2 - Sedative Hypnotics Flashcards
Sedatives: Defined (3) and what level of CNS depression (1)
Decreases activity
Moderates excitement
Calms the recipient
Lowest level of CNS depression
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
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
Classification of Sedative-Hypnotics: Short Acting Barbiturates (2)
Pentobarbital
Secobarbital
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
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
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)
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
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)
Zolpidem and Zaleplon MOA
Bind to GABA-A receptor isoforms that contain Alpha-1 subunits
Pharmacokinetics: Barbiturates
Activity of hepatic microsomal drug (CYP) –> metabolizing enzymes may be increased, so interfere with other drugs
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)
Sedative-Hypnotics Actions on CNS (2)
CNS: Dose dependent effects
Sedation (anxiolysis) –> sleep (hypnosis) –> anaesthesia –> coma
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
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)
Sedative-Hypnotics: Effects on Sleep Patterns (5)
1. Decreases latency of sleep onset
- Duration of stage 2 increased*
- Sleep duration
- Duration of stage 2 increased*
- 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
- Phenobarbitone - Generalized tonic clonic seizures and status epilepticus (3rd line)
- 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)
- Psychomotor dysfunction:
- Hangover – Barbs and BZDs metabolites which have long half life
- Dependence
- Overdosage (Acute barbiturate poisoning)
* 5. Porphyria – barbiturates (activates ALA synthase)* –> CONTRAINDICATED - Can exacerbate breathing problems –COPD, OSA
- Drug interactions with barbiturates (OCP and Warfarin)
Sedative-Hypnotics: Treatment of Barbiturate Poisoning (5)
- Gastric lavage
- Oxygen, supportive measures
* 3. Forced alkaline diuresis: i.v sodium bicarbonate/NAHCO3* - Hemodialysis
- No specific antidote
Sedative-Hypnotics: Benzodiazepines Overdosage (Facts and Treatment, 3)
Is not as fatal as barbiturates
Specific antidote
Treatment: Flumazenil (BZD antagonist)
