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PBT 3 Exam 2 > Opioid tolerance, dependence, and abuse > Flashcards

Opioid tolerance, dependence, and abuse Flashcards

1
Q

Tolerance

A

gradual reduction in efficiency of drug. Narrows TI -> need more drug to achieve same effect.

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2
Q

Dose response curve shifts to right/left with tolerance

A

right

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3
Q

Two types of tolerance

A

pharmacokinetic

pharmacodynamic

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4
Q

pharmacokinetic tolerance

A

increased capacity to metabolize/excrete drug due to repeated exposure. Thought to be due to induction of metabolic enzymes
Less drug reaches site of action -> need more drug

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5
Q

pharmacodynamic tolerance

A

changes to neurons that requires pt to need more drug
lower response from neurons when drug binds
Need more drug

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6
Q

How to address tolerance?

A

increase the dose OR remove the drug - applies to both PD and PK

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7
Q

Development of opioid tolerance appears to be primarily due to pharmacodynamic/ kinetic changes?

A

pharmacodynamic

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8
Q

Possible mechanisms of opioid tolerance (3)

A

Receptor desensitization
changes in downstream signalling
immunological mechanisms

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9
Q

receptor desensitization

A

ligand binds and DOES NOT produce an effect/same effect. Could be due to receptor expression, phosphorylation, etc

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10
Q

Changes in downstream signalling

A

signal transduction pathways are working differently -> pathway may not work so others have to work differently. Many reasons why this could happen

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11
Q

Immunological mechanisms

A

opioids can activate immune cells (microglia) -> they release proinflammatory factors -> factors reduce how neurons respond to opioids.

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12
Q

Key properties in opioid tolerance

A

tolerance can be overcome by increasing drug dose
reversible over time upon discontinuation
different physiological responses develop tolerance at different rates
cross-tolerance can occur

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13
Q

Rapid tolerance

A

happen quickly - analgesia, euphoria, sedation, respiratory depression. If you take the drug for a long time, you won’t show tolerance

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14
Q

Slow tolerance

A

miosis and constipation. You won’t develop tolerance to these issues

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15
Q

Cross-tolerance

A

develop tolerance to one drug, give the pt a second drug, pt shows tolerance to that drug even though thye’ve never taken it. Typically happens with drugs in the same class

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16
Q

Opioid rotation

A

take pt off one drug and put on another to gain efficacy. Useful in tolerance and when pt cannot handle SE of current drug

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17
Q

Opioid rotation used in specific circumstances

A

complete/full cross tolerance

incomplete/partial cross tolerance

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18
Q

complete/full cross tolerance

A

develop tolerance to one drug, switch to second drug, pt shows just as much tolerance

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19
Q

incomplete/partial tolerance

A

develop complete tolerance to one drug, switch to second, get partial effect

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20
Q

When switching to second opioid due to tolerance, should new opioid be more/less potent

A

more potent

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21
Q

Are NMDA receptors located in the spinal cord

A

Yes

22
Q

What happens if you antagonize NMDA receptors

A

analgesia -> antagonize, block glutamate from binding ->less activation of projection neuron -> inhibit ascending pathway

23
Q

What is ketamine

A

NMDA receptor agonist

24
Q

Ketamine plus opioid combined produces

A

analgesia

25
Q

ketamine issues

A

hard to get therapeutic dose

lots of SE

26
Q

Opioid physical dependence

A

Body becomes used to having the drug in order to function normally. When drug isn’t there, you get withdrawal sx. Pt has changes on cellular level

27
Q

physical withdrawal sx

A 
hyperalgesia
hyperthermia
hypertension
diarrhea
pupillary dilation
28
Q

affective withdrawal sx

A

agitation
anxiety
depression
dysphoria

29
Q

Opioid withdrawal

A

pt feels like they’re going to die

easiest way to relieve sx is to take more drugs

30
Q

Superactivation hypothesis

A

cAMP pathway is downregulated with continued opioid use -> other signal transduction pathways activate to compensate -> stop taking meds, cAMP is no longer inhibited and reactivates at much higher level -> compensation systems are still working -> hyper-excitatory state due to increased cation influx

31
Q

Tx of opioid withdrawal

A 
taper drugs
pharmacological options:
methadone
buprenorphine
clonidine
32
Q

Do most people who use opioids develop dependence

A

NO

33
Q

How does methadone work

A

maintenance tx for people who cannot get off opioids -> give just enough so they don’t experience withdrawal. Racemic mixture -> L is NMDA receptor antagonist, D helps in process. Key is to maintain steady state. It is both a mu receptor agonist and NMDA antagonist

34
Q

Methadone maintenance tx

A

long duration of action, moderate doses can prevent withdrawal without producing rewarding effects

35
Q

Buprenorphine tx

A

Partial agonist. Able to treat physical sx without high effect -> pt less likely to become dependent on it, but not a sure thing -> some people get stuck on it

36
Q

key property of partial agonist

A

display both agonist and antagonist effects. In presence of full agonist, partial will act as antagonist to compete for receptor and reduce the ability of full agonist to produce max effect

37
Q

Clonidine tx

A 
alpha-2 adrenergic agonist (autoreceptor). Blocks autonomic sx of withdrawal:
HTN
Tachycardia
Nausea
Vomiting
Sweating
38
Q

Best long term tx to keep pt opioid free

A

Buprenorphine > methadone> clonidine

39
Q

Naltrexone

A

(revia, vivitrol)
opioid receptor antagonist
Pt MUST be drug free for 7-14 days
Crosses BBB
oral dosing not recommended b/c too easy to skip dose -> IM best
Won’t work if given to pt with drugs in system b/c tx antagonizes opioid receptors -> will get severe withdrawal sx

40
Q

Can patient become sensitized to long term tx with Naltrexone

A

YES

41
Q

What will happen if patient takes opioid agonist after using naltrexone long term

A

Huge response to the opioid/agonist due to upregulation of opioid receptors

42
Q

Naloxone

A

opioid receptor antagonist

short acting -> IV in case of OD

43
Q

Big problem with opioids?

A

mental and psychological aspects

44
Q

what is psychological dependence

A

when you need to drug to feel good -> people look for a “high”. Very difficult to treat

45
Q

Pathway in brain responsible for pleasure

A

mesolimbic. Releases dopamine

46
Q

Where is DA released

A

in the ventral striatum

47
Q

What happens with increased levels of DA

A

increased -> pleasureable high effect (abuse levels)

too much -> positive sx of schizophrenia

48
Q

Drug craving

A

Intense preoccupation with obtaining the drug. Can linger for years.

49
Q

Do cravings develop independent of tolerance

A

yes

50
Q

How do opioids produce rewarding effect (mesolimbic pathways)

A
  • Dopeminergic neuron in VTA -> releases dopamine in ventral striatum
  • GABAergic neuron in VTA -> inhibits dopaminergic neuron
  • GABAergic neuron has mu opioid receptor
  • Enkephalinergic neuron also in VTA -> releases enkephalin to INHIBIT GABAergic neuron
  • if GABAergic neuron inhibited, Dopaminergic neuron can release DA into Ventral striatum and activate D2 receptor (which is inhibitory)
51
Q

What is addiction

A

purely psychological -> feeling high, drug cravings. Can lead to compulsive search for drugs

PBT 3 Exam 2 (8 decks)

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