Benzodiazepines Flashcards
Name 8 effects of benzodiazepines?
- sedation
- anxiolysis
- anticonvulsion
- hypnosis
- skeletal muscle relaxation
- antegrad amnesia (humans)
- reduction of dosages of other anaesthetics (e.g. propofol, barbiturates)
- apetite stimulation
What is the mechanism of action of benzodiazepines?
- bind to receptors that facilitate the inhibitory actions of the neurotransmitter GABA
- antagonism of serotonin
- diminished release or turnover of acetylcholine in the CNS
Where in the body do benzodiazepines mediate their mechanism of action?
- limbic, thalamic, and hypothalamic levels of the CNS
Where are benzodiazepines metabolised and excreted?
metabolized in the liver to active metabolites that, after conjugation, are excreted in the urine
What are the major differences between diazepam and midazolam?
Diazepam:
- not water soluble as it is formulated in a 40% propylene glycol and 10% alcohol vehicle
- better rectal bioavailability
Midazolam:
- water soluble –> well absorbed after i.m. injection
- poor bioavailability when given rectally –> not recommended
- can be given peripherally as CRI
- shorter duration of action
Both can be given intranasally.
Why should diazepam be only given via a central vein?
Diazepam is formulated in a 40% Propylene glycol (and 10% alcohol) vehicle. Propylene glycol is an irritant to blood vessels and causes phlebitis and thrombosis after repeated or continuous administration through a peripheral vein.
Name adverse effects of diazepam related to its content of propylene glycol (particularly in cats)?
propylene glycol toxicity leading to:
- metabolic acidosis
- hyperosmolality
- neurologic abnormalities
- organ dysfunction
Diazepam infusions are therefore not recommended in cats.
What characteristics of diazepam and midazolam have to be kept in mind with CRI administration?
Diazepam:
- adsorbs to plastic (should not be stored in plastic syringer for a longer period of time, infusion lines may require precoating)
- should be protected from light
Midazolam:
- should be protected from light
Name undesired side effects of benzodiazepines?
- aberrant behavior including excitation, irritability, and depression
- healthy patients may demonstrate dysphoria (more likely when given as sole agent)
Why is oral diazepam in cats contraindicated?
- oral diazepam can lead to fulminant hepatic failure (rare) via an idiosyncratic reaction resulting in acute hepatic necrosis
Successful treatment with recovery appears to be rare, but has been reported.
What is the proposed mechanism of liver failure after oral diazepam administration in cats?
idiosyncratic reaction resulting in acute hepatic necrosis
What is neuroleptanalgesia?
combination of benzodiazepines with oipiods
Name 2 water soluble benzodiazepines?
- Midazolam
- Lorazepam
What is the recommended sedative dose of diazepam?
- IV: 0.2-0.6mg/kg
-CRI: 0.1-1mg/kg/hr (central vein)
What is the recommended sedative dose of midazolam?
- IV or IM: 0.1-0.4mg/kg
- CRI: 0.1-0.5mg/kg/hr
What is the recommeded dose of diazepam for anticonvulsant therapy?
- IV, intranasal: 0.5-1mg/kg
- PR: 2mg/kg - can be repeated 2-3 times
- CRI: 0.5-1mg/kg/hr (cental vein)
What is the recommeded dose of midazolam for anticonvulsant therapy?
- IV, IM, intranasal: 0.2-0.5mg/kg - can be repeated 2-3 times
- CRI: 0.2-0.5 mg/kg/hr
Discuss benzodiazepines role as appetite stimulans? What is the recommended dose?
- especially in cats
- effect is separate from sedation or anxiolysis
- involves binding to benzodiazepine receptors
- increases attraction to tastes
- increases the amount of food consumed and the rate of consumption
- dose: 0.005 to 0.4 mg/kg IV q24h or 1 mg orally q24h (risk of hepatic toxicity)
- onset of action: few seconds
What was the finding of Charalambous et al. study “Intranasal midazolam versus rectal diazepam for the management of canine status epilepticus: a multi- center randomized parallel-group clinical trial” in JVIM 2017? What were the side effects noted?
Intranasal midazolam is more affective than rectal diazepam:
- IN-MDZ and R-DZP terminated status epilepticus in 70% and 20% of cases, respectively.
- All dogs showed sedation and ataxia.
Name the 3 most important adverse effects after a long-term benzodiazepine infusion?
- dysphoric signs
- excitatory signs
- delayed awakening
Name 2 possible agents to reverse benzodiazepine induced CNS depression or dysphoria, recommended dosages and their mechanism of action?
- Flumazenil
- antagonist
- IV: 0.01-0.02mg/kg (Alternative routes are effective, with some limitations)
- CRI: 0.005 to 0.02 mg/kg/hr - if frequent dosing is needed - Sarmazenil
- inverse agonist
What does SACCM state about the routine use of benzodiazepine reversal agents flumazenil and sarmazenil?
Neither can be recommended for routine use in stable conditions
Toxic effects generally can be managed with supportive care and administration of emetics and/or activated charcoal.
The use in critically ill patients with cardiovascular or pulmonary instability is more commonly justified
Name 3 possible adverse effects of the reversal benzodiazepines agents (flumazenil + sarmazenil)?
Adverse effects:
- seizure
- Marked excitement and dysphoria
- acute benzodiazepine withdrawal
Discuss the role of flumazenil vs. sarmazenil in hepatic enceophalopathy and the proposed pathophysiology in humans and dogs/cats?
Flumazenil:
- Human patients with HE have occasionally shown arousal following administration of the benzodiazepine antagonist flumazenil.
- increased endogenous benzodiazepine agonist activity may be involved in HE
- A lack of arousal in dogs and cats (endogenous benzodiazepines are not increased in this syndrome)
Sarmazenil:
- The inverse agonist sarmazenil in animal research models of both acute and chronic HE has resulted in improvement of encephalopathic signs
- consistent with increased GABAergic constitutive activity in HE, rather than an increase in endogenous benzodiazepine agonist ligands
(Sarmazenil should not be considered part of the therapeutic modality for HE)
