GABA(A) Receptor is (monomer/trimer/pentamer) with which subunits?
Pentamer;
alpha, beta, and either gamma or delta
(X) number of GABA bind to activate GABA(A) Receptor. (Y) number of benzos bind to modulate.
X = 2 Y = 1
“Phasic” GABA(A) R location is (X) and has (gamma/delta) subunit.
X = at synapse
Gamma
“Tonic” GABA(A) R location is (X) and has (gamma/delta) subunit.
X = extra-synaptic
Delta
T/F: All GABA(A) receptors are responsive to benzos.
False - tonic GABA(A) R are not
(Tonic/phasic) GABA(A) receptors have very fast response.
Phasic (at synapse)
Most common GABA(A) receptor subtype.
alpha(1)beta(2)gamma(2)
Which alpha subunit sbind benzos most efficiently?
Alpha(2) and Alpha(3)
List the various effects of the Benzos.
- Anxiolytic action
- Sedation/hypnosis and muscle relaxant
- Anticonvulsant action
T/F: Benzo-like drugs are indicated for alcohol/cocaine withdrawal.
True (BUT be careful since benzos plus EtOH can be fatal!!)
Benzos are contraindicated in patients with which diseases?
- COPD
- Alcohol abuse
- Sleep apnea
Benzos should be administered with caution in which patients?
- Elderly (decrease clearance)
- Suicidal (abuse potential)
- Lung, liver, kidney disease
T/F: Benzodiazepines have replaced barbiturates as sedative-hypnotic drugs.
True (safer, higher therapeutic index)
T/F: Barbiturates have greater specificity of action in CNS than Benzos.
False
Benzos are fairly (lipo/hydro)-philic, administered (IV/po) with (slow/quick) onset of CNS effect.
Lipophilic;
Both (high bioavailability and safety via p.o.)
Quick (immediate in case of IV)
T/F: Benzos are primarily cleared without modification/transformation into metabolites.
False - biotransformation (CYP450) into active metabolites
T/F: Duration of action of benzos is dependent strictly on the life of the parent drug.
False - depends also on active metabolites
T/F: Chronic benzos use leads to psych and physical dependence.
True
T/F: Signs of benzos withdrawal are typically (mild/severe) and worse with (short/long)-acting benzos.
Mild (anxiety, sleep issues);
Short
T/F: Benzos efficacy is greater than barbiturates.
False
List the few clinical uses of barbiturates in US.
IV: rapid onset/offset anesthesia (thiopental)
PO: intractable seizures in kids (phenobarbital)
T/F: Barbiturates act as GABA(A) receptor agonists.
True (at high concentrations); thus can act as potentiators or agonsts
(X) is the most commonlyused IV general anesthetic in the U.S. It acts as a(n) (Y) receptor (agonist/antagonist/modulator).
X = propofol Y = GABA(A)
Positive modulator (increase affinity of receptor for GABA)
Drugs used for simple (no loss of consciousness) seizures. Star the “drugs of choice” (as opposed to the alternatives).
- Lamotrigine*
- Carbamazepine*
- Phenytoin
Phenytoin mechanism of action. Which drugs work in the same way?
Prolongs Na channel inactivation state
Lamotrigine, carbamazepine
Drugs used for complex (impaired consciousness) seizures. Star the “drugs of choice” (as opposed to the alternatives).
- Lamotrigine*
- Carbamazepine*
- Phenytoin
SAME AS SIMPLE SEIZURES
Drugs used for simple (with secondarily generalized tonic/clonic) seizures. Star the “drugs of choice” (as opposed to the alternatives).
- Lamotrigine*
- Carbamazepine*
- Phenytoin
SAME AS COMPLEX SEIZURES
Drug(s) of choice used for generalized tonic/clonic seizures.
Valproate
Valproate MOA
- Enhance GABA transmission (increase its synthesis, inhibits its degradation by GABA transaminase)
- Reduce Ca flow through T-type Ca channels
Drug(s) of choice used for generalized absence seizures.
- Ethosuximide
2. Valproate
T/F: Benzos are used to generalized (tonic-clonic, absence, myoclonic) seizures.
True - Clonazepam is used as “alternative” (not drug of choice)
Ethosuximide
Reduce Ca flow through T-type Ca channels
Drug(s) of choice used for generalized myoclonic seizures.
- Valproate
2. Lamotrigine
Drug(s) of choice for refractory seizures.
Benzos (diazepam, lorazepam)
Starting epilepsy treatment is typically done after (X) number of unprovoked seizure if it occurs (Y) time after the first.
X = 2nd Y = over 24h
T/F: Monotherapy is the gold standard of treatment for epilepsy.
True - only a very small percentage of patients cannot be treated with a single drug.
What are recommendations regarding switching anticonvulsant drug from brand to generic?
Physicians are urged to keep patients on the medication that is currently managing their disease - increased chance of breakthrough seizures if switched to generic
List three older AEDs that are used less due to disadvantages such as CYP450 interactions.
- Carbamazepine
- Phenytoin
- Valproate
(X) is an old AEDs that is used less due to disadvantages such as potentially fatal hepatotoxicity.
X = Valproate
(X) is an old AEDs that is used less due to disadvantages such as diplopia and ataxia.
Carbamazepine and Phenytoin