Pharm2 - #04 - Pharm Of Sedative-Hypnotic Drugs

Front 1

Benzodiazepines?

Back 1

"I AM PAM, a LAM"
Alprazolam
Clonazepam
Diazepam
Estazolam
Flurazepam
Flunitrazepam
Lorazepam
Oxazepram
Temazepam
Triazolam

Front 2

Non-benzodiazepines? (3)

Back 2

Eszopiclone
Zolpidem
Zaleplon

Front 3

Tricyclic Antidepressants? (3)

Back 3

Amitryptyline
Doxepin
Imipramine

Front 4

Barbituates? (3)

Back 4

Pentobarbital
Phenobarbital
Thiopental sodium

Front 5

What is a common characteristic of all sedative-hypnotics?

Back 5

produce a GRADED dose-dependent depression of CNS function

Front 6

MOA of sedative-hypnotic drugs?

Back 6

facilitate GABA transmission via actions at GABA-a receptors

Front 7

what is a sedative (anxiolytic)?

Back 7

reduces anxiety and exerts a calming effect

Front 8

what is a hypnotic?

Back 8

produces drowsiness and facilitates the onset and maintenance of sleep (involves a greater depression of CNS than sedation)

Front 9

what is a GABA receptor?

Back 9

a major inhibitory AA neurotransmitter receptor in the brain

Front 10

Action of GABA-A receptors?

Back 10

-ionotropic receptor
-increases opening of chloride channels --> inhibitory post-synaptic potential (hyperpolarization)

Front 11

Actions of GABA-B receptors?

Locations of this receptor?

Back 11

-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

Front 12

MOA of baclofen?
Use of baclofen?

Back 12

baclofen: a selective GABA-B agonist

an anti-spastic drug

Front 13

Stx of GABA-A receptor?

Back 13

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**

Front 14

what structural features of GABA receptors primarily determines the benzodiazepine binding site?

Back 14

the type of alpha subunit that is co-assembled w/ the gamma-2* subunit

(see pic)

Front 15

4 things that bind to GABA receptor?

Back 15

1. picrotoxin
2. GABA
3. barbituates
4. benzos

Front 16

MOA: non-selective benzo agonists?

Back 16

benzos that bind to both BZ1 and BZ2 sites

DO NOT directly compete with GABA at its binding site

Front 17

What drugs are non-benzodiazepine agonists?

Back 17

Imidazopyridines: Zolpidem and Zaleplon (BZ1 agonists)

Pyrrolopyrazine: Eszopiclone (Lunesta)

Front 18

MOA of benzo antagonists?

Back 18

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

Front 19

why do benzos exhibit variable rates of absorption w/in the class?

Back 19

all are lipid soluble, but lipophilicity varies up to 50-fold

Front 20

bioavailability of benzos?

Back 20

-very good: 60-100%

-protein-bound: 70 (alprazolam) to 99% (diazepam)

Front 21

MOA of benzos?

Back 21

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

Front 22

sedative-hypnotics and pregnancy?

Back 22

-all of them cross the placental barrier and appear in breast milk

-may reduce neonatal vital fxns
-may be teratogenic

Front 23

what largely determines the clinical applications of benzos?

Back 23

pharmacokinetic differences

Front 24

-what drugs are 2-keto derivatives

-metabolism phase(s)

-how do the parent compounds differ from the active metabolites?

Back 24

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**

Front 25

7-nitro derivatives?

metabolism phase?

Back 25

Clonazepam and Flunitrazepam

-phase I and II metabolism

Front 26

What drug is known as the "date rape" pill?

Back 26

Flunitrazepam

Front 27

triazolo derivatives?

metabolism phase?

Back 27

Midazolam
Alprazolam
Triazolam

-phase I and II metabolism

Front 28

3-hydroxy derivatives?

-metabolism phase(s)

Back 28

**Oxazepram, Lorazepam, Temazepam**

-metabolism: phase II, so conjugated and not metabolized to bioactive substances

Front 29

**what benzos are best for elderly patients and those with impaired hepatic fxn and why?**

Back 29

3-hydroxy derivatives: Oxazepram, Lorazepam, Temazepam
-not metabolized to bioactive substances with long half-lives
-only undergo conjugation (phase 2)

Front 30

frequent S/Es of benzos?

Back 30

drowsiness
ataxia
amnesia

Front 31

occasional S/Es of benzos?

Back 31

confusion*
paradoxical excitement* (kids and elderly)
dizziness

Front 32

rare S/Es of benzos?

Back 32

paradoxical rage reaction*
extrapyramidal symptoms w/ chlordiazepoxide
allergic rxn

Front 33

what S/Es are middle age and elderly pts especially susceptible to when given high doses of benzos (i.e. trazolam)?

Back 33

-confusion
-paradoxical excitement
-paradoxical rage rxn

Front 34

cross-tolerance developed w/ benzo use?

Back 34

to ethanol and other sedative-hypnotics

Front 35

problems w/ benzos?

Back 35

-cross tolerance (EtOH and other sedatives)
-psychological dependence
-abused along with alcohol
-withdrawl symptoms (anxiety and insomnia) occur after stopping frequent use

Front 36

mneumonic for barbituates?

Back 36

"AL the barbituate"

Front 37

What barbituates are most commonly used today?

Back 37

Phenobarbital
Methohexital
Thiopental

Front 38

**MOA of barbituates?**

Back 38

Bind to sites on ionotropic GABA-A receptors (diff sites than benzos)

-binding INCREASES THE DURATION of opening of chloride channels**

Front 39

What does it mean that barbituates can be "GABA-mimetic"?

Back 39

GABA-mimetic = at high concentrations barbituates can directly activate the opening of chloride channels in absence of GABA

Front 40

Picrotoxin?

Back 40

a barbituate agonist --> induces convulsions by directly blocking chloride channel

Front 41

Strychnine?

Back 41

a glycine antagonist; convulsant effects

Front 42

how are barbituates classified?

Back 42

by duration of action

Front 43

short-acting barbituates?

Back 43

Thiopental
Mexihexital

Front 44

intermediate-acting barbituates?

Back 44

Amobarbital
Secobarbital
Pentobarbital

Front 45

Long-acting barbituate?

Back 45

Phenobarbital

Front 46

4 adverse effects of barbituates?

Back 46

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)**

Front 47

Clinical uses of barbituates?

Back 47

1. Epilepsy (phenobarbital)

2. Induction of anesthesia (thiopental and methohexital)

Front 48

Clinical use of the Carbamates (Meprobamate)?

Back 48

rarely used -- anti-anxiety drug

Front 49

Older sedative-hypnotics?

Back 49

1. Carbamates
2. Alcohol

Front 50

Ramelteon:

MOA?

Approved for?

Back 50

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

Front 51

Adverse effects of Ramelteon?

Back 51

headache, fatigue, dizziness, nausea, exacerbated insomnia

Front 52

What Benzos have both Phase I & II metabolism?

Back 52

Diazepam
Flurazepam
Clonazepam
Flunitrazepam

short Phase I:
Midazolam
Alprazolam
Triazolam

Front 53

What Benzos only have Phase II conjugation?

Back 53

Oxazepam
Lorazepam
Temazepam

Front 54

What is an active metabolite of Diazepam and other benzos?

Back 54

Desmethyldiazepam

Front 55

Which hypnotic is a melatonin receptor agonist?

Back 55

Ramelteon