Drugs -Sedative Hypnotics (Kinder) Flashcards
Prototype Benzodiazepines
Alprazolam Clonazepam Diazepam Midazolam Triazolam
Flumazenil
Benzodiazepine Antagonist
Phenobarbital
barbituate
“barbital”
what is a sedative
i) Reduces anxiety and exerts a calming effect
ii) Sedation is a side effect of many drugs that are not general CNS depressants (e.g., antidepressants, antihistamines, neuroleptics/antipsychotics)
iii) Agents that produce sedation as a side effect can intensify the effects of CNS depressants
what is a hypnotic
i) Produces drowsiness and facilitates the onset and maintenance of a state of sleep
ii) Hypnotic effects involve more pronounced depression of the CNS, which can be achieved with many sedative-hypnotics by increasing the dose
MOA of benzodiazepines
i) MOA: promotes binding of γ-aminobutyric acid (GABA), major inhibitory neurotransmitter, to the GABAA receptor; enhances GABA-induced ion currents (increases frequency of channel opening)
sedation, hypnosis, muscle relaxation, anxiolytic and anticonvulsant effects
iv) Because of their low capacity to produce fatal CNS depression, benzodiazepines have displaced barbiturates as preferred sedative-hypnotic agents
NOTE:
(2) The benzodiazepines DO NOT substitute for GABA but enhance the effects of GABA allosterically (bind to the receptor at a site other than the active site) without directly activating GABAA receptors or opening the chloride channel
how do benzodiazepines (newer) versus barbituates and older typical type sedative-hypnotics differ in dose response curve
Graded dose-dependent depression of CNS function is a characteristic of most sedative-hypnotics. The linear slope of drug A is typical of many of the older sedative-hypnotics, such as barbiturates and alcohols. Drug B represents benzodiazepines and certain newer hypnotics, where proportionately greater dosage increments are required to achieve CNS depression that is more profound than hypnosis.
MOA of barbituates
i) MOA: bind to GABAA receptors and potentiate GABA-induced chloride currents (increases duration of channel opening)
ii) Can activate the channel directly by acting as a GABA-mimetic at high concentrations
iii) Capable of causing a wide spectrum of effects, from mild sedation to anesthesia, including anxiolytic, hypnotic and anticonvulsant effects
iv) Barbiturates possess a narrow therapeutic index and it is often not possible to achieve a desired effect without evidence of general depression of the CNS
Ramelteon
Activates melatonin receptors MT1 and MT2
metabolism of benzodiazepines
(1) Hepatic metabolism accounts for the clearance of all benzodiazepines; most undergo phase I reactions, predominantly by CYP3A4, then glucuronidation (phase II)
what type of receptor is GABA A and what is its function
i) The GABAA receptor is a ligand-gated ion channel (ionotropic) made up of five subunits that, when activated by the endogenous compound GABA, allows chloride ions to enter the cell
ii) One major isoform of the GABAA receptor in the brain is composed of two α1 subunits, two β2 subunits, and one γ2 subunit
iii) Under normal physiological conditions, GABA activation causes normal chloride influx and polarization; reduces the number of action potentials
iv) GABAA receptors are responsible for most inhibitory transmission in the CNS
what type of receptor is GABA A and what is its function
i) The GABAA receptor is a ligand-gated ion channel (ionotropic) made up of five subunits that, when activated by the endogenous compound GABA, allows chloride ions to enter the cell
ii) One major isoform of the GABAA receptor in the brain is composed of two α1 subunits, two β2 subunits, and one γ2 subunit
iii) Under normal physiological conditions, GABA activation causes normal chloride influx and polarization; reduces the number of action potentials
iv) GABAA receptors are responsible for most inhibitory transmission in the CNS
why doesn’t flumazenil work as a barbituate antagonist
(a) Block the actions of benzodiazepines, eszopiclone, zaleplon, and zolpidem but do not antagonize the actions of barbiturates, meprobamate, or ethanol because these compounds bind at a different site
Buspirone
stimulates 5-HT1A receptors
use of sedative hypnotics in anesthesia
(1) High doses of certain sedative-hypnotic agents, particularly the barbiturates and older sedative-hypnotics, depress the CNS to the point known as stage III general anesthesia
effects of sedative hypnotics on the resp and CV system
(1) Sedative-hypnotics can produce significant dose-dependent respiratory depression in patients with pulmonary disease
(2) Depression of the medullary respiratory center is the usual cause of death due to overdose of sedative-hypnotics
(3) At normal doses, sedative-hypnotics can cause cardiovascular depression in patients with diseases that impair cardiovascular function (heart failure, hypovolemia), most likely a result of depression of the medullary vasomotor centers
(4) At toxic doses, myocardial contractility and vascular tone may both be depressed and could lead to circulatory collapse
(5) Effects on respiration and cardiovascular function are more marked when agents are given intravenously
pharmacodynamic example of tolerance
(1) Pharmacodynamic example: benzodiazepine tolerance in animals has been associated with down-regulation of brain GABAA receptors. Down-regulation of receptors leads to hyperexcitability of the CNS during periods of withdrawal, leading to the symptoms characteristic of sedative-hypnotic withdrawal.
pharmacokinetic example of tolerance
(2) Pharmacokinetic example: barbiturates stimulate the production of higher levels of hepatic CYPs, causing more rapid removal and breakdown of barbiturates from the circulation. This results in a decrease in their efficacy.
what are the overall actions of sedative-hypnotic drugs
sedation hypnotic anesthesia anticonvulsants muscle relaxation resp and CV depression
what schedule are most the sedative hypnotic drugs
schedule III or IV drugs
III Less than I or II Current accepted medical use. Moderate or low potential for physical dependence and high potential for psychologic dependence.
IV Less than III Current accepted medical use. Limited potential for dependence.
why must you taper sedative hypnotics
- abrupt withdrawal leads to more serious withdrawal signs
(2) To avoid withdrawal symptoms (particularly in patients taking benzodiazepines and/or barbiturates), the dose of sedative-hypnotics are tapered gradually over time
why is it important to know that flumazenil’s t1/2 is shorter than benzo’s t1/2
b) PK: short t1/2 due to hepatic clearance (0.7-1.3 hours); longer t1/2 of benzodiazepines cause the recurrence of sedation and requires repeated administration of flumazenil
treatment of anxiety states
i) Benzodiazepines are widely used for the management of acute anxiety states (situational anxiety) and rapid control of panic attacks as well as long-term management of generalized anxiety disorder and panic disorders
iv) Currently, use of newer antidepressants [selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs)] preferred in treatment of generalized anxiety disorders/certain phobias, although benzodiazepines still used for acute anxiety states
v) Concomitant treatment of anxiety on a short-term basis with benzodiazepines and SSRIs is useful until SSRIs become effective (on the order of 4-6 weeks, after which benzodiazepines would be removed from treatment)
benefits of using benzo’s for anxiety
(1) Risk of dependence
(2) Depression of CNS functions
(3) Amnestic effects
(4) Additional CNS depression when combined with other drugs (including ethanol)
