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55 Cards in this Set
- Front
- Back
Benzodiazepines?
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"I AM PAM, a LAM"
Alprazolam Clonazepam Diazepam Estazolam Flurazepam Flunitrazepam Lorazepam Oxazepram Temazepam Triazolam |
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Non-benzodiazepines? (3)
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Eszopiclone
Zolpidem Zaleplon |
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Tricyclic Antidepressants? (3)
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Amitryptyline
Doxepin Imipramine |
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Barbituates? (3)
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Pentobarbital
Phenobarbital Thiopental sodium |
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What is a common characteristic of all sedative-hypnotics?
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produce a GRADED dose-dependent depression of CNS function
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MOA of sedative-hypnotic drugs?
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facilitate GABA transmission via actions at GABA-a receptors
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what is a sedative (anxiolytic)?
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reduces anxiety and exerts a calming effect
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what is a hypnotic?
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produces drowsiness and facilitates the onset and maintenance of sleep (involves a greater depression of CNS than sedation)
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what is a GABA receptor?
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a major inhibitory AA neurotransmitter receptor in the brain
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Action of GABA-A receptors?
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-ionotropic receptor
-increases opening of chloride channels --> inhibitory post-synaptic potential (hyperpolarization) |
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Actions of GABA-B receptors?
Locations of this receptor? |
-metabotropic G-protein-linked receptor
-located on: 1. presynaptic terminals controlling release of GABA ("homoreceptors") or other NTs ("heteroreceptors") via decreases in Ca++ conductance 2. postsynaptic membranes producing hyperpolarization of the membrane via increases in K+ conductance |
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MOA of baclofen?
Use of baclofen? |
baclofen: a selective GABA-B agonist
an anti-spastic drug |
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Stx of GABA-A receptor?
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Heteropentameric glycoprotein**
Each subunit has 4 transmembrane domains Both amino* AND carboxy terminus in extracellular side Two intracellular loops for phosphorylation Majority have two alpha-1, two beta-2, and one gamma-2 subunits** |
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what structural features of GABA receptors primarily determines the benzodiazepine binding site?
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the type of alpha subunit that is co-assembled w/ the gamma-2* subunit
(see pic) |
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4 things that bind to GABA receptor?
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1. picrotoxin
2. GABA 3. barbituates 4. benzos |
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MOA: non-selective benzo agonists?
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benzos that bind to both BZ1 and BZ2 sites
DO NOT directly compete with GABA at its binding site |
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What drugs are non-benzodiazepine agonists?
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Imidazopyridines: Zolpidem and Zaleplon (BZ1 agonists)
Pyrrolopyrazine: Eszopiclone (Lunesta) |
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MOA of benzo antagonists?
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Competitive antagonists w/ high affinity for benzo (BDZ) receptor.
Blocks actions of benzos and imidazopyradine, but does not antagonize actions of barbituates, meprobamate, or ethanol |
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why do benzos exhibit variable rates of absorption w/in the class?
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all are lipid soluble, but lipophilicity varies up to 50-fold
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bioavailability of benzos?
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-very good: 60-100%
-protein-bound: 70 (alprazolam) to 99% (diazepam) |
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MOA of benzos?
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modulate activity of GABA-a receptor-mediated inhibition
-binding of a benzo to GABA-a receptor increases affinity of GABA for its site and increases frequenzy of opening of chloride channels |
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sedative-hypnotics and pregnancy?
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-all of them cross the placental barrier and appear in breast milk
-may reduce neonatal vital fxns -may be teratogenic |
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what largely determines the clinical applications of benzos?
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pharmacokinetic differences
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-what drugs are 2-keto derivatives
-metabolism phase(s) -how do the parent compounds differ from the active metabolites? |
Diazepam and Flurazepam
Phase I and II metabolism Parent compounds have short 1/2-lives Active metabolites have 1/2-lives b/w 50-100 hrs** |
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7-nitro derivatives?
metabolism phase? |
Clonazepam and Flunitrazepam
-phase I and II metabolism |
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What drug is known as the "date rape" pill?
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Flunitrazepam
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triazolo derivatives?
metabolism phase? |
Midazolam
Alprazolam Triazolam -phase I and II metabolism |
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3-hydroxy derivatives?
-metabolism phase(s) |
**Oxazepram, Lorazepam, Temazepam**
-metabolism: phase II, so conjugated and not metabolized to bioactive substances |
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**what benzos are best for elderly patients and those with impaired hepatic fxn and why?**
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3-hydroxy derivatives: Oxazepram, Lorazepam, Temazepam
-not metabolized to bioactive substances with long half-lives -only undergo conjugation (phase 2) |
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frequent S/Es of benzos?
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drowsiness
ataxia amnesia |
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occasional S/Es of benzos?
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confusion*
paradoxical excitement* (kids and elderly) dizziness |
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rare S/Es of benzos?
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paradoxical rage reaction*
extrapyramidal symptoms w/ chlordiazepoxide allergic rxn |
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what S/Es are middle age and elderly pts especially susceptible to when given high doses of benzos (i.e. trazolam)?
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-confusion
-paradoxical excitement -paradoxical rage rxn |
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cross-tolerance developed w/ benzo use?
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to ethanol and other sedative-hypnotics
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problems w/ benzos?
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-cross tolerance (EtOH and other sedatives)
-psychological dependence -abused along with alcohol -withdrawl symptoms (anxiety and insomnia) occur after stopping frequent use |
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mneumonic for barbituates?
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"AL the barbituate"
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What barbituates are most commonly used today?
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Phenobarbital
Methohexital Thiopental |
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**MOA of barbituates?**
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Bind to sites on ionotropic GABA-A receptors (diff sites than benzos)
-binding INCREASES THE DURATION of opening of chloride channels** |
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What does it mean that barbituates can be "GABA-mimetic"?
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GABA-mimetic = at high concentrations barbituates can directly activate the opening of chloride channels in absence of GABA
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Picrotoxin?
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a barbituate agonist --> induces convulsions by directly blocking chloride channel
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Strychnine?
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a glycine antagonist; convulsant effects
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how are barbituates classified?
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by duration of action
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short-acting barbituates?
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Thiopental
Mexihexital |
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intermediate-acting barbituates?
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Amobarbital
Secobarbital Pentobarbital |
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Long-acting barbituate?
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Phenobarbital
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4 adverse effects of barbituates?
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1. low therapeutic index** - depress respiration especially w/ EtOH
2. produce physical dependence --> life-threatening withdrawl syndrome 3. stimulate cyp450 activity and induce hepatic microsomal oxidases --> pharm tolerance, cross-tolerance, drug interactions 4. **barbituates can induce anaesthesia (benzos cannot)** |
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Clinical uses of barbituates?
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1. Epilepsy (phenobarbital)
2. Induction of anesthesia (thiopental and methohexital) |
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Clinical use of the Carbamates (Meprobamate)?
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rarely used -- anti-anxiety drug
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Older sedative-hypnotics?
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1. Carbamates
2. Alcohol |
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Ramelteon:
MOA? Approved for? |
Novel sedative-hypnotic
MOA: melatonin receptor agonist w/ high affinity for MT1 & MT2 melatonin receptors (i.e. mimics actions of melatonin that maintains circadian sleep rhythms) Use: tx of insomnia characterized by difficulty in falling asleep |
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Adverse effects of Ramelteon?
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headache, fatigue, dizziness, nausea, exacerbated insomnia
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What Benzos have both Phase I & II metabolism?
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Diazepam
Flurazepam Clonazepam Flunitrazepam short Phase I: Midazolam Alprazolam Triazolam |
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What Benzos only have Phase II conjugation?
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Oxazepam
Lorazepam Temazepam |
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What is an active metabolite of Diazepam and other benzos?
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Desmethyldiazepam
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Which hypnotic is a melatonin receptor agonist?
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Ramelteon
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