Block 4 Lecture 1 -- Alcohol and the BBB Flashcards
What are the drug targets of EtOH under the legal limit?
1 mM -- delta GABAa potentiation 10 mM -- GlyR potentiation -- inhibition of... ----- a7 nAChR ----- NMDAr ----- vgCa channels
What are the targets of EtOH at 50 mM?
GABAa potentiation
a4 nAChR potentiation
5-HT3 potentiation
AMPA, kainate receptor inhibition
What are the targets of EtOH at 100 mM?
vgNa channel inhibition
– respiratory, motor impairment
What is the legal limit for EtOH in the US?
.08%, 17 mM
In the naive user, what does EtOH cause at percentages under the legal limit?
.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
What does alcohol do to the user at 0.14-0.15%?
ataxia, loss of mental control
What does alcohol do to the naive user at .20 - 0.30%?
CNS depression, loss of body control
What does alcohol do the naive user at 0.40 - 0.50%?
unconscious, coma
respiratory depression
death
DSM-5 criteria for AUS needs what?
in a single 12-month period, clinical impairment and reduced QoL
mild: 2-3 symptoms
moderate: 4-5 symptoms
severe: 6+ symptoms
What are the categories of symptoms for AUD in DSM?
loss of control
preoccupation
tolerance and withdrawal
How did DSM-4 differ from 5?
1 symptom: abuse
3 or more: dependence
What are alcohol’s actions that cause positive reinforcement? negative?
positive
- increased pleasure
- altered level of perception
- peer acceptance
negative reinforcement
- relief of anxiety, stress
- relief of withdrawal symptoms
What is the MoA of alcohol?
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
The molecular actions of EtOH indicate several drug interactions. What are they?
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
Tolerance to EtOH is accomplished by:
PK and PD changes
What systems are adversely affected by EtOH?
1) GI
2) CV
3) hepatic
4) CNS
What are the GI ADRs of EtOH?
inflammatory
colorectal cancer
mucosal damage
– altered absorption
What are the CV ADRs of EtOH?
HTN
stroke
cardiomyopathy
What are the hepatic ADRs of EtOH?
cirrhosis (fatal) fatty liver disease ROS inflammation CYP induction
What are the CNS ADRs of EtOH?
reduced neurogenesis tremor withdrawal seizures encephalopathy korsakoff's psychosis and wernickes encephalopathy
What causes wernicke’s encephalopathy and korsakoff’s psychosis?
nutritional and cognitive deficiencies
What drugs are used to prevent relapse?
disulfiram
naltrexone
How is EtOH withdrawal treated?
1) BZDs in a positively-supporting environment
- - treat symptoms
- - vitamins, anti-HTN clonidine
2) acamprosate
- - reduces symptoms
What is the MoA of acamprosate?
taurine analog
– potentiates GABAa
– NMDAr-subunit inhibitor
reduces sxs
What is the acamprosate dosage?
666 mg
2 tabs of 333 mg
What is the MoA of disulfiram?
blocks acetaldehyde DH
– build-up of acetaldehyde
What symptoms does acetaldehyde build-up cause?
In what population is this common?
flushing, n/v, hyperthermia, pounding HA
Asians (lower ALDH, mutation)
What is the MoA of naltrexone?
competitive mu-opiate receptor antagonist to block b-endorphin
- reduces EtOH craving and relapse
- best with CBT
How is naltrexone supplied?
monthly depot injection
What are ADRs of naltrexone?
hepatotoxic at high dose, or if hepatitis damage is present
What does excess EtOH exposure cause?
time- and dose-dependent brain degeneration
- neurotoxic
- esp. frontal lobes
worse with nutritional/vitamin deficiency
How is methanol poisoning treated?
first-line: fomepizole
EtOH if no other option
What is the MoA of fomepizole?
ADH inhibitor
– methanol or ethylene glycol (antifreeze) poisoning
How is fomepizole supplied?
injection
What is the MoA of EtOH in MeOH poisoning?
competitive ADH inhibitor
What is the culprit for damage in MeOH poisoning?
formate
- metabolic acidosis
- tissue injury
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
What areas don’t have a BBB?
circumventricular organs
- area postrema (CTZ)
- median eminence of HT
- neurohypophysis
- pineal gland, subfornical organ
What is the largest potential growth sector for Pharma and why?
CNS disorders
– only 5% of drugs cross BBB
What characteristics does a drug need to cross the BBB?
1) lipid soluble
2) uncharges
3) MW less than 400 Da
What drugs do not cross the BBB?
H2O-soluble
anti-sense oligonucleotides
siRNA
viral vectors
What are the 5 pathways to cross the BBB?
1) paracellular (rare)
2) transcellular
3) transport proteins
4) receptor-mediated transcytosis
5) adsorptive transcytosis
What things cause via transport proteins in the BBB?
glucose
AA
nucleosides
What things cross via receptor-mediated transcytosis?
insulin
What things cross the BBB via adsorptive transcytosis?
albumin
plasma proteins
How often is CSF turnover?
4-5 hours
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
What transporters may be useful to get drugs across the BBB via transporter-mediated transport?
GLUT-1: glucose
LAT-1: large amino acids
Why are nanoparticles and liposomes useful?
to avoid efflux transporters
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
Describe drug distribution after ICV injection?
exponentially more concentrated in the ventricles
Describe intra-parenchymal injection.
better option than ICV
continuous infusion with low-flow implantable pumps
How can the BBB be permeabilized?
osmotically
biochemically
How is the BBB osmotically opened?
mannitol, intracarotid injection
– transient shrinkage of endothelial cells
How is the BBB biochemically opened?
1) Regadenoson
2) Lobradimil
What is the MoA of regadenoson?
selective Adenosine 2a receptor agonist
- (on surface of brain capillary endothelium)
- reversibly increases permeability, but non-specific
What is the MoA of lobradimil?
bradykinin (B2) receptor agonist
– more effective at blood-tumor barrier
What are disadvantages of permeabilizing the BBB?
non-specific
– leakage of plasma protein and macrophages can be toxic
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
What are the advantages/disadvantages of intranasal delivery?
not efficient
non-invasive, good compliance, few ADRs, readily available
What is the ViaNase Electronic Atomizer?
drug delivery system
– electronically-controlled particle dispersion
