Slides 4 Flashcards
What are Sedative-Hypnotic drugs?
Drugs which cause sedation with concomitant relief of anxiety or encourage sleep.
What is the drug classification of Sedative-Hypnotics?
Clinical rather than chemical, because these drugs have diverse chemical structure.
What is the function of a sedative (anxiolytic) agent?
Reduces anxiety and exerts a calming effect.
What is the function of a hypnotic agent?
Produces drowsiness and encourages the onset and maintenance of sleep.
Which agent involves more pronounced depression of the CNS and how?
Hypnotic agents; by increasing the dose.
What are the classifications of Sedative-Hypnotics?
1) Benzodiazepines
2) Barbiturates
3) Chloral hydrate
What are some examples of Benzodiazepines?
1) Diazepam
2) Chlordiazepoxide
3) Flurazepam
4) Oxazepam
5) Lorazepam
6) Nitrazepam
7) Triazolam
8) Alprazolam
What are some examples of Barbiturates?
1) Phenobarbital
2) Pentobarbital
3) Secobarbital
4) Thiopental
What are some new drugs for sleep disorders?
1) Zolpidem
2) Zaleplon
3) Eszopiclone
What is an example of a Melatonin receptor agonist (hypnotic)?
Ramelteon
What is an example of an Anxiolytic agent?
Buspirone
What does the absorption of sedative-hypnotic drugs after oral administration depend on?
Lipid solubility (Most are well absorbed)
What does the passage to CNS of sedative-hypnotic drugs depend on?
Lipid solubility (Rapid onset of action)
Which sedative-hypnotic drugs are highly lipid soluble?
1) Thiopental
2) Triazolam
Can sedative-hypnotic drugs cross the placental barrier? What happens if given before delivery?
Yes; they may depress neonatal vital functions
If sedative-hypnotic drugs are given to pregnant women, where can we detect them?
In breast milk = depressant effect on the infant
What is the main mechanism of elimination of most sedative-hypnotics?
Metabolic transformation
What accounts for the clearance of all benzodiazepines?
Hepatic metabolism
What is the path of metabolism for most sedative-hypnotics?
Oxidation by cytochrome P450 enzymes (CYP3A4), and subsequently conjugated to glucuronides that are excreted in urine.
Many products of oxidation of benzodiazepines are:
Pharmacologically active (some have longer half lives than the parent)
What is the half-life of desmethyldiazepam?
> 40 hours
What affects the metabolism of sedative-hypnotics?
Inhibitors and inducers of CYPs.
Which drug is conjugated directly?
Lorazepam
What is the metabolism pathway of barbiturates?
Mainly metabolized by oxidation pathways then conjugated.
Phenobarbital is -% excreted unchanged in urine, and its excretion is increased by:
20-30%; alkalinization of urine.
The rate of metabolism is usually __(fast/slow), with
__(long/short) elimination half-lives.
Slow; long
What is the half life of Secobarbital and pentobarbital?
18 - 48 hours.
What is the half life of Phenobarbital?
4-5 days.
Multiple dosing of Secobarbital, pentobarbital, and Phenobarbital can lead to:
Cumulative effects
Zolpidem, Zaleplon, and Eszopiclone are metabolized to:
Inactive metabolites by CYP3A4
Which drugs inhibit the metabolism of Zolpidem, Zaleplon, and Eszopiclone?
1) Cimetidine
2) Ketoconazole
Which drug induces the metabolism of Zolpidem, Zaleplon, and Eszopiclone?
Rifampin
What is GABA and where is it released from?
Inhibitory neurotransmitter; typically released from local interneurons.
Where are Interneurons that release GABA found?
Throughout the CNS, including the spinal cord.
GABA receptors are divided into 2 main types:
1) GABAA
2) GABAB
IPSPs (inhibitory postsynaptic potentials) in the brain have a fast and a slow component. The fast component is mediated by __ receptors and the slow component by __ receptors
GABAA; GABAB
GABAA receptors are __ receptors and are selectively permeable to __.
ionotropic; Cl-
What are GABAA receptors selectively inhibited by?
Convulsants:
1) Picrotoxin
2) Bicuculline
GABAB receptors are __ receptors and are selectively activated by __.
Metabotropic; Antispastic drug Baclofen
GABAB receptors are coupled to __ that either inhibit __ or activate __.
G proteins; Ca2+ channels; K+ channels
Which drugs bind GABAA receptors in neuronal membranes in CNS? What do they do?
1) Benzodiazepines
2) Barbiturates
3) Zolpidem
4) Zaleplon
5) Eszopiclone
6) Many other drugs;
Enhance effects, NOT agonists.
Which drug’s binding site is different from all the other?
Barbiturates
Where does the binding of benzodiazepines and the newer hypnotic drugs such as zolpidem occur?
A single site between α and γ subunits, facilitating the process of chloride ion channel opening.
Which drug can bind at the same site as benzodiazepines and the newer hypnotic drugs such as zolpidem?
The benzodiazepine antagonist Flumazenil can reverse the hypnotic effects of zolpidem
What do Barbiturates do?
Depress the actions of the excitatory neurotransmitters (glutamic acid), and exert nonsynaptic membrane effects.
Why do we rarely use barbiturates?
They’re less selective than BDZs, and have a more pronounced central depressant action and a low margin of safety.
What does Flumazenil do?
Blocks the action of benzodiazepines, eszopiclone, zaleplon, and zolpidem; but NOT barbiturates, meprobamate, or ethanol.
What do β-Carbolins do?
1) Negative allosteric modulators (inverse agonists) of GABA-receptor function = anxiety and seizures.
2) Block the effects of BDZs.
What are the organ system effects of sedative-hypnotic drugs?
1) Sedation
2) Hypnosis
3) Anesthesia
4) Anticonvulsant effects
5) Muscle relaxants
6) Respiratory depression
7) Cardiovascular depression
How does sedation occur?
By depressant action on psychomotor and cognitive functions.
What is sedation?
Calming effect with concomitant reduction of anxiety (at relatively low doses).
Which drugs induce hypnosis?
All of the sedative-hypnotics induce sleep if enough doses are given.
What happens if you use sedative-hypnotics for more than 1-2 weeks?
Tolerance to their effects on sleep patterns.
What are the properties of Thiopental and methohexital?
1) Very lipid soluble
2) Penetrate brain tissue rapidly after IV administration
3) Useful for induction of anesthesia
Why do Thiopental and methohexital have short durations of action?
Because of rapid tissue redistribution
What can be used IV in anesthesia in combination with other drugs?
Benzodiazepines
If benzodiazepines are used at large doses, what can happen and how can it be cured?
Postanesthetic respiratory depression (long t½ and active metabolites); Flumazenil
How do sedatives-hypnotics have anticonvulsant effects?
By inhibiting the development and spread of epileptiform electrical activity in the CNS.
What is the selectivity that happens with the anticonvulsant action of sedative-hypnotics?
It is not associated with marked CNS depression, but psychomotor function may be impaired.
Which drugs are sufficiently selective to be used as
anticonvulsants (acutely)?
Several benzodiazepines:
1) Clonazepam
2) Nitrazepam
3) Lorazepam
4) Diazepam
Which drug is effective in the management of generalized tonic-clonic seizures (long-term
use)?
Phenobarbital
Which drugs lack anticonvulsant activity and why?
1) Zolpidem
2) Zaleplon
3) Eszopiclone;
Because of more selective binding to GABAA
receptor isoforms than that of benzodiazepines.
Which drugs exert inhibitory effects on polysynaptic reflexes?
1) Meprobamate
2) Benzodiazepines
Which drugs DON’T produce muscle relaxation?
1) Zolpidem
2) Zaleplon
3) Eszopiclone
Respiratory depression is __, and can be:
Dose-related; the cause of death with overdose.
Sedative-hypnotics, even at therapeutic doses, can produce significant respiratory depression in which patients?
Patients with pulmonary diseases.
Respiratory effects are more marked after __ administration.
IV
How can sedative-hypnotics depress the CVS?
By depressing the medullary vasomotor center in:
1) Hypovolemic states
2) When cardiac function is impaired
What happens in the CVS with sedative-hypnotics overdose?
Myocardial contractility and
vascular tone may be depressed = circulatory collapse.
Cardiovascular effects are more marked after __ administration.
IV
