Drug tolerance

What started the opioid crisis in Canada?

When they started being prescribed while the effects were underestimated

Between opioids (mostly fentanyl) and stimulants (cocaine), which drug resulted in more deaths in 2025?

Opioids (2k more)

What’s the added danger of ipioids?

Some of them are cut with synthetic molecules

Is there still a drug overdose crisis in the US?

Yes but the pandemic peak is over

How are illegal drugs detected in Canada?

The Canadian Wastewater Survey collects samples

Regarding household income, how frequent is heavy drinking and smoking?

More drinking in high income households but More smoking in low income households

What is the synthetic opioid that is the newest killer?

Nitazenes: 4300 times stronger than morphine

How much more toxicity capactiyy does a nitazine compound have compared to fentanyl?

20 times = Toxic brain injury

What makes nitazenes dangerous?

1. Their synthetic nature allows for continual synthesis of new variants.

2. They are sold in many easy-to-use forms (vape, injection, nasal spray)

What is tolerance to a drug?

When the person no longer responds AND/OR needs a higher dose to get the same effect

How is tolerance studied?

Rats that can self administer morphine through a lever and IV

What is drug addiction?

When the person is physically AND psychologically (pleasure) dependent on a drug

What are examples of dependence due to the fact that there’s no psychological component to make it an addiction?

1. Nasal spray: your blood vessels get used to needing the drug

2. Antihypertensive: lower BP and HR

What was observed in the Human experience in 1952?

Injections a day (3x) AND the dose (20x) increased

What are the 2 types of tolerance?

1. Acute

2. Chronic

What is acute tolerance in relation to time?

A single dose of the drug creates a peak of tolerance which lowers over time

What is chronic tolerance in relation to time?

Repeated administration creates a peak of tolerance that plateaus

What are the next 2 types of tolerance?

1. Pharmacodynamic

2. Pharmacokinetic

What is pharmacokinetic tolerance?

Increased metabolism of the drug (no change in responding cell) leads to a decreased plasma drug concentration = less response

What is pharmacodynamic tolerance?

The same plasma drug concentration leads to less of a response (adaptation of the responding cell)

How does chemotherapy affect the cell?

Combined mechanisms allow for both PK and PD tolerance.

What is acute tolerance in terms of plasma concentration?

As the concentration increases, the effect lessens due to rapid adaptation of the metabolism: protective mechanism (seen w/ cocaine)

What is drug dependence?

They need of a drug to avoid withdrawal or its physiological consequences

How can dependence be explained in terms of inhibition and excitation balance?

Chronic tolerance ends up balancing inhibition and excitation by increasing one or the other BUT, as withdrawal starts, the adaptation mechanism is still in place which makes for extreme symptoms

What makes drugs perform so well in the body?

The fact that there are many sites for neurons to adapt

What functions of the synapse can adjust?

1. Presynaptic

2. Postsynaptic

How can presynaptic functions be adjusted?

By altering transmitter synthesis factors: enzyme, substrate, cofactor availability

How can presynaptic adaptation be characterised?

As insurmountable bc the transmitter becomes depleted

How can postsynaptic functions be adjusted?

By up-regulating or down-regulating receptors

How can postsynaptic adaptation be characterised?

As surmountable because spare receptors are available

What are the types of tolerance regarding neuroplasticity (2)?

1. Cross tolerance

2. Differential tolerance

What is cross tolerance?

When the tolerance to a drug leads to the tolerance to all the drugs in the same family

What is differential tolerance?

When the body doesn’t become equally tolerant to every effect to a drug (analgesia VS pupillary constriction or respiratory depression)

Finally, what is behavioral tolerance?

When the body has a conditionned response from taking the drug at the same place

When does behavioral tolerance become dangerous?

Risk of overdose is greater in an unfamiliar environment bc new protective mechanisms have to be put in place

What is the timeline of opioid withdrawal? (3)

1. Start

2. Peak

3. Subside

How long can symptoms persist?

Weeks, months or years

How do withdrawal symptoms relate to the severity of the addiction?

Directly proportional

How do withdrawal symptoms relate to the drug’s half-time?

Directly proportional

What makes quitting difficult in addition to symptoms?

Guilt and emotional triggers

What are the 4 withdrawal methods?

1. Decrease the dose

2. Substitute then lower the dose

3. Partial agonist or antagonist use

4. Therapy and altered lifestyle

What gives an administration type the highest addiction potential?

Rapid onset + High blood concentration

What explains the psychological aspect of addiction?

The mesolimboc dopaminergic or reward pathway

What other mechanism is usually linked to drug addiction?

Obesity