Linger Pharmacodynamics Office Mix

Question 1

Types of Drug-Receptor Interactions

Answer 1

Agonist: full, partial, or inverse

Antagonist: competitive vs. noncompetitive

Allosteric modulators: enhance or inhibit agonist action

Question 2

Receptor Occupancy Theory

Answer 2

As drug concentration increases:
Binding of drug to receptors increases until all of the receptors are occupied
Kd = the drug concentration at which half-maximal receptor binding occurs
Drug effect increases until some maximal effect occurs
EC50 = the drug concentration at which half-maximal effect occurs
Note that Kd and EC50 could be, but often are not, identical

Question 3

Concentration Versus Dose

Answer 3

Concentration is known for in vitro studies
Dose is known for in vivo studies
What is the concentration of free drug at the receptor site in the human body? (unknown)

Question 4

Efficacy vs Potency

Answer 4

Efficacy refers to the capacity of a drug to activate the receptor-effector system
Independent of binding affinity

Potency refers to the amount or concentration of drug necessary to produce a particular effect
Dependent on how tightly a drug binds the receptor (binding affinity)
Also dependent on the efficacy of drug-receptor coupling to physiologic response (intrinsic efficacy)

Question 5

EC50 or ED50

Answer 5

The concentration (or dose) or drug required to achieve half-maximal response

= potency

Question 6

Partial Agonists

Answer 6

Bind to receptors and stimulate a response
Response is less than maximal, even at high concentrations
In the absence of a full agonist, they behave like agonists and stimulate a partial response
Compete with full agonists for receptor binding
In the presence of a full agonist, they behave like competitive antagonists

Question 7

Apriprazole

Answer 7

partial agonist example for clinical relevance

Aripiprazole is a partial agonist at dopamine receptors in the brain
In the absence of full agonist, aripiprazole stimulates a partial response
When dopamine (full agonist) is present, aripiprazole can achieve only 75% functional blockade
Haloperidol is a competitive antagonist at dopamine receptors
Aripiprazole is used to treat bipolar depression and schizophrenia

Question 8

Agonist effects on efficacy

Answer 8

full agonist- max efficacy
partial agonist- not max efficacy
inverse agonist- inactivates and works in the opposite direction

Question 9

antagonist effects on potency and efficacy

Answer 9

comp. ant. affects potency, not efficacy
Noncomp. antagonist does not affect potency, does affect efficacy
Noncompetitive allosteric antagonist does not affect potency, does affect efficacy

allosterics always noncompetitive

Question 10

Receptor Antagonists

Answer 10

Most have no intrinsic efficacy (cannot activate the receptor)
These are called neutral antagonists
Can be very efficacious drugs in terms of physiologic effects because they prevent the action of physiologic agonists
Typically very potent (high binding affinity = low Kd)

Question 11

Competitive Antagonists

Answer 11

Bind reversibly to receptors
Compete with agonists for binding to the receptor active site
Blockade can be overcome by increasing concentrations of agonist
Increases the concentration of agonist (EC50) required for a given response (dose-response curve shifts to the right)

Question 12

Noncompetitive Antagonists

Answer 12

Exhibit two different binding mechanisms

1. Covalent binding to the active site
   - Essentially irreversible
   - Pseudo-irreversible: no covalent bond but binds so tightly that dissociation is extremely slow
2. Reversible or irreversible binding to an allosteric site

Regardless of the binding mechanism, blockade cannot be overcome by increasing agonist concentration
Increases the concentration of agonist required for a given response
Reduces maximal response
EC50 (based on the new maximal response) does not change
Very few clinically useful drugs are noncompetitive active site antagonists

Question 13

Receptor Occupancy Theory assumes

Answer 13

that all receptors must be occupied to achieve maximal response

Question 14

Spare Receptors

Answer 14

half-maximal and maximal responses produced by drug binding to fractions of that amount of the receptors

Max response occurs at a lower agonist concentration than max binding, EC50 is less than Kd.

Question 15

Quantal Dose-Response Curves

Answer 15

Defined response is binary (it occurs or it doesn’t)
Death
Sleep
Reduction in blood pressure > 10 mmHg
Indicate the potential variability in responsiveness of individuals

Question 16

Therapeutic Index

Answer 16

Median effective dose (ED50)
Median toxic dose (TD50)
Median lethal dose (LD50)
Therapeutic Index = TD50/ED50
Indicates relative safety of the drug
Larger numbers = more safe
Acceptability of risk depends on the severity of disease

Question 17

Drug Selectivity and Therapeutic Window

Answer 17

Selectivity: a drug’s tendency to elicit therapeutic effects versus adverse effects
Dose-dependent
Can be measured by comparing Kd for different drugs or ED50 for different effects

Individual response will vary considerably

Drugs Are Selective, NOT Specific

Question 18

Opportunities for Selectivity

Answer 18

Ligand
Receptor
Classes (e.g., nicotinic vs. muscarinic AChRs)
Subtypes, subunit composition (M1, M2, M3, etc.)
May activate different G proteins
Expression of diverse effectors in various cell types may alter signaling pathways, and functional effects (e.g., tamoxifen has differential effects in mammary tissue and bone)

Question 19

Variation in Drug Responsiveness

Answer 19

Four basic mechanisms:

• Alteration in concentration of drug that reaches the receptor (pharmacokinetics)
• Variation in concentration of an endogenous receptor ligand; particularly relevant for partial agonists
• Alterations in number or function of receptors
• Changes in patient characteristics (age, general health, severity and pathophysiological mechanism of disease, presence of compensatory mechanisms) or physician contributions (accuracy and completeness of diagnosis)