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Flashcards in Sedative-Hypnotic Drugs Deck (29)
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What defines an effective sedative drug?

Should reduce anxiety and exert a calming effect with little or no effect on motor or mental function


What defines a hypnotic drug?

Produce drowsiness and encourage the onset and maintenance of a state of sleep that as far as possible resembles the natural sleep state.
--achieved by increasing the dose of sedative drugs


Older sedative-hypnotics, including barbiturates and alcohols show what kind of dose response relationship?

Linear slope
--increase in dose above that needed for hypnosis may lead to a state of general anesthesia


Deviations from a linear dose response relationship will require proportionately greater dosage increments in order to achieve CNS depression more profound than hypnosis. What drugs do this?

--offering a greater margin of safety


What are the various classifications of sedative-hypnotic drugs?

1. Benzodiazepines: Alprazolam, Clonazepam, Diazepam, Flurazepam, Lorazepam, Midazolam, Oxazepam, Temazepam, Triazolam
2. Barbiturates: Phenobarbital, Pentobarbital, Thiopental
3. Non-Benzodiazepine Benzodiazepine-Receptor Agonists (NBBRA): Zolpiden, Zaleplon, Eszopiclone
4. 5-HT1A Partial Agonist: Buspirone
5. Melatonin Receptor Agonist: Ramelteon
6. Older Sedative Hypnotics: Meprobamate, Chloral Hydrate and Paraldehyde
7. B blockers: Propanolol
8. Alpha 2 Agonist: Clonidine
9. Anti-Histamines: Hydroxyzine, Diphenhydramine and Doxylamine


Benzos have replaced barbiturates in the treatment of anxiety due to their safety and effectiveness. What is the MOA of benzos?

--binds to GABAa receptors (functions as a Cl channel and is activated by inhibitory GABA)
--Binding sites for GABA are located between adjacent alpha and beta subunits
--Benzos bind between alpha and the gamma subunit (benzo receptor): BZ1 (Alpha 1 subunit) and BZ2 (Alpha 2 subunit) receptor
--GABA is an inhibitory neurotransmitter in the CNS. Binding of GABA to its receptor opens the Cl channel, leading to an increase in Cl influx (causes hyperpolarization and inhibits AP)
--Benzos potentiate GABAergic inhibition: enhance GABAs effects allosterically (therefore increase in frequency of Cl channels)


Benzodiazepine receptor interactions, there are agonists, antagonists and inverse agonist, what drugs are these?

Agonist: facilitate GABA action by acting as positive allosteric modulators of GABAa receptor function
Antagonist: Flumazenil (block the action of benzos and NBBRAs)
Inverse Agonist: Negative allosteric modulators of GABA receptor: cause anxiety and seizures. Beta-Carbolines


All benzodiazepines exhibit the following actions to a greater or lesser extent

1. Sedation: exert calming effects with reduction of anxiety
2. Anticonvulsant Effects: clonazepam, nitrazepam, lorazepam and diazepam
3. Muscle Relaxation: relax the spasticity of skeletal muscle
4. Anesthesia: diazepam and midazolam, used for IV anesthesia


Compare the duration of action of Benzos

Long Acting (1-3 days): Diazepam and Flurazepam
Intermediate Acting (10-20h): Alprazolam, Lorazepam and Temazepam
Short Acting (3-8h): Oxazepam and Triazolam
--the longer acting agents form active metabolites with long half lives


Most benzos undergo phase I reactions mainly by CYP3A4 (therefore inhibitors of CYP3A4 can inhibit the metabolism of benzos), the metabolites are then conjugated to phase II to form glucuronides that are excreted in the urine. Which benzos are conjugated directly to their glucuronides?

Oxazepam, Lorazepam and Temazepam are conjugated directly to their glucuronides mainly in the liver and are not metabolized by the P450 system
--therefore their plasma levels are not affected in liver disease


Lets go through the therapeutic uses of Benzodiazepines.

1. Anxiety Disorder: produce pharmacologic dependence and have limited benefit in OCD or PTSD
--recommended for short term use
--alprazolam is effective for panic disorder but can cause rebound anxiety between doses
2. Muscular Disorders: Diazepam for skeletal muscle spasms
3. Seizures: Clonazepam (epileptic) and Lorazepam (status epilepticus)
4. Drug Withdrawal: Chlordiazepoxide, Clorazepate, Diazepam and Oxazepam: from ethanol
5. Anesthesia: diazepam and midazolam


The three most prescribed for sleep disorders are long acting Flurazepam, Intermediate acting Temazepam and short acting Triazolam. What are the effects of sedative-hypnotics on patterns of normal sleep?

1. Latency of sleep onset is decreased
2. Duration of stage 2 NREM sleep is increased
3. Duration of REM sleep is decreased
4. Duration of stage 4 NREM slow wave sleep is decreased


Moving on to the adverse effects of benzos.

1. Drowsiness and Confusion: most common side effects
2. Ataxia: occurs at high doses
3. Cognitive Impairment: decreased long term recall
4. Adverse Psychological Effects: paradoxical effects
--increase the incidence of nightmares, anxiety
--bizarre uninhibited behavior is noted by some users, while hostility and rage may occur in others. -- called disinhibition or dyscontrol reactions.


What is the dependence for Benzos?

Can develop if high doses are given over prolonged periods
Abrupt discontinuation leads to withdrawal symptoms: confusion, anxiety and agitation


Benzos are considerable less dangerous than other anxiolytics and hypnotic drugs. As a result...?

A drug overdose is seldom lethal
--unless something like alcohol is taken with it


Moving on to the one Benzodiazepine Antagonist: Flumazenil. What are some features?

1. Blocks actions of benzos and BZRAs
--does not antagonize other sedative-hypnotics
2. Approved for reversing the CNS depressant effects of benzos overdose
3. IV admin only: onset is rapid but duration is short so may have to give frequent doses
4. May precipitate withdrawal in physiologically dependent patients or may cause seizures if a benzo is used for seizure control.
--if TCAs and benzos taken then seizures and arrhythmias after admin of flumazenil


Moving on to the barbiturates. Why have they been replaced with benzos?

Induce tolerance, drug metabolizing enzymes, physical dependence, severe withdrawal symptoms, coma
--some barbiturates are used as a very short acting thiopental for anesthesia induction


What is the MOA for barbiturates?

Potential actions of GABA
--increase duration of the GABA gated chloride channel openings
--block glutamate receptors
---high concentrations of pentobarbital block sodium channels
Multiplicity of sites of action is the basis for their more pronounced central depressant effects which result in their low margin of safety


Barbiturates are classified according to their duration of action....

1. Thiopental: acts within seconds and has 30 minutes of action -- used in IV induction of anesthesia
2. Phenobarbital: duration of action of less than a day --use is seizures
3. Pentobarbital, secobarbital, and amobarbital are short acting (3-8 hours)


Describe the depression of CNS, respiratory depression and enzyme induction for Barbiturates..

Depression of CNS
--any degree of CNS depression is possible depending on the dose
Respiratory Depression
--suppress the hypoxic and chemoreceptor response to CO2
Enzyme Induction:
--induce P450 enzymes in the liver; diminishes the action of many drugs that are dependent on P450 metabolism to reduce their concentrations


What are the therapeutic uses for barbiturates?

1. Anesthesia: ultra short acting (thiopental)
2. Anticonvulsant: Phenobarbital (tonic clonic, status epilepticus and eclampsia)
3. Hepatic Metabolic Uses: Hepatic glucuronyl Transferase and the bilirubin binding Y protein are increased by the barbiturates, phenobarb treats hyperbilirubinemia and kernicterus in neonates. N-phenylbarbital works well too


Moving on to the pharmacokinetics of Barbiturates, what is the primary mechanism of termination of action of thiopental and similar short acting barbiturates?

Redistribution from the brain to other compartments
--this accounts for the short duration of action


Except for the less liposoluble phenobarbital, nearly complete metabolism and/or conjugation of barbiturates in the liver precedes their renal excretion. About 25% of phenobar is excreted?

In the urine
--wherease the amount of other barbiturates excreted unchanged in the urine is negligible


Finally lets discuss the AE of Barbiturates.

1. CNS: drowsiness, impaired concentration
2. Paradoxical Excitement: excitement rather than depression
3. Hypersensitivity: allergic reactions
4. Drug Hangover: hypnotic doses produce a feeling of tiredness well after patient awakes.
5. Precautions: induce P450 system and therefore decrease the effect of drugs that are metabolized by these hepatic enzymes
6. Barbiturates Increase Porphyrin Synthesis: do not give to acute intermittent porphyria, variegate porphyria, hereditary coproporphyria or symptomatic porphyria
7. Do not give in the presence of Pulmonary Insufficiency
8. Rapid IV injection: cardiovascular collapse
9. Slow IV injection: apnea, laringospasm, coughing and other resp problems
10. Addiction: abrupt withdrawal can cause tremors and even cardiac arrest
11. Poisoning: leading cause of death among drug overdoses.


The next class of drugs are the Non-Benzodiazepine Benzodiazepine Receptor Agonists (NBBRA). These drugs act only on the BZ1 subtype (Alpha 1 subunits). The first drug is Zolpidem. What are features of this drug?

1. Binds to the GABAa receptor and facilitates GABA mediated neuronal inhibition
2. Antagonized by flumazenil
3. Hypnotic with short duration of action
4. Minimal muscle relaxing and anticonvulsant effects
5. Few withdrawal effects and minimal rebound insomnia
6. Metabolized to inactive metabolites by CYP3A4
7. Indicated for short term treatment of insomnia (problems with sleep initiation)
8. AE: nightmares, agitation, headache, GI upset


The next NBBRA drug is Zaleplon. What are some features?

1. Similar to Zolpidem in hypnotic effects
2. Fewer residual effects on psychomotor and cognitive functions compared to zolpidem or benzos.
3. Metabolized by aldehyde oxidase and CYP3A4


The third and last NBBRA drug is Eszopiclone, what are some features?

1. Active enantiomer of Zopiclone, higher affinity for its receptor target site
2. Approved for tx of insomnia
3. Decreases sleep latency and improves sleep maintenance
4. Elimination half life is 6 hours
5. AE: anxiety, dry mouth, headache, peripheral edema, somnolence


The next class of drugs is 5-HT1a partial agonists. There is only one drug in this category, Buspirone, what are some features?

1. 5-HT1a partial agonist
2. No hypnotic, anticonvulsant or muscle relaxant properties. Only anxiolytic
3. Doesnt interact with GABA receptors
4. Management of anxiety disorders
5. Onset 2-3 weeks
6. Slow onset has led to belief that buspirone works by adaptive neuronal and receptor events.
--action appears to be analogous to antidepressants


What are advantages of Buspirone?

1. Less psychomotor impairment
2. No drug interaction with EtOH, benzos or other sedative-hypnotics
3. No rebound anxiety or withdrawal from abrupt discontinuance
4. No dependence