Anxiolytics and Sedatives Flashcards
GABA
(γ-aminobutyric acid)
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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
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GABA interneurons:
- Cortex
- Limbic areas including hippocampus, amygdala and septum
- Basal ganglia and cerebellum
- Raphe nuclei
- Medulla
- Spinal cord
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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
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GABA
Shunt
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
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GABA
Synaptic Activity & GABA Loop
- 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
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Anxiety
Pharmacological Treatment
Anxiolytic drugs:
- Until the 1960’s, anxiety generally tx by relatively nonselective, sedating agents such as barbiturates
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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
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Benzodiazepines
Mechanism of Action
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
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BZD binds @ allosteric site (benzodiazepine receptors) on GABA-A receptors
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↑ binding affinity of GABA for the active site
- ↑ affinity but not efficacy of GABA
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↑ frequency of channel openings produced by GABA
- Do not open channels themselves
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↑ binding affinity of GABA for the active site
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Benzodiazepine Receptors
BZ1 ⇒ sedation and anti-convulsant actions
BZ2 ⇒ antianxiety and impairment of cognitive functions
- Benzodiazepines enhances activity of both BZ1 and BZ2
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Zolpidem [Ambien] (not a benzo) ⇒ specifically stimulates BZ1 receptors
- Used as a sedative/hypnotic
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Flumazenil
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
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Barbiturates
MOA
- 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
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Barbiturates
Indications
Relatively non-selective sedating agents
Not widely used
- Phenobarbital used for seizures
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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
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Benzodiazepines
Pharmacokinetics & Metabolism
- 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:
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2-step metabolism: N-dealkylation and/or hydroxylation → conjugation via glucuronidation
- Ex. diazepam (Valium), chlordiazepoxide (Librium), flurazepam (Dalmane)
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Glucuronidation only
- Ex. oxazepam (Serax) and lorazepam (Ativan)
- Products of glucuronidation are inactive
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Conversion to active metabolites of uncertain clinical significance
- Ex. alprazolam (Xanax), triazolam (Halcion) and temazepam (Restoril)
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2-step metabolism: N-dealkylation and/or hydroxylation → conjugation via glucuronidation
- BZDs do not induce hepatic microsomal enzymes
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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
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Old age, hepatic damage, and other drugs (e.g., cimetidine) can reduce the rate of oxidative biotransformation of certain BZDs
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Selective Benzodiazepines
Pharmacokinetics Properties
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Benzodiazepines
Adverse Effects
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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
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May potentiate actions of other sedating drugs (eg, ethanol, barbiturates)
- Sometimes leading to cardiovascular and respiratory depression
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Benzodiazepines
Tolerance
- 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
Benzodiazepines
Physical Dependence
- Physical dependence develops to BZDs
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Appearance of sx upon withdrawal
- ↑ Risk w/ higher doses and/or prolonged/repeated use
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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
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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
Benzodiazepines
Toxicity
Impaired judgment, slurred speech, incoordination, stupor, respiratory depression, death
Use flumazenil to treat a significant OD
Benzodiazepines
Other Therapeutic Uses
Besides use as anxiolytic agents:
- Hypnotic agents for inducing sleep
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Adjunctive agents in surgical anesthesia and sometimes as the primary sedative/amnestic agents in certain nonsurgical procedures
- Lorazepam, diazepam, midazolam
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Anticonvulsants
- Status epilepticus (diazepam, lorazepam)
- Metit mal and myoclonus (clonazepam, nitrazepam)
- Muscle relaxants in treating spasticity (diazepam)
- Controlled replacement drugs in withdrawing pts from ethanol toxicity
Non-benzodiazepine Anxiolytic Agents
- Other agents increasingly gained use in managing other forms of anxiety:
- Situational anxiety
- Phobic disorders accompanied by panic attacks
- Obsessive-compulsive disorder (OCD)
- Buspirone (Buspar®) became the first new anxiolytic based on a specific 5-HT target
Buspirone (Buspar)
Overview
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
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Buspirone
Mechanism of Action
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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
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Buspirone
Pharmacokinetic and Therapeutic Considerations
- Rapidly absorbed after oral administration
- Highly bound to plasma proteins (> 90%)
- Metabolized by hepatic oxidation to 1-pyrimidinyl piperazine (active)
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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
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Anxiety Disorders
Management
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Acute anxiety disorder
- Can result from things like illness or separation
- BZD ⇒ short-term relief
- Propranolol ⇒ acute situational anxiety or performance anxiety
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Generalized anxiety disorder
- A persistent state of fear concerning future events
- BZD ⇒ tx acute symptoms and exacerbations
- Buspirone ⇒ a good alternative that is non-sedating, but takes several weeks before anxiolytic effect is felt
Obsessive-Compulsive Disorder
Management
- By definition characterized by obsessions and compulsions
- Drug of choice is an SSRI
- Previously was clomipramine (TCA, potent 5-HT reuptake inhibitor)
- SSRIs equally effective but safer
- SNRI’s are also effective in OCD
- Buspirone not effective
- Benzodiazepines used as adjunct to reduce anxiety routinely experienced by OCD pts
Panic Disorder
Management
- Characterized by recurrent panic attacks which may occur spontaneously and/or elicited by phobic stimuli
- Abrupt onset of symptoms
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Benzodiazepines (ex. Alprazolam) ⇒ immediate relief during early phase of an attack
- Doses of alprazolam for tx of panic disorder 2-10x higher than used for generalized anxiety disorder
- Concern for adverse effects and withdrawal
- Doses of alprazolam for tx of panic disorder 2-10x higher than used for generalized anxiety disorder
- SSRI’s (ex. Fluoxetine) ⇒ long-term treatment
Phobic Disorder
Management
Patient is overly fearful about a particular situation
- Psychotherapy
- Pharmacological tx guidelines similar to that of panic disorder
- BZD ⇒ acute
- SSRIs ⇒ maintenance
Sleep Disorders
Management
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Non-pharmacological tx for insomnia should be tried first
- Behavioral modifications such as diet, exercise, avoiding stimulants at bed time, and comfortable sleep environment
- If pharmacological intervention is necessary, it should be used for a limited period
- Abrupt d/c of drugs like BZD can lead to rebound insomnia or more serious problems such as convulsion
- Barbiturates are not routinely used
- Should not be combined w/ other agents that cause CNS depression such as ethanol or opioids
- If insomnia does not correct in a short-period, then it may be due to a psychiatric or organic illness
- Long-term use of hypnotics is not recommended
Normal
Sleep Architecture
- Sleep has 5 distinct types of brain wave activity based on EEG findings
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Sleep stages can be divided into non-rapid eye movement (NREM) and rapid eye movement
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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
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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
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Benzodiazepines
- ↓ Slow wave and REM sleep
- ↑ Stage 1 and 2
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Benzodiazepines
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Insomnia
Sleep Architecture
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Benzodiazepines
Treatment of Insomnia
- 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
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Non-benzodiazepines
Treatment of Insomniaa
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Works as well as benzodiazepines w/o the disruption of sleep architecture
- Only activate the BZ1 receptor
- Rapid onset, modest day-after sedation and few amnestic effects
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Can cause sleep-related behavior, including sleep-driving, making phone calls, and preparing and eating food while asleep
- Zolpidem ⇒ ataxia, nightmares, headache, confusion
- Zaleplon ⇒ same but shorter half-life, so it can be taken when patient wakes in the middle of the night
- Eszopiclone ⇒ 1st sleep medication approved to be taken on a long-term basis
Suvorexant
Orexin antagonist
- Helps the patient fall asleep faster and stay asleep
- Does not disrupt sleep architecture
- Next day drowsiness could be problem
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Antihistamines
Treatment of Insomnia
- Includes diphenhydramine
- ⊗ Histamine-1 receptors and cholinergic muscarinic receptors in the CNS
- Drugs in this class are used in several OTC sleep medications
Melatonin
- Synthesized in the pineal gland
- Involved in the regulating the body’s biological clock
- Released just before sleep and can induce sleep
- Used to treat jet lag and insomnia in shift-change workers
- Relatively safe but can cause fatigue and lethargy
- It is available OTC
Ramelteon
- New drug available by prescription
- Activates melatonin 1 and 2 receptors
- Not a controlled substance