Drug Receptors

Receptor

component of a cell or organism that interacts with a drug an initiates the chain of events leading to the drug’s observed effect

Receptors largely determine the quantitative relations between ____ or _____ of drug and pharmacological effects

Dose or concentrations

Affinity of drug for receptor determines what

The concentration f drug needed to form significant number of drug receptor complexes, and the total number of the receptors may limit the maximal effect a drug may produce

Receptors are responsible for what

The selectivity of drug action

Receptors ___ the actions of pharmacological agonists and antagonists, and dictate the biological functions to follow

Mediate

Most receptors for clinically relevant drugs are

Proteins

In the past, drug binding was used to ___ or ___ proteins from tissues extracts, and therefore receptors were discovered after the drugs that bind them

Identify; purify receptor

Advances in molecular biology and genomics has changes this and we can identify receptors by ____ on _____

prediction based; structure

Regulatory proteins

Mediate the actions of endogenous chemical signals (ie neurotransmitters)

Enzymes

Biological catalysts for specific biochemical reactions

Enzyme Examples

HMG-CoA reductase, receptor for statins

Transport proteins

Membrane bound receptors that facilitate movement of molecules across cell membranes

Transport Proteins Example

Norepinephrine and serotonin receptors, receptor for antidepressants

Structural proteins

Components of cells that provide structural support

Structural proteins example

Tubulin, receptor for colchicine (pain/inflammation)

Agonist

Substance which initiates a physiological response when combined with a receptor

In both animals or patients the response to drug at low doses ___ in direct ___ to dose

Increases; proporition

As dose increases the response…

Plateaus, meaning no further response can be attained with increasing drug

Agonist vs effect equation

E= (Emax * C)/( C + EC50)

Agonist vs effect relationship resembles the

Law of mass action and suggests that agonist act by binding or occupying, a distinct class of biological molecules with a characteristic affinity for the agonist

Law of mass action

More mass= more reaction action= response

Agonist “occupying” a receptor equation

B= (Bmax*C)/(C+Kd)

B max

The maximum concentration of receptor sites bound by drug at exceedingly high agonist concentration

Kd in the Bmax equation

The drug concentration at which half maximal binding or occupancy is achieved

Dissociation constant

Kd

Kd characterizes

The binding affinity for a given agonist/receptor relationship in a reciprocal fashion

The lower the Kd

The higher the affinity

Coupling

The overall transduction process linking receptor occupancy to response, and is determined by downstream biochemical events that transduce the occupancy into cellular response

Spare receptors concepts

Receptors are spare for a given relationship when a maximal response can be achieved at a concentration of agonist that does not result in occupancy of all available receptors

-Receptors may be spare in number or over abundant relative to the number of downstream mediators

-Maximal activation/response is elicited by activation of relatively few receptors

The Kd for a given agonist receptor interaction determines what fraction (____) of total receptors will be occupied at a given free concentration of agonist, regardless of the receptor amount

B/Bmax

B

Bound receptors

Bmax

Total receptors

C

Concentration of agonists

Anarogonists

Bind to receptors but do not active them, primarily causing reduced effects if agonists (other drugs or endogenous ligands) that normally activate a receptor

Inverse agonist

An antagonists that reduces receptor activity or response below basal levels in the bsence of any agonist

Competitive antagonist

Progressively inhibit agonist response with increasing concentration by competing for binding with agonist. Presence of an antagonist increases the concentration of an agonist need to elicit a given degree of response.

[l]

Antagonist

Inhibitory constant (Ki)

Describes the potency of an inhibitory drug relative to a given agonist receptor interaction.

Lower the Ki

Higher the potency

Degree of inhibition produced by a competitive antagonist depends on

Concentration of antagonist

Clinical responses depend on the concentration of what that is competing for binding at receptors

Agonist

Non-competitive antagonism aka irreversible antagonism

Binding of a receptor in a way that an agonist cannot surmount the inhibitory effect exerted no matter the [agonist] present.

Therapeutically irreversible antagonists may provide a distinct advantage, and sometime disadvantage. Once bound, the duration of action is ___ of its own ___ rate and more in the turnover of the drug receptor

Independent; elimination

Negative all’osteria modulation

Non-competitive binding of an receptor at a site different that the site to which the agonist binds on a given receptor, inhibiting the biological effect in a reversible manner

Positive all’osteria modulation

Same as negative, but elicit a response not inhibition of a response

Partial agonists

Produce a lower respinse at full receptor occupancy based on the max response when all receptors are occupied

Lack of maximal response=

Decreased affinity

Not all mechanisms of antagonism involve _____ of drugs or ligands at a single receptor and some types ___ involve receptors at all

Interactions; do not

Physiologic antagonism

Sometimes endogenous pathways oppose each other and can be skewed in disease. We can modulate one pathway to counteract a disturbance in the other. Are not always easy to predict/manage and responses can vary widely.