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55 Cards in this Set

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Benzodiazepines?
"I AM PAM, a LAM"
Alprazolam
Clonazepam
Diazepam
Estazolam
Flurazepam
Flunitrazepam
Lorazepam
Oxazepram
Temazepam
Triazolam
Non-benzodiazepines? (3)
Eszopiclone
Zolpidem
Zaleplon
Tricyclic Antidepressants? (3)
Amitryptyline
Doxepin
Imipramine
Barbituates? (3)
Pentobarbital
Phenobarbital
Thiopental sodium
What is a common characteristic of all sedative-hypnotics?
produce a GRADED dose-dependent depression of CNS function
MOA of sedative-hypnotic drugs?
facilitate GABA transmission via actions at GABA-a receptors
what is a sedative (anxiolytic)?
reduces anxiety and exerts a calming effect
what is a hypnotic?
produces drowsiness and facilitates the onset and maintenance of sleep (involves a greater depression of CNS than sedation)
what is a GABA receptor?
a major inhibitory AA neurotransmitter receptor in the brain
Action of GABA-A receptors?
-ionotropic receptor
-increases opening of chloride channels --> inhibitory post-synaptic potential (hyperpolarization)
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
MOA of baclofen?
Use of baclofen?
baclofen: a selective GABA-B agonist

an anti-spastic drug
Stx of GABA-A receptor?
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**
what structural features of GABA receptors primarily determines the benzodiazepine binding site?
the type of alpha subunit that is co-assembled w/ the gamma-2* subunit

(see pic)
4 things that bind to GABA receptor?
1. picrotoxin
2. GABA
3. barbituates
4. benzos
MOA: non-selective benzo agonists?
benzos that bind to both BZ1 and BZ2 sites

DO NOT directly compete with GABA at its binding site
What drugs are non-benzodiazepine agonists?
Imidazopyridines: Zolpidem and Zaleplon (BZ1 agonists)

Pyrrolopyrazine: Eszopiclone (Lunesta)
MOA of benzo antagonists?
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
why do benzos exhibit variable rates of absorption w/in the class?
all are lipid soluble, but lipophilicity varies up to 50-fold
bioavailability of benzos?
-very good: 60-100%

-protein-bound: 70 (alprazolam) to 99% (diazepam)
MOA of benzos?
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
sedative-hypnotics and pregnancy?
-all of them cross the placental barrier and appear in breast milk

-may reduce neonatal vital fxns
-may be teratogenic
what largely determines the clinical applications of benzos?
pharmacokinetic differences
-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**
7-nitro derivatives?

metabolism phase?
Clonazepam and Flunitrazepam

-phase I and II metabolism
What drug is known as the "date rape" pill?
Flunitrazepam
triazolo derivatives?

metabolism phase?
Midazolam
Alprazolam
Triazolam

-phase I and II metabolism
3-hydroxy derivatives?

-metabolism phase(s)
**Oxazepram, Lorazepam, Temazepam**

-metabolism: phase II, so conjugated and not metabolized to bioactive substances
**what benzos are best for elderly patients and those with impaired hepatic fxn and why?**
3-hydroxy derivatives: Oxazepram, Lorazepam, Temazepam
-not metabolized to bioactive substances with long half-lives
-only undergo conjugation (phase 2)
frequent S/Es of benzos?
drowsiness
ataxia
amnesia
occasional S/Es of benzos?
confusion*
paradoxical excitement* (kids and elderly)
dizziness
rare S/Es of benzos?
paradoxical rage reaction*
extrapyramidal symptoms w/ chlordiazepoxide
allergic rxn
what S/Es are middle age and elderly pts especially susceptible to when given high doses of benzos (i.e. trazolam)?
-confusion
-paradoxical excitement
-paradoxical rage rxn
cross-tolerance developed w/ benzo use?
to ethanol and other sedative-hypnotics
problems w/ benzos?
-cross tolerance (EtOH and other sedatives)
-psychological dependence
-abused along with alcohol
-withdrawl symptoms (anxiety and insomnia) occur after stopping frequent use
mneumonic for barbituates?
"AL the barbituate"
What barbituates are most commonly used today?
Phenobarbital
Methohexital
Thiopental
**MOA of barbituates?**
Bind to sites on ionotropic GABA-A receptors (diff sites than benzos)

-binding INCREASES THE DURATION of opening of chloride channels**
What does it mean that barbituates can be "GABA-mimetic"?
GABA-mimetic = at high concentrations barbituates can directly activate the opening of chloride channels in absence of GABA
Picrotoxin?
a barbituate agonist --> induces convulsions by directly blocking chloride channel
Strychnine?
a glycine antagonist; convulsant effects
how are barbituates classified?
by duration of action
short-acting barbituates?
Thiopental
Mexihexital
intermediate-acting barbituates?
Amobarbital
Secobarbital
Pentobarbital
Long-acting barbituate?
Phenobarbital
4 adverse effects of barbituates?
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)**
Clinical uses of barbituates?
1. Epilepsy (phenobarbital)

2. Induction of anesthesia (thiopental and methohexital)
Clinical use of the Carbamates (Meprobamate)?
rarely used -- anti-anxiety drug
Older sedative-hypnotics?
1. Carbamates
2. Alcohol
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
Adverse effects of Ramelteon?
headache, fatigue, dizziness, nausea, exacerbated insomnia
What Benzos have both Phase I & II metabolism?
Diazepam
Flurazepam
Clonazepam
Flunitrazepam

short Phase I:
Midazolam
Alprazolam
Triazolam
What Benzos only have Phase II conjugation?
Oxazepam
Lorazepam
Temazepam
What is an active metabolite of Diazepam and other benzos?
Desmethyldiazepam
Which hypnotic is a melatonin receptor agonist?
Ramelteon