Midazolam and the benzodiazepines Flashcards
Describe the various effects of benzodiazepines
Varying degrees of:
- Hypnotic (reduce MAC)
- Sedative
- Anxiolytic
- Anticonvulsant
- Muscle Relaxant
- Anterograde Amnesic
Classify benzodiazepines with examples
Short acting (T1/2 < 6 hours) 1. Midazolam
Intermediate (T1/2 6 - 24 hours)
- Lorazepam
- Alprazolam
- Oxazepam
Long
- Diazepam (T1/2 > 24 hours)
- Clonazepam
- Chlordiazepoxide
What is the mechanism of action of benzodiazepines
Specific benzodiazepine receptors found throughout CNS
- Especially in cortex and midbrain
Benzodiazepine receptors are closely linked to GABA receptors – facilitate the activity of GABA receptors leading to opening of chloride ion chennel through the GABA receptor which hyperpolarize the synaptic membrane
What are the subtypes of GABA receptors and the mechanisms associated with them
GABA - main inhibitory neurotransmitter in the CNS
GABAa
- Ligand gated Cl ion channel
- 5 subunits: 2 alpha, 2 beta and gamma
GABAb
What are the subtypes of GABA receptors and the mechanisms associated with them
GABA - main inhibitory neurotransmitter in the CNS
Benzos –> allosteric potentiation of GABA receptors
GABAa
- Ligand gated Cl ion channel
- 5 subunits: 2 alpha, beta, delta and gamma
- GABA increases opening of Cl- channels
- hyperpolarize
- Chloride ion conductance is potentiated by binding of the benzodiazepines to the alpha subunits of the activated GABA receptor potentiating conductance of CL ions through the channel enhancing hyperpolarization
- benzodiazepine locks the GABAa receptor into a conformation where the GABA has much higher affinity for the GABAa receptor
- Mainly pre-synaptic
GABAa
- -> GABAa 1: Spinal cord and cerebellum - anxiolysis
- -> GABAa 2: Spinal cord and hippocampus and cortex - sedative and anxiolytic activity
GABAb (increases potassium conductance –> hyperpolarization)
- Metabotrophic
- Acts via G protein and second messenger system
- Increases potassium conductance acting to hyperpolarize the neuronal membrane
- Pre and post synaptic
How are benzodiazepines metabolized
DIAZEPAM metabolized in the liver by oxidation to the following active metabolites:
- Desmethyl-diazepam (T1/2 = 30 - 90 hours)
- Oxazepam
- Temazepam
MIDAZOLAM metabolized in liver by hydroxylation to the active compound:
- 1 alpha-hydroxy-midazolam (T 1/2 1 - 3 hours)
- -> conjugated with glucoronic acid and excreted in urine - Oxazepam (<5%)
OXAZOPAM and LORAZEPAM are conjugated with glucoronic acid to produce inactive metabolites that are excreted in urine
What are the advantages of Midazolam
- LESS PAIN ON INJECTION as water soluble at pH 3.5
Presented at pH 3.5 its ring structure is open –> ionized molecule and water soluble which therefore causes less pain on injection.
When pH is greater than 4 the ring structure closes and therefore becomes lipid soluble.
pKa of midazolam is 6.5. Therefore at physiological pH it is 90% unionized and able to cross lipid membranes.
2. MULTIPLE PREPARATIONS Oral (bio 40%) SC Bucally Intranasal Intramuscular Intravenous
- SUITABLE for INFUSION: Short elimination half life 1 - 4 hours and large clearance 6 - 10 ml/kg/minute making it more suitable for infusion. (compared to other benzos)
- REDUCE INTUBATION RESPONSE when combined with fentanyl: reduces intubation response.
- REDUCED MAC requirements by 15%
What are tautomers. Give two examples
Tautomers are structural isomers of chemical compounds that readily interconvert.
MIDAZOLAM
Midazolam is stored at pH 3.5 is ionic and hence water soluble and therefore less pain on injection simple preparation without needing reconstitution.
At pH > 4 the midazolam structural ring closes forming a lipid soluble molecule. The pKa is 6.5 and hence at physiological pH the midazolam is 90% unionized and can therefore cross lipid membranes.
THIOPENTONE
Stored as a yellow powder with NaCO3 and N2 instead of air. NaHCO3 is formed when reconstituted with H2O and no CO2 in N2 can affect the reconstituted pH of 10.5 favouring the ENOL form of the thiopentone molecule = water soluble.
After injection and at physiological pH the KETO form predoninates which is lipid soluble and can cross lipid membranes to its site of action (the brain).
Summarise the management of benzodiazepine overdose
HHH ABCDE Recognition Declaration and communication Assessment and resuscitation Treatment
FiO2
Call for help
Most NB: Good Supportive care: ABCDE
Decontamination
- activated charcoal (< 2 hours + Aspiration risk minimal)
Specific antidote
- Flumazenil
What is the mechanism of action of flumazenil
Competitive antagonist of benzodiazepines in the CNS
Competitively inhibits the activity of the benzodiazepine recognition site on the GABA benzo receptor complex
Onset of reversal 1 - 3 minutes
Peak effect 6 -10 minutes
Duration and degree of reversal related to plasma conc. of benzo + dose of flumazenil given
What is the mechanism of action of flumazenil
Competitive antagonist of benzodiazepines in the CNS
Competitively inhibits the activity of the benzodiazepine recognition site on the GABA benzo receptor complex
What is the dose of flumazenil
- 1 - 0.2 mg: partial antagonism
0. 4 - 1 mg: complete antagonism (in patients who’ve received usual sedating dose of benzo)
How long does flumazenil last
Distribution T1/2 - 4 - 11 minutes
Elimination T 1/2 - 40 - 80 minutes
Relatively short half life compared to the benzodiazepines and hence further doses or and infusion may be required
Describe the protein binding and metabolism and excretion of flumazenil
50% protein bound
Extensive hepatic metabolism to inactive compounds that are renally excreted
How long does it take for flumazenil to work
Onset: 1 -2 minutes
80% effect at 3 minutes
Peak effect 6 - 10 minutes
Duration and degree of reversal vary according to plasma concentration of benzodiazepine and dose of flumazenil administered
