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PHS 931 > Block 4 Lecture 1 -- Alcohol and the BBB > Flashcards

Block 4 Lecture 1 -- Alcohol and the BBB Flashcards

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1
Q

What are the drug targets of EtOH under the legal limit?

A 
1 mM
-- delta GABAa potentiation
10 mM
-- GlyR potentiation
-- inhibition of...
----- a7 nAChR
----- NMDAr
----- vgCa channels
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2
Q

What are the targets of EtOH at 50 mM?

A

GABAa potentiation
a4 nAChR potentiation
5-HT3 potentiation

AMPA, kainate receptor inhibition

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3
Q

What are the targets of EtOH at 100 mM?

A

vgNa channel inhibition

– respiratory, motor impairment

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4
Q

What is the legal limit for EtOH in the US?

A

.08%, 17 mM

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5
Q

In the naive user, what does EtOH cause at percentages under the legal limit?

A

.02-0.03%
– anxiolysis, mood elevation
– slight muscle relaxation
0.05-0.06%
– relaxation, vasodilation, increased reaction time, relaxation
.08-.09%
– impaired balance, speech, vision, hearing, coordination

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6
Q

What does alcohol do to the user at 0.14-0.15%?

A

ataxia, loss of mental control

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7
Q

What does alcohol do to the naive user at .20 - 0.30%?

A

CNS depression, loss of body control

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8
Q

What does alcohol do the naive user at 0.40 - 0.50%?

A

unconscious, coma
respiratory depression
death

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9
Q

DSM-5 criteria for AUS needs what?

A

in a single 12-month period, clinical impairment and reduced QoL

mild: 2-3 symptoms
moderate: 4-5 symptoms
severe: 6+ symptoms

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10
Q

What are the categories of symptoms for AUD in DSM?

A

loss of control
preoccupation
tolerance and withdrawal

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11
Q

How did DSM-4 differ from 5?

A

1 symptom: abuse

3 or more: dependence

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12
Q

What are alcohol’s actions that cause positive reinforcement? negative?

A

positive

    • increased pleasure
    • altered level of perception
    • peer acceptance

negative reinforcement

    • relief of anxiety, stress
    • relief of withdrawal symptoms
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13
Q

What is the MoA of alcohol?

A

unknown

1) indirect interactions with target proteins
- - simple membrane fluidization
- - redistribution of lateral membrane pressures
- - replacement of H2O at lipid/protein interfaces
- - changes NT binding, desensitizes receptors, internalizes receptors

2) direct interaction with allo-/ortho-steric binding sites
- - low -affinity

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14
Q

The molecular actions of EtOH indicate several drug interactions. What are they?

A

1) increase in DA, endorphins
- - additive effects with opiates
2) decrease in ACh, 5-HT
- - nicotine co-admin is common, may increase ACh back to normal
3) inhibits ADH release
4) potentiates GABA
- - BZDs, barbs

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15
Q

Tolerance to EtOH is accomplished by:

A

PK and PD changes

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16
Q

What systems are adversely affected by EtOH?

A

1) GI
2) CV
3) hepatic
4) CNS

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17
Q

What are the GI ADRs of EtOH?

A

inflammatory
colorectal cancer
mucosal damage
– altered absorption

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18
Q

What are the CV ADRs of EtOH?

A

HTN
stroke
cardiomyopathy

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19
Q

What are the hepatic ADRs of EtOH?

A 
cirrhosis (fatal)
fatty liver disease
ROS
inflammation
CYP induction
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20
Q

What are the CNS ADRs of EtOH?

A 
reduced neurogenesis
tremor
withdrawal seizures
encephalopathy
korsakoff's psychosis and wernickes encephalopathy
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21
Q

What causes wernicke’s encephalopathy and korsakoff’s psychosis?

A

nutritional and cognitive deficiencies

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22
Q

What drugs are used to prevent relapse?

A

disulfiram

naltrexone

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23
Q

How is EtOH withdrawal treated?

A

1) BZDs in a positively-supporting environment
- - treat symptoms
- - vitamins, anti-HTN clonidine
2) acamprosate
- - reduces symptoms

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24
Q

What is the MoA of acamprosate?

A

taurine analog
– potentiates GABAa
– NMDAr-subunit inhibitor
reduces sxs

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25
What is the acamprosate dosage?
666 mg | 2 tabs of 333 mg
26
What is the MoA of disulfiram?
blocks acetaldehyde DH | -- build-up of acetaldehyde
27
What symptoms does acetaldehyde build-up cause? In what population is this common?
flushing, n/v, hyperthermia, pounding HA Asians (lower ALDH, mutation)
28
What is the MoA of naltrexone?
competitive mu-opiate receptor antagonist to block b-endorphin - - reduces EtOH craving and relapse - - best with CBT
29
How is naltrexone supplied?
monthly depot injection
30
What are ADRs of naltrexone?
hepatotoxic at high dose, or if hepatitis damage is present
31
What does excess EtOH exposure cause?
time- and dose-dependent brain degeneration - - neurotoxic - - esp. frontal lobes worse with nutritional/vitamin deficiency
32
How is methanol poisoning treated?
first-line: fomepizole | EtOH if no other option
33
What is the MoA of fomepizole?
ADH inhibitor | -- methanol or ethylene glycol (antifreeze) poisoning
34
How is fomepizole supplied?
injection
35
What is the MoA of EtOH in MeOH poisoning?
competitive ADH inhibitor
36
What is the culprit for damage in MeOH poisoning?
formate - - metabolic acidosis - - tissue injury
37
What future drugs may be used to treat EtOH withdrawal?
1) bupropion 2) varenicline 3) 5-HT3 antagonists (ondansetron) 4) CRH antagonists 5) anticonvulsants 6) mGluR5 antagonists
38
What areas don't have a BBB?
circumventricular organs - - area postrema (CTZ) - - median eminence of HT - - neurohypophysis - - pineal gland, subfornical organ
39
What is the largest potential growth sector for Pharma and why?
CNS disorders | -- only 5% of drugs cross BBB
40
What characteristics does a drug need to cross the BBB?
1) lipid soluble 2) uncharges 3) MW less than 400 Da
41
What drugs do not cross the BBB?
H2O-soluble anti-sense oligonucleotides siRNA viral vectors
42
What are the 5 pathways to cross the BBB?
1) paracellular (rare) 2) transcellular 3) transport proteins 4) receptor-mediated transcytosis 5) adsorptive transcytosis
43
What things cause via transport proteins in the BBB?
glucose AA nucleosides
44
What things cross via receptor-mediated transcytosis?
insulin
45
What things cross the BBB via adsorptive transcytosis?
albumin | plasma proteins
46
How often is CSF turnover?
4-5 hours
47
How can drug be delivered to the brain?
1) intracerebroventricular injection 2) intraparenchymal injection 3) permeabilization 4) nanoparticles and liposome 5) transporter-mediated 6) receptor-mediated 7) intra-nasal
48
What transporters may be useful to get drugs across the BBB via transporter-mediated transport?
GLUT-1: glucose | LAT-1: large amino acids
49
Why are nanoparticles and liposomes useful?
to avoid efflux transporters
50
What are the disadvantages of ICV injection?
1) limited by CSF turnover and diffusion - - bulk flow removes to venous circulation 2) invasive: surgical team and equipment 3) risk of increased ICP, bleeding, infection
51
Describe drug distribution after ICV injection?
exponentially more concentrated in the ventricles
52
Describe intra-parenchymal injection.
better option than ICV | continuous infusion with low-flow implantable pumps
53
How can the BBB be permeabilized?
osmotically | biochemically
54
How is the BBB osmotically opened?
mannitol, intracarotid injection | -- transient shrinkage of endothelial cells
55
How is the BBB biochemically opened?
1) Regadenoson | 2) Lobradimil
56
What is the MoA of regadenoson?
selective Adenosine 2a receptor agonist - - (on surface of brain capillary endothelium) - - reversibly increases permeability, but non-specific
57
What is the MoA of lobradimil?
bradykinin (B2) receptor agonist | -- more effective at blood-tumor barrier
58
What are disadvantages of permeabilizing the BBB?
non-specific | -- leakage of plasma protein and macrophages can be toxic
59
What are emerging methods to circumvent the BBB?
1) block pGp 2) direct injection of embryonic tissue/cells 3) direct injection of viral vectors to express specific proteins 4) prodrugs 5) ultrasound, microbubbles
60
What are the advantages/disadvantages of intranasal delivery?
not efficient non-invasive, good compliance, few ADRs, readily available
61
What is the ViaNase Electronic Atomizer?
drug delivery system | -- electronically-controlled particle dispersion

PHS 931 (29 decks)

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