Arnold hayes epilepsy, head injury, alcoholism Flashcards
MOA of benzodiazepines in seizure control
Diazepam, Lorazepam, Midazolam
MOA
-Benzodiazepines enhance the activity of GABA to cause opening of neuronal chloride channels causing hyperpolarisation of the post-synaptic neuron—> reduces its excitability, preventing excessive depolarizations and seizure generation.
-It does so by binding to its site on the GABA-A receptor between the alpha-1 and gamma-2 subunit.
- Benzo’s only work in the presence of GABA
What is the name of the benzo antagonist that can be given to reverse the effects of benzo?
Flumazenil
Describe the synthesis and degradation of GABA
Synthesis:
-Glutamic acid is converted to GABA by glutamic acid decarbozylase + VIT B6 (cofactor)
-Following synthesis it is stored in vesicles by vesicular inhibitory amino acid transporters (VIAATs)
Degradation:
-GABA is reuptaken from the synaptic cleft into GABAergic neurons or nearby glial cells via GABA transporter GAT.
-It can be restored for use or degraded by GABA transaminase to succinate-semi-aldehyde
What effect would the addition of Vigabatrin or Tiagabine have to a treatment regimen for epilepsy
Vigabatrin inhibits the degradation of GABA by GABA transmaminase.
Tiagabine reduces reuptake of GABA by GAT-1 thereby increasing into post-synaptic effects
MOA of sodium valproate and 2 drug interactions
(1) Efects on GABA
- Increases its synthesis
-reduces its degradation by GABA-T
- Increases its release.
(2)Other effects
-Use dependant blockade on VG sodium channels
-Blockade of T-type calcium channels (involved in absence seizures)
Drug interactions
-Lamotrigine levels increase in the presence of sodium valproate due to SV’s inhibition of Glucoronidation enzymes
-Carbapenams reduce sodium valproate levels
MOA of barbiturates in epilepsy control
(1) Phenobarbital binds to the GABA-A receptor and directly activates it causing chloride influx and neuronal hyperpolarisation. It also enhances the effects of GABA. It can work independantly of GABA unlike benzos
(2) Primidone has 3 active moieties that work the same as phenobarbital-> Primidone, phenobarbital and phenylethylmalonamide.
STRONG INDUCERS OF CYP450
Carbamazepine MOA - what effect has it on COCP?
Preferentially inhibits VG sodium channels in their inactive state thereby preventing them from causing repetitive, successive depolarisations and glutamate release from neurons.
Effect on COCP
- Reduces the contraceptive effects of the COCP by increasing its metabolism (induces CYP450 enzymes). Its affects can last for 4 weeks after cessation of carbamezepine.
ADRS
-Dilutional hyponatremia through enchanced ADH activity.
-double vision
-Drowsiness
-Teratogenic
-Skin rash
Lamotrigine MOA and 2 interactions
MOA: Use dependant inhibition of VG sodium channels (i.e. those which are most active) —> prevents repeated depolarisations. Can also inhibit VG N-type and P/Q-type calcium channels, thereby inhibiting synaptic vesicle exocytosis of glutamate.
Interactions
- Sodium valproate: Lamotrigine levels rise in presence of SV due to inhibition of Glucoronidation enzymes.
-COCP causes reduced Lamotrigine levels by increasing its metabolism via glucoronidation.
Why is it important to monitor plasma levels of pheytoin?
Phenytoin is a use-dependant inhibitor of VG sodium channels.
It is important to monitor its plasma concentrations for 2 reasons
1. it has a narrow therapeutic index meaning dosing must be stringtly monitored to avoid toxicity.
2. At therapeutic levels its elimination moves from first order to zero order elimination. This is because the first order enzymes are saturated at therapeutic doses and so zero order (concentration INdependant) elimination takes over. For this reason, a small change in dose can cause a greatly increase the drug plasma levels —> toxicity
Signs of toxicity:
-Nystagmus
-double vision
-Ataxia
-Confusion
-Hyperglycemia
-CVS and respiratory collapse
-Arrythmias
What are the 3 stages of alcoholic liver disease
- Alcoholic Fatty liver (steatosis) - reversible
- Alcoholic hepatitis - reversible
- Cirrhosis - irreversible
Describe the pathogenesis of alcoholic fatty liver disease (steatosis)
(1) Decreased NAD+/NADH Ratio:
Alcohol metabolism by alcohol dehydrogenase produces excess NADH and depletes NAD+, shifting liver metabolism towards fat synthesis (lipogenesis) and inhibiting fatty acid oxidation. This promotes fat accumulation within hepatocytes.
(2) Hepatocyte Toxicity:
Alcohol and its metabolite, acetaldehyde, are toxic to liver cells, leading to oxidative stress and inflammation. This damage impairs the liver’s ability to metabolize and export lipids efficiently
.
(3) Impaired Apoprotein Production:
Alcohol disrupts the production of apoproteins necessary for forming very-low-density lipoproteins (VLDL), which transport triglycerides out of the liver. As a result, triglycerides build up within the liver.
Overall Result: Increased fat synthesis, reduced fat breakdown, and impaired fat export cause fat accumulation in hepatocytes, leading to steatosis.
Name 3 types of liver cirrhosis, which type is mostly associated with alcoholism?
Micronodular
Macronodular
Mixed
Micronodular cirrhosis = alcohol
List 5 pathological features of alcoholic hepatitis
(1) Necrosis of hepatocytes
(2) Ballooning of cells
(3) Mallory bodies - eosinophilic inclusions
(4) Collagen deposition (in space of disse)
(5) steatosis
Describe the pathogenesis of liver cirrhosis
-(1) Stellate Cell Activation and Collagen Deposition:
-In response to liver injury and inflammatory cytokines, hepatic stellate cells become activated, transforming into myofibroblast-like cells that produce and deposit collagen and other extracellular matrix components in the space of Disse.
-This matrix buildup leads to architectural distortion of the liver and disrupts normal sinusoidal blood flow, contributing to vascular resistance, ischemia, and further hepatocyte injury.
(2) Kupffer Cell Involvement:
-Kupffer cells (resident liver macrophages) play a central role by releasing cytokines, such as TGF-beta and TNF-alpha, that activate stellate cells and drive extracellular matrix deposition, perpetuating the cycle of fibrosis.
(3)Hepatocyte Injury and Fibrogenic Signaling:
-Injured hepatocytes release reactive oxygen species (ROS), fibrogenic mediators, and apoptotic signals, all of which stimulate stellate cell activation.
Key cytokines and growth factors involved in this process include platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-beta), and tumor necrosis factor-alpha (TNF-alpha), which collectively enhance the fibrogenic response.
Progression to Cirrhosis:
With repeated injury and chronic inflammation, the cycle of stellate cell activation and collagen deposition leads to irreversible fibrosis and architectural distortion of the liver, ultimately resulting in cirrhosis.
List 4 effects of Thiamine on the CNS
(1) Energy metabolism: provides necessary precursors for carbohydrate metabolism, contributing to the production of ATP for normal neuronal function
(2) Supports the production of glutathione, a necessary antioxidant which protects against oxidative stress.
(3) Neurotransmitter synthesis especially Ach
(4) Myelin sheath maintenance and protection
