Introduction to CNS Pharmacology pt2 Flashcards
What is GABAa receptor comprised of?
Comprised of 5 individual protein subunits arranged around a central pore permeable to chloride and bicarbonate.
How many GABAa receptor subunits have been identified?
Nineteen GABAA receptor subunits have been identified to date (alpha1-6, beta1-3, gamma1-3, delta, epsilon, theta, pi, and rho1-3)
What do GABAa receptors which mediate transient currents at inhibitory synapses typically comprise?
GABAA receptors mediating transient currents at inhibitory synapses typically comprise two alpha-, two beta-, and one gamma-subunit.
What does the activation of GABAa receptor lead to?
Activation of GABAA receptor leads to chloride ion flux, hyperpolarisation of neuronal membrane, and therefore inhibition.
What drugs act on the GABAa receptor?
Site of action of barbiturates (e.g. phenobarbital) and benzodiazepines (e.g. diazepam).
How do phenobarbital and benzodiazepines enhance the binding of GABA to GABAa receptor and what is the effect called?
PB and DZP bind to distinct sites on receptor complex and enhance response to binding of GABA.
DZP binds at boundary of a- and Y-subunit, PB binds to TM3 of β-subunits (speculative).
Effect is termed “positive allosteric modulation”.
Can Barbiturates activate the GABAa receptor in the absence of GABA?
Barbiturates can activate receptor in absence of GABA.
Which drug activates receptors containing a3 subunits and delta-subunits?
STP activates receptors containing a3 subunits, also effective at those containing d-subunit (BZD insensitive)
Search google for AED effects on GABAa receptors or look at slide 15 of anticonvulsant drugs
Well, did you look?
Where do Gabapentin and pregabalin bind on P/Q - type calcium channels?
Gabapentin, pregabalin bind to the ancillary a2-d1 subunit of the voltage-gated calcium channel.
The a2-d1 subunit of the voltage-gated calcium channel is associated with Cav2.1 a-subunit to form the P/Q-type channel.
Involved in neurotransmitter release at synapse; glutamate?
Highly effective in pain therapy
What is Perampanel?
Perampanel is a selective, non-competitive antagonist at AMPA subtype of glutamate receptor.
How does Perampanel work?
Binds at boundary of extracellular and transmembrane domains; affects conformation
No efficacy at NMDA or kainate receptors
AMPA receptors involved in fast excitatory synaptic transmission
Perampanel appears well tolerated; unlike most glutamate receptor antagonists
How does Levetiracetam treat epilepsy?
It is shown to bind selectively to SV2A (synaptic modulation glycoprotein 2A) with no binding being shown at SV2B or SV2C.
It is unclear what SV2A does or what LEV does to SV2A. But we do know that it is involved in the coupling of calcium entry to NT release at synapse.
What Valproate proposed to do? And what other diseases may it treat?
Valproate (aka valproic acid or sodium valproate)
Efficacy discovered 1962, first used clinically 1967, mechanism unknown
Proposed to:
Block sodium channels
Block T-type calcium channels
Enhance effects of GABA at GABAA receptor
Promote GABA synthesis and inhibit GABA metabolism
Reduce brain aspartate concentration
Drug also effective in bipolar disorder and migraine and under investigation in schizophrenia, HIV infection, and cancer; pharmacology is complex!
Inhibits histone deacetylase in the nucleus and has epigenetic effects; may influence the expression of multiple brain proteins
Go to slide 20 of anticonvulsant drugs to see the principal targets for AEDs.
Look at them for real tho!
What is a focal seizure?
Focal seizures, also called focal seizures, begin in one area of the brain, but can become generalized and spread to other areas.
What are Na+ channel blockers effective against?
Na+ channel blockers (e.g. CBZ & LTG) are effective against focal seizures and generalised tonic-clonic seizures.
What type of drugs are effective against absence seizures?
T-type Ca2+ channel blockers (e.g. Ethosuximide) are effective against absence seizures.
What drugs have efficacy against focal seizures and most generalized seizure types?
GABAA receptor drugs (e.g. PB & BZDs) are broad-spectrum, with efficacy against focal seizures and most generalized seizure types
Besides PB and BZDs what other drugs are also considered broad spectrum
AEDs with multiple mechanisms (e.g. VPA) are also broad-spectrum.
What are the most commonly prescribed AEDs in the UK?
sodium valproate. carbamazepine. lamotrigine. levetiracetam. topiramate.
What are some of the general adverse effects of AEDs?
All AEDs cause dose-related CNS adverse effects such as somnolence, dizziness, fatigue, ataxia, and headache
What are some of the more specific adverse effects of AEDs?
Most AEDs have one or more “characteristic” adverse effects, including:
Hypersensitivity (i.e. skin rash): CBZ, PHT, LTG, OXC, ESL
Blood dyscrasias: PHT, CBZ, VPA, LTG, FBM
Weight gain: VPA, PGB
Teratogenicity: VPA
Visual field constriction: VGB
Blue pigmentation: RTG
What % of AED patients experience Hypersensitivity?
And what does it necessitate?
Mild rash: 5-10% exposures to CBZ, PHT, LTG, etc.
Titration and co-medication dependent
Necessitates withdrawal
What is the prevalence of severe hypersensitivity?
Severe reaction: 1 in 10,000 exposures to CBZ, PHT, LTG.
What can a severe adverse reaction to an AED lead to?
Stevens-Johnson syndrome / toxic epidermal necrolysis
Skin blistering ~30% body area
Mortality 10-30%
Unpredictable, not dose-related
Some members of the population are genetically predisposed to a severe reaction.
The Genotype HLA-B*15:01 in Han Chinese particularly.
What are the adverse reactions of VPA?
Valproate
Weight gain and PCOS: common
- Disruption of hormonal balance (incl. insulin)
Hepatotoxicity: 1 in 10,000 exposures
- Generation of toxic 4-ene-VPA metabolite
Teratogenicity: 1 in 10 exposures
- Birth defects including cleft lip/palate & spina bifida
Neurodevelopmental delay: 1 in 4 exposures
- Significant reduction in IQ of exposed child
What are some of the Adverse reactions of FBM?
Felbamate
Launched in 1993
First new AED in the US for 15 years
110,000 exposures in the first year
32 aplastic anemia (14 fatal): 145 days
18 liver failure (9 fatal): 217 days
Atropaldehyde metabolite*
Never approved for routine use in UK
Still used on a named-patient basis
What are some of the factors influencing drug choice in epilepsy?
The type of seizure
The syndrome
If it is a new-onset
If epilepsy is chronic
What are some of the factors influencing drug choice in epilepsy regarding the patient?
- Age
- Gender
- Reproductive Status
- Learning Difficulties
- Co-morbidities
- Patient’s views
- Likely adherence
- Drug history
- Ethnicity
What are some of the factors influencing drug choice in epilepsy regarding the drug itself?
- Mechanism of action
- Formulations
- Pharmacokinetics
- Drug interactions
- Spectrum of activity
- Efficacy
- Titration schedule
- Idiosyncratic reactions
- Other adverse effects
- Cost
What is the prognosis of treated epilepsy?
Seizures may remit spontaneously; most patients will have epilepsy for life
Only ~40% of patients will be seizure-free for ≥12 months on first AED
Around 65-70% of patients enter remission with optimized drug treatment
Generalized epilepsies are more responsive than focal epilepsies
Males are more responsive than females (marginally)
No. of seizures prior to starting treatment is a strong predictor of outcome
Patients who fail 3 AED regimens due to lack of efficacy have less than a 5% chance of ever achieving a 12-month period of seizure-freedom
