Lecture 19

Question 1

Desensitization

Answer 1

-Loss of response following agonist exposure
-Cells seek balance, compensatory mechanisms exist to prevent overstimulation of key pathways
EX: Rapid desensitization with rapid recovery

Question 2

Mechanisms of Desensitization

Answer 2

• Combinations of mechanisms are usually employed
• May be prolonged or brief depend on mechanism

Mechanisms:

• Substrate depletion
• Limiting cofactors
• Limiting downstream signaling molecules
• Post-transcriptional modification (phosphorylation, ubiquitination, etc.)
• Receptor internalization (sequesteration)
• Receptor degradation or decreased synthesis

Question 3

Tolerance

Answer 3

-Reduction of receptor or response with prolonged drug exposure
-Increased doses are required to achieve biological effect
-PK tolerance - example is induction of enzymes that increase metabolism and clearance
-PD tolerance - example is decreased response based on receptor of cell mechanism
EX: caffeine and opioids

Question 4

Opioids

Answer 4

• Due to changes in drug affinity or receptor down regulation
• Cross-tolerance develops where drugs share the same receptor (morphine, codeine, heroin, etc.)

Question 5

Tachyphylaxis

Answer 5

-Rapid development of drug resistance after dose
-Not readily overcome with increased dosing
EX: release of stored neurotransmitters, store is depleted and need to recover

Question 6

Sensitization

Answer 6

• Opposite of Tolerance
• Supersensitivity can develop after chronic receptor blockade
• Often due to increase of receptors to compensate for loss of signal due to blockage

Question 7

Receptor Number + Function

Answer 7

• *Difference in response max and sensitivity to a dose can be dictated by receptors or other mechanisms**
• Receptor number or mutation - responsible for tissue specific response (ex: estrogens or androgens)
• Endogenous ligand levels - most relevant to competitive antagonists and partial agonists

Question 8

EGFR TKI Inhibitors

Answer 8

• Receptor mutations help drive tumor growth

- Also makes it most receptive to targeted therapy by increasing its affinity for chemotherapy drug

Question 9

PD

Answer 9

-Variation in concentrations of endogenous agonist is important in response to therapeutic antagonist and partial agonist

Question 10

Quantal Response

Answer 10

• Population based
• Percent of individuals v.s. log[Drug in plasma]
• Understanding of a dose’s effectiveness in a population of people
• FREQUENCY of response to a given [drug] within a population
• At each dose, some % of the population responds (“yes” or “no” response, not a magnitude)

Question 11

Cumulative Quantal

Answer 11

• Converts the Dose-Effect Bell Curve to a dose response S-curve
• Cumulative % of subjects responding
• EC50 = 50% of subjects respond to that drug dose
• ED50 = EC50 (same thing)

Question 12

Comparing Doses

Answer 12

• ED = effective dose
• LD = lethal dose
• TD = toxic dose
• Therapeutic Index (TI) = LD50/ED50
• Higher the ratio (favoring ED50), safer the drug

Question 13

TI + Drugs

Answer 13

• Human studies use TD50 as measure for safety index
• Most drugs have large TIs (>100)
• Drugs with low TIs (2-3) require monitoring

Drugs with low TIs:

• Warfarin
• Digoxin
• Lithium
• Phenytoin
• AZT
• Cancer chemotherapies

Question 14

Beneficial v.s. Toxic Response

Answer 14

• Toxicity could be due to therapeutic actions of the drug (bleeding from an anticoagulant)
• Many require drug response monitoring and additional therapeutics may be required to offset the action of one drug
• Toxicity could also be due to targeting receptors in different tissues (glucocorticoids)
• Manage by using lowest ED, combine with other drugs to reduce dose, target delivery to reduce exposure to other tissues

Question 15

Selectivity

Answer 15

-Although drugs are selective, not 100% SPECIFIC
-Many interact with multiple members of a receptor family or very different targets
-May have a lower affinity for the unintended target, interactions with that target is a function of the drug concentration
EX: Loratidine has a lower ability of crossing the BBB, causes less sedation than other medicines of its class

Question 16

Methods to Reduce Interactions with Unintended Targets (3)

Answer 16

1. Use lowest dose that gives beneficial effect
2. Drug targeting to tissue or organ necessary to give therapeutic effect
3. Development of drugs with increased affinity for intended target

Question 17

Dose Response Curve Summary

Answer 17

• Different dose response curves provide different information
• Drug binding=Kd
• Response=EC50, potency, efficacy
• Population response (quantal)=TI, therapeutic window and other safety measures

Question 18

Differences in response at site of action (receptor)

Answer 18

Pharmacokinetic (concentration of drug at receptor)

Pharmacodynamic (receptor activity)

Question 19

Toxicity can be due to…

Answer 19

• Therapeutic activity (response at intended site of action)
• Drug response at unintended site of action