Sedatives/Hypnotics Flashcards
(46 cards)
What determines the effect of a sedative/hypnotic?
Dose
Increasing dose –> increased sedation up to coma/death
Which class of sedatives tapers off in effect with dose?
Benzodiazepines
Which class of sedatives continues to increase sedative effects with dosage?
Barbiturates
What type of receptors are GABA-A receptors?
Ionotropic
How do GABA A receptors work?
GABA binding increases the chloride channel opening, leading to an inhibitory post-synaptic potential, hyperpolarization and decreased neuron firing
Which GABA receptor is bound by sedative hypnotics?
GABA-A - they modulate the receptor
Describe the basic structure of the GABA-A receptor
5 subunits assemble to form a hetero-pentameric glycoprotein receptor
7 polypeptide classes –> multiple isoforms
Each polypeptide has 4 transmembrane loops
WHat three isoforms of the gaba polypeptide are required to form a functional GABA-a receptor?
alpha, beta and gamma
What is the composition of the most common GABA-a receptor?
two alpha
two beta
one gamma
Which GABA-a subunit isoform determines ability to be modulated by benzos, imidazopyradine and pyrrolopyrazines?
alpha subunit isoform
WHich interface is the pharmacore that binds the GABA
alpha/beta interface
Which is the allosteric modulatory site responsible for binding benzodiazapines, imidizopyridines and pyrrolopyrazines?
alpha/gamma
Which sites are bound by benzodiazepines?
BZ1 (alpha1) and BZ2 (alpha2)
What type of ligands are benzodiazepines and non-benzodiazepine agonists?
Positive allosteric modulators- they require GABA binding as well for the receptor to open the chloride channel
Do benzodiazepines increase frequency or duration of Cl- channel opening?
Increase frequency
How do barbiturates affect chloride channel opening?
Increase duration
Where do neuroactive steroids bind on GABA-A receptors? What is their effect?
They bind receptors not containing BZ1 or BZ2 receptor sites
They can facilitate or attenuate GABAergic transmission depending on structure
WHat do we have to be concerned with when mixing ethanol and barbiturates/benzos?
Ethanol can potentiate the effects of other GABAa receptor modulators
They target a very different part of the receptor -> potentiation of effects
Which class of drugs is safer- benzodiazepines or barbiturates?
Benzodiazepines- their dose effects taper out with limited capacity for producing potentially fatal CNS depression
Concerns only with polypharmacy and other respiratory problems
Describe the protein binding of benzos in the blood
very good: 60-100%.
Potentially knocked off by other highly protein bound drugs
Describe the metabolism of benzodiazepines:
Phase I: oxidation by P450 family CYP3A4 and CYP2C19
Phase II: Conjugation –> urinary excretion
Which three benzodiazepines are metabolized directly by phase II?
LOT;
Lorazepam
Oxazepam
Temazepam
Why does it take so long for the sedative effects of a benzodiazepine to wear off?
Long half lives
Long half lives of active metabolite
What are common side effects of benzodiazepines?
drowsiness, ataxia, amnesia
