Lecture 19 Flashcards
Receptors + Individual Response
Desensitization
-Loss of response following agonist exposure
-Cells seek balance, compensatory mechanisms exist to prevent overstimulation of key pathways
EX: Rapid desensitization with rapid recovery
Mechanisms of Desensitization
- 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
Tolerance
-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
Opioids
- Due to changes in drug affinity or receptor down regulation
- Cross-tolerance develops where drugs share the same receptor (morphine, codeine, heroin, etc.)
Tachyphylaxis
-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
Sensitization
- 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
Receptor Number + Function
- *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
EGFR TKI Inhibitors
- Receptor mutations help drive tumor growth
- Also makes it most receptive to targeted therapy by increasing its affinity for chemotherapy drug
PD
-Variation in concentrations of endogenous agonist is important in response to therapeutic antagonist and partial agonist
Quantal Response
- 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)
Cumulative Quantal
- 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)
Comparing Doses
- ED = effective dose
- LD = lethal dose
- TD = toxic dose
- Therapeutic Index (TI) = LD50/ED50
- Higher the ratio (favoring ED50), safer the drug
TI + Drugs
- 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
Beneficial v.s. Toxic Response
- 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
Selectivity
-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
