Pharmacodynamics Flashcards
Drug/receptor binding may…
1) do nothing
2) lead to undesired effect
3) lead to desired therapeutic effect
Binding reaction driven by…
Chemical/physical forces
Binding strength determined by…
Size, shape, charge, hydrophobicity etc.
Small changes can greatly change binding characteristics
Drug receptor
Site of binding and initial effect for any drug
Pre-existing receptor whose normal function is signaling in response to an endogenous ligand
Broad - Drug can bind to enzyme, structural element, DNA, protein etc.
Specific - Cell receptors bind drugs and then transduce and amplify intracellular signal that changes cell function
Agonist
Mimic endogenous ligand and activate receptor
Intrinsic activity
Antagonist
Bind receptor but do not activate it
Block agonist response
May bind with greater affinity
No intrinsic activity
Drug action
Molecular mechanism
Drug effect
Physiological change
Potency
If drug binds tightly it will be a potent modulator of activity
Amount of drug needed to produce a certain response
X axis
Lower doses have higher affinity and are more potent
Intrinsic activty
Ability to activate the receptor
Law of mass action
Drug binding to receptor is a reversible reaction
From this reaction equation an dissociation constant can be derived (Kd)
Low Kd
High affinity for the receptor
Kd
Drug concentration at which 50% of receptors are bound
As you increase concentration, there is more drug available to bind receptors until receptors reach a saturation point
EC50 or ED50
Amount of drug needed to reach 50% maximum effect
May equal Kd but usually doesn’t
Provides some measure of affinity (potency)
Drug effect is proportional to number of receptors occupied
Limitations of dose-receptor/effect curves
Not all drugs activate receptors
Sometimes activation makes it so not all receptors have to be bound to have 100% effect
Dose vs Concentration
In vitro = concentration
In vivo = dose (amount that actually reaches the receptor in unknown)
Efficacy
Capacity of a drug to produce a pharmacological response
Full agonist
Able to produce maximal response
Partial agonist
Also termed partial antagonist (takes up/compete for receptors from full agonists but also produce some level of response)
Produce any degree of efficacy between the two extremes
LDR Curve slope
Steeper slope increases risk of adverse consequences
Graded response
Any action or effect of drug that is continuously variable
Limited in its application to patients due to the great amount of variability in their ability to absorb, distribute, and metabolize the drug as well as their sensitivity to the drug
Quantal response
Specified effect or response
“yes or no”
Used to establish safety and efficacy in a large population
Cumulative frequency distribution
Quantal dose-response curve
Looks at % of total individuals experiencing quantal response at that dose or lower
Helps to compare desired effect and undesired side effect
What dose is effective for a majority of the population but has bad side effect for a low proportion of the population
LD50
Dose that kills 50% of population
More important for animal models
TD50
Dose that is toxic to 50% of the population
Some toxic effect happens at lower doses, these are listed as side effects (risk vs benefit)
More important for human trials
Drugs with high therapeutic index
Can still produce lethal effects
Minimum dose producing desired effect in 100% of population would be lethal to some members of population
Drug selectivity
No drug is “specific” but they can be selective for a receptor
Drugs can bind a subtype of receptor anywhere in the body it is found - this produces wanted effects as well as extra unwanted effects
A drug may prefer one receptor over another but at higher doses the unwanted receptor will be increasingly bound
Hyperreactive to drug
Respond to unexpectedly low dose
Hyporeactive to drug
Require unexpectedly high dose
Hypersensitive to drug
Allergic rxn
Tolerance to drug
Hyporeactivity that is acquired
Negative intrinsic activity
Antagonist can block normal response causing a decrease in activity that is seen as an effect
These drugs are efficacious but still don’t have intrinsic activity
Competitive antagonism
Most antagonists bind reversibly
Agonist must compete for open receptors
**LDR shifts to the right
High concentrations of agonist will overcome antagonist (use this concept to treat overdose)
Noncompetitive antagonism
Few antagonists bind irreversibly - function of agonist depends on how many spare receptors are left
**LDR shifts right and decrease maximum/change curve
Effects of these drugs are more prolonged
Signal transduction
A single agonist can bind several receptors and convey a different intracellular signal in each one
Amplification
Steps in the signaling cascade that multiply the intensity of the signal
Increases sensitivity of the signal and allows for points of regulation
Strong input and prolonged input and cell sensitivity
Cell decreases sensitivity and decreases number of receptors
Uncouple g-protein, desensitize ion channel, down regulate receptor formation
Diminished input and cell sensitivity
Cell increases sensitivity and increases number of receptors
If input rapidly increases, cell will go cray
