Anxiolytics and Sedatives Flashcards by Quynh Tran

GABA

(γ-aminobutyric acid)

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

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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
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
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
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
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

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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
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
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:
- 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)
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

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Selective Benzodiazepines

Pharmacokinetics Properties

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Benzodiazepines

Adverse Effects

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

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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

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Benzodiazepines

Physical Dependence

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 1^st 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

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Benzodiazepines

Toxicity

Impaired judgment, slurred speech, incoordination, stupor, respiratory depression, death

Use flumazenil to treat a significant OD

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Benzodiazepines

Other Therapeutic Uses

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Besides use as anxiolytic agents:

Hypnotic agents for inducing sleep
Adjunctive agents in surgical anesthesia and sometimes as the primary sedative/amnestic agents in certain nonsurgical procedures
- Lorazepam, diazepam, midazolam
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

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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

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1^st 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

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

Buspirone

Pharmacokinetic and Therapeutic Considerations

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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

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
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

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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

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Characterized by recurrent panic attacks which may occur spontaneously and/or elicited by phobic stimuli
- Abrupt onset of symptoms
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
SSRI’s (ex. Fluoxetine) ⇒ long-term treatment

Phobic Disorder

Management

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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

* **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 * **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_ * 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

Insomnia Sleep Architecture

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**

Non-benzodiazepines Treatment of Insomniaa

* **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** * _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** ⇒ 1^st 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

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

Anxiolytics and Sedatives Flashcards

(33 cards)