Pharmacokinetics and Benzodiazepines: Introduction and Overview

• Overview:⁵

  • Benzodiazepines have a prominent role in anesthesia that only because of their amnestic effects but also because of their anxiolytic actions.

  • They frequently prescribed benzodiazepine, diazepam (Valium), was introduced over 40 years ago, whereas the more water-soluble midazolam (Versed) product has been available for about 25 years. 

    • Midazolam (Versed) exhibits excellent anxiolytic,  anterograde amnestic properties and may be used to treat certain seizure disorders.

      • Midazolam for Managing Seizure Clusters⁶

        ;

        Wheless J Treating Seizure Clusters with Midazolam https://www.youtube.com/watch?v=DAA75On8D9c  (12/2019) Neurology Live Youtube Channel https://www.youtube.com/channel/UCHZXb4_PakzEjV9AWNZSQEA

  • Benzodiazepines affect GABA-mediated systems. 

    • The neurotransmitter GABA is an inhibitory neurotransmitter and controls the state of a chloride ion channel. 

    • Activation of this chloride ion channel results in neuronal hyperpolarization (increased membrane potential in the direction away from the threshold potential) and accounts for the classification of the GABA system as "inhibitory". 

      • Benzodiazepines increase the inhibitory action at the GABA receptor.  

  • Midazolam (Versed) exhibits significant lipid solubility, following injection, because the previously open imidazole ring closes at physiological pH (7.4).

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    Midazolam (Versed)

     

• Pharmacokinetics ⁵

  • In the anesthesia setting, benzodiazepine action following single bolus injection is terminated by redistribution, much in the manner of lipid-soluble barbiturates (e.g. thiopental (Pentothal)). 

    • The mechanism is essentially the same in that the lipid-soluble compound, e.g. midazolam (Versed), readily enters the brain and that is subject to redistribution to other tissues to receive a reduced percentage of cardiac output.

  • Ultimately, the benzodiazepines are metabolized using the drug microsomal metabolizing system (P450) or the phase I system as well as glucuronide conjugation, an example of a phase II reaction.

  • An important consideration in understanding benzodiazepine pharmacokinetics is that some benzodiazepines have no active metabolites.

    • Midazolam (Versed) is a good example; however, diazepam (Valium) is metabolized to oxazepam (Serax) and desmethyldiazepam, which themselves have sedative properties.

    • Therefore, midazolam (Versed) would be considered short-acting (halftime between 1.5 and 3 hours).

    • Diazepam (Valium) is long-acting, with a long elimination halftime (20-50 hours) in part because of several active metabolites.

    • Despite similar degrees of protein binding and comparable volumes of distribution, midazolam (Versed) has a relatively high clearance, 6-11 ml/kg/minute; by contrast, diazepam (Valium) exhibits comparatively low clearance, 0.2-0.5 ml/kg/minute. 

      • Consequently, when redistribution mechanisms are not prominent such as following repeated doses, midazolam (Versed) blood levels will fall more rapidly  compared to diazepam (Valium) due to significantly higher hepatic clearance.

• Benzodiazepine pharmacology:   a summary of organ system and other effects:⁵

  • CNS:

    1. Benzodiazepines cause a reduction in cerebral oxygen metabolism and blood flow.

    2. Benzodiazepines appear to protect against cerebral hypoxia and are very effective anticonvulsant agents against local anesthetic-caused seizures. 

       1. Intravenous benzodiazepine administration, such as IV diazepam (Valium), is very effective in terminating many seizures including status epilepticus.

  • Pulmonary:

    1. These drugs certainly can depress respiration following administration by IV, although generally respiratory depression is more typically associated with barbiturates and opioids. 

       1. Nevertheless midazolam (Versed) for example can cause an increase in P_aCO₂ and respiratory depression is certainly important in the intraoperative setting with peak  respiratory depression occurring within three minutes {midazolam (Versed) at  (0.1-0.2 mg/kg) and lasting for 1-2 hours.

    2. Synergistic effects: In terms of respiratory depression sedative-hypnotics would be synergistic with opioids. 

       1. Therefore increase respiratory depression would be expected upon combination of opioids with benzodiazepines.

  • Reversal of benzodiazepine effects:

    • A specific benzodiazepine antagonist (Flumazenil [Romazicon]) acting at the receptor can reverse excessive sedation or respiratory depression due to benzodiazepine effects.

    • Flumazenil (Romazicon) is a specific drug that acts by competitively blocking benzodiazepine receptors thereby preventing benzodiazepine-receptor interactions.

      • An important pharmacokinetic aspect of flumazenil (Romazicon) is its very short half-life (elimination halftime of 0.7-1.3 hours). 

        • Flumazenil (Romazicon)'s half-life is shorter than those exhibited by benzodiazepines and as a result it would be possible to reverse benzodiazepines-mediated respiratory depression only to have it reoccur upon flumazenil (Romazicon)'s elimination. 

          • Consequently either repetitive flumazenil (Romazicon) dosing or continues infusion (0.5-1 ug/kg/min.) may be required to ensure sustained recovery from benzodiazepines mediated effects.

          • Two other points:

            • Flumazenil (Romazicon) reversal tends to have a greater effect on respiratory depression and sedation than on benzodiazepine amnestic properties.

            • The requirement that multiple flumazenil (Romazicon) doses may be required to ensure sustained reversal of  benzodiazepine effects is similar to the requirement that multiple doses of naloxone (Narcan) would be required to ensure sustained reversal of opioid overdose effects.

              • This observation follows from the short half-life associated with naloxone (Narcan) compared to opioid half-lives.

               

• Midazolam (Versed)- benzodiazepine agonist	Flumazenil (Romazicon)-competitive benzodiazepine antagonist