Asst. Prof. Dr. Emre HamurtekinEMU Faculty of Pharmacy

DRUG-RECEPTOR DRUG-RECEPTOR INTERACTIONSINTERACTIONS

CHAPTER I: SIGNAL TRANSDUCTIONCHAPTER I: SIGNAL TRANSDUCTION

RECEPTOR FAMILIESRECEPTOR FAMILIES

1. LIGAND-GATED ION CHANNELS

2. G PROTEIN-COUPLED RECEPTORS

3. ENZYME-LINKED RECEPTORS

4. INTRACELLULAR RECEPTORS

RECEPTOR FAMILIESRECEPTOR FAMILIES

TRANSMEMBRANE LIGAND-GATED ION TRANSMEMBRANE LIGAND-GATED ION CHANNELSCHANNELS

These are responsible for regulation of the flow of ions across cell membranes.

Response to these receptors is very rapid.Have role in;

neurotransmissioncardiac conductionmuscle contraction etc...

Cholinergic nicotinic receptors is an example to these type of receptors.

G PROTEIN-COUPLED G PROTEIN-COUPLED RECEPTORSRECEPTORS

They are made of a single α – helical peptide that has seven membrane spanning regions.

G PROTEIN-COUPLED G PROTEIN-COUPLED RECEPTORSRECEPTORS

DAGCa

Second MessengersEssential in conducting and amplifying signals

from G-protein coupled receptors.

cAMP cGMP IP3

cAMP

cAMP

IP3 and DAG

ENZYME-LINKED RECEPTORS Spans the membrane once and may form dimers. These receptors also have cytosolic enzyme activity as an

integral component of their structure.MetabolismGrowth Differentiation

Duration of responses to stimulation

minutes to hours

important functions controlled by these receptors.

Most Common Enzyme-Linked Receptors•EGFEGF•PDGF PDGF tyrosine kinase tyrosine kinase activityactivity•ANPANP•InsulinInsulin

INSULIN RECEPTOR

INTRACELLULAR RECEPTORSReceptor is entirely intracellular.Ligand must have sufficient lipid solubility.Ligands are mostly attached to plasma proteins

in the blood circulation.Primary targets of these ligand-receptor

complexes are transcription factors.DNA RNA proteinsSteroid hormones exert their effects by this

receptor mechanism.Time course of activation and duration of the

response is much longer than the other type of receptors.

Asst. Prof. Dr. Emre HamurtekinEMU Faculty of Pharmacy

DRUG-RECEPTOR DRUG-RECEPTOR INTERACTIONSINTERACTIONS

CHAPTER II: DOSE-RESPONSE RELATIONSHIPSCHAPTER II: DOSE-RESPONSE RELATIONSHIPS

GRADED DOSE-RESPONSE RELATIONSAs the concentration of a drug increases,

the magnitude of its pharmacological effect also increases.

GRADED DOSE-RESPONSE RELATIONSTwo important properties of drugs can be

determined by graded-dose response curves;POTENCYEFFICACY

POTENCYPOTENCY:Measure of the amount of drug necessary to

produce an effect of a given magnitude.Concentration of drug producing an effect

that is 50% of the maximum effect (EC50EC50)

POTENCY

GRADED DOSE-RESPONSE RELATIONSEFFICACYEFFICACY:

Ability of a drug to elicit a response when it interacts with a receptor.

Efficacy is dependent on; the number of drug-receptor complexes formed efficiency of the coupling of receptor activation to cellular

responses. Maximal efficacy of a drug assumes that all

receptors are occupied by the drug and if more drugs are added, no additive response will be observed.

Maximal response (efficacy) is more important than drug potency.

A drug with greater efficacy is more therapeutically beneficial than the one that is more potent.

EFFICACY

DRUG CONCENTRATION and RECEPTOR BINDING

[DR] [D] [Rt] Kd+[D]

Kd can be used to determine the affinity of a drug for its receptor.Affinity: strength of interaction between a ligand and its receptor.High Kd: weak interaction-low affinityLow Kd: strong interaction-high affinityAs the concentration of free drug increases, the ratio of the concentrations of bound receptors to total receptors approaches unity.

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DRUG BINDING and PHARMACOLOGIC EFFECT

[E] [D] [Emax] Kd+[D]

ASSUMPTIONS: 1.Binding exhibits no cooperativity.2.Magnitude of the response is proportional to the amount of bound receptors.3.Emax occurs when all receptors are bound.

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AGONISTSAGONISTSAn agonist binds to a receptor and

produces a biological response.1. Full agonists2. Partial agonists3. Inverse agonists

Full agonist:If a drug binds to a receptor and produces a maximal biological response that mimics the response to the endogenous ligand, it is known as a full agonist.

Full agonist stabilizes the receptor in its active state. α-1 adrenoceptors

phenylephrinephenylephrine

Ca BPrises

PARTIAL AGONISTPARTIAL AGONISTPartial agonist: Have efficacies greater then

zero but less then that of a full agonist.A partial agonist may have an affinity that

is greater than, less than or equivalent to that of a full agonist.

Example: aripiprazole, an atypical neuroleptic agent.

INVERSE AGONISTINVERSE AGONISTThey produce a

response below the baseline responses measured in the absence of drug.

This decreases the number of activated receptors to below observed in the absence of the drug.

They exert the opposite pharmacological effect of receptor agonists.

INVERSE AGONISTINVERSE AGONIST

ANTAGONISTSANTAGONISTSAntagonists are drugs that decrease the actions

of another drug or an endogenous ligand.An antagonist has no effect if an agonist is not

present.Antagonists produce no effect by themselves.

Competetive antagonistsNon-competetive (irreversible) antagonists Competetive antagonists: both the antagonist and

agonist bind to the same site on the receptor.Non-competetive antagonists: An irreversible

antagonist causes a downward shift of the maximum. And can not be overcome by adding more agonist.

i. Covalent binding to the active site of the receptor

ii. Allosteric binding

ANTAGONISTSANTAGONISTS

FUNCTIONAL and CHEMICAL FUNCTIONAL and CHEMICAL ANTAGONISMANTAGONISMFunctional (physiological) antagonism: An

antagonist may act at a completely separate receptor initiating effects that are functionally opposite those of the agonist.Example: HistamineHistamine vs. EpinephrineEpinephrine on

bronchiolesChemical antagonism: Prevents the actions

of an agonist by modifying or sequestering the agonist, thus agonist can not bind and activate its receptor.Example: HeparineHeparine (acidic)vs. Protamine Protamine

sulphatesulphate (basic)

THERAPEUTIC INDEX (TI)THERAPEUTIC INDEX (TI)It is the ratio of the dose that produces

toxicity to the dose that produces effective response.

TI = TD50 / ED50

Therapeutic index is a measure of drug safety

Small therapeutic index: Warfarin

Large therapeutic index: Penicilin

THERAPEUTIC INDEX (TI)THERAPEUTIC INDEX (TI)