PD Principles: Drug-Receptor Interactions and Dose Response Curves; Part 2 Flashcards
General Principle of Drug-Receptor Interactions:
***Lock and Key***
• ***The intensity and duration of a drug’s effects are a function of the drug dose and drug concentration at the site of action
o [Drug] at the site of action is a function of dose administered
o Response magnitude is a function of [drug] at the site of action***
**Most Drug-Receptor Interactions (i.e. binding) are REVERSIBLE
Why do we need to quantify the drug-receptor relationship?
o Helps us compare the potency and efficacy of different drugs
o Facilitate comparisons of alternative medications for the same indication.
o Helps us predict the effects of changing the dose. o Helps us determine the dose range for patients
• Therapeutic window and avoid toxic effect
How do we quantify drug-receptor relationships?
o Drug/ Dose or concentrations Binding Curves (DBC or CBC)
o Drug/ Dose or concentration Response Curves (DRC or CRC)
- Graded dose-response curves
- Quantal dose-response curves
Dose - Binding Curves:
Basis:
Just measures the receptor occupancy, NOT effect
Dose - Binding Curves:
What do they tell us?
o Affinity of the drug (Kd)
• The lower Kd =
o the higher the affinity = higher the potency
o Total number occupied by the drug (Bmax)
Dose - Response Curve
***Endpoints***
• Graded
o Continuous scale (dose→Response(effect))
o Measured in a single biologic unit
o Relates dose to intensity of effect
• Quantal
o Binary scale (All-or-none pharmacologic effect)
o Population studies
o Relates dose to frequency of effect
Dose - Response Curve
***What do they tell us?***
• Efficacy (Emax)
o Effectiveness of a drug
Maximum effect/response produced by the drug
Determined by the height of the response
o Agonist, partial agonist, antagonist, inverse agonist
• Potency (EC50)
o Dose of drug
Concentration of a drug that produces 50% of
the maximum response
Lower EC50 , greater the potency
1) Morphine
2) Aspirin
Dose - Response Curve
***Two state model***
Full Agonist: shifts equilibrium “fully” to the active receptor conformation
Partial Agonist: Shift equilibrium “partially” to the active conformation
o ↓ efficacy
Antagonist:
o Competitive
- Bind agonist site
- Does NOT shift equilibrium (neutral)
o Non-Competitive:
• Allosteric vs Irreversible
Inverse agonist:
o Shifts equilibrium towards the inactive receptor conformation
***Drug Agonist in combination with Antagonists***
• Competitive antagonist:
Shifts DRC to the RIGHT
↑EC50only=↓Potency
Efficacy is Unchanged
• Non-Competitive:
o Allosteric antagonist:
- Shifts DRC DOWN
- ↓Emaxonly=↓Efficacy
- Potency is Unchanged
o Irreversible antagonist:
• Initially, shifts DRC to the right
o ↑ EC50 = ↓ Potency
o ↓Emax = ↓ Efficacy
• Net effect: ↑ EC50 and ↓Emax
Dose - Response Curve (DRC)
Agonists and Antagonists
Dose - Response Curve (DRC)
***Drug Safety and Therapeutic Window***
• The greater the TI,
o the greater the therapeutic index = the greater the therapeutic window
