Pharm 2: Mechanisms of Drug Action and Pharmacodynamics

Affinity

How strongly a ligand binds its receptor; defines the likelihood that a drug will bind a receptor

Graded dose-response relationship

1. Concentration or dose of drug vs. % of maximum effect

   1. Plotted on linear scale: hyperbolic

   2. Plotted on logarithmic scale: sigmoid

EC50 or ED50

Effective concentration or dose required to produce ½ of the max effect

Efficacy

1. The ability of a drug to bind a receptor and generate an effect; reflects intrinsic activity of a drug or how well a drug generates an effect; how well a drug works

2. Defined by the maximum effect a drug can produce

Potency

1. Relative concentration of drug required to produce a given effect (ED50); how relatively “strong” a drug is

2. All four drugs elicit the same degree of response (all are equally efficacious), but the concentrations required to meet their EC50s differ

Degree of safety

The ___ of a drug administration depends on an adequate separation between doses producing therapeutic effects (e.g., the ED50) and doses producing undesirable or toxic effects (e.g., the LD50)

Therapeutic index (TI)

LD50 / ED50

1. Should be greater than 1, and bigger is better

2. Ideally should be greater than 10

3. Based on population response, but importance is separation of therapeutic benefit and toxic doses in individuals

Margin of safety index (MI)

LD1 / ED99

• A more conservative index, comparing the extremes of the dose response curves to indicate any overlap

• Should be greater than 1, and bigger is better

Receptors

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

Have endogenous ligands that modulate physiologic effects

Some drugs do not have these

Effectors

Component of system that accomplishes biological effect after the receptor is activated

Sometimes called “second messengers” or “signaling pathways”

Coupled to receptors; sometimes mechanism is part of the receptor

Can greatly amplify the signal from the receptor

Also can prolong effect of drug long after drug leaves receptor

e.g., cAMP, IP3, G-proteins, Ca2+, protein kinases, transcription factors

Agonist

Drug that binds to receptor and activates it

Antagonist

Drug that binds to receptor but does not activate it and prevents activation by an agonist

Competitive antagonist

(Reversible) antagonist that can be overcome by increasing concentration of agonist

Non-competitive antagonist

(Irreversible) antagonist that can’t be overcome by increasing concentration of agonist

Physiologic antagonist

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

1. e.g., hypertensive drug that works on heart and antihypertensive drug that works on kidney

Chemical inhibitor

Drug that causes effects by binding to another agonist; chelators of heavy metals, antacids, antibodies that bind to cytokines or growth factors

Full agonists

1. Produce the same maximal effect as the endogenous ligand

   1. Efficacy is 100% compared to endogenous ligand

2. Binding activates the receptor’s signaling pathway

3. Full agonists can differ in their potency but not their efficacy

4. The smaller the EC-50, the higher the potency

Competitive antagonists

1. Freely bind and dissociate from receptor

2. Do not produce effect on their own → have affinity but not efficacy

3. Compete with the endogenous ligand for binding

4. Can be overcome by large amounts of endogenous ligand (i.e., reversible)

   1. Therefore affects potency of the endogenous ligand

Non-competitive antagonists

1. Do not dissociate from receptor when bound → irreversible

2. Do not produce effect on their own → have affinity but not efficacy

3. Prevent the endogenous ligand from binding

4. Cannot be overcome by increasing amounts of endogenous ligand

   1. Reduced number of receptors are available for binding

5. Therefore affects efficacy of the endogenous ligand

Agonist binding site (receptor site)

Initiates signaling pathway when drug binds to receptor

Allosteric site (modulatory site)

Does not interfere with agonist binding but modulates activity of agonist when drug binds to receptor

Allosteric modulators

1. Modify function by binding at a site other than the active site (allos from Greek other)

2. No effect on their own

Positive modulators

Can increase potency or efficacy of the endogenous ligand– referred to as “agonists”

1. Benzodiazepines and GABA

Negative modulators

Can decrease potency or efficacy of the endogenous ligand– referred to as “inverse agonists”

1. Fipronil and GABA

Tachyphylaxis

Rapid protection

Desensitization

1. Loss of responsiveness to a drug over time

2. Occurs over minutes to days depending on mechanism

3. Can try to overcome by increasing dose

Tolerance

Similar term to desensitization but often used in context of chronic, longer-term dosing

1. Changes in receptor function

2. Changes in available receptor number

3. Exhausting mediators

4. Induced drug metabolism

5. Physiologic compensation

Mechanisms of desensitization and tachyphylaxis

Partial (mixed) agonists

1. Produce a sub-maximal effect compared to the endogenous ligand

   1. Efficacy is <100% compared to endogenous ligand

2. Binding does not fully activate the receptor’s signaling pathway, so efficacy is reduced

Competitive, noncompetitive, uncompetitive, inhibition

Mechanisms of enzyme inhibition

Bioactivation

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

Prodrug

An inactive form of drug that binds the active site of the target enzyme and is activated by the enzyme– sometimes cytochrome P450s, which generate an active drug

P-gp/mdr1/abcb1

Protective function by transporting substrates that enter cells either back where they came from or into the adjacent elimination site; prevents accumulation of substrate

Multi-drug resistance (mdr)

Found to make some tumors resistant to multiple different classes of drugs

Back into intestinal lumen

Where does P-gp transport substrates that enter enterocytes?

Back into capillary lumen

Where does P-gp transport substrates that enter endothelial cells in the brain?

Into biliary canaliculi

Where does P-gp transport substrates that enter hepatocytes?

Into tubule lumen

Where does P-gp transport substrates that enter renal proximal tubule cells?

Inhibit transporter function with drugs, prevent transporter function with mutations

Ways to interfere with function of transporters

mdr1, stop codons, truncated protein

Some dogs have a non-functional P-gp.

A frameshift mutation of ___ results in ___ and a ___ that is 90% absent.

P-gp substrates

Macrocyclic lactones, loperamide, acepromazine, anti-neoplastics

What drugs are dogs with mutated P-gp sensitive to?

P-gp inhibitors, P-gp substrates

Combining which two types of drugs can elevate concentrations of either drug in tissues that P-gp normally protects?