Please enable JavaScript.
Coggle requires JavaScript to display documents.
Sedative-Hypnotic Drugs (Benzodiazepines (Therapeutic Uses (Long-acting…
Sedative-Hypnotic Drugs
Overview
-
-
Hypnotic - produces drowsiness & facilitates the onset & maintenance of sleep that resembles natural sleep
Hypnotic effects involve more pronounced CNS depression than sedative effects "increasing dose, increasing CNS depressant effect"
Sedative - exerts a calming effect, with concomitant relief of anxiety (anxiolytic)
-
Benzodiazepines
Pharmacodynamics
Agonists - Benzodiazepines (multiple BZ binding sites); Zolpidem, zaleplon & eszopiclone (selective agonists at BZ1 receptor)
-
Pharmacokinetics
Metabolism - most are metabolized in liver; longer-acting agents (eg: flurazepam) converted in liver to active metabolite, some with longer half-lives than parent drug [half-life of flurazepam in plasma is 2 hrs, but major active metabolite N-desalkyl-flurazepam is 50 hrs]; short-acting compound (eg:oxazepam) metabolized directly by conjugation with glucuronide
Elimination - drug's effect terminated by excretion & re-distribution; BZDs excreted in urine as glucuronides or as oxidized metabolites; also cross placental barrier & secreted into breast milk
Absorption & Distribution - BZDs are lipophilic, they are rapidly & completely absorbed after oral administration & distribute throughout the body
Mechanism of Action
-
GABA: major inhibitory neurotransmitter in CNS; GABA receptors: composed of α, β & γ subunit families, contains binding sites for BZDs & barbiturate
When receptor binds to GABA, it induces opening of Cl- channel, hyperpolarization of neuron occurs, REDUCES NEURAL EXCITABILITY
In presence of BZD, it binds specifically to a regulatory site of GABA receptor (distinct from GABA-binding site) & act allosterically to increase affinity of GABA for receptor, enhance GABAergic synaptic inhibition, leading to further REDUCTION IN NEURAL EXCITABILITY
-
-
-
Overview
Most widely used sedative (anxiolytic) drugs; largely replace barbiturates & meprobamate in treating anxiety as it is safer & more effective
Therapeutic Uses
Long-acting BZDs - for intense & sustained/prolonged anxiety; Intermediate acting alprazolam - effective in treatment of panic disorders & agoraphobia; Short-acting BZDs - when anxiety is provoked & likely to be of short duration
Treatment of sleep disorders - has (1) rapid onset of action when taken at bedtime, (2) sufficient duration of action to facilitate sleep throughout the night, (3) minimal "hang-over" effects the following day "not all BZDs are useful as hypnotic agents although they all have sedative effects
Treatment of anxiety state - most widely used drugs for management of acute & chronic anxiety due to (1) rapid onset of action, (2) availability of flumazenil for treatment of overdose, (3) low risk of drug interactions, (4) minimal effects on CVS or ANS
Long-acting (flurazepam) - sleep throughout night, may results in daytime sluggishness or drug hangover; Intermediate acting (temazepam) - for patients who experience frequent awakening or having difficulty to stay asleep; Short-acting (triazolam) - for patients who have difficulty going to sleep & also avoid hangover problem
Treatment of muscle disorders - long acting diazepam is useful in treating skeletal muscle spasms which occurs during muscle strain, & in neuro-generative disorders such as multiple sclerosis & cerebral palsy
Anti-convulsant in treatment of seizure - Clonazepam, diazepam, lorazepam are used in treating epilepsy
Amnesia - BZDs used for anxiety-inducing & unpleasant procedures (eg: endoscopy, bronchoscopy, angioplasty & certain dental procedures; Conscious sedation, allow the person to be repetitive to instructions during these procedures (eg: midazolam used to facilitate amnesia while causing sedation prior to anesthesia
Adverse Effects
Dose-dependent CNS depression - most common adverse effects: drowsiness, excessive sedation, ataxia (impaired motor coordination)- affect driving skill, confusion, memory loss, cognitive impairment (decrease long-term recall & retention of new knowledge
Overdoses with BZDs commonly occur, but fatal toxic occurences are rare; more likely to occur in children, individuals with respiratory difficulties, individuals who consumed another CNS depressant (eg: alcohol); additive effect with other CNS depressants will enhance CNS depression
-
Tolerance
-
However, tolerance with BZDs is less than with barbiturates
Decrease responsiveness to drug following repeated exposure, need to increase dose
Dependence
Abrupt withdrawal causes withdrawal symptoms (confusion, agitation, restlessness, tension, rarely seizure); rebound insomnia & anxiety may exceed that which preceded the treatment; lessen likelihood of withdrawal reactions by gradual reduction of dose until it is eventually discontinued
-
BZDs with long half-lives (eg: flurazepam) - withdrawal symptoms occur slowly with few physical symptoms & last a number of days after discontinuation
-
-
Barbiturates
Effects
-
-
-
-
CVS depression, which is most evident in patients with hypovolemic states, HF & other diseases that impair CV function
Mechanism of Action
-
At high conc, barbs may also be GABA-mimetic, directly activating chloride channels
-
Barbs are less selective in their actions than BZDs; also depress actions of excitatory NT glutamate via binding to AMPA receptor
Multiplicity of sites of action induce full surgical anesthesia & more pronounced central depressant effects compared with BZDs & newer hypnotics
Overview
-
It (1) induce tolerance (2) induce drug-metabolizing enzymes (3) cause physical dependence (4) cause very severe withdrawal symptoms (5) cause coma at toxic doses
-
Clinical Uses
-
-
Anesthesia - selection is strongly influenced by the desired duration of action. Ultrashot-acting barbs, thiopental, is used IV to induce anesthesia
Adverse Effects
Respiratory depression - supresses the response to hypoxic & chemoreceptor response to CO2. Overdose will lead to depression & death
-
CNS depression - at low dose, cause sedative calming effect. At higher dose, progression from hypnosis, anesthesia, finally coma & death
Tolerance & dependence
Abrupt withdrawal from barbs may cause tremors, anxiety, weakness, restlessness, nausea, vomiting, seizures, delirium & cardiac arrest
-
-
Drug Interactions
Barbs combine with other CNS depressants to cause severe CNS depression, esp ethanol
Barbs induce hepatic CYP450; chronic administration may diminishes action of many drugs that are dependent on CYP450 metabolism
-