Substance Abuse Neurobiology

Front 1

what is substance abuse?

Back 1

"maladaptive pattern of use that causes clinically significant impairment"

pts don't experience tolerance and withdrawal

Front 2

what is substance dependence?

Back 2

"maladaptive pattern of substance use with adverse clinical consequences"

pts can experience tolerance and withdrawal

Front 3

Who has a higher risk of developing alcohol dependence:

person with high or low tolerance?

Back 3

High tolerance

Front 4

what is the genetic nature of alcoholism?

Back 4

many genes have been found to increase risk of alcohol dependence

some genes promote addiction by increasing tolerance, some protect pt by generating adverse response to alcohol

Front 5

Give an example of genetic "protection" against alcoholism?

Back 5

Asians only have one copy of aldehyde dehydrogenase --> low tolerance to alcohol

Front 6

What is the nature of cortical activity in alcoholics?

Back 6

Prefrontal cortex is diminished and hypoactive

Decreased decision making

Front 7

What is the nature of the limbic system in alcoholics?

Back 7

Hyperactive, sensitized

Front 8

What neurotransmitter is important in the reward system?

Back 8

Dopamine

Front 9

What affect does alcohol have on stress?

Back 9

Decreases cortisol levels, leading to decreased stress

Front 10

Is alcohol a stimulant or sedative?

Back 10

Both. At low doses, alcohol is a stimulant; at high doses, it's a sedative

Front 11

Explain the pharmacodynamics of alcohol at low doses

Back 11

Acts on many membrane proteins, binds hydrophobic pockets, displaces water

Works as a stimulant

Front 12

Explain the pharmacodynamics of high doses of alcohol

Back 12

Disrupts membrane functioning
Increases GABA by binding to Cl- channel
Inhibits glutamate

Front 13

What is the mechanism of action of alcohol?

Back 13

Non-specific. No one receptor for alcohol. Recall low and high dose effects

Front 14

How does tolerance increase?

Back 14

Alcohol binds Cl-channel associated with GABA, but over time, Cl- channel becomes less sensitive to GABA, reducing the effect on post-synaptic neuron

Front 15

Explain the biology of alcohol dependence

Back 15

Over time, GABA binding alcoholic Cl-channel has less effect. Therefore, alcohol must now be taken in order to achieve normal level of GABA-binding effect

Front 16

Explain the biology alcohol withdrawal

Back 16

Because the Cl-channel has become desensitized to the agonist effect of alcohol over time and thus returning GABA effects to normal, removing alcohol from the channel will decrease GABA's affect on the opening of the Cl-channel, thus decreasing the hyperpolarizing effect by decreasing the duration of channel opening.

Front 17

What are the symptoms of withdrawal?

Back 17

Wide spectrum of symptoms, ranging from no symptoms to seizures and delirium tremens (DT)

Front 18

What is delirium tremens (DT)?

Back 18

DT is an acute episode of delirium that can result in *death*

Front 19

How do you treat delirium tremens (DT) and why?

Back 19

-Treat w/ benzodiazepines, anticonvulsants, & barbiturates (GABAergics)

- Slowly weans pt off alcohol, allows minimal withdrawal, slowly resensitizes channel to GABA

Front 20

What is a common nutrition deficiency for alcoholics and why?

Back 20

Thiamine deficiency because active transport of thiamine in the jejunum & ileum is inhibited by alcohol

Front 21

If an alcoholic presents in the ER with malnutrition, what type of treatment should he/she receive?

Back 21

Parenteral thiamine, not PO (per oral)

To give PO would be *malpractice* because cannot absorb (transport blocked)

Front 22

Can you give an alcoholic patient an IV glucose drip?

Back 22

NO!

Only give IV glucose AFTER parenteral thiamine has been administered, otherwise will cause cause Wernicke's encephalopathy, which leads to neurotoxicity

Front 23

What is Wernicke's encephalopathy?

Back 23

Thiamine deficiency causes decreased reuptake of glutamate, leading to neuronal death due to excitotoxicity

Presents first as confusion, ophtalmoplegia, and ataxia. Progresses to Korsakoff's psychosis, coma, & death

Front 24

Name 3 common pharmacotherapies for alcohol dependence

Back 24

Disulfiram (Antabuse)
Acamprosate (Campral)
Naltrexone (ReVia)

Front 25

What is the mechanism of action for Disulfiram and clinical effect?

Back 25

Mechanism: irreversible inhibitor of aldehyde dehydrogenase, preventing breakdown of toxic byproduct, acetaldehyde

Effect: Vasodilation, hypotension, nausea, vomiting
*death for pts who abuse alcohol while on drug

Front 26

How does alcohol facilitate dopamine release?

Back 26

releases opioid peptides (i.e. endorphins), which bind to receptors on presynaptic neuron (mu opioid receptors)

disinhibit dopamine release --> pleasure!

Front 27

Do alcoholics have higher or lower levels of beta endorphins?

Back 27

Lower

Front 28

What is the mechanism of Naltrexone and in what form is it administered?

Back 28

Reversible opioid antagonist, blocking disinhibition of dopamine

Long-acting injectable, given once/month (= higher compliance)

Front 29

What is the mechanism of Acamprosate?

Back 29

NMDA antagonist, damps down excitatory response

GABA agonist

Therefore, counteracts effects of withdrawal: upregulated NMDA, downregulated GABA receptors in order to restore normal balance of glutamate and GABA

Front 30

What type of GABA receptors have receptors for benzodiazepines and barbiturates?

Back 30

GABA-A receptors

Front 31

What is the general rule of withdrawal?

Back 31

Withdrawal causes the opposite effects of the drug

Therefore, a withdrawal from a stimulant --> depression

Withdrawal from a sedative --> stimulation/excitation

Front 32

How is cessation of opioid use different from cessation of alcohol?

Back 32

Opioid cessation is not life-threatening

Cessation of alcohol is.

Front 33

How does detox in a neonate differ from detox in an adult?

Back 33

Neonates can get seizures. Must be treated with barbiturates and anticonvulsants

Adults never get seizures during opiate detox

Front 34

What is the treatment for pregnant opioid addicted mother?

Back 34

Mother should continue maintenance use of opioid because detox during pregnancy is of more harm to fetus than maintenance

Treat baby with barbiturates and anticonvulsants post-natally

Front 35

Methods of opioid detox (5)

Back 35

Substitution (Methadone, Buprenorphine)
Alpha-2 agonists (Clonidine, Lofexidine) - blocks sympathetic discharge
Promethazine - antiemetic
Benzodiazepines - anxiety, restlessness, insomnia
Ibuprofen - muscle cramps, joint pain

Front 36

What effects does methadone have?

Back 36

No euphoria or sedation
Relieves narcotic craving
Blocks effects of normal street doses via cross-tolerance
Minimal side effects

Front 37

What's the time limit on methadone use?

Back 37

None. Some pts use methadone as a lifelong therapy

Front 38

What's one major con of methadone use?

Back 38

Difficult withdrawal. Must be tapered. Effectiveness increases with length of taper.

Front 39

What is the mechanism of Buprenorphine?

Back 39

Substitution med
- mu and kappa agonist and antagonist
- partial agonist at low dose
- antagonist at high dose

Front 40

What benefit does Buprenorphine have over Methadone?

Back 40

Milder withdrawal upon its discontinuation

Front 41

What pharmacotherapy used for alcohol is also useful for opiate dependence?

Back 41

Naltrexone - mu opioid receptor antagonist

Blocks the effects of morphine, heroin, etc

Front 42

What is the first step in the treatment of substance dependence?

Back 42

Detoxification