Pharmacodynamics II Flashcards
Antagonists Types (3)
Chemical: Combines with the agonist and thereby disallows interaction with its site of action
Physiological: Activates an opposing physiological input
- Could be an agonist
Pharmacalogical: Blocks the effects of the agonist at its site of action (i.e. receptor)
Types of Competitive pharmacological antagonist (2)
1) Competitive equilibrium antagonist
2) Irreversible, competitive antagonist
Competitive equilibrium antagonist (Characteristics)
- Reversible and can be surmounted by agonist
- EC50’ is the EC50 for the agonist in the presence of a given concentration of antagonist (KI is the KD of the antagonist for the receptor)
- EC50’ = EC50 (1+ ([antagonist]/KI))
- The ability of the agonist to produce a response in the presence of a competitive, equilibrium antagonist is dependent upon the affinity of the antagonist for the receptor and its concentration
Competitive Equilibrium Antagonist: In the box below, D is the agonist and A is the antagonist - What are the implications for the therapeutic use of this type of antagonist?
1) The ability of the antagonist to be effective is dependent upon both its concentration and the concentration of agonist that is present
2) All else being equal, the antagonist with the highest affinity for the receptor will produce the greatest inhibition
Irreversible, competitive antagonist (non-surmountable): Characteristics
- Binds to the agonist binding site in a covalent or very slowly reversing manner
- Once the receptors are bound by this type of antagonist, they cannot be activated by agonist. This reduces the receptor pool.
- In the presence of a non-surmountable antagonist, the EC50 value does not change but the Emax is reduced
Therapeutic implications of using a non-equilibrium antagonist
- New receptor synthesis is the only way to overcome the effects of the antagonist
- The degree of inhibition produced is not influenced very much by the concentration of agonist present
What type of antagonist is this?
Irreversible, competitive antagonist (also called non-equilibrium or non-surmountable)
Noncompetitive pharmacological antagonists (characteristics)
1) Blocks the activation of the receptor by an agonist at a site other than the agonist binding site
2) D + R ⇔ DR ≠ Effect
3) The agonist concentration curves look the same as the effect of an irreversible, competitive antagonist
- Emax is reduced
- EC50 does not change
- Not influenced by spare receptors
Therapeutic implications of noncompetitive antagonists (2)
1) Antagonist effect is essentially independent of agonist concentration at the receptor
2) Can be used to inhibit the effects of multiple agonists that use the same signal transduction cascade
Partial agonist/partial antagonist (PA)
Ligands that have affinity for the receptor and an intrinsic activity between 1 and 0
When a partial agonist is present alone, one sees an agonist effect
When a partial agonist is present in combination with a full agonist, one sees an antagonist-like effect
What do these arrows represent?
1) Full agonist
2) Partial agonist
Ri ⇔ Ra
What does this equilibrium equation represent?
How does it relate to agonists and antagonists?
Useful to think about receptors as in equilibrium between actively signaling (Ra) and inactive (Ri) forms
An agonist shifts the equilibrium of this relationship towards more receptors in the Ra form
A true antagonist has no effect, and therefore does not affect this equilibrium at all
There is a class of ligand that can shift the equilibrium toward the Ri form - called “inverse agonists”
The Dose-Response relationship
1) A fundamental of therapeutics is that a relationship exists between the dose of a drug administered and its therapeutic effect
2) Idealized dose response curves mirror the concentration-effect curves one obtains in the laboratory
3) However, many factors can intervene between the site of drug administiration and its ultimate site of action
Potency
Potency is the relationship between the amount of drug administered and its effect
How are potency and ED50 (effective dose for 50% of the population) related
ED50 value is inversely related to potency
Potency determines the position of the curve on the x-axis
Efficacy
Efficacy is the maximal effect that is produced by a drug
Determinants of efficacy include:
Intrinsic activity
Characteristics of the effector
Limitations on the amount of drug that can be administered (often due to adverse effects)
Deviations in the shape of this curve can occur because of:
1) Additive effects of the drug
2) Threshold effects
3) Antagonist effects
Biological variability among patients
Rarely is a physician able to determine a dose-response curve in an individual patient
Therefore, need an idea of the dose response relationship in an entire population of patients
Most drug effects follow a log-normal distribution
What is a cumulative frequency distribution?
The total of a frequency and all frequencies below it in a frequency distribution
Reasons for variations in responses among individuals
Pharmacokinetic differences
Variations in the amount of endogenous agonist present
Changes in the number or functioning of the drug target
Differences in a component distal to the drug target
Biological variability: Idiosyncratic drug response
Unexpected based upon the mechanism of action of the drug
Biological variability: Hyporeactive or hyperreactive
At the tails of the frequency distribution
Biological variability: hypersensitivity
Allergic or inflammatory response to the drug
Biological variability: tolerance
Slowly developing resistance to the drug
Biological variability: Tachyphylaxis
Rapidly developing resistance to the drug
Therapeutic Index
The ratio of TD50/ED50
TD50 = Dose at which toxicity occurs in 50% of patients
ED50 = effective dose for 50% of patients
