Thursday, July 21, 2016
PHARMACODYNAMIC.
A. PHARMACODYNAMICS is a description of the properties of drug-receptor interactions
B. DRUGS BIND to specific receptors with
1. Ionic bonds (electrostatic attractions)
2. Hydrogen bonds
3. Van der Waals forces, which are weak but necessary for a good fit
4. Covalent bonds, which are uncommon and are usually irreversible
C. DOSE–RESPONSE CURVES show the relationship between the concentration of a
drug and the magnitude of its effect.
1. The potency (affinity) of a drug is inversely related to the median effective dose
(ED50), where ED50 is the dose that produces the desired effect in 50% of the
subjects.
2. The efficacy (intrinsic activity) is equivalent to the maximal effect of the drug.
3. The potency and intrinsic activity are independent.
a. In Figure 1-4, drug B has a higher efficacy than drug A (80 vs. 40 read off the
Y-axis).
b. Drug A is approximately 10 times more potent than drug B, because the ED50
of drug A is 10% the ED50 of drug B (10 vs. 100 read off the X-axis).
4. Drug A is a partial agonist (or a partial antagonist), because the maximal response
is smaller compared to drug B (40 versus 80)
D. AGONISTS change the effector site and lead to biological responses that mimic the
responses of the natural ligand.
1. The drug–receptor interaction follows the laws of mass action.
a. Drug molecules bind to receptors at a rate that is dependent on the drug concentration.
b. The number of drug–receptor interactions determines the magnitude of the
drug effect.
c. Types of receptors include ligand-gated ion channels, G protein-coupled
receptors, kinase-linked receptors, and intracellular receptors.
2. This leads to dose–response curves, which can be
a. Quantal (all or none [e.g., death])
b. Graded (e.g., blood pressure)
3. As seen in Figure 1-4, agonists can be full agonists (have the same maximal effect
as the natural ligand-curve B) or partial agonists (have a lower maximal effect compared
to the natural ligand-curve A)
E. ANTAGONISTS are drugs with a high affinity for a receptor and no intrinsic activity.
They alter the dose-response curves for the agonists.
1. Competitive surmountable (reversible) antagonists induce a parallel shift of
the agonist dose-response curve to the right with no change in intrinsic activity
(Figure 1-5A). The effect of the antagonist can be surmounted by increasing the
concentration of the agonist.
2. The maximal effect of a specific agonist is reduced (increasing the concentration
of the agonist will not surmount the effect of the antagonist) with little or no
change in the ED50 of the agonist (Figure 1-5B) by
a. Competitive insurmountable (irreversible) antagonists, which often bind
covalently to a receptor
b. Noncompetitive antagonists, which often act at a site other than the receptor
for the agonist
3. Other types of antagonism can occur.
a. Functional (physiological) antagonism involves the opposing actions of two
agonists at different receptors (e.g., acetylcholine [ACh] and norepinephrine
[NE] on heart rate).
b. Chemical antagonism involves the direct binding of a drug by another drug
without the involvement of a receptor (e.g., heavy metal chelators).
c. Partial agonists will act as antagonists in the presence of a full agonist, since the
intrinsic activity of the partial agonist is lower than the intrinsic activity of the
full agonist.
F. THE THERAPEUTIC INDEX (TI [therapeutic window]) measures the relationship
between the efficacy and safety of a drug (Figure 1-6).
1. LD50 is the dose that kills 50% of the subjects.
2. TD50 is the dose that induces a toxic effect in 50% of the subjects.
3. A large TI is desirable in order to avoid overlap between the toxic and therapeutic
ranges of the drug. (See Figure 1-6A versus Figure 1-6 B.)
