1. DRUG-RECEPTOR INTERACTIONS
CHAPTER I: SIGNAL TRANSDUCTION
Asst. Prof. Dr. Emre Hamurtekin
EMU Faculty of Pharmacy

2. RECEPTOR FAMILIES LIGAND-GATED ION CHANNELS
G PROTEIN-COUPLED RECEPTORS
ENZYME-LINKED RECEPTORS
INTRACELLULAR RECEPTORS

3. RECEPTOR FAMILIES

4. TRANSMEMBRANE LIGAND-GATED ION CHANNELS
These are responsible for regulation of the flow of ions across cell membranes.
Response to these receptors is very rapid.
Have role in;
neurotransmission
cardiac conduction
muscle contraction etc...
Cholinergic nicotinic receptors is an example to these type of receptors.

7. G PROTEIN-COUPLED RECEPTORS
They are made of a single α – helical peptide that has seven membrane spanning regions.

8. G PROTEIN-COUPLED RECEPTORS

9. Second Messengers cAMP cGMP Ca DAG IP3
Essential in conducting and amplifying signals from G-protein coupled receptors.
cAMP
cGMP Ca
DAG
IP3

10. cAMP

11. cAMP

13. IP3 and DAG

15. 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.
Metabolism
Growth
Differentiation
Duration of responses to stimulation
important functions controlled by these receptors.
Most Common Enzyme-Linked Receptors
EGF
PDGF tyrosine kinase activity
ANP
Insulin
minutes to hours

16. INSULIN RECEPTOR

18. INTRACELLULAR RECEPTORS
Receptor 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 proteins
Steroid 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.

20. DRUG-RECEPTOR INTERACTIONS
CHAPTER II: DOSE-RESPONSE RELATIONSHIPS
Asst. Prof. Dr. Emre Hamurtekin
EMU Faculty of Pharmacy

21. GRADED DOSE-RESPONSE RELATIONS
As the concentration of a drug increases, the magnitude of its pharmacological effect also increases.

22. GRADED DOSE-RESPONSE RELATIONS
Two important properties of drugs can be determined by graded-dose response curves;
POTENCY
EFFICACY
POTENCY:
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 (EC50)

23. POTENCY

24. GRADED DOSE-RESPONSE RELATIONS
EFFICACY:
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.

25. EFFICACY

27. 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 affinity
Low Kd: strong interaction-high affinity
As the concentration of free drug increases, the ratio of the concentrations of bound receptors to total receptors approaches unity. =

28. DRUG BINDING and PHARMACOLOGIC EFFECT
[E] [D]
[Emax] Kd+[D]
ASSUMPTIONS:
Binding exhibits no cooperativity.
Magnitude of the response is proportional to the amount of bound receptors.
Emax occurs when all receptors are bound. =

29. AGONISTS
An agonist binds to a receptor and produces a biological response.
Full agonists
Partial agonists
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.
phenylephrine
α-1 adrenoceptors BP
rises Ca

30. PARTIAL AGONIST
Partial 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.

32. INVERSE AGONIST
They 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.

33. INVERSE AGONIST

34. ANTAGONISTS
Antagonists 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 antagonists
Non-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.
Covalent binding to the active site of the receptor
Allosteric binding

35. ANTAGONISTS

36. FUNCTIONAL and CHEMICAL ANTAGONISM
Functional (physiological) antagonism: An antagonist may act at a completely separate receptor initiating effects that are functionally opposite those of the agonist.
Example: Histamine vs. Epinephrine on bronchioles
Chemical antagonism: Prevents the actions of an agonist by modifying or sequestering the agonist, thus agonist can not bind and activate its receptor.
Example: Heparine (acidic)vs. Protamine sulphate (basic)

37. 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

38. THERAPEUTIC INDEX (TI)