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Therapeutics P2 Winter Semester > PHRM845 Exam 4 > Flashcards

PHRM845 Exam 4 Flashcards

Pathophysiology of anxiety and sleep disorders

1
Q

What is a sedative?

A

Calms anxiety, decreases excitement and activity, does not produce drowsiness, or impair performance

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2
Q

What is an anxiolytic?

A

Antianxiety, relieves anxiety without sleep or sedation (not all anxiolytics are sedatives)

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3
Q

What is a hypnotic?

A

Induces sleep, implies restful, refreshing sleep, not “hypnotized!”, natural sleep (medial use term: sleeping-inducing)

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4
Q

What is a narcotic?

A

Actually means “sleep producing”, now refers to opioids or illegal drugs

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5
Q

What is the reticular formation and where is it located?

A

-An intricate system composed of loosely clustered neurons in what is otherwise white matter
-The reticular formation extends through the central core of the medulla oblongata, pons, and midbrain.
-It is very complex; contains dopamine, adrenergic, serotonergic, and cholinergic neurons
-Regulates sleep-wake transitions and synchronization of EEG.

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6
Q

Stages of sleep

A

-Wakefulness
-Non-rapid eye movement (NREM) slow-wave sleep
-Rapid eye movement (REM) sleep

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7
Q

NREM sleep stages

A

Stage 1 (dozing)
Stage 2 (unequivocal sleep)
Stage 3 (voltage increase, frequency decrease)
Stage 4 (delta waves)

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8
Q

EEG for REM sleep is similar to EEG when ___

A

Awake

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9
Q

Sleep deprivation means a decrease in time in ___

A

Total Sleep
Delta Sleep
REM

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10
Q

Factors that regulate sleep

A

-Age: Decreases with age due to changes in activity of reticular formation
-Sleep History: Rebound of REM sleep
-Drug Ingestion: Acute and withdrawal produce rebound effects
-Circadian Rhythms: “Normal sleep cycle”

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11
Q

How long is an Ultradian Rhythm?

A

90 minutes

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12
Q

Biological regulators of sleep

A

Neurotransmitters (almost all):
-Catecholamines (e.g., epinephrine, norepinephrine, and dopamine)
-Serotonin (5HT)
-Histamine
-Acetylcholine (ACh)
-Adenosine
-GABA (main target for current medications)
Neuromodulators:
-Growth Hormone (GH)
-Prolactin
-Cortisol
-Melatonin — “hormone of darkness”
-Endogenous Peptides

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13
Q

What neurotransmitter is the main target for current medications?

A

GABA

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14
Q

What is GABA?

A

Major inhibitory signal that quiets the brain down.

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15
Q

Explain impact of GABA in seizures and anxiety

A

Seizure-too much excitability (not enough GABA)
Anxiety-want to quiet excitatory neurons

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16
Q

With GABA-A receptors, we want more ___ influx.

A

Cl-; chloride channel causes more negative charge and membrane becomes hyperpolarized making it harder to activate an action potential.

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17
Q

How do benzodiazepines bind to GABA-A receptor?

A

They bind at an allosteric binding site to allow more Cl- to enter.

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18
Q

GABA-A receptor/chloride ion channel complex is a target for

A

Sedative-hypnotics

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19
Q

Most common CNS GABA-A receptors

A

2a1, 2b2, 1g2

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20
Q

Orthosteric and allosteric sites on GABA-A receptor

A

Orthosteric site: GABA (a1 and b2)
Allosteric Sites- benzodiazepine (BZD) site (a1 and g2)
-Barbiturate
-Ethanol
-Glucocorticoid
-?
Channel pore (picrotoxin)

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21
Q

Ligands acting at the BZD Receptor

A

-Benzodiazepines: Facilitate GABA action (e.g., a1-5), increase frequency, require intact GABA system (internal safety system)
-Non-Benzodiazepines (Z-Hypnotics): zolpidem (Ambien®), zaleplon (Sonata®), eszopiclone (LunestaTM) – BZ1 receptors of a1
-BZD Antagonists: flumazenil (Romazicon®), overdose treatment
-Inverse BZD Agonists: B carbolines

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22
Q

Benzodiazepines are (very/not very) specific. They are also (addictive/not addictive).

A

Not very specific
Addictive because it binds so many different targets.

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23
Q

Z-hypnotics have (more/less) side effects because binding is very (specific/non-specific).

A

Less
specific

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24
Q

Modulation of the GABA-A receptor
a. BZD
b. Barbiturates
c. Alcohol
d. GABA channel blockers
e. Etomidate and propofol
f. Neurosteroids

A

BZDs: Increase frequency of channel opening,
Barbiturtates (Bbt): Increase duration of channel opening, and direct effects on GABAA (high doses)

Alcohol: Enhances actions of GABA at GABAA receptor

GABA channel blockers: picrotoxin

Etomidate and Propofol (Diprovan; aka “milk of amnesia”): b2 and b3 subunit containing receptors

Neurosteroids (e.g., progesterone and deoxycortisone) for treating depression, etc

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25
Q

Importance of GABA channel blocker: Picrotoxin

A

Toxic, so don’t use as a drug.
Directly blocks ion conduction pathway,

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26
Q

Structure Activity relationships of Benzodiazepines

A

1 Position alkylation  source of active metabolites
**Annealating the 1-2 bond with an “electron rich” ring (triazole or imidazole) yields high affinity and decreased half-life

27
Q

Half-life of diazepam

A

Long

28
Q

Use of Chlordiazepoxide (Librium®)

A

1st benzodiazepine, used as an anxiolytic and for alcohol withdrawal, accumulation of metabolites

29
Q

Use of Diazepam (Valium®)

A

Prototypical benzodiazepine, used as an anxiolytic, for alcohol withdrawal, and for treatment of convulsive disorders (seizures), accumulation of metabolites

30
Q

Use of Flurazepam (Dalmane®)

A

Used as a hypnotic, accumulation of metabolites

31
Q

Use of Clorazepate (Tranxene®)

A

Used as an anxiolytic, for alcohol withdrawal, and for treatment of convulsive disorders, accumulation of metabolites

32
Q

Use of Quazepam (Doral®)

A

Used as a hypnotic, accumulation of metabolites (good or bad for helping sleeping?)

33
Q

Use of Prazepam (Currently unavailable in the US)

A

Used as an anxiolytic

34
Q

Meds with slow elimination rates: all have active metabolites

A

Chlordiazepoxide (Librium®)
Diazepam (Valium®)
Flurazepam (Dalmane®)
Clorazepate (Tranxene®)
Quazepam (Doral®)
Prazepam

35
Q

Meds with intermediate elimination rates

A

Alprazolam
Lorazepam
Clonazepam
Oxazepam
Temazepam

36
Q

Use of Alprazolam (Xanax®)

A

Withdrawal symptoms can present if abrupt discontinuation occurs, used as an anxiolytic and anesthetic

37
Q

Use of Lorazepam (Ativan®)

A

Used as an anxiolytic and as a hypnotic

38
Q

Use of Clonazepam (Klonopin®)

A

Tolerance may develop with prolonged use, used as an anticonvulsant

39
Q

Use of Oxazepam (Serax®)

A

Used as an anxiolytic and for alcohol withdrawal

40
Q

Use of Temazepam (Restoril®)

A

Used as a short-term hypnotic

41
Q

Meds with rapid elimination rates

A

Midazolam and Triazolam

42
Q

Use of Midazolam (Versed)

A

Rapid anesthesia

43
Q

Importance of rapid elimination rates

A

Get in fast–>do job–>get out
**Good for seizures

44
Q

Benzodiazepines usage

A

Slow Elimination
-Accumulation
-Active Metabolites
-Drowsiness and Sedation
-Useful in patients who “wake up”

Intermediate to Rapid Elimination
-Preferable in patients with hepatic problems
-Preferable in elderly patients
-Drugs that alter liver enzymes
-Rapid tolerance
-Rebound Insomnia

45
Q

Which meds should we be careful with in elderly patients and why?

A

Benzodiazepines
Increase risk of falls, mobility, driving, and increase cognitive issues.

46
Q

General considerations for benzodiazepines

A

-Readily absorbed (can delayed by food)
-have active metabolites or are converted to active forms
-Increased lipid solubility will increase speed of delivery to brain
-Redistribution to highly perfused tissue may decrease duration of action
-Cross placental barrier and are detected in breast milk
-Extensive protein binding, but not clinically significant

47
Q

Are barbituates or benzodiazepines more dangerous?

A

Barbituates; as you increase the dose, you just keep increasing the side effects
-If you keep increasing the dose, it can lead to sedation; if increasing it more, it can cause seizure–>coma

-In a coma, the brain does not have much activity (“brain dead”) and many cannot wake up
-Increases frequency of Cl- opening and too many Cl- influx.

48
Q

Is it easy or hard to OD on benzodiazepines?

A

Hard; easy on barbiturates

49
Q

Pharmacological properties of benzodiazepines

A

-Anxiolytic
-Sleep Physiology
-Reduce sleep latency
-Increase total sleep time
-Increase stage 2
-Decrease REM
-Decrease stage 3 and 4 (good or bad?)–bad because you still feel like you did not get enough sleep
-Tolerance and rebound to delta and REM
-Anticonvulsant activity
-Muscle relaxant
-Cardiovascular and respiratory depression (major issue when combine with other agents)
-Anterograde amnesia
-Unable to recall events that occurred
**Not as commonly used as sleeping agents as before
**You increase total sleeping time, but decrease amount of time in REM

50
Q

Toxicology of benzodiazepines

A

Side Effects (Dose dependent)
-Sedation
-Confusion
-Ataxia
-Daytime Sedation
-With longer acting agents, tolerance develops
-Weakness, Headache, Vertigo, Nausea, Paradoxical effects
Precautions and Interactions
-Other sedatives, Alcohol
-Pregnancy and breast-feeding
-Drug Dependence and Abuse
-Abuse Potential –>Low vs barbiturates
-Small “Kick” (Often when in combination with other drugs of abuse)
**Does not lead to coma
**Often OD from multiple agents
**Alcohol also acts on GABA receptor, so pt can get pleasure from EtOH and BZD

51
Q

BENZODIAZEPINE ANTAGONIST

A

Flumazenil (Romazicon®)
-Therapeutic use–>treat BZD overdose
Side Effects
-Induce Convulsions*
-Panic Attacks*
-Agitation
-Confusion
-Nausea and Vomiting
-Headache
*are for those who developed dependence

52
Q

Is flumazenil a barbituate antagonist?

A

NO

53
Q

Non-Benzos (Z-Hypnotics): act as a BZD binding site

A

-BZ1 receptor

54
Q

Examples of Z-hypnotics

A

Zolpidem (Ambien®, Ambien CRTM)
Short-term treatment of insomnia
With difficulty of sleep-onset
Ambien CRTM for sleep maintenance

Zaleplon (Sonata®)
Short-term treatment of insomnia (7-10 days)
Rapid acting, Rapidly eliminated
Little tolerance or dependence

Eszopiclone (LunestaTM)
Active enantiomer of zopiclone
50 times greater affinity
Treatment of insomnia
Approved for long-term use

**These have a very specific binding
**Some take zolpidem (short term) version for longer time, but not great practice

55
Q

Common features of Z-hypnotics
-Metabolism
-OD tx

A

Metabolism
CYP3A4 to some extent

Overdose Treatment
Flumazenil (Romazicon®)

56
Q

Z-hypnotics side effects

A

-Daytime drowsiness, dizziness, ataxia, nausea, and vomiting
-Cause less negative effects on sleep patterns vs. BZD
-Sleep-driving, sleep-cooking, sleep-eating, sleep-sex (FDA: warn your patient)

57
Q

Illicit Use of Sedative-Hypnotics That Target the Benzodiazepine Binding Site

A

Benzodiazepines
-Flunitrazepam (C-IV)
~Not Available in United States
~“Roofies”
~DEA recommends changing to C-I
~Anterograde Amnesia
>Dangerous aid for sexual assault (mainly combine with alcohol)

-Clonazepam (C-IV) (research use in treating social deficits of autism)
Klonopin®

Nonbenzodiazepines
Zolpidem (C-IV)
Ambien® and Ambien CRTM
“A-minus” and “Zombie Pills”
Dangerous aid for sexual assault
Teen party drug

58
Q

Barbiturates Long acting

A

Anticonvulsants
-Phenobarbital (Luminal®)
-Mephobarbital (Mebaral®)

59
Q

Barbiturates short to intermediate acting

A

Sedative-Hypnotics
-Amobarbital (Amytal®)
-Butabarbital (Butisol Sodium®)
-Pentobarbital (Nembutal®)
-Secobarbital (Seconal®)
-Aprobarbital (Alurate®)

60
Q

Barbiturates ultra-short acting

A

IV Anesthetics
-Thiopental (Pentothal®)
-Methohexital (Brevital® Sodium)
-Thiamylal (Surital®)

61
Q

Pharmacology of barbiturates

A

-Anticonvulsant
-Idiosyncratic excitement and pain
-Dependence
-Tolerance
-Abuse
-Withdrawal
-Overdose
-“After Effect” (Hangover, Accumulation)
-Sleep Physiology
-Comparable to BZD
-Decrease REM
-Slow Deep Sleep
-Cardiovascular Depression (at high doses)
-Respiratory Depression (death)
-Enzyme Interactions
-Compete for Cytochrome P450s for metabolism
-Enzyme Induction

62
Q

PK of barbiturates

A

Duration of Action
-Inversely proportional to lipid solubility
Decrease of Activities
-Metabolic transformations and redistribution

Ultra-Short and Short Acting
-Determined by redistribution
Anesthetics
-Determined by lipid solubility and rapid redistribution

Long Half-life
-Accumulation

63
Q

Summary of BZD and barbiturates

A

-Barbiturtates (BBT): bind to all GABAA a1-5; Increase the duration of channel opening; and direct effects on GABAA channel (high doses); higher risk
-Benzodiazepines (BZDs): bind to all GABAA a1-5; Increase frequency of GABAA channel opening; medium risk
-Z-Hypnotics: bind to GABAA BZ1 receptors of a1; Increase frequency of GABAA channel opening; lower risk
-The use and limitation of Flumazenil
**Flumazenil is used for BZD and Z-hypnotic OD
**Flumazenil cannot be used for barbiturate OD

-New GABA drugs are being tested to treat a variety of conditions and target different subunits.
-Depression, autism (excitation/inhibition imbalance)–>ketamine is the most effective drug for depression
-GABAA, GABAB

Therapeutics P2 Winter Semester (29 decks)

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