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📖PHARM: Psych, RA & Gout > 2-17 Sedatives / Hypnotics / Insomnia > Flashcards

2-17 Sedatives / Hypnotics / Insomnia Flashcards

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1
Q

What are the clinical uses of sedative hypnotics? (5)

A
  • insomnia
  • anxiety disorders
  • alcohol withdrawal
  • ANTI-convulsants
  • an adjunct to anesthesia prior to medical purposes
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2
Q

Define sedative-hypnotic

A

Sedative (Anxiolytic) – reduces anxiety (think: lyse anxiety) and exerts a calming effect.

Hypnotic – produces drowsiness and facilitates the onset and maintenance of sleep (more CNS depression than sedation).

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3
Q

TWO commonalities of sedative-hypnotics

A
  1. All sedative‐hypnotics produce graded dose‐dependent depression of CNS function.
    * magnitude of the depression of CNS function with INCREASED dose is not the same for all classes of sedative‐hypnotic drugs.
  2. All sedative‐hypnotic drugs produce their effects by interacting with GABAA receptors and potentiating GABAergic activity from spinal cord to cerebral cortex.
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4
Q

What are the classes of sedative-hypnotic drugs and their HAM friends?

A. (4) that target GABA-A receptors

B. (3) “other”

A
  • A. Drugs that target GABAA receptors
    • benzodiazepines
    • NON-benzodiazepines agonists
      • Imidazopyridines and Pyrrolopyrazines
    • barbiturates
    • ethanol
  • B. Other:
    • Herbal preparations
    • ANTI-histamines
    • Melatonin receptor agonists
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5
Q

What is this mystical GABA thingy? (3 main points)

A
  • Synthesized in the nucleus accumbens
  • Is the major INHIBITORY neurotransmitter in the CNS
    • ~30% of synapses the cerebral cortex are GABAergic
  • TWO major classes of GABA receptors have been identified based on function:
      1. GABAA
      1. GABAB
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6
Q

GABAA receptors

A. type of receptor

B. modulation

C. Example

A
  • A. ION-otropic receptors
  • B. **sedative-hypnotic drugs modulate only GABAA receptor function (they lead to INCREASED efficacy of GABA signaling)
  • C. Both the prototypic agonist (Musimol) & prototypic antagonist (Bicuculline) bind to the same site (i.e. the same pharmacophore) on the receptor that GABA binds to.
    • Musimol mimics & bicuculline antagonize GABA’s effects.
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7
Q

GABAB Receptors

A. Type

B. modulation

C. PRE-synaptic

D. POST-synaptic

A
  • A. METABOtropic G-protein linked receptor located on pre-synaptic terminals and post-synaptic membranes
  • B. GABAB receptors are NOT modulated by either benzodiazepines nor other sedative‐hypnotics
  • C. PRE-synpatic terminals
    • ​via DECREASE in Ca2+ conductance control the release of:
      • GABA from GABAergic neurons (“homoreceptors”)
      • –or– other neurotransmitters from respective terminals (“heteroreceptors”)
  • D. POST-synaptic membranes
    • ​producing HYPERpolarization of the membrane via an INCREASE in K+ conductance
    • Ex: Baclofen (Lioresal®) is a selective GABAB agonist used clinically as an anti‐spastic drug
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8
Q

Structure of GABAA receptor

A. overall structure

B. isoforms

C. polypeptide subunits

A
  • A. heteroPENTAmeric glycoprotein receptors
  • B. 7 polypeptide classes and multiple isoforms
  • C. formed from the co‐assembly of five polypeptide subunits
    • each subunit is a polypeptide (420‐450 amino acids) from various polypeptide classes (alpha, beta, gamma and delta, epsilon, pi, rho)
    • each subunit has:
      • 4 transmembrane domains with both the amino and carboxy terminus in the extracellular side
      • 2 intracellular loops provide sites for phosphorylation
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9
Q

Which isoforms are required for a functional GABAA receptor?

A
  • alpha, beta, and gamma are all required for a FUNCTIONAL GABAA receptor
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10
Q

What subunit isoforms have been identified for alpha, beta, gamme, and rho?

A
  • 6 isoforms of alpha subunit (D1‐6)
  • 3 isoforms of beta subunit (E1‐3)
  • 3 isoforms of gamma subunit (J1‐3)
  • 3 isoforms of rho subunit (U1‐3)
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11
Q

What are the most common GABAA receptor subtypes?

A
  • **2 alpha
    • **the alpha subunit isoform determines the GABAA subtype and its ability to be modulated by:
      • benzodiazepines, imidazopyridines, and pyrrolopyrazines
  • 2 beta
  • 1 gamma
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12
Q

What is the relative abundance of GABAA receptor subtypes?

A. majority

B. minority

A
  • A. majority (~60%) are BZ1 (alpha1-beta 2-gamma 2)
    • benzodiazepines
    • imidazopyridines
    • pyrrolopyrazines
  • B. fewer BZ2
    • ~15-20% alpha2-beta3-gamma2
      • only benzodiazepines
    • 10-15% (alpha3-alpha5)-beta[n]-gama2
      • only benzodiazepines
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13
Q

What drugs do GABAA receptors respond to? (2)

A
  • 85-95% respond to benzos
  • 60% respond to BZ-1 selective drugs
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14
Q

What are the important functional aspects of the

A. alpha/beta interface

B. alpha/gamma interface

A
  • A. alpha/beta interface (2 sites)
    • pharmacophore that binds GABA agonists and antagonists
  • B. alpha/gamma interface (1 site)
    • allosteric modulatory site (“BZ/omega receptor site”)/”binding pocket”
    • for any drug that binds to this “receptor” to alter function of the GABAA receptor, also need GABA to be present
    • binding site for:
      • benzos
      • imidazopyridines
      • pyrrolopyrazines
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15
Q

BZ1/omega1

A. most common isoform

B. (3) drug classes that it binds

A

A. BZ1/omega1 containing the α1 isoform, is the most common, and bind three drug classes:

B.

  1. benzodiazepines
  2. imidazopyridines: Zolpidem (ambien®), Zaleplon (sonata®)
  3. pyrrolopyrazine: Eszopiclone (lunestra®)
    (bonus: Flumazenil)
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16
Q

BZ2/omega2

A. subunits

B. drugs it can bind

A
  • A.contains the α2, α3, or α5 subunit
  • B.can only bind one drug class: Benzos
    • (bonus: Flumazenil)
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17
Q

What is important to note about the α-isoform?

A
  • The alpha isoform determines the binding abilities (affinities) of specific drugs for the BZ binding site
    • GABAA receptors with α1,2,3 & 5: sensitive to Diazepam
    • GABAA receptors with α4 & α6 are Diazepam‐insensitive
    • GABAA receptors have different selectivity to the Imidazopyridine class drug Zolpidem
      • ​α1 > α2 = α3 >> α5)
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18
Q

Sedative hypnotic drugs that modulate GABAA receptor pharmacodynamics (5)

A
  1. benzos (non-selective agonists; BZ1 and BZ2)
  2. BZ1 site selective (non-benzo) agonists
  3. inverse agonist
  4. antagonist
  5. barbiturates, neuroactive steroids, and ethanol all hit other parts of GABA
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19
Q

MOA of Benzodiazepines (NON-selective agonists) (4)

A
  • Nonselective: Bind to both BZ1 and BZ2 (up to 90% of GABA-A receptors)
  • Positive allosteric modulators of GABA-A receptors and are ineffective unless GABA (or GABA agonists) are present
  • DO NOT compete directly with GABA binding to its pharmacophore at the alpha/beta interface on the GABA-A receptor
  • Increases GABA’s affinity for its GABA-A receptor binding sites leading to increased frequency of opening Cl- channels -> IPSP (hyperpolarization decreases neuron firing)
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20
Q

Effect of benzos on alpha 1, 2, and 5

A. alpha 1

B. alpha 2

C. alpha 5

A
  • A. alpha 1: mediate sedative, amnesia and ataxic efects
  • B. alpha 2 (and possible alpha 3): mediate the anxiolytic and muscle relaxant effects
  • C. alpha 5: may mediate memory impairment and tolerance development to benzos’ sedative effects
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21
Q

MOA of NON-benzo agonists: Imidazopyridines and Pyrrolopyrazine (3)

A
  • bind selectively to BZ1/omega1 sites
  • act as positive allosteric modulators of GABA-A receptor function
  • ineffective unless GABA (or GABA agonists) are present
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22
Q

MOA of Inverse Agonists (beta-carbolines) (3)

A
  • act as negative allosteric modulators of GABA-A receptor function
    • DECREASE affinity for binding GABA and DECREASE frequency of Cl- channel opening
  • bind to BZ1 /omega1 & BZ2/omega2 modulatory sites
  • produce anxiety and seizures (via reducing GABA receptor function) as well as block the effects of drugs that bind to BZ1 /omega1 & BZ2/omega2 sites.
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23
Q

ANTagonists (Flumazenil; Romazicon)

A. MOA

B. PK

A

A. MOA

  • competitive antagonist with high affinity for the BZ1 /omega1 and BZ2/omega2 receptor
  • blocks the actions of BZ, imidazopyradine & pyrrolopyrazine drugs
  • does not antagonize the actions of:
    • other sedative‐hypnotics (barbiturates, meprobamate or ethanol)
    • GABA agonists

B. PK

  • Given i.v., it acts rapidly and has a short t1/2 (0.7‐1.3h)
  • rapid hepatic clearance
  • May precipitate withdrawal in pts physiologically dependent on benzos
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24
Q

What are some clinical uses of FLUMAZENIL (2)

A
  • tx BZ overdose and reverse BZ-induced sedation after surgical/diagnostic procedure (e.g. versed reversal)
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25
Q

MOA of BARBITURATES (4)

A
  • Bind to GABA-A receptor at separate sites from the BZ1 & BZ2 benzo binding sites
    • likely the intramembrane lipophilic regions of the beta subunit
    • no specificity for any one isoform of GABA-A receptor
  • binding INCREASES duration of the Cl- channel opening in presence of GABA
  • At very high concentrations, can directly produce Cl- channel opening.
  • effects potentiated by ethanol or other drugs that potentiate GABA-A receptor function
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26
Q

Neuroactive steroids MOA (3)

A
  • affect separate GABA-A receptor binding sites from the benzodiazepines
  • Can facilitate or attenuate GABA-A function depending on steroid structure
  • At high concentrations, some (e.g. alphaxalone) may directly open chloride channels.
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27
Q

Ethanol MOA (4)

A
  • produces many effects of the benzodiazepines (e.g., anxiolysis, sedation, CNS depression) but can potentiate the effects of other GABA-A receptor modulators (e.g. BZs)
  • stimulates Cl‐ uptake into isolated brain vesicles
  • thought to alter GABA-A neurotransmission
  • effects may vary due to regional differences in the relative abundance of GABA-A receptor subtype(s)
28
Q

BZ Class of Drugs-Meet the Players (9+2)

A

“If its AM, PAM, or Lem Atanga McCormick, its likely a benzo”

  • Midazolam (Versed®)
  • Triazolam (Halcion®)
  • Alprazolam (Xanax®)
  • Estazolam (ProSom®)
  • Lorazepam (Ativan®)
  • Oxazepam (Serax®)
  • Temazepam (Restoril®)
  • Clonazepam (Klonopin®)
  • Diazepam (Valium®)
  • Exceptions (but their active metabolite is desmethyldiazePAM)
    • Chlorazepate (Tranxene®)
    • Chlordiazepoxide (Librium®)
29
Q

BZ

A. General (4)

B. Clinical Uses

B-i. Common (6)

B-ii. Less common (2)

A
  • A. Introduced in the 1960s, remain among the most widely prescribed drugs in the world
  • Safer than barbiturates and older sedative‐hypnotics-higher therapeutic index
  • less likely to result in fatal CNS depression.
  • In healthy pts, hypnotic doses of benzodiazepines produce no significant effects on respiration and cardiovascular function
  • B. Clinical uses:
    • i. Common: Anxiety disorders, Insomnia (sleep disorders), Anesthesia (adjuncts), relaxation of skeletal muscles, Alcohol Withdrawal, Seizures
    • Less common: Night terrors, sleepwalking
30
Q

BZ Pharmacokinetics

A. Absorption & Distribution

B. Bioavailability

C. Protein Binding

D. **Metabolism**

E. Pregnancy

A
  • A. Absorption & Distribution:
    • all lipid soluble, but lipophilicity can vary over 50–fold and contributes to differences in rates of absorption, onset of action, & redistribution (all of these contribute to their abuse potential)
  • B. Bioavailability ‐ very good; ranges from 60‐100%
  • C. Protein binding
    • moderate (70%‐Alprazolam) to high, (99%‐Diazepam);
    • drug interactions with other highly protein bound agents are likely
  • D. ***Metabolism***:
    • Most metabolized via:
      • Phase I: microsomal oxidation by the P450 family CYP3A4 and CYP2C19
      • Phase II: conjugation to form glucuronides that are excreted in the urine
    • ***Three benzodiazepines only go through Phase II
      • ( L O T ) Lorazepam, Oxazepam, & Temazepam
  • E. Pregnancy:
    • All sedative‐hypnotics cross the placental barrier and appear in breast milk
    • Teratogenic?
      • initial reports suggested an increased risk of cleft lip and palate
      • more recent reports show no association between benzo exposure and risk for cleft lip or palate
31
Q

PK differences largely determine the BZ clinical applications, what are the FOUR important factors for consideration?

A

A. Duration of action: Half‐life of parent drug & any bioactive intermediates

B. Rapidity of onset of effects

C. Drug potency

D. Pt’s age, medical condition, and prior drug history

32
Q

Duration of action: Half-life of parent drug and any bioactive intermediates–Phase I and Phase 2 Metabolism

A. general

B. Long t1/2

C. short t1/2

A
  • A. Elimination half‐life of bioactive intermediates is often longer than that of the parent compound
    • Why? due to (Phase I) formation of > 1 bioactive metabolite(s) which may be active until conjugated and excreted (Phase II).
  • B. Long t1/2:
    • Parent compounds half‐lives (t 1⁄2 = 0.1 ‐ 35 hr)
    • Bioactive metabolite’s half‐lives between 50‐100 hr.
    • Chlordiazepoxide->->->N‐desmethyldiazepam
    • 2‐keto derivative: Diazepam->N‐desmethyldiazepam
    • 2‐keto derivative: Flurazepam->N‐desalkylflurazepam
    • 7‐Nitro derivative: Flunitrazepam (Rohypnol®) the “date rape” drug; not approved in the US
    • 7‐Nitro derivative: Clonazepam (t 1⁄2 = 22‐33 hr)
  • C. Short(er) t1/2:
    • Triazolo derivative: Midazolam (t 1⁄2 = 2.5 hr)
    • Triazolo derivative: Alprazolam (t 1⁄2 = 11 hr)
    • Triazolo derivative: Triazolam (t 1⁄2 = 1.5‐5.5 hr)
33
Q

Duration of action: Half-life of parent drug and any bioactive intermediates–Phase 2 metabolism only (4)

A
  • not metabolized to bioactive intermediates
  • preferred for geriatric patients and pts with impaired hepatic function
  • t 1⁄2 half‐lives 5 ‐25 hr
  • 3‐hydroxy derivative: ( L O T ) Lorazepam, Oxazepam, & Temazepam
34
Q

BZ concentration differences due to drug t1/2 differences (2)

A
  • Drugs with long half‐lives (either the parent compound or active metabolite) will accumulate with prolonged use (see figure).
  • may become over-sedated either from drug itself or other added effects-ie drinking
  • (Note on the figure: A accumulates then drops, whereas B stays constant)
35
Q

Rapidity of onset of effects of BZ (3)

A
  • Rapid: within 15 mins:
    • Midazolam (IV most rapid); Diazepam, Flurazepam, Lorazepam (SL, IV)
  • Intermediate: 15‐30 mins
    • Alprazolam, Clonazepam, Lorazepam (PO), Chlordiazepoxide
  • Slow: 30‐60 mins
    • Oxazepam, Temazepam
36
Q

Drug Potency (equivalent dosages) BZ (7)

A
  • 0.25-CT (clone ran a triathalon for a quarter)
    • clonazepam 0.25 mg
    • triazolam 0.25 mg
  • alprazolam 0.5 mg
  • 1mg-EL chapo is the #1 drugpin
    • estazolam 1 mg
    • lorazepam 1 mg
  • diazepam 5 mg
  • 10 mg-CT (team clora the explorer has 10 players)
    • clorazepate 10 mg
    • temazepam 10 mg
  • 15 mg-OF (15 oxtails had the flu)
    • flurazepam 15 mg
    • oxazepam 15 mg
  • chlordiazepoxide 25 mg
37
Q

BZ

A. elderly pts metabolism

B. type of conjugation

A
  • A. Benzodiazepine half‐lives are longer in older people
    • Elderly metabolize the drugs slower (see figure).
    • Daily dosed drugs will accumulate more in elderly than in a younger pt.
  • B. Least likely for BZ going through Phase II conjugation only.
    • No active metabolites: ( L O T ) Lorazepam, Oxazepam, & Temazepam
    • Most likely for drugs with bioactive metabolites:
      • Chlordiazepoxide->->->N‐desmethyldiazepam
      • Diazepam->N‐desmethyldiazepam
      • Flurazepam->N‐desalkylflurazepam
38
Q

BZ SE

A. frequent (6)

B. occasional

C. rare

A
  • A. Frequent:
    • Sedation & Drowsiness‐most common
    • also: ataxia, dizziness, cognitive impairment, amnesia (for events during the drug’s effect).
  • B. Occasional: Confusion
  • C. Rare: Paradoxical aggression
39
Q

BZ

A. Psychological dependence

B.Tolerance

C. Physiologic Dependence and Withdrawal

C-i. Common withdrawal (10)

C-ii. rare withdrawal (5)

A
  • A. Psychological Dependence on BZ
    • ​Similar to the behavioral pattern observed with heavy coffee drinkers or cigarette smokers.
    • May contribute to physiologic dependence and tolerance.
  • B. Tolerance
    • With chronic use there is a DECREASE in the drug’s effects so need INCREASED doses to achieve original effects.
    • May be analogous to the desensitization phenomena and is due to DECREASE in BZ binding sites.
    • Tolerance to the sedating effects of BZ has been observed but NOT to their anxiolytic or muscle relaxant effects.
    • Additionally, cross tolerance can develop to ethanol and other sedative‐hypnotics that affect GABA-A receptor function.
  • C. Physiologic Dependence
    • removal of the drug (“withdrawal”) produces unpleasant symptoms that are usually opposite (compensatory) to the drug’s effects.
    • Common withdrawal symptoms include:
      • **may last 2-4 wks: anxiety, insomnia
      • last up to 2 wks: loss of appetite, HA, muscle aches/twitches, nausea, tremor, sweating, and irritability
    • rare withdrawal symptoms:
      • confusion, delirium, psychosis, seizures, catatonia
40
Q

BZ Tolerance and Dependence: PD and PK considerations; (5)

A
  • propensity to develop a substance use disorder, tolerance and dependence, and more severe withdrawal depends on the following 5 criteria:
  • 1) Drug’s duration/half‐life
    • decreased half‐life, increased risk
  • 2) Amount of time to onset of drug’s affect.
    • decreased time, increased risk
  • 3) Drug’s potency.
    • increased potency, increased risk
  • 4) Dose of drug taken.
    • increased dose, increased risk
  • 5) Time length drug has been taken.
    • increased time length, increased risk

Ex: cocaine; Intranasal is less addcitive than crack-due to quicker arrival

  • highly LIPOPHILIC BZ which cross the BBB (i.e. Diazepam) and agents with short half-life and high potency (Alprazolam, Lorazepam) are the most reinforcing BZ and most likely associated with abuse
  • BZ are rarely the preferred or sole drug of abuse. Estimated 80% of BZ abuse is part of polydrug abuse, most commonly with opioids
41
Q

Discontinuation Strategy

A. general

B. 2 options

A

A.

  • **severe withdrawal from BZ and some other sedative hypnotic drugs may be fatal–should NEVER be discontinued abruptly
  • general advice: BZ tx should be short-term and limited to 1-3 mo
  • B.
  • Step 1: taper down dose and/or
  • Step 2: switch to a longer half-life drug (preferably one of lower potency and less rapid onset of effect (so as to decrease the reinforcement properties of the drug)
42
Q

BZ1/omega 1 site-selective NON-BZ drugs-Overview

A
  • Who are they?
  • Imidazopyridine drugs:
    • 1) Zolpidem (Ambien®)
    • 2) Zaleplon (Sonata®)
  • Pyrrolopyrazine drug:
    • 3) Eszopiclone (Lunesta®)
  • General info:
    • bind selectively to BZ1 /omega1 sites
    • act as positive allosteric modulators of GABA-A receptor function
    • ineffective unless GABA (or GABA agonists) are present
43
Q

BZ1/omega 1 site-selective NON-BZ drugs-Clinical Indications

A
  • Primarily used to tx sleep disorders, but lack the anxiolytic, anticonvulsant and muscle relaxant efficacy of benzodiazepines
  • May be habit forming with long‐term use (decreased risk compared to barbiturates or benzodiazepines)
  • Even in OD do not produce a dangerous degree of CNS depression; however, can be lethal if taken in combo with other CNS depressants
  • Effects can be antagonized by the BZ1 & BZ2 antagonist, Flumazenil
44
Q

Zolpidem (Ambien®) – extended release form (Intermezzo)

A. What is it?

B. Absorption & Distribution

C. Metabolism

D. t1/2

A
  • A. the first FDA‐approved BZ1 selective drug
  • B. rapidly & completely absorbed from GI tract, reaches peak plasma levels in 1‐2 hrs.
  • C. metabolized via Phase I and Phase II liver metabolism
  • D. t1/2 of 1.5‐3 hrs.
    • prolonged in elderly and pts with liver disease, so DECREASE dose
45
Q

Zaleplon (Sonata®)

A. What is it?

B. Absorption & Distribution

C. Metabolism

D. t1/2

A
  • A. resembles zolpidem in its effects.
  • B. rapidly absorbed from the GI tract, reaches peak concentration in 1 hr
  • C. metabolized via Phase I and Phase II metabolism‐‐no active metabolites
    • metabolism inhibited by histamine‐2 receptor blocker, cimetidine ( Tagamet®)
  • D. very short t1/2 of 1.0 hr.
    • prolonged in elderly and pts with liver disease, so DECREASE dose
    • morning after sedation/hangover effect less common than zolpidem or other sedative‐hypnotics
46
Q

Eszopiclone (Lunesta)

A. What is it?

B. Absorption & Distribution

C. t1/2

A
  • A. S(+) isomer of zopiclone (a pyrrolopyrazine drug approved for use in Canada)
    • no structural similarity to zolpidem, zaleplon or the benzodiazepines
    • not restricted to short‐term use
  • B. rapid absorption from the GI tract; reaches peak concentrations in 1‐2 hrs
  • C. t1/2 approx 6 hrs: prolonged in the elderly so DECREASE dose
47
Q

“AL” the Barbarian (BARBITURATES)-

A. Who? (3)

B. MOA(4)

A

A.

  1. PhenobarbitAL
  2. MethohexitAL
  3. ThiopentAL

B.

  • MOA:
    • Bind to sites on the ionotropic GABA-A receptors at regions (likely on lipophilic pt of beta-subunits) different from where benzodiazepines bind (alpha-gamma interface)
    • Do not exhibit specificity to a GABA-A receptor isoform subtype, will affect more subtypes
    • At different doses:
      • At low doses: Binding INCREASES duration of the chloride channel opening in presence of GABA
      • At very high concentrations, can directly produce Cl- channel opening (GABA not needed)
    • Depresses actions of excitatory NT & exerts non‐synaptic membrane effects.
48
Q

“AL” the Barbarian (BARBITURATES)-PK

A. short

B. intermediate

C. Long

A
  • Like benzodiazepines, classified primarily based on their duration of action
  • A. Short Acting (t1/2=hrs)
    • ​Thiopental, Mexihexital
    • rapid onset – both used for anesthesia induction
  • B. Intermediate Acting (t1/2=18‐48hrs)
    • ​Amobarbital (Amytal), Secobarbital (Seconal), Pentobarbital (Nembutal)
    • used to commonly be used to induce/maintain sedation and sleep
  • C. Long acting (t1/2=4‐5 days)
    • ​Phenobarbital (Luminol Sodium)
    • used in epilepsy treatment
49
Q

“AL” the Barbarian (BARBITURATES)-SE/the reason Barbiturates have limited clinical use (3)

A
    1. Low therapeutic index‐due to potency to depress respiration (especially in combination with alcohol).
      * A lethal dose can be < 10x the prescribed hypnotic dose.
    1. INCREASED Risk of Abuse, Physical Dependence and Withdrawal vs. BZs
      * discontinuation after repeated use may lead to life threatening withdrawal syndrome-very difficult to treat.
    1. Stimulate CYP450 activity & induces hepatic microsomal oxidases.
      * a. Pharmacokinetic tolerance – over time, INCREASED barbiturate doses may be required due to the INCREASE in their own metabolism.
      * b. Cross tolerance ‐ to BZs and other sedative hypnotics
      * c. Drug interactions – from metabolism of other drugs also metabolized by microsomal oxidases
50
Q

Ramelteon (Rozerem)-Clinical Indication

A
  • a melatonin receptor agonist used in the tx of initial insomnia
  • no evidence of physical dependence or abuse potential
  • appears to be well tolerated if administered for long treatment courses
51
Q

Ramelteon (Rozerem)-MOA (3)

A
  • selectively binds to MT1 and MT2 melatonin receptors
  • mimics & enhances the actions of melatonin which has been associated with the maintenance of circadian sleep rhythms.
    • BUT, has higher affinity for MT1 and 2
  • No measurable affinity for BZ1 or BZ2 receptors or other sites.
52
Q

Ramelteon (Rozerem)-PK

A. Absorption & Distribution

B. Protein binding, Vd

C. Metabolism

D. t1/2

A
  • A. rapid absorption – high fat meals delays T-max and increases AUC (| 30%)
  • B. moderate protein binding (82%), large Vd (approx 74 L)
  • C. extensive first pass metabolism
    • via CYP 1A2, 2C9, 3A4
  • D. t1/2=1‐3 hrs (short)
53
Q

Ramelteon (Rozerem)-SE (6)

A
  • occurs at rates comparable to placebo
  • incude: HA, somnolence, fatigue, dizziness, nausea, exacerbated insomnia
  • well tolerated even if taken for extended periods
  • no physical dependence or abuse potential
54
Q

What is essential to do before perscribing sleeping pills? (4)

A
  • In prescribing drugs for “insomnia”, it is essential to first establish the etiology of the disorder (e.g…)
    • drug dependence
    • sleep apnea (sleep hygiene)
    • restless leg syndrome
    • psychiatric illness (mood or anxiety disorders)
  • If a rational basis for hypnotics can be established, then various factors can be considered in choosing an appropriate hypnotic drug.
55
Q

What are the sedative-hypnotic options that are most often used to treat sleep disorders? (5)

A
  • a. BZ (that bind to both BZ1 and BZ2 sites on the GABA-A receptor)
  • b. drugs that bind selectively to the BZ1 receptors
  • c. Melatonin receptors agonists
  • d. other classes of sedating drugs with anti‐histaminergic actions
  • e. herbal preparations with compounds that may affect GABA neurotransmission.
  • **Barbiturates generally NOT perscribed to tx sleep disorders due to:
    • low therapeutic index
    • greater abuse liability
56
Q

Which BZ are specifically approved for the tx of insomnia? (6)

A
  • ***BZ should only be used on a short-term basis (1-3mo)
  • EstazoLAM (Prosom®)
  • TemazePAM (Restoril®)
  • QuazePAM (Doral)
  • FlurazePAM (Dalmane)
  • TriazoLAM (Halcion®): high abuse potential, avoid if possible
  • LorazePAM (Ativan®): commonly prescribed, not FDA‐approved for insomnia
57
Q

BZ tx for the Elderly

A
  • The elderly metabolize drugs slower, so the BZ half‐lives will be longer in this population.
  • Drugs with longer half‐lives accumulate with prolonged use
    • if dosed daily, BZ concentrations will be significantly greater than intended.
    • Most likely for drugs with bioactive metabolites such as:
      • chlordiazepoxide, diazepam, flurazepam, chlorazepate
    • Least likely for drugs that only go through Phase II metabolism and have no active metabolites such as:
      • ( L O T ) Lorazepam, Oxazepam, & Temazepam
58
Q

BZ issues with treating insomnia (5)

A
    1. Rebound insomnia: upon stopping medication, original symptoms may recur, sometimes with greater intensity
    1. Psychological Dependence-contributes to risk of tolerance and physiologic dependence
    1. Tolerance
    1. Physiologic Dependence and risk of withdrawal-want to stop meds slowly, over a few wks
    1. Risk of Substance Use Disorder
      * less risky than barbiturates
      * can occur in treating sleep disorders long-term with benzos
      * highest risk: pts with hx of (POLY)substance use
59
Q

What are the NON-BZ, BZ-1 selective sedative-hypnotics approved for sleep disorders? (4)

A
  • 1. Imidazopyridines
    • Zolpidem
    • Zaleplon
  • 2. Pyrrolopyrazines
    • Eszopiclone
  • 3. M1 and M2 receptor agonist
    • Ramelteon
  • 4. Sedating drugs with ANTI-histaminergic actions
    • TCAs
      • Amitriptyline
      • Doxepin
      • Imipramine
    • Mixed Action Atypical ANTI-depressants
      • Mirtazapine
      • Trazadone
      • Nefazodone
    • ANTI-histamines-H-1 histamine receptor ANT-agonists
      • Cyclobenzaprine
      • Hydroxyzine
      • Diphenhydramine (OTC Benadryl)
        • the active ingredient in OTC ZzzQuil
60
Q

Insomnia tx with herbal preparations (4)

A
  • Valeriana officinalis (Valerian)
    • Sesquiterpenes=active compounds that mediate GABA release & theinhibition of GABA breakdown.
      • useful for up to 4 wks in treating insomnia
      • No “next day” hangover or other aversive effects
      • No serious drug interactions.
  • Chamomile (Matricaria recutita)
    • BZ agonist, active ingredient is Apigenin
    • Chamomile tea is relaxing when ingested at bedtime.
  • Kava
    • Facilitates the binding of GABA
    • active component=Kava lactones;
    • Reported to have calming effects.
  • “Passion flower”
    • BZ partial agonist
    • Chrysin = active compound
    • Reported to be an effective and safe hypnotic (not substantiated)
61
Q

OTC Insomnia Meds (4)

A
  • Compoz ‐ methapyrilene and pyrilamine
  • Nytol ‐ methapyrilene and salicylamide (salicyate)
  • Sleep‐Eze ‐ methapyrilene and scopolamine
  • Sominex ‐ methapyrilene, scopolamine and salicylamide (salicyate)
62
Q

OTC Sleep Aids (2)

A
  • Unisom ‐ contains the anti-histamine, doxylamine, as the active ingredient.
  • ZzzQuil‐ diphenhydramine (anti-histamine as well)
63
Q

What are the (3) steps of GABA activation?

A
  1. activation by GABA
  2. INCREASE in opening of Cl- channels
  3. inhibitory post-synaptic potential (IPSP)
    1. HYPER-polarization leads to DECREASED neuron firing
64
Q

BZ1/omega 1 site-selective NON-BZ drugs-SE (10)

A
  • similar to BZ
  • HA, dizziness, somnolence; N/V/D, **anterograde amnesia and rebound insomnia (especially at high doses)
  • can cause “sleep‐driving” or “sleep‐eating” without any memory of the event
65
Q

Eszopiclone (Lunesta)-Drug Interactions

A. inhibitors

B. inducers

A
  • A. CYP3A4 inhibitors INCREASE serum concentrations and prolong the duration of action
    • Itraconazole (Sporanox), Clarithyromycin (Biaxin), and Ritonovir (Norvir)
  • B. CYP3A4 inducer can DECREASE serum concentrations and eszopiclone’s effectiveness
    • Rifampin

📖PHARM: Psych, RA & Gout (6 decks)

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