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Therapeutics P2 Winter Semester > PHRM845 Exam 4 (Yang) > Flashcards

PHRM845 Exam 4 (Yang) Flashcards

Sedative, hypnotics, and anxiolytics Part 2

1
Q

Additional Sedative-Hypnotics. Primarily focusing on which receptor?

A

GABA-B

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2
Q

GABA-B is (metabotropic/ionotropic)

A

Metabotropic; it is a GPCR

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3
Q

GABA-B is a ____ receptor. This means it is (excitable/inhibitory).

A

Gi/o-coupled receptor
Inhibitory (increase Cl- influx)

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4
Q

Heterodimers in GABA-B

A

Two related seven-transmembrane domain receptors subunits
GABAB1
GABAB2

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5
Q

Location of heterodimers

A

Brain
Limbic System

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6
Q

How do GABA-B receptors impose their inhibitory effect?

A

Presynaptic-Decrease Ca2+ conductance
Postsynaptic-Increase K+ conductance

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7
Q

Agonists of GABA-B

A

Baclofen
-Skeletal Muscle Relaxant (treatment of alcoholism)
Gamma-Hydroxybutyric Acid (GHB)
-Central Nervous System Depressant

**These enhance the inhibitory effect of GABA-B

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8
Q

Antagonist of GABA-B

A

Phaclofen, Saclofen, and 2-Hydroxysaclofen
**Mainly used for research

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9
Q

What does increasing potassium conductance do to a cell?

A

Hyperpolarizes it

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10
Q

Cataplexy definition

A

Sudden and transient episode of muscle weakness accompanied by full conscious awareness, typically triggered by emotions such as laughing, crying, terror, etc

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11
Q

Xyrem (sodium oxybate, GHB)

A

C-I  Illicit use and C-III  Medical use (liquid)
-Available only to prescribers enrolled in the Xyrem® Patient Success Program®
-Actions
With concomitant stimulant use…
~Decrease Excessive Daytime Sleepiness
~Increase Daytime Wakefulness
~Decrease Cataplexy
-Pharmacology
~GABAB, GABAA, and GHB (?) Receptors
-Concerns
~Mechanism (?)
~Combined with other agents
~Red Tape
~Abuse and Misuse

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12
Q

Xyrem has (no/strong) color and odor

A

No

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13
Q

Why must prescribers be enrolled in Xyrem patient success programs?

A

There is huge abuse potential. Get people high which leads to addiction.

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14
Q

Gamma-Hydroxybutyric Acid (GHB)

A

Street Names
-“Liquid Ecstasy“, “Liquid X”, “Juice”, “Grievous Bodily Harm”, “Scoops”, “Georgia Home Boy”
Background
-1960’s to Today: Anesthetic, Fat Burner, Growth hormone Promoter, “Raves”, Date Rape, and Bodybuilding
Pharmacology
-CNS Depression (Dose dependent)
-Dizziness
-Drowsiness
-Coma (with increasing dose; like barbiturates)
-Patients often awaken spontaneously
-Prodrugs
~Gamma-Butyrolactone (GBL)
~1,4-Butanediol

**Combined use with marijuana and alcohol have an unknown effect (AVOID USE)

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15
Q

Acute effects and concerns of GHB

A

Acute Effects
-Loss of Consciousness and Reflexes
-Amnesia
-Nausea and Vomiting
-Headache
-Seizures
-Death
Concerns
-Supportive Treatment — No antagonist
-Other Sedative-Hypnotics — Including alcohol
-Amnesia
-Date Rape — Examinations and counseling (liquid, odorless, tasteless, etc)

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16
Q

Ramelteon (RozeremTM): Melatonin Agonist

A

Mechanism of Action
-High affinity for MT1 and MT2 melatonin receptors
-Receptors located in the suprachiasmatic nucleus (SCN)
-Serves as the “master clock” by regulating circadian rhythms — Loss of melatonin in aging and Alzheimer’s
Metabolism
-CYP1A2 substrate
-Treatment of insomnia characterized by difficulty with sleep onset
-Non-Controlled Substance sleep aid
-No abuse, withdrawal, or dependency (GOOD!)
-Negligible risk for next-day “hangover” effects

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17
Q

Tasimelteon (HetliozTM): Melatonin Agonist

A

Mechanism of Action
-High affinity for MT1 and MT2 melatonin receptors

-Treatment of Non-24-hour sleep wake disorder (non-24) in blind individuals

-Orphan product registration
1. Small population for clinical trial
2. Patent lasts longer
3. Fast FDA approval

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18
Q

Orexin neurons/hypocretin system

A

The orexin neurons innervate and excite many brain regions that drive arousal and attention, including the locus coeruleus and the dorsal raphe. Rewarding stimuli trigger release of dopamine from the mesolimbic projections between the ventral tegmental area and the nucleus accumbens, and orexins enhance signaling in this pathway. As Brisbare-Roch et al. have found, an orexin antagonist that blocks these signals can promote sleep (by reducing arousal) and possibly aid in the treatment of drug addiction (by dampening reward signals).

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19
Q

Suvorexant (Belsomra): Orexin Receptor Antagonist

A

Mechanism of Action
-High-affinity antagonist (sub nanomolar) for OX1 and OX2 orexin receptors–so you are not as wakeful
-Receptors located in the hypothalamus
-Decrease arousal and attention via receptors in locus coeruleus and the raphe.
-Reduce rewarding stimuli (DA release) via receptors that modulate the mesolimbic projections between the VTA and the nucleus accumbens.
-Treatment of insomnia
-Morning impairment likely/possible (use the lowest dose possible)
-Scheduled CIV

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20
Q

FDA Requests Label Change for All Sleep Disorder Drug Products

A

Including the newer nonbenzodiazepine drugs
Eszopiclone
Ramelteon
Zaleplon
Zolpidem

FDA required labeling needs to include information about Sleep-Related Behaviors
-Sleep-driving
-Cooking and eating food (while sleeping)
-Making phone calls (while sleeping)

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21
Q

MORE SEDATIVE-HYPNOTICS (in history)

A

Trazodone
-Antidepressant (lots of targets)
-Hypnotic-Unlabeled/Investigational Use
Antihistamines (OTC Drugs)
-Diphenhydramine
-Doxylamine
-Pyrilamine

22
Q

Concern with herbal/natural sedative hypnotics

A

They contain less than 1/2 the ingredients that the labels claim–quality is difficult to control

23
Q

Tryptophan herbal

A

Dietary Supplement
5HT Precursor
Withdrawn from market due to contamination
Caused eosinophilia-myalgia syndrome

24
Q

Melatonin herbal

A

Nutraceutical
Travelers’ Jet Lag
Work Shifts — Insomnia
Sleep Disturbances
Signs and Symptoms of Overdose
Ataxia

25
Q

Lemon balm herbal

A

Herb
Use with caution in patients with thyroid problems

26
Q

Valerian (Valeriana officinalis)

A

Herb
Insomnia
Hepatotoxicity has been noted

27
Q

Chamomile

A

Matricaria chamomilla
Matricaria recutita
Herb
Mild Sedative
Avoid use in patients with a ragweed allergy
Use with caution in patients using cytochrome P450 substrates

28
Q

Kava Kava

A

Herb
Insomnia
Possibly hepatotoxic

29
Q

SEDATIVE-HYPNOTICS OVERDOSE

A

Incidence and Severity
-Commonly encountered in emergency room
-Benzodiazepines or Z-hypnotics in combination with other agents
Causes
-Suicide and Suicide Gesture
-Drug Abuse
Signs and Symptoms
-Depressed respiration
-Blood Pressure
-Reflexes
-Hypothermia
Treatment
-Supportive Treatment
-Maintain Respiration
-Maintain Cardiovascular Function
-Flumazenil for Benzodiazepines or Z-hypnotics

30
Q

What are anxiolytic agents used for?

A

Anxiety

31
Q

What is anxiety?

A

Fear or apprehension of something dreadful

32
Q

When does anxiety need to be treated?

A

When it interferes with normal life
When it interferes with part of another disease

33
Q

Feelings of anxiety

A

-Uncomfortable feeling of vague fear or apprehension, accompanied by characteristic physical sensations:
-Mental features: worry, fear, impaired concentration
-Physical features: racing heart, shortness of breath, pacing

34
Q

We need anxiety to do some things, but if it is too strong then we have a problem. To perform your best/stay alert, it is best to have ___% of anxiety.

A

20-30

35
Q

Types of Anxiety

A

-Generalized Anxiety Disorder (GAD)
-Panic Disorder
-Social Anxiety Disorder or Social Phobia
-Obsessive-Compulsive Disorder (OCD)
-Post-Traumatic Stress Disorder (PTSD)
*Anxiety Associated with other Medical Issues (e.g., autism, depression)

36
Q

Drug- and Disease-Induced Anxiety

A

Drugs
-Cocaine
-Beta Agonists
-Psychostimulants (caffeine)
-Corticosteroids
Diseases
-CHF
-COPD
-Diagnosis of Terminal Diseases
Withdrawal
-Antidepressants
-Anxiolytics
-Drugs of Abuse
-Cell phone/social media? (intentionally put these away so it is easier to focus)

37
Q

Neurotransmitters and Anxiety

A

Norepinephrine (NE)
-Over-active locus coeruleus-release NE
-Stimulate autonomic nervous system

-Dysregulated in GAD and other types of anxiety
-Projects to the amygdala (fear center)–if no fear ever, the brain amygdala region does not light up–NO anxiety/fear

38
Q

GABAergic system in anxiety

A

-Normally counteracts/balances stimulatory effects of excess NE
-Hypothesis proposes reduced GABAergic signaling. Agents that increase GABA signaling are anxiolytic
-GABA/Glutamate (I/E) balance (Glutamate is converted to GABA by glutamic acid decarboxylase -> GAD in the CNS)
-Involved in GAD and Panic Disorder

39
Q

Serotonin for anxiety

A

-May reflect tone at multiple receptors/SSRIs have efficacy

-Partial agonist of 5HT1A receptors effective
-May involve amygdala and balance with NE
-GAD, Panic, OCD, Social Anxiety

40
Q

Corticotropin-Releasing Factor (CRF) and the HPA Axis

A

Hyperregulation
Suppression after treatment in PTSD

41
Q

Drug tx for anxiety

A

Benzodiazepines (quick acting, effective)-target GABA-A

Antidepressants (SSRIs, SNRIs, TCAs, take weeks–very slow acting which is bad because it does not help depressed pts quickly); new breakthrough: ketamine (nasal spray esketamine, very quick acting, game changer)

Buspirone (BuSpar®)

Beta Blockers

42
Q

Buspirone

A

-Partial agonist on brain 5HT1A receptors
-Moderate affinity for brain dopamine D2 receptors
-Longer onset of action than BZD (adaptive response)
-Low abuse potential, no or little withdrawal
Uses
-GAD, Social Anxiety, or Comorbid Depression
-Adjunct use with OCD, PTSD
-Not good for panic disorders (BZD is much faster)

43
Q

Partial agonists only give ___ effect

A

Partial; this is good because pts normally don’t need 100% effect and 100% effect can sometimes be bad.

44
Q

Beta blocker: propranolol

A

Uses (may need test dose initially)–if dose too high, you go to sleep
Social Anxiety
-PTSD — Nightmares
-CNS Penetration — Lipophilic
-Decreased Peripheral Symptoms of Anxiety (ex: sweating)
Monitor Cardiovascular Effects
-Heart Rate
-Blood Pressure
Side Effects
-Hallucinations
-Vivid Dreams
-Lethargy
-Impotence

**MUST titrate

45
Q

Miscellaneous anxiolytic: Hydroxyzine (Vistaril)

A

Histamine H1 antagonist

46
Q

Miscellaneous anxiolytic: Clonidine (Catapres)

A

-Alpha2 Agonist
-Uses: Panic attacks, anxiety associated with withdrawal

47
Q

Investigational anxiolytic: Serotonin Receptor Antagonist

A

5HT3 — Ondansetron (Zofran®)
5HT2 — Ketanserin (Unavailable in the US)

48
Q

Investigational anxiolytic: GABA uptake blocker

A

Tiagabine (Gabitril®)

49
Q

Investigational anxiolytic: Partial Benzodiazepine Receptor Agonists

A

No drugs yet :)

50
Q

Investigational anxiolytic: Glutamatergic agents

A

-NDMA receptor modulators: d-cycloserine, memantine
-mGluR5 antagonist: fenobam
-mGluR2/3 agonist: LY354740

Therapeutics P2 Winter Semester (29 decks)

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