Pharmacodynamics- Drug Receptor Interactions Flashcards
Binding site
Can bind a substance but are not themselves capable of initiating a subsequent response
Receptors
Can bind a substance and are capable of initiating a subsequent response
Receptor fractional occupancy
Dependent only on the drug’s affinity and concentration (or dose)
Kd
Equilibrium dissociation constant
Koff/Kon
Measure of drug’s propensity to bind to a given receptor (aka AFFINITY). More affinity, lower value
Dose-response relationship
Correspondence between the amount of drug and the magnitude of the effect
Increasing the dose, increases the effect in a graded manner
Potency
Concentration or dose of drug needed to produce 50% of that drug’s maximal response
EC50 or ED50 value
Depends on affinity for receptor and efficiency with which the receptor activation is coupled to response
Maximal efficacy
Maximal response produced by the drug
Competitive antagonism
Surmountable
Shift to the right in DR curve
Increase in ED50
No change in Emax
Non-competitive antagonism
Insurmountable
Decrease in Emax
No change in ED50
Quantal dose response curve
Relationship between drug dose and a specified effect in a population of individuals
Can determine median effective dose
Therapeutic Index
TI = Toxic Dose50/ Effective Dose50
Therapeutic Window
Dosage range between minimum effective therapeutic dose and minimum toxic dose
Pharmacophore
Drug recognition site on receptor
Ligand-Regualted Transmembrane Enzyme Receptors
ie Protein Tyrosine Kinase
Polypeptides that cross membrane once
Phosphorylate tyrosines or serines on various downstream proteins
Autophosphorylation of tyrosines on receptor’s cytoplasmic side can intensify/prolong the duration of activations
Ex of substances: insulin, EGF, ANF
Cytokine Receptors
Resemble tyrosine kinase receptors but utilize a SEPARATE protein tyrosine kinase that binds non-covalently and is NON-INTRINSIC to the receptor
The protein can then dissociate and travel to nucleus to regulate gene transcription
Ligand-Gated Channel Receptors
Ie Nicotinic Cholinergic Receptor
Drug binds to subunit and produce a conformational change and opens the channel
Allows ions or substances to pass into the cell
Very fast
G-Protein Linked Receptors
Single polypeptide chain that transverse membrane 7 times
3rd intracellular loop regulates the ability to interact with specific G-proteins (activation of G protein conveys effects of drug to 2nd messenger enzymes)
Carboxyl terminus contain serine residues that can be phosphorylated and regulate receptor function
Activation of Adenylyl Cyclase
- Multiple G proteins activated
- Activation of catalytic units of adenyl cyclase
- Conversion of ATP to cAMP
- cAMP activates multiple cAMP dependent kinases (PKA)
- PKA phosphorylates multiple downstream proteins
- Amplified final response
Activation of Phosphoionositide Hydrolysis Pathway
IP3 and DAG
- Multiple G proteins activated
- Activation of catalytic units of Phospholipase C
- Conversion of PIP2 to TWO second messengers DAG and IP3
- DAG activates multiple PKC enzymes (>9)
- Multiple PKCs phosphorylate various downstream proteins
- IP3 release of large intracellular stores of Ca2+
- Ca2+ activates multiple Calmodulin dependent kinases (PKA)
- Multiple PKAs phosphorylate multiple downstream proteins
- HIGHLY AMPLIFIED/DIVERSE FINAL RESPONSE
Tachyphalaxis
Rapid development of diminished responsiveness to a drug
Pharmacodynamic Tolerance (desensitization)
Decreased responsiveness to hormonal stimulation that occurs SLOWLY over time
Desensitization is NOT restricted to only the receptor population activated by the drug (think about heterlogous desensitization)
Supersensitivity
Compensatory receptor mechanism where loss of activity on receptors leads to an increase in receptor density and/or enhanced receptor-effector coupling
