2 - Sedative Hypnotics Flashcards by G V

Sedatives: Defined (3) and what level of CNS depression (1)

Decreases activity

Moderates excitement

Calms the recipient

Lowest level of CNS depression

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Hypnotics Defined And Used for What?

Produces drowsiness and facilitates the onset and maintenance of a state of sleep that resembles natural sleep and form which the recipient can be aroused easily

Used for insomnia, for high doses

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Classification of Sedative-Hypnotics: Long Acting Barbiturates (1) and Barbiturates in general bind between what 2 subunits?

Phenobartbital

Bind between alpha 1 and beta 2

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Classification of Sedative-Hypnotics: Short Acting Barbiturates (2)

Pentobarbital

Secobarbital

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Classification of Sedative-Hypnotics: Ultra Short Acting Barbiturates and are type of soluble? (3)

Thiopentone (Pentothal) –> lethal injection/truth serum

Methohexitone

Lipid-soluble, enter brain within seconds of IV administration

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Classification of Sedative-Hypnotics: Benzodiazepines (BZDS) (10) and also bind between what 2 subunits?

Diazepam (Valium)
Chlordiazepoxide (Librium)
Clonazepam
Oxazepam
Lorazepam (Ativan)
Triazolam
Flunitrazepam (Rohypnol, “Roofies”, anterograde amnesia)
Nitrazepam (also a date rape drug)
Alprazolam (Xanax, short acting)
Midazolam (shortest acting, used in aneasthesia)

Bind between interface of alpha1 and gamma2

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Classification of Sedative-Hypnotics: Newer Hypnotics (3) and effect on REM upon discontinuation

Zolpidem

Eszopiclone

Zaleplon

Don’t increase REM sleep duration upon discontinuation (less effect on sleep pattens)

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Barbiturates: MOA (Pathway and 2 Facts)

Act on GABA-A (ionotropic) receptor Cl channel complex —>

Prolong DURATION of GABA-mediated chloride channel OPENINGS –>

Membrane hyperpolarization – inhibition

Also have inhibitory effects on glutamate receptors

High doses: GABA mimetic action

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Benzodiazepines (BZDs) MOA Pathway

Act on GABA-A receptor Cl channel complex –>

Increased FREQUENCY of GABA-mediated chloride channel openings cause chloride influx –>

Membrane Hyperpolarization (membrane inhibition)

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Zolpidem and Zaleplon MOA

Bind to GABA-A receptor isoforms that contain Alpha-1 subunits

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Pharmacokinetics: Barbiturates

Activity of hepatic microsomal drug (CYP) –> metabolizing enzymes may be increased, so interfere with other drugs

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Pharmacokinetics: Benzodiazepines - Phases 1 and 2 (2) and Exception (1)

Phase 1: undergo metabolism in liver

Phase 2: conjugation reaction outside of liver

Major route of metabolism for oxazepam and lorazepam –> conjugation (skip phase 1 and go directly to phase 2)

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Sedative-Hypnotics Actions on CNS (2)

CNS: Dose dependent effects

Sedation (anxiolysis) –> sleep (hypnosis) –> anaesthesia –> coma

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Sedative-Hypnotics Actions on CNS: Pentobarbital example, and curve for barbiturates and benzos

Low doses causes sedation (50-100 mg)

Hypnosis (100-200 mg)

Anesthesia (300-400 mg)

High doses can cause death (>600 mg)

Barbiturates: Curve is steep –> coma and death

Benzos –> Eventually flat, may not cause coma and death, so may be safer

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Sedative-Hypnotics: Smaller Doses Effects (6)

Reduction in anxiety
Drowsiness
Impaired motor coordination
Impaired learning and memory
Euphoria, impaired judgment, and loss of self-control (paradoxical reaction, due to LOSS of inhibition; dysinhibition of previously suppressed behavior)
Anterograde amnesia (hangover movie)

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Sedative-Hypnotics: Effects on Sleep Patterns (5)

1. Decreases latency of sleep onset

1. Duration of stage 2 increased*
  - Sleep duration

REM sleep is decreased
Duration of stage 3 and 4 NREM slow-wave sleep is decreased
On discontinuation
- Rebound increase in REM sleep
- Worsening insomnia irritability, dizziness, mood upset

Sedative-Hypnotics: Anaesthesia in High Doses (3)

Depress the CNS - general anaesthesia
Thiopental, methohexital (ultra short acting) - inducing anaesthesia only
Diazepam, lorazepam, and midazolam i.v anaesthesia, along with other agents to maintain anaesthesia

Sedative-Hypnotics: Anticonvulsants (Benzos and Barbiturates) - MOA

Inhibit the development and spread of epileptiform electrical activity

Sedative-Hypnotics: Anticonvulsants (Benzos and Barbiturates) - Drugs (4)

Clonezepam

Nitrazepam

IV Diazepam (1st line status epilepticus)

Phenobarbital (3rd line for status epilepticus)

Sedative-Hypnotics: Skeletal Muscle Relaxation (Benzos only) (2)

Inhibitory effects polysynaptic reflexes and internuncial transmission and at high doses

May also depress transmission at the skeletal NMJ

Sedative-Hypnotics: Effect on Respiratory System in High Doses (Barbiturates)

Lead to respiratory depression

Sedative-Hypnotics: Effect on CVS in High Doses

Lead to fall in blood pressure

Sedative-Hypnotics: Tolerance (1) and with Barbiturates and Benzos

Repeated use = a decrease in responsiveness

Barbiturates: induce their own metabolism so become less effective over time

Benzos: Receptors become desensitized, so need to increase the dose (may lead to addiction)

Sedative-Hypnotics: Psychological Dependance

Compulsive use of the drug to relieve anxiety

Sedative-Hypnotics: Physiologic Dependance

Altered physiologic state that requires continuous drug administration to prevent an abstinence or withdrawal syndrome (CNS excitation --> anxiety, insomnia, convulsions)

Sedative-Hypnotics: Clinical Uses - Insomnia (3)

Barbiturates NOT preferred due to addiction risk and other side effects Short acting BZDs: Flurazepam, Triazolam, Alprazolam BEST: Zolpidem and Zaleplon --> less cognitive impairment, no rebound insomnia

Sedative-Hypnotics: Clinical Uses - Anxiety (3 Drugs)

Alprazolam, Lorezepam, and Clonezepam --> more efficacy

Sedative-Hypnotics: Clinical Uses - Epilepsy

1. Phenobarbitone - Generalized tonic clonic seizures and status epilepticus (3rd line) 2. BZDs- Diazepam-Status epilepticus (1st line), tetanus, febrile convulsions

Sedative-Hypnotics: Induction of GA (2 Drugs)

Thiopentone, Midazolam

Sedative-Hypnotics: Other Uses - Endoscopy and Bronchoscopy (2 Drugs)

Diazepam Midazolam

Sedative-Hypnotics: Other Uses - Premedication prior to?

Anesthesia to remove anxiety for surgery

Sedative-Hypnotics: Other Uses - During Withdrawal from Physiologic Dependence on Ethanol (2 Drugs)

Long Acting Benzos: Diazepam and Chlordiazepoxide

Sedative-Hypnotics: Other Uses - Delirium Tremens (Severe Alcohol Withdrawal) (1 Benzo drug)

Lorazepam --> preferred due to avoidance of metabolism in liver

Sedative-Hypnotics: Other Uses - Central Muscle Relaxants (1)

Diazepam for spastic conditions (cerebral palsy)

Sedative-Hypnotics: Adverse Effects (7)

1. Psychomotor dysfunction: 2. Hangover – Barbs and BZDs metabolites which have long half life 3. Dependence 4. Overdosage (Acute barbiturate poisoning) * 5. Porphyria – barbiturates (activates ALA synthase)* --> CONTRAINDICATED 6. Can exacerbate breathing problems –COPD, OSA 7. Drug interactions with barbiturates (OCP and Warfarin)

Sedative-Hypnotics: Treatment of Barbiturate Poisoning (5)

1. Gastric lavage 2. Oxygen, supportive measures * 3. Forced alkaline diuresis: i.v sodium bicarbonate/NAHCO3* 4. Hemodialysis 5. No specific antidote

Sedative-Hypnotics: Benzodiazepines Overdosage (Facts and Treatment, 3)

Is not as fatal as barbiturates Specific antidote Treatment: Flumazenil (BZD antagonist)