Sedative Hypnotics & Alcohol Flashcards
Sedative
reduces anxiety (anxiolytic) and irritation, produces a calming effect
Hypnotic
produces drowsiness, aids sleep onset or maintenance
Sedative Hypnotics Uses
- Anxiety Disorder
- Anesthesia
- Seizure Disorders
- Treating Withdrawal-Benzodiazepines (first line)
- Sleep Disorder- Hypnotic
Sedative-hypnotics are drugs that produce…
…sedation at lower doses AND hypnosis at higher doses
ALCOHOL USE DISORDER (AUD)
- impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences
- Severity (mild, moderate or severe) is determined by number of clinical criteria (DSM-5) met during a 12-month period
Alcohol tolerance
with chronic use, same alcohol amount produces less effect
Alcohol dependence
chronic use produces physiological changes that can result in alcohol withdrawal (potentially fatal condition) on stopping alcohol use
At low doses alcohol produces anxiolysis, disinhibition and relaxation via:
- Agonist activity at GABAA receptors
- Agonist activity at inhibitory glycine receptors
- Antagonist at excitatory NMDA (glutamate) receptors
Glutamate
major excitatory neurotransmitter in brain, and the most abundant (80% of all neurons); increases likelihood of action potentials firing
GABA
major inhibitory neurotransmitter (20% of all neurons); both produce fast, powerful effects on other neurons
ALCOHOL CNS DEPRESSANT EFFECTS
- Balance between excitatory and inhibitory neurotransmission is often synchronized and rhythmic, oscillating on small (msec) and large-scale (day/night)
- Rhythmic electrical activity is involved in regulating sleep/wake, consciousness / unconsciousness, seizures, etc.
- Alcohol CNS depressant effects range through relaxation, anti-convulsant effects, sleep, unconsciousness, coma and death
EUPHORIA AND REWARDING EFFECTS
- Result from activation of the brain’s major reward circuit, the mesolimbic dopamine pathway
- When neurons in the ventral tegmental area (VTA) detect a rewarding stimulus, they release dopamine onto the nucleus accumbens (NAc) → reward sensation
Affects of Alcohol on Rewarding Effects
- Alcohol increases firing of dopamine VTA neurons
* VTA releases dopamine onto NAc, signaling reward
NAc (Nucleus accumbens)
selectively activated during the perception (or imagining) of pleasant, (positive emotion) situations
CHRONIC CNS EFFECTS (DEPENDENCE)
• CNS responds to chronic ethanol with compensatory changes to counteract acute ethanol effects (attempt to normalize CNS activity level)
When you build tolerance to alcohol you will…
(1) more alcohol needed to produce same effect
2) abrupt removal of alcohol results in CNS hyperexcitation (withdrawal symptoms
Drugs for managing alcohol withdrawal
Thiamine and Benzodiazepines
Drugs for preventing alcohol dependence relapse
Naltrexone, Acamprosate, Disulfiram, Topiramate, Gabapentin
Benzodiazepines
- treating agitation and minimizing symptom progression (moderate to severe withdrawal)
- gradually re-equilibrate GABAergic neurotransmission levels) - dose must be tapered off gradually
- Chlordiazepoxide, diazepam, and lorazepam
NALTREXONE
- USE: First-line for treating moderate to severe AUD and preventing relapse - Available PO or long-acting injectable
- MOA: Long-acting mu opioid receptor antagonist, blocks reward signaling
- Also used to treat opioid addiction → screen for concurrent opioid use to avoid triggering opioid withdrawal
ACAMPROSATE
- USE: PREVENTING RELAPSE; alternative to naltrexone, patient with liver disease - administered 3x daily
- MOA: Weak NMDA glutamate receptor antagonist (and possibly weak GABAA agonist) - slow normalization of compensatory neurochemical changes
- Primarily renally-excreted
- Contraindicated in renal dysfunction
DISULFIRAM
- USE: PREVENTING RELAPSE; use is limited to certain motivated patients; efficacy is weaker
- MOA: acetaldehyde causes unpleasant effects (e.g., sweating, headache, nausea, vomiting) when alcohol is consumed by irreversibly inhibiting ALDH enzyme → causes acetaldehyde to accumulate
- Requires 48 hours of total abstinence before use
- Appropriate counseling and patient consent is always necessary
- AE: hepatotoxicity and psychosis
Topiramiate
- USE: PREVENTING RELAPSE; Anticonvulsant drug (also used for migraine)
- MOA: increasing GABAA activity and reducing glutamate signaling
- Preferred for patients who have a seizure disorder that can be treated with topiramate, and who have failed initial treatment with naltrexone or acamprosate
Gabapentin
- USE: PREVENTING RELAPSE; Anticonvulsant drug (also used for neuropathic pain),
- MOA: interferes with voltage-dependent calcium channel activity in the brain
- Good efficacy in patients who failed other options
- Disadvantage: addictive potential
LIST OF BARBITURATES DRUGS (-tal)
- Thiopental (ultra short-acting)
- Secobarbital (short-acting)
- Amobarbital (intermediate)
- Phenobarbital (long-acting)
LIST OF BENZODIAZEPINES DRUGS (-lam, -pam, -poxide)
• Midazolam (short-acting)
- Alprazolam (intermediate)
- Clonazepam (intermediate)
- Lorazepam (intermediate)
- Diazepam (long-acting)
- Chlordiazepoxide (long-acting)
BENZODIAZEPINE ANTAGONIST DRUG
Flumazenil
Other Sedative Hypnotics Drug
Ethanol
BARBITURATES USES
- Seizure disorders (phenobarbital has some use in partial epilepsy)
- Anesthesia induction (thiopental has rapid onset / offset of effect)
- Medically-induced coma (pentobarbital or thiopental)
- Lethal injection, assisted suicide (secobarbital, pentobarbital)
- Most are rarely used today, due to danger in overdose, dependence risk → replaced by newer, safer agents
- A few are currently used as antiepileptics or anesthetics
BARBITURATES MOA
• MOA:
- bind the GABAA receptor at multiple sites (can bind to α or β subunits), distinct from GABA and other drug binding sites
- positive allosteric modulators of GABAA , increasing the duration of Cl- ion channel opening when GABA binds
- antagonist at glutamate AMPA receptors
- primary GABAA receptor agonist (at high concentrations, opens channel on own)
BARBITURATES DRUG INTERACTIONS
- CNS depression - dose-dependent barbiturate effect; interaction with other CNS depressants can produce lethal effects
- Enzyme induction - chronic barbiturate use markedly increases CYP enzyme levels → drug interactions
BARBITURATES ADVERSE EFFECTS & RISKS
- Risk of abuse - disinhibition, sleep promotion and euphoric effects make these very abuse-liable (DEA schedule II-IV)
- Dependence risk - tolerance development (similar to alcohol dependence, neuronal adaptations result in withdrawal symptoms if drug is stopped)
- Overdose risk - dose-dependent CNS, cardiovascular and respiratory depression
BENZODIAZEPINES USES
- Status epilepticus: diazepam or lorazepam are first-line - IV diazepam has nearly instant onset of effect
- Pre-surgery sedation: midazolam (Versed)
- Short-term treatment of anxiety: alprazolam (Xanax) or beta blockers; SSRIs antidepressants are used for long-term treatment
- Management of alcohol withdrawal: chlordiazepoxide (Librium) is first-line (long duration provides smooth tapering of GABAA activation)
BENZODIAZEPINES MECHANISM OF ACTION
- positive allosteric modulators of GABAA , but they increase the frequency of channel opening (opens at lower GABA concentration)
- Bind GABAA receptor at a single site (only at interface between an α and γ subunit)
BENZODIAZEPINE ADVERSE EFFECTS & RISKS
- CNS depression - Like barbiturates, benzos can potentiate CNS depressant effects of other drugs - Agents with active metabolites require caution, particularly in elderly
- Risk of abuse - disinhibition, sleep promotion and euphoric effects
- Dependence risk - moderate dependence risk (potential for withdrawal symptoms) is the main reason that benzodiazepines are usually recommended only for short-term use
- Overdose risk - much less dangerous than barbiturates, due to:
- Shallower dose-response curve (does not progress to coma / death)
- Availability of an antidote: flumazenil
BENZODIAZEPINE ADVERSE EFFECTS & RISKS
- CNS depression - Like barbiturates, benzos can potentiate CNS depressant effects of other drugs - Agents with active metabolites require caution, particularly in elderly
- Risk of abuse - disinhibition, sleep promotion and euphoric effects
- Dependence risk - moderate dependence risk (potential for withdrawal symptoms) is the main reason that benzodiazepines are usually recommended only for short-term use
- Overdose risk - much less dangerous than barbiturates, due to:
- Shallower dose-response curve (does not progress to coma / death)
- Availability of an antidote: flumazenil
Flumazenil
- an imidazobenzodiazepine, is the only GABAA receptor antagonist
- flumazenil occupies the benzodiazepine binding site without producing any effect (competitive GABAAR antagonist)
- Reverses CNS depressant effects produced by overdoses of benzodiazepines and Z-drugs
- Flumazenil is short-acting; additional doses must be administered until the agonist is cleared from the body
Sleep Disorders
conditions that cause persistent interference with sleep amount (too much / too little) and/or quality, causing distress and impairment
LIST OF Z-DRUGS
- Eszopiclone
- Zaleplon
- Zolpidem
LIST OF MELATONIN AGONISTS
- Ramelteon
* Tasimelteon
LIST OF OREXIN AGONIST
• Suvorexant
Z-DRUGS MOA
- Z-drugs bind to the same site on the GABAA receptor as benzodiazepines, and also increase Cl ion conductance
- z-drugs bind selectively between α1 and γ subunits only (much more selective than benzodiazepines, which bind between any α and γ subunit)
Z-DRUGS EFFECTS AND USES
- USE: insomnia only
- EFFECTS:
- Shortened time to sleep onset (by about 20 min)
- Small increase in sleep time / quality
• PK & DOSING:
- Rapid onset of action (take ~30m before bed)
- Effect duration intended to be <8hr (so you can wake up!)
Z - DRUGS ADVERSE EFFECTS & RISKS
Common effects: dizziness, memory loss, disinhibition, GI upset, hallucinations
Parasomnias (less common)
Abuse: abuse risk
Dependence: after ~2 weeks of use, taper dose to avoid withdrawal symptoms
MELATONIN RECEPTOR AGONISTS MOA
Ramelteon and tasimelteon are agonists at melatonin MT1 and MT2 receptors (reset circadian rhythms)
MELATONIN RECEPTOR AGONISTS USES
- Insomnia with sleep onset difficulty
* Non-24-hour sleep-wake disorder
MELATONIN RECEPTOR AGONISTS EFFICACY, SIDE EFFECTS, AND ADVANTAGES
Efficacy: Modest improvement in time to sleep onset vs. placebo
Side Effects: Generally mild - headaches, vivid dreams
Advantages: No CNS depressant effects, negligible tolerance / dependence / abuse risk → not a scheduled substance
OREXIN RECEPTOR ANTAGONISTS MOA
Suvorexant is a dual antagonist at orexin OX1R / OX2R receptors (reduces activity of wake-promoting neurons in hypothalamus)
OREXIN RECEPTOR ANTAGONISTS USES
Insomnia due to difficulty with sleep onset or sleep maintenance
OREXIN RECEPTOR ANTAGONISTS EFFICACY AND SIDE EFFECTS
Efficacy: reduces sleep latency (~20 min), increases duration (~20 min)
Side Effects: somnolence, headache
Warnings: complex sleep behaviors, increased suicide risk
Tolerance / dependence / abuse risk is present (schedule IV agents)
LIST OF SEDATIVES/ANXIOLYTICS
Buspirone
LIST OF SEDATIVE OF OTHER DRUGS FOR MANAGING ANXIETY
- Antidepressants
* Beta Blockers
Buspirone
MOA: serotonin 5HT1A receptor agonist (actual mechanism of anxiolysis unknown)
USES: long-term anxiety disorders
Effects: Anxiolytic effects only
Dosing / PK:
• Slow onset of action (like antidepressants, takes 3-4 weeks for full effect to develop) • Metabolized by CYP3A4
Advantages:
• No CNS depressant effects
• Negligible tolerance / dependence / abuse risk
• Apparently safe in pregnancy
Side Effects: tachycardia, paresthesia, nausea
