Pharmacology Flashcards
Applications of benzodiazepines in critically ill
Sedation
Anxiolysis
Anticonvulsant
Muscle relaxant
Appetite stimulant
Minor cardiovascular and respiratory effects
Used as part of an anesthetic induction protocol for balanced anesthesia
They do NOT provide analgesia
Are benzodiazepines scheduled substances?
Yes, class IV
MOA of benzodiazepines
- Act primarily via the inhibitory neutrotransmitter GABA - bind to stereospecific receptors that facilitate the inhibitory actions of GABA
- May also involve antagonism of serotonin and diminished release or turnover of Ach in the CNS
- They act at the limbic, thalamic and hypothalamic levels of the CNS
- Metabolized in the liver to active metabolites, then after conjugation, excreted in urine
Diazepam vs midazolam - differences
Diazepam:
- Not water soluble - formulated in 40% propylene glycol and 10% alcohol vehicle.
- Propylene glycol - irritant to blood vessels -> causes phlebitis and thrombosis after repeated administration through peripheral vein -> give as CRI or through central line.
- Prolonged admin of diazepam -> propylene glycol toxicity -> metabolic acidosis, hyperosmolality, neurologic abnormalities and organ dysfunction. Important in CATS.
- Absorbs to plastic - infusion lines require pre-coating.
- Both midazolam and diazepam should be protected from light
Midazolam:
- Water soluble
- Well absorbed after IM injection.
- Poorly available when given IR.
- Can be given as CRI through peripheral vein.
- JVIM 2018 - intranasal midazolam terminated status epilepticus in 70% of cases compared to rectal diazepam, 20% of cases. All dogs showed sedation and ataxia.
Does benzodiazepines have always sedative effects?
No.
Some animals might demonstrate excitation, irritability and depression.
Patients already obtunded most likely will be sedated, especially if combined with an opioid.
Healthier dogs and cats may demonstrate dysphoria, especially if given as solo agent.
Complication of oral diazepam in cats
Idiosyncratic reaction - fulminant hepatic failure - acute hepatic necrosis.
Not reported with other routes of administration.
Which one is shorter acting, diazepam or midazolam
Midazolam - short elimination Half-life and duration of action - more suitable for CRI than diazepam
Half-life of diazepam - 3 to 6 h
Half-life of midazolam - 1h
How can we reverse benzodiazepines?
Flumazenil - antagonist
Sarmazenil - inverse agonist
Marked excitement and dysphoria can be precipitated by either drug.
Significant adverse effects like seizures and acute benzodiazepine withdrawal have been reported
Indications for flumazenil
Doses
- Due to the severe adverse effects, even in cases of benzodiazepines overdose, toxic effects can be managed with supportive care.
- Rarely indicated in stable patients.
- Used in critically ill patients with cardiovascular or pulmonary instability.
- 0.01 to 0.02 mg/kg IV.
- If requiring frequent dosing - CRI at 0.005 to 0.02 mg/kg/h
Benzos as anticonvulsant therapy
Doses for sedation / anticonvulsant
- Diazepam IM not recommended - IR route preferred
- Intranasal midazolam preferred over IR diazepam (JVIM 2018)
Benzodiazepines and appetite stimulant
- Low doses benzodiazepines can stimulate appetite, specially in cats
- MOA - involves binding to benzodiazepine receptors and appears to increase attraction to tastes.
- Increases both amount of food and rate of consumption.
- Diazepam at 0.005 to 0.4mg/kg IV q24h or 1mg orally q24h (risk of hepatic toxicity in cats)
- Food should be readily available - they might begin to eat within a few seconds of administration.
Hepatic encephalopathy and benzos
- Human patients with HE show arousal after flumazenil - suspected increased endogenous benzodiazepines agonist activity.
- Lack of arousal in other species including dogs and cats.
- Administration of inverse agonist sarmazenil in research models of acute and chronic HE - improvement of encephalopathies signs - consistent with an increased GABAergic constitutive activity in HE rather than an increase in endogenous benzodiazepine agonist ligands.
- Sarmanezil should not be considered part of the therapy of HE.
Percentage of cases reporting to veterinary referral centers involving epilepsy
0.6% to 2.3%
Age of idiopathic epilepsy
1 to 5 years old, but onset has been reported in both older and younger dogs.
Idiopathic epilepsy incidence
Higher in dogs, whereas in cats reactive (metabolic or toxic disturbance) and symptomatic (underlying intracranial dz) are more common than idiopathic epilepsy.
Most common anticonvulsants
Phenobarbital
Bromide (potassium bromide, sodium bromide)
Zonisamide
Levetiracetam
Felbamate - not used very commonly
Benzodiazepines (diazepam, midazolam, lorazepam, clorazepate) - short life and development of tolerance - used only in emergency treatment.
Phenobarbital MOA and metabolism
- Facilitates GABA-ergic activity - prolongs opening of Cl- channels
- Believed to inhibit glutamate receptors and voltage-gated calcium channels
- High bioavailability after PO admin - 86% - 96% - absorbed in 2h, maximal concentration in 4-8h when given PO
- Protein bound - 45%
- Metabolized in the liver primary by CYP450 - potent inducer of CYP450 → induces its own metabolism and that of other drugs (benzos, levetiracetam, zonisamide)
- Medications that inhibit CYP450 → may inhibit phenobarbital metabolism, increasing plasma concentrations and the risk of toxicity.
- 25% - 33% excreted unchanged in the kidneys
How long does it takes to achieve therapeutic levels of phenobarbital
15 to 20 minutes with phenobarbital IV
Clinical response to phenobarbital
>50% reduction in seizure frequency in 60% to 80% of dogs with idiopathic epilepsy
Phenobarbital doses in cats
Starting dose of 1.5 - 2.5mg/kg PO / IV q12h suggested
Loading doses of phenobarbital
- If a patient comes with cluster seizures or SE, 16-20mg/kg loading dose can be given
- Divide in 4-6 equal doses over a 24h period.
- Intent to achieve serum phenobarbital concentrations of 15-35mcg/mL
- Monitor closely for extreme sedation (loss of gag reflex), hypoventilation and/or hypotension → delay next dose if that happens.
Serum phenobarbital levels that has risk of hepatotoxicity?
>40mcg/mL
Half-life of phenobarbital
- Varies over time - suspected due to autoinduction
- Dogs - from 37 to 89 hours
- Cats - from 34 to 43 hours
- Serum steady-state levels reached in 97% of patients after 5 half-lives
Phenobarbital monitoring
- 2 and 6 weeks after starting phenobarbital
- 2 weeks after a dose change
- Due to auto induction of hepatic enzymes - monitor serum levels q6-12 months.