Anxiolytics and Sedatives Flashcards
1
Q
GABA
(γ-aminobutyric acid)
A
-
Major inhibitory neurotransmitter in the CNS
- Widely distributed
- [GABA] is 1,000x higher than monoamines
- Long-axon tracts connecting regions of the basal ganglia, including a pathway to the substantia nigra
-
GABA interneurons:
- Cortex
- Limbic areas including hippocampus, amygdala and septum
- Basal ganglia and cerebellum
- Raphe nuclei
- Medulla
- Spinal cord
-
GABA also colocalized within neurons with other classical neurotransmitters and peptides:
- With 5-HT in neurons of the dorsal raphe
- With cholecystokinin in the cortex
2
Q
GABA
Shunt
A
C__losed loop of GABA synthesis, degradation, and replenishment
Glucose is the precursor for almost all synthesis of GABA
Conversion of glutamate → GABA by glutamic acid decarboxylase (GAD) ⇒ 1° immediate pathway for forming GABA
Steps in the GABA shunt are:
- Glucose → α-Ketoglutarate via Kreb’s cycle → glutamic acid by GABA-T (α-oxoglutarate transaminase)
- Glutamic acid → GABA via decarboxylation by glutamic acid decarboxylase (GAD)
- GABA → succinic semialdehyde by GABA-T (α-oxoglutarate transaminase)
- Succinic semialdehyde → succinic acid via oxidation by succinic semialdehyde dehydrogenase (SSADH)
- Succinic acid reenters the Krebs cycle
3
Q
GABA
Synaptic Activity & GABA Loop
A
- Depolarization of GABAergic neurons ⇒ releases GABA from vesicles into the synaptic cleft
- GABA acts at postsynaptic receptors ⇒ opening of Cl- channels ⇒ hyperpolarization
- Action terminated by reuptake into the presynaptic nerve terminal and also into proximal glial cells
- Reuptake into GABAergic nerve terminals via GABA transporter
- Can be reused as a neurotransmitter or degraded
- Taken up via active transport into glia
- Cannot be reconverted to GABA because glia do not contain GAD
- Reuptake into GABAergic nerve terminals via GABA transporter
- GABA can ultimately be restored to neuronal GABA through the glutamine loop
- In this loop, GABA reenters the Krebs cycle → glutamate → glutamine
- Glutamine returned to the GABAergic terminal ⇒ reconverted to glutamate
- Glutamate then decarboxylated by neuronal GAD to GABA
4
Q
Anxiety
Pharmacological Treatment
A
Anxiolytic drugs:
- Until the 1960’s, anxiety generally tx by relatively nonselective, sedating agents such as barbiturates
-
Beginning in the 1960’s, benzodiazepines used (eg, diazepam and chlordiazepoxide)
- Generally safer and more efficacious
- BZD dose-response curve plateaus
- Barbiturate dose-response curve progresses all the way up to coma
- Generally safer and more efficacious
- During the past decade, other agents increasingly gained use in managing other forms of anxiety
5
Q
Benzodiazepines
Mechanism of Action
A
Anxiolytic, sedative-hypnotic, anticonvulsant, and skeletal muscle relaxant actions
Allosterically enhance the actions of GABA at the GABA-A receptors
- GABA opens the pore for Cl- conductance
-
BZD binds @ allosteric site (benzodiazepine receptors) on GABA-A receptors
-
↑ binding affinity of GABA for the active site
- ↑ affinity but not efficacy of GABA
-
↑ frequency of channel openings produced by GABA
- Do not open channels themselves
-
↑ binding affinity of GABA for the active site
6
Q
Benzodiazepine Receptors
A
BZ1 ⇒ sedation and anti-convulsant actions
BZ2 ⇒ antianxiety and impairment of cognitive functions
- Benzodiazepines enhances activity of both BZ1 and BZ2
-
Zolpidem [Ambien] (not a benzo) ⇒ specifically stimulates BZ1 receptors
- Used as a sedative/hypnotic
7
Q
Flumazenil
A
Benzodiazepine antagonist
- Binds to the benzodiazepine site
- Prevents or reverses the actions of positive allosteric modulators (ie, therapeutic benzodiazepines)
- Does not alter the actions of GABA
8
Q
Barbiturates
MOA
A
- Bind an allosteric site on GABA-A receptor different than BZ1/BZ2
- Prolongs the actions of GABA and ↑ duration of channel opening
- Barbiturates, at higher concentration, can open the channels by themselves
- Are more dangerous drugs than benzodiazepines
9
Q
Barbiturates
Indications
A
Relatively non-selective sedating agents
Not widely used
- Phenobarbital used for seizures
-
Sodium thiopental ⇒ ultra-short acting anesthetic agent
- Discontinued in the US
- Travels rapidly to the brain but then redistributes to other tissues, hence terminating it anesthetic action
10
Q
Benzodiazepines
Pharmacokinetics & Metabolism
A
- After PO admin, benzos generally are completely absorbed but rates of absorption differ
- Highly bound to plasma proteins
- Varied metabolism via hepatic cytochrome P-450 system:
-
2-step metabolism: N-dealkylation and/or hydroxylation → conjugation via glucuronidation
- Ex. diazepam (Valium), chlordiazepoxide (Librium), flurazepam (Dalmane)
-
Glucuronidation only
- Ex. oxazepam (Serax) and lorazepam (Ativan)
- Products of glucuronidation are inactive
-
Conversion to active metabolites of uncertain clinical significance
- Ex. alprazolam (Xanax), triazolam (Halcion) and temazepam (Restoril)
-
2-step metabolism: N-dealkylation and/or hydroxylation → conjugation via glucuronidation
- BZDs do not induce hepatic microsomal enzymes
-
Old age, hepatic damage, and other drugs (e.g., cimetidine) can reduce the rate of oxidative biotransformation of certain BZDs
- ↑ accumulation & prolong duration of action
- Use agents such as oxazepam or lorazepam if the liver is not functioning properly
-
Old age, hepatic damage, and other drugs (e.g., cimetidine) can reduce the rate of oxidative biotransformation of certain BZDs
11
Q
Selective Benzodiazepines
Pharmacokinetics Properties
A
12
Q
Benzodiazepines
Adverse Effects
A
-
Sedation is a prominent effect of BZDs
- Generally dose-related
- Magnitude and duration of the sedation ∝ T ½ of parent compound and any active metabolites produced
- Can ↑ risk of fractures in the elderly
-
May potentiate actions of other sedating drugs (eg, ethanol, barbiturates)
- Sometimes leading to cardiovascular and respiratory depression
13
Q
Benzodiazepines
Tolerance
A
- Generally dose-related
- D/t desensitization of GABA receptors & sensitization of glutamate receptors
- Tolerance develops to all the effects of benzodiazepines but at different rates
- Sedative/hypnotic effects ⇒ within days-weeks
- Anticonvulsant & muscle relaxant ⇒ several weeks
- Antianxiety effects ⇒ a few months
- Cognitive effects ⇒ little to no tolerance
- Pts will tend to escalate their dose to maintain the effect
14
Q
Benzodiazepines
Physical Dependence
A
- Physical dependence develops to BZDs
-
Appearance of sx upon withdrawal
- ↑ Risk w/ higher doses and/or prolonged/repeated use
-
W/d symptoms may be mild (anxiety, insomnia)
- May represent the return or unmasking of the original problems
- Time of appearance of w/d sx vary depending on the type of BZD
- Sx may appear many days after d/c of drugs w/ active metabolites and long half-lives
- Rebound anxiety and rebound insomnia seen after 1st dose of BZDs w/ very short half-lives
-
Abrupt stop of BZDs after long-term use w/ high doses ⇒ serious consequences, including seizures
- Esp. drugs w/ relatively short half-lives and w/o active metabolites
- Tapering off generally needed
15
Q
Benzodiazepines
Toxicity
A
Impaired judgment, slurred speech, incoordination, stupor, respiratory depression, death
Use flumazenil to treat a significant OD
18
Q
Buspirone (Buspar)
Overview
A
1st drug that modulates serotonergic function in the brain
- Advantages of buspirone:
- Relatively non-sedating profile
- Failure to potentiate the depressant effects of ethanol
- Buspirone takes days or weeks after starting to establish an anxiolytic effect
- Sometimes used to augment the effect of SSRI’s in unresponsive pts
19
Q
Buspirone
Mechanism of Action
A
-
Partial agonists at both presynaptic and postsynaptic 5-HT1A receptors
- ⊗ normal inhibitory feedback of 5-HT ⇒ ↑ serotonin release
- ⊕ postsynaptic 5-HT1A receptors
- Buspirone also blocks DA-2 receptors
20
Q
Buspirone
Pharmacokinetic and Therapeutic Considerations
A
- Rapidly absorbed after oral administration
- Highly bound to plasma proteins (> 90%)
- Metabolized by hepatic oxidation to 1-pyrimidinyl piperazine (active)
-
T ½ of parent drug is < 3 hours
- Parent compound accounts for < 50% of urinary excretion of a dose
- Does not pose problems for drug interactions w/ ethanol
- Pts previously on benzodiazepines for anxiolytic therapy frequently report dissatisfaction w/ buspirone and discontinue its use
26
Q
Normal
Sleep Architecture
A
- Sleep has 5 distinct types of brain wave activity based on EEG findings
-
Sleep stages can be divided into non-rapid eye movement (NREM) and rapid eye movement
-
NREM sleep can be further subdivided into four stages:
- Stages 1 and 2 are characterized by high frequency/low amplitude activity
- Stages 3 and 4 are characterized by low frequency/high amplitude activity called slow wave sleep
- REM is sometimes called paradoxical sleep because the EEG pattern is very similar to the awake state
-
NREM sleep can be further subdivided into four stages:
- A normal adult cycles through the sleep stages every 90 minutes
- Benzodiazepines and barbiturates disrupt sleep architecture
-
Benzodiazepines
- ↓ Slow wave and REM sleep
- ↑ Stage 1 and 2
-
Benzodiazepines
27
Q
Insomnia
Sleep Architecture
A
28
Q
Benzodiazepines
Treatment of Insomnia
A
- Daytime sedation is common particularly w/ those agents that have long-acting active metabolites
- Tolerance can occur leading the patient to ↑ the dose
- Anterograde amnesia
30
Q
Suvorexant
A
Orexin antagonist
- Helps the patient fall asleep faster and stay asleep
- Does not disrupt sleep architecture
- Next day drowsiness could be problem
