounted by any concentration of agonist will decrease the Emax, but will not affect the EC5o for agonists (see panel B below)
If spare receptors are present, the EC50 will be shifted to the right by low doses of the antagonist until all the spare receptors are blocked Further increases in the antagonist dose will then decrease the Emax
Drug-Drug Antagonism
Physiologic antagonism Binding of an agonist drug to a receptor
that produces effects opposite to the effects of another agonist drug acting at a second receptor
Effects on Emax and EC50 are dose- and drug-dependent
Drug-Drug Antagonism
Physiologic antagonists may be very effective and rapid acting
Ex. Epinephrine is the drug of choice for anaphylaxis Epinephine acts as a physiologic
antagonist to leukotrienes and other mediators that do not act at epinephrine receptors
Drug-Drug Antagonism
Chemical antagonism A drug that chemically binds an agonist
drug and prevents it from acting on its receptors is a chemical antagonist
Drug-Drug Antagonism
Partial agonist effect Drugs within a chemical family bind to
the same receptor but not all produce the same maximum effect (Emax)
Partial agonists - drugs that produce less than the full effect observed for that receptor system, even when given in doses that fully saturate receptors▪ Bind reversibly to the same receptors▪ Act like competitive pharmacologic
antagonists when combined with full agonists