Week 3: How we Adapt to Drugs – Tolerance, Sensitization, and Expectation Flashcards
Tolerance
= Decreased effectiveness of a drug that results from repeated administrations
- This means a higher dose is required to elicit the same effect
Different effects of drugs undergo tolerance at different rates due to targeting different mechanisms in the brain and body
Many mechanisms likely involved in tolerance to different drug effects
Acute tolerance
= a defined as a decreasing drug effect relative to drug-plasma levels (DPL) over a period of minutes to a few hours
This is rapid tolerance developing during a single session.
In this, during the rise of the drug curve, at a given blood level the effect of the drug is higher than when the blood level returns to the same level in the fall of the drug curve. So, the subjective experience of the drug, despite an identical blood profile has reduced with time
Tolerance is
transient
Will disappear with time if drug use is discontinued
Cross tolerance
= where use of one drug may also diminish the effects of other drugs
- Usually seen between members of the same drug class (e.g., opioids)
- Sometimes taken as evidence that effects are due to common mechanisms
Pharmacokinetic tolerance
caused by an increase in the rate or ability of the body to metabolize the drug
Usually results from enzyme induction
resulting in less of the drug being available at the site of action.
Pharmacodynamic tolerance
arises from adjustments made by the body to compensate for an effect of the drug
Homeostasis
This is believed to be on the basis of a physiological compensatory action used to reinstate homeostasis in the body and mitigate the effects of the drug. This homeostatic processes strengthen with repeated use
Homeostasis and drugs
- Drug responses/mitigation much like many of the body’s physiological processes are controlled by feedback loops.
- with repeated administration, the homeostatic mechanisms used by the body to restore homeostasis adapt more quickly
- therefore, the drug has a smaller effect the more it is administered
- When drug administration is discontinued, the compensatory process weakens, but can take some time before disappearing completely
One example of pharmacodynamic tolerance is …
upregulation and downregulation of neurotransmitter receptors
- This process may take a few weeks
Partially responsible for the delayed effect of antidepressants
Withdrawal
= Physiological changes that occur when use of a drug is stopped or the dosage is decreased
Different drugs produce different withdrawal symptoms, but drugs from the same family generally produce similar withdrawal
Withdrawal can be stopped almost immediately by giving the drug
Drugs from the same family often stop withdrawal as well= aka . Cross dependence
Degree of withdrawal varies across drugs
Some drugs you can only detect withdrawal with sensitive instruments
Some drugs withdrawal can be fatal
Withdrawal usually starts several hours after the drug has been discontinued
Can be produced in minutes if an antagonist drug is administered
Giving naloxone to morphine-dependent humans or nonhumans
Cross-dependence
When there is dependence on a drug in the same class (as one where there is an existing dependence/addiction) and this second drug is used to mitigate the withdrawals from the first drug implicated in a dependence/addiction
Dependence
This term is surrounded by confusion and misunderstanding
Historically, it has meant both:
A state in which discontinuation of a drug causes tolerance
A state in which a person compulsively takes a drug
The relationship between dependence and addiction is complex
People can take a drug compulsively in the absence of withdrawal
People can have withdrawal without taking a drug compulsively
Dependence, physical dependence, and physiological dependence
Used to describe a state where withdrawal will occur if use of a drug is discontinued
Solomon and Corbit 1974 Opponent Process Theory
Suggests that when the body comes to learn that a drug produces a certain physiological effect, it’ll begin to introduce opponent compensensatory responses to reinstate homeostasis.
Eg. Instigated dysphoria to mitigate a euphoria inducing drug
eg. Drug A produces euphoria (high)
Process B which is compensatory, produces dysphoria
Barret and Smith 2005 - study on opponent process theory for drug tolerance
- Trained rats in a drug discrimination procedure (where the drug responds with a lever to indicate which drug they’re feeling the effects of)
Chlordiazepoxide (CDP) – tranquilizer – anxiolytic
Pentylenetetrazol (PTZ) – causes tension – anxiogenic - Once the discrimination was learned, tested rats with one injection of (Chlordiazepoxide) CDP then observed responses over time
Results;
- after 8 hours, the mice would respond using the lever that indicated they were feeling the effects of the anxiolytic drug (they didn’t have anxiety)
- After 16 hours, the mice would respond suggesting they were feeling very anxious as if under the influence of an anxiogenic drug.
This suggests their withdrawal produced an opponent experience (as they should’ve felt neutral without the drug)
Opponent Process Theory and Withdrawal
If you take a drug continuously for weeks or months you:
Maintain enough of the drug in the body so that withdrawal symptoms never occur
The compensatory response, however, builds in strength (tolerance)
Conditioning of drug effects
Principles of classical conditioning pertain to drug effects
Drug effects can be classically conditioned
Anything that reliably predicts drug administration can come to be a CS
Pavlov’s dogs (again)
Conditioned effects tend to be somewhat less in magnitude than when the drug is administered