6) Regulation, Desensitization, & Variability

Status quo

A drug could be “perceived” as disrupting homeostasis so body attempts to restore status quo

Tolerance

Reduced effects / reaction to drug following repeated use

Dependence

Baseline functionality becomes dependent on drug

• Not same as addition

• Examples:

  • coffee (can be dependent but not addictive)

  • morphine (can be be dependent and addictive or neither)

Tachyphylaxis

1. Decline in response to a drug with repeated administration

2. Physiological basis (i.e. nonrandom process)

Fade

Long term tolerance (decline in response with time)

Attenuation

Decrease of response at the receptor level

Desensitization

Decrease response to drug binding

Downregulation

Decreased expression of drug target 🎯

Sensitization

Also called reverse tolerance

• Increased response to a drug with prolonged use

• May be concurrent with tolerance

• Chronic use of antagonist may lead to receptor upregulation

Upregulation

Also called sensitization

Chronic use of antagonist may lead to receptor upregulation

Reverse tolerance

Also called sensitization

• Increased response to a drug with prolonged use

• May be concurrent with tolerance

• Chronic use of antagonist may lead to receptor upregulation

Supersensitivity

Abrupt removal of antagonist results in increased receptor activity

Biomarker

Genetics

Particularly important for newer cancer therapies

Example: V600E mutation in RAF-B is required to use vemurafenib for melanoma

Practice question 1

Downregulation

Practice question 2

Tachyphylaxis

Practice question 3

Dependence

Practice question 4

Reverse tolerance

Practice problem 5

Supersensitivity