drug receptors and pharmacodynamics.pptx

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


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


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


Types of drug receptors Regulatory proteins (mediate action of

endogenous chemical signals) Enzymes Transport proteins (ion channels) Structural proteins (tubulin)


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


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


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


Schild Equation

Used primarily to determine Ki (dissociation constant)


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)


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


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

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


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


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


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)


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


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


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


Chemical antagonism A drug that chemically binds an agonist

drug and prevents it from acting on its receptors is a chemical antagonist


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

drug receptors and pharmacodynamics.pptx

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