Lecture 2 - Drug actions and pharmacodynamics

What are examples of drug targets?

1. Regulatory proteins

2. Enzymes

3. Transport proteins

4. Structural proteins

What are 5 types of receptors?

1. Steroid

2. Tyrosine kinase

3. JAK-STAT

4. Ion Channel

5. G-Protein receptor

What is affinity?

How strongly a ligand binds to receptors

What is the EC50/ED50?

The effective concentration or dose required to produce ½ the maximum effect (Emax)

What is efficacy?

Ability of a drug to bind to a receptor and generate an effect (how well a drug works)

What is potency?

Relative concentration of drug required to produce a given effect (how strong a drug is)

What is the degree of safety?

Separation between dose producing therapeutic effects and dose producing undesirable effect

What is the LD50

Dose where half of the animals die

What is the quantal dose response?

Graph of dose response used to calculate therapeutic index

What is the therapeutic index (TI)? What should it be greater than?

-TI = LD50/ED50

-Should be greater than 1 (ideally greater than 10)

What is the margin of safety index (MI)? How is it calculated?

-Dose where first animal dies

-MI = LD1/ED99

What are receptors?

Macromolecule that drugs interact with to modify or produce a physiologic effect

Effectors

Accomplishes biological effect after the receptor is activated

What is an agonist?

Drug that binds to receptor and activates it?

What is an antagonist?

Drug that binds to receptor but does not activate it

What is a competitive antagonist (reversible)? Does it affect efficacy or potency of the endogenous ligand?

-Antagonist that can be overcome by increasing concentration of agonist

-Affects potency (since it’s reversible)

What is a noncompetitive antagonist (irreversible)? Does it affect efficacy or potency of the endogenous ligand?

-Antagonist that cannot be overcome by increasing concentration of agonist

-Affects efficacy (less receptors available)

What is a physiologic antagonist?

Drug that counters the effect of another drug by binding to a different receptor and causing apposing effects

What is a chemical inhibitor?

Drug that causes effects by binding to another agonist

What is a full agonist? What do they not differ in?

-Produces the same maximal effect as endogenous ligand

-Do not differ in efficacy

What is an allosteric modulator?

-Modify function by binding at a site other than the active site

-Have no effect on their own?

What is a positive modulator?

-Activator (agonist)

-Increases potency or efficacy of endogenous ligand

What is a negative modulator?

-Inhibitor (inverse agonist)

-Decrease potency or efficacy of endogenous ligand

What is desensitization and tachyphylaxis?

Loss of responsiveness to a drug over time (similar to tolerance)

What is a partial agonist?

Has a little bit of activity on it’s own but will act as antagonist when combined with full agonist

What are the mechanisms of enzyme inhibition binding?

-Competitive

-Noncompetitive

-Uncompetitive

-Irreversible

What is bioactivation?

Conversion of a relatively inactive form of a xenobiotic to an active form

What is a prodrug?

-Inactive from of drug that binds to the active site of target enzyme and is activated

What is the function of P-glycoprotein (P-gp)?

Transports substances to prevent substrate accumulation

What happens if P-gp is nonfunctional?

Animals are more sensitive to many drugs that are P-gp substrates (ex. macrocyclic lactones, loperamide, acepromazine, anti-neoplastics)