Sedatives/Hypnotics Flashcards
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
What puts you at risk for psychological dependence on benzodiazepines?
Long-term use, high doses
What two effects of benzodiazepines do not develop tolerance?
Anxiolytic and muscle relaxant effects do not develop tolerance
How does a drug’s half life affect its risk of tolerance and dependence?
Shorter half life –> increased risk
How does a drug’s time to onset affect its risk of tolerance and dependence?
Shorter time to onset –> increased risk
Route of administration can have a major effect
How does a drug’s potency affect its risk of tolerance and dependence?
HIgher potency, higher risk
How does a drug’s dose affect its risk of tolerance and dependence?
increased dose, increased risk
How does a drug’s length of time taken affect its risk of tolerance and dependence?
Longer time, greater risk
Name three BZ1 site-selective non-benzodiazepines.
Zolpidem
Zaleplon
Eszopiclone
Which two BZ1 site-selective benzos are imidazopyridines?
Zolpidem
Zaleplom
Which BZ1 site-selective drug is a pyrrolopyrazine?
Eszopiclone
What is the risk of dependence of BZ1 site-specific agonists compared to benzos?
Are they habit forming?
Decreased risk of tolerance
Long term use –> habit forming
Can overdose with BZ1 site specific agonists be lethal?
Overdose does not produce dangerous CNS depression but can be lethal when taken with other CNS depressants
What are weird/dangerous side effects associated with BZ1 site-specific agonists?
Sleep-driving and sleep-eating
What is the metabolism of the three BZ-1 specific agonists?
Phase I and II in the liver
What are the comparative half lives of the BZ-1 specific agonists?
short (1-3 hours) for the immidazopryidines
Longer (6 hours) for the pyrrolopyrazine (Eszopiclone)
Name the three barbiturates
Phenobarbital
Methohexital
Thiopental
What is the MOA of barbiturates?
Binds to ionotropic GABA-a receptors at regions distinct from BZ1 and BZ2 sites
Likely binds to lipophilic portions of the beta subunits
Differentiate low dose from high dose barbiturate binding effects
Low dose: binding increases duration of Cl- channel opening
High dose; directly activates chloride channel opening, independent of GABA –> no ceiling effect of CNS depression
Compare the half-lives of phenobarbital, thiopental and methohexital
Thiopental and methohexital- short acting
Phenobarbital- long acting
Describe the withdrawal associated with barbiturate use
Discontinuation after repeated use may lead to life-threatening withdrawal that is very difficult to treat
What are the clinical uses of barbiturates?
Limited..
How does Ramelteon work?
Melatonin agonist - selectively binds to MT1 and MT2 melatonin receptors
