Dose Resonse Relationships Flashcards
EC50 or ED50
Potency, drug concentration the produces fifty percent of maximal effect
Potency does not equal Kd
Receptor occupancy equation
[DR] = R_t [D] / K_d + [D]
Similar terms to Michaelis-Menten description of an enzymatic reaction for binding of ligands
Assumptions: one drug combines one receptor, all receptors are identical and equally accessible, effective drug concentrations does not change during binding, the magnitude of responses is proportional to the number of receptors occupied
Efficacy
The capacity of drugs to excite
Ability to change/activate a receptor
Affinity
Capacity of drugs to bind
Response observed depends on
Density of receptors
Amount of downstream signaling proteins
Amplification of signal between signaling cohorts
Maximal effect
Activation of less than the full amount of cell surface receptors
May activate all the available G protein and thus produce a maximal signaling effect
Less than full receptor occupancy
Signal amplification
Occupancy of a low percentage of the total receptors produces maximal activation of downstream signaling proteins
Left shift each curve
Competitive antagonism
Agonist surmountable antagonism
Need more amount of agonist to overcome the competitive antagonist
DRC is the same but shifted to the right with increasing antagonist amount
Degree of response depends on the extent of receptor occupied by agonist equal agonist occupancies in the absence or presence of antagonist old produce equal responses
High recent age of FDA drugs
Keeps the same maximal effect but change in efficacy
Noncompetitive antagonism
Insurmountable antagonism
Antagonism binds irreversibly to the receptor binding pocket, covalent
Antagonist binds elsewhere to allosterically inhibit binding or function
Decreases the maximal effect, may be no change in potrncy
Inverse agonism
Receptors exist in either an inactive basal state or chive conformation
Favor inactive states
Bind to inactive state
Inhibit basal activity of the cell, ie the activity of receptors that occur independently of activation by the neurotransmitter or hormone ago ist
Negative antagonist
Agonists
Favor the active state
Produce an effect from the receptor
Quantal responses
All or none sort of responses
Dose response curves relate the frequency at which a given dose gives an all or none effect
ED50-mean effective dose, dose at which 50% would exhibit the specified quantal effect
Pharmacodynamic variability
Slope on the cumulative frequency is an expression of the pharmacodynamic variation
If a population was more diverse, would be more flat as there is a higher range
Clinical efficacy and irrelevance of potency
Can be potent but produce a low clinical effect
The potency is pointless here
Therapeutic index
ED50–mean therapeutic dose or effective dose
LD50–men lethal dose, toxic dose TD50
Therapeutic index = LD50 / ED50
If this value was one, two curves would overlap, problem
Want LD50 to be higher
