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

Block 4 Lecture 1 -- Alcohol and the BBB Flashcards

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
Q

What is the acamprosate dosage?

A

666 mg

2 tabs of 333 mg

26
Q

What is the MoA of disulfiram?

A

blocks acetaldehyde DH

– build-up of acetaldehyde

27
Q

What symptoms does acetaldehyde build-up cause?

In what population is this common?

A

flushing, n/v, hyperthermia, pounding HA

Asians (lower ALDH, mutation)

28
Q

What is the MoA of naltrexone?

A

competitive mu-opiate receptor antagonist to block b-endorphin

    • reduces EtOH craving and relapse
    • best with CBT
29
Q

How is naltrexone supplied?

A

monthly depot injection

30
Q

What are ADRs of naltrexone?

A

hepatotoxic at high dose, or if hepatitis damage is present

31
Q

What does excess EtOH exposure cause?

A

time- and dose-dependent brain degeneration

    • neurotoxic
    • esp. frontal lobes

worse with nutritional/vitamin deficiency

32
Q

How is methanol poisoning treated?

A

first-line: fomepizole

EtOH if no other option

33
Q

What is the MoA of fomepizole?

A

ADH inhibitor

– methanol or ethylene glycol (antifreeze) poisoning

34
Q

How is fomepizole supplied?

A

injection

35
Q

What is the MoA of EtOH in MeOH poisoning?

A

competitive ADH inhibitor

36
Q

What is the culprit for damage in MeOH poisoning?

A

formate

    • metabolic acidosis
    • tissue injury
37
Q

What future drugs may be used to treat EtOH withdrawal?

A

1) bupropion
2) varenicline
3) 5-HT3 antagonists (ondansetron)
4) CRH antagonists
5) anticonvulsants
6) mGluR5 antagonists

38
Q

What areas don’t have a BBB?

A

circumventricular organs

    • area postrema (CTZ)
    • median eminence of HT
    • neurohypophysis
    • pineal gland, subfornical organ
39
Q

What is the largest potential growth sector for Pharma and why?

A

CNS disorders

– only 5% of drugs cross BBB

40
Q

What characteristics does a drug need to cross the BBB?

A

1) lipid soluble
2) uncharges
3) MW less than 400 Da

41
Q

What drugs do not cross the BBB?

A

H2O-soluble
anti-sense oligonucleotides
siRNA
viral vectors

42
Q

What are the 5 pathways to cross the BBB?

A

1) paracellular (rare)
2) transcellular
3) transport proteins
4) receptor-mediated transcytosis
5) adsorptive transcytosis

43
Q

What things cause via transport proteins in the BBB?

A

glucose
AA
nucleosides

44
Q

What things cross via receptor-mediated transcytosis?

A

insulin

45
Q

What things cross the BBB via adsorptive transcytosis?

A

albumin

plasma proteins

46
Q

How often is CSF turnover?

A

4-5 hours

47
Q

How can drug be delivered to the brain?

A

1) intracerebroventricular injection
2) intraparenchymal injection
3) permeabilization
4) nanoparticles and liposome
5) transporter-mediated
6) receptor-mediated
7) intra-nasal

48
Q

What transporters may be useful to get drugs across the BBB via transporter-mediated transport?

A

GLUT-1: glucose

LAT-1: large amino acids

49
Q

Why are nanoparticles and liposomes useful?

A

to avoid efflux transporters

50
Q

What are the disadvantages of ICV injection?

A

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
Q

Describe drug distribution after ICV injection?

A

exponentially more concentrated in the ventricles

52
Q

Describe intra-parenchymal injection.

A

better option than ICV

continuous infusion with low-flow implantable pumps

53
Q

How can the BBB be permeabilized?

A

osmotically

biochemically

54
Q

How is the BBB osmotically opened?

A

mannitol, intracarotid injection

– transient shrinkage of endothelial cells

55
Q

How is the BBB biochemically opened?

A

1) Regadenoson

2) Lobradimil

56
Q

What is the MoA of regadenoson?

A

selective Adenosine 2a receptor agonist

    • (on surface of brain capillary endothelium)
    • reversibly increases permeability, but non-specific
57
Q

What is the MoA of lobradimil?

A

bradykinin (B2) receptor agonist

– more effective at blood-tumor barrier

58
Q

What are disadvantages of permeabilizing the BBB?

A

non-specific

– leakage of plasma protein and macrophages can be toxic

59
Q

What are emerging methods to circumvent the BBB?

A

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
Q

What are the advantages/disadvantages of intranasal delivery?

A

not efficient

non-invasive, good compliance, few ADRs, readily available

61
Q

What is the ViaNase Electronic Atomizer?

A

drug delivery system

– electronically-controlled particle dispersion

PHS 931 (29 decks)

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