Sedative-Hypnotics Flashcards Preview

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Flashcards in Sedative-Hypnotics Deck (73):
1

Clinical uses of sedative hypnotics

Insomnia
Anxiety disorders
Alcohol Withdrawal
Anticonvulsants (some)
Adjunct to anesthesia (some)

2

Classes of Sedative Hypnotic Drugs

GABAa receptor:
Benzodiazepines
Non-benzodiazepines (Imidazopyridines, pyrrolopyrazine)
Barbituates
Alcohol

Others:
Melatonin receptor agonists
Anti-histamines
Herbal preparations

3

GABAa receptors

Ionotropic receptors
Activated by GABA
Increase Cl channel opening
Inhibit post-synaptic potential
Hyperpolarization
Decreased neuron firing

4

Which type of GABA receptors do sedative-hypnotic drugs modulate?

Only GABAa, no not interact with GABAb

5

GABAb receptors

Metabotropic G-protein linked receptors
At presynaptic terminals, regulate the release of GABA (homoreceptors), or other neurotransmitters (heteroreceptors)
At postsynaptic membranes, activation produces hyperpolarization

6

Polypeptide classes and isoforms of GABAa receptor complex

7 polypeptide classes
• α 1 2 3 4 5 6
• β 1 2 3
• γ 1 2 3
• δ
• ε
• π
• ρ 1 2 3

7

How many transmembrane domains does each polypetide subunit of GABAa have?

4

8

How many subunits assemble to form the GABAa hetero-pentameric receptor ?

5

9

Which isoforms are required for a functional GABAa receptor

α, β, γ

10

What are the most common GABAa receptor subtypes?

two (2) α subunits
two (2) β subunits
one (1) γ subunit

11

Which subunit isoform determines the GABAa subtype and its ability to be modulated by certain drugs?

α subunit

12

What are the majority of GABAa subtypes?

BZ1 (α1β2γ2) -60%

13

Which drugs can bind the BZ1 subtype?

Benzodiazepines
Imidazopyridines
Pyrrolopyrazines

14

What isoforms form BZ2?

~15-20% (α2β3γ2)
10-15% ([α3,α5]βnγ2)

15

Which drug can bind BZ2?

Benzodiazepines

16

What percentage of GABAa receptors respond to benzos?

85-95%

17

What percentage of GABAa receptors respond to BZ-1 selective drugs (imidazopyridine, pyrrolopyrazine)

60%

18

α/β interface
-# of sites?
-what does is bind?

-2 sites
-binds GABA

19

α/γ interface
-# of sites?
-what does is bind?
-what does it require?

-1 site
-allosteric modulatory site
-Binds benzodiazepines, Imidazopyridines, pyrrolopyrazines
-needs GABA bound at α/β site

20

Which α-isoforms are found at BZ1 site?

α1

21

Which α-isoforms are found at BZ2 site?

α2, α3, α5

22

Which sites do benzodiazepines bind?

BZ1 and BZ2

23

Which site(s) do imidazopyridine bind?

BZ1

24

Which site(s) do pyrrolopyrazine bind?

BZ2

25

Which sites do Flumazenil bind?

BZ1 and BZ2

26

Benzodiazepines

Bind to BZ1 and BZ2
Positive allosteric modulators of GABAa receptor
GABA required for GABAa receptor to open Cl channels

27

Non-benzodiazepine selective agonists

Selectively bind BZ1
Imidazopyridine: zolpidem, Zaleplon
Pyrrolopyrazine: eszopiclose
Positive allosteric modulators of GABAa receptor
GABA required

28

Mechanism for BZ1 and BZ2 positive allosteric modulation:

Benzo/ selective BZ1 bind >
Increased GABA affinity for GABAa receptor >
Increased FREQUENCY of Cl channels opening >
Inhibitory post synaptic potential >
Hyperpolarization >
Decreased neuron firing

29

Inverse "agonists" (β-Carbolines)

Require GABA's presence
Negative allosteric modulators of GABA receptor (decrease binding at the receptor and decrease frequency of Cl channel opening)
Binds to BZ1 or BZ2 site
Produce anxiety, seizures, block benzo effects

30

Antagonist
(Flumazenil)

High affinity competitive antagonist
No effect alone, blocks effects of drugs binding to BZ1/BZ2
NOTE: will NOT antagonize (GABA agonists, barbituates, meprobamate, ethanol)

31

Clinical uses of flumazenil

Treat BZ overdose
Can precipitate withdrawal in patients dependent on benzos
Reverse BZ-induced sedation

32

Barbituates

Bind to GABAa receptor at site distinct from BZ binding sites
No specificity for isoform
Increases DURATION of Cl channel opening
At high concentrations can directly open Cl channels (no GABA needed)
Effects can be potentiated by alcohol, other drugs that increase GABAa receptor function

33

Why are barbituates more dangerous than benzos?

no specificity for isoform, work on all isoforms
Barbituates do not GABA
Flumazanil does not counteract effect

34

Neuroactive steroids

Affects regions of GABAa receptors distinct from BZ1/BZ2
Affects GABAa receptor isoforms (not containing BZ1/BZ2)
Facilitates GABAergic transmission
At high concentrations can directly produce Cl channel opening

35

Ethanol

Known site of action
Thought to alter GABAa neurotransmission
Effect similar to BZs
Can potentiate the effects of other GABAa receptor modulators

36

Treatment of alcohol withdrawal

Benzodiazepine

37

Benzodiazepine drugs

Midazolam
Triazolam
Alprazolam
Estazolam
Lorazepam
Oxazepam
Temazepam
Clonazepam
Diazepam
*Chlordiazepoxide
*Chlorazepate
(*active metabolite = desmethldiazepam)
"If its AM, PAM, LAM, likely a benzodiazepine"

38

What are the five most prescribed benzodiazepines

Alprazolam
Lorazepam
Clonazepam
Diazepam
Temazepam

39

Clinical use for Benzodiazepines

ANXIETY DISORDERS
SLEEP DISORDERS
Anticonvulsant effects (some)
EtOH withdrawal treatment
Relaxation of skeletal muscles (some)
Adjuncts for anesthesia (some)

40

When do fatality concerns come into play with benzos?

Patient has significant pulmonary illness
Patient has taken multiple meds that have CNS depression effects

41

Pharmacokinetics of Benzos

All lipid soluble
Very good bioavailability
Highly protein bound

42

Metabolism of Benzos

Most metabolized by Phase I and Phase II
3 benzos go directly through Phase II only! : LOT

43

Which 3 benzos only go through Phase II metabolism?

Lorazepam
Oxazepam
Temazepam

44

Abuse of benzos- methadone

Diazepam and alprazolam used w/ methadone to increase euphoric effect

45

Abuse of benzos- cocaine

Use benzos to relieve side effects (irritability and agitation)

46

Abuse of benzos- alcohol

augment its effect and take the edge off withdrawal states

47

Which benzos have short half lives?

Alprazolam
Triazolam
Also "LOT"

48

Which benzos have long half lives?

Diazepam, prazepam, clorazepate, chlordiazepoxide, Flurazepam
(chlordiazepoxide has additional Phase I intermediate with long half life)

49

Which benzos are preferred for geriatric patients or patients with impaired hepatic function?

LOT!
Lorazepam, Oxazepam, Temazepam

50

Side effects of benzos

Frequent: Drowsiness, ataxia, amnesia
Occasional: confusion, paradoxical excitement, dizziness
Rare: paradoxical rage, allergic rxn

51

Tolerance to benzos

Tolerance to sedating effects
NO tolerance to anxiolytic or muscle relaxant effects
Cross tolerance can occur with ethanol

52

Physical dependence and Benzos

Drug removal produces unpleasant symptoms , occur when abruptly stop benzo or rapidly decrease the dose

53

Symptoms of Benzo withdrawal

Common: anxiety, insomnia, loss of appetite, headache, muscle aches, nausea, tremor, sweating, irritability
Rare: confusion, delirium, psychosis, seizures, catatonia

54

Taping benzo dosage

Most you decrease dose is 50% at one time, wait at least a week before lowering dose again

55

Drug duration effect on tolerance/dependence

Shorter half-life = increased risk for dependence/tolerance

56

Amount of time to drug onset effect on tolerance/dependence

Decreased time = increased risk for dependence/tolerance
*route of administration

57

Drug's potency effect on tolerance/dependence

Increased potency = increased risk for dependence/tolerance

58

Dose of drug taken effect on tolerance/dependence

Increased dose = increased risk for dependence/tolerance

59

Time length drug taken effect on tolerance/dependence

Increased time length = increased risk for dependence/tolerance

60

BZ1 site selective Non-benzo Drugs

Imidazopyridines: Zolpidem, Zaleplon
Pyrrolopyrazine: Eszopiclone

61

BZ1 site selective Non-benzo Drugs MOA

Binds BZ1 selectively
Positive modulator of GABAa receptor
Decreased risk of dependence than benzos
Overdose does NOT produce dangeous CNS depression
Flumazenil can block effects

62

BZ1 site selective Non-benzo Drugs Side Effects

Headache, dizziness, somnolence, anterograde amnesia, rebound insomnia, sleep driving, sleep eating

63

Which BZ1 site selective drug has the longest half life?

Eszopiclone

64

What are the benefits of BZ1 site selective drugs over benzos?

Less morning hangover effect
Not restricted for short term use
No effect on stages of sleep

65

Barbiturate Drugs

Phenobarbital
Methohexital
Thiopental
"AL" the barbiturates

66

Barbiturate MOA

Binds to ionotropic GABAa receptors at regions distinct from BZ1/BZ2
Likely binds intramembrane lipophillic portions of β subunits
No specificity for isoform subtype
Low doses: increases DURATION of Cl channel opening (needs GABA)
High doses: Can directly activity Cl channel opening (no GABA)

67

Short acting Barbituates

t1/2= hours
Thiopental, Mexihexital
Rapid onset, induce anesthesia

68

Intermediate acting Barbiturates

t1/2=18-48 hours
Amobarbital, Secobarbital, Pentobarbital
Now replaced by benzos

69

Long acting Barbiturates

t1/2 = 4-5 days
Phenobarbital
Used for epilepsy

70

Barbiturates Side Effects

Low therapeutic index
Lethal

71

Ramelteon MOA

Melatonin agonist
Selectively binds MT1 & MT2 melatonin receptors
No affinity for BZ1/BZ2

72

Ramelteon Pharmacokinetics

Rapid absorption
Moderate protein bidning
Large volume distribution
Extensive 1st pass metabolism
Short half life

73

Ramelteon Side effects

Comparable to placebo
(headache, somnolence, fatigue, dizziness, nausea, worsened insomnia)
Well tolerated even if taken for long period
No physical dependence or abuse potential!