Midazolam Flashcards
What makes benzodiazepines unique among the non-opioid intravenous anesthetics?
They have a selective antagonist, Flumazenil
what are the most commonly used benzodiazepines in perioperative
setting?
midazolam, diazepam, Lorazepam
What is Midazolam’s Antagonist?
Flumazenil (8-15 mcg/kg)
What are the most desired effect Midazolam (or benzos in general)
anxiolysis, anterograde amnesia
Anterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact.
What are the physiochemical characteristics of benzodiazepines?
Chemial: benzene ring attached to seven-member Diazepine ring
physiological: Highly lipophilic, highly protein bound (especially albumine)
Midazolam at PH rapid onset of action
Diazepam and lorazepam have poor water solubility, the organic solvent propylene glycol is used to dissolve diazepam and it is the most likely cause for intramuscular and intravenous pain during injection
What is pharmacokinetics, and what is the pharmacokinetics of benzodiazepines?
Pharcokinetics describe the process of absorption, distribution and elimination that links the drug administration to drug concentration in plasma and at the site of drug effect. Absorption is not relevant to IV administration. Distribution is the instantaneous distribution and dilution in to blood volume and subsequent partitioning of drug into peripheral compartments. Clearance describe the elimination of the drug , typically through hepatic metabolism and renal elimination, or in case of inhaled anesthetic removal via lungs.
Benzodiazepines pharmacokinetics:
Distribution:
Rapid onset due to high lipid solubility and entrance into CNS, followed by redistribution to inactive tissue sites and subsequent termination of drug effects
Metabolism: Via oxidation and conjugation through liver( CYP450 is responsible for oxidation especially CYP4503A4, and conjugation converts the hydrophobic molecules into water-soluble molecules which kidney can excrete). The main pathway for metabolism of benzodiazepines is oxidation by CYP4503A4 which is more susceptible to age, liver cirrhosis or other drugs that modulate the efficacy of enzyme system.
Oxidation is the primary pathway of elimination of benzos, it converts Diazepam into active metabolites (hence the prolonged effect of the drug and Midazolam into one inactive metabolite.
Elimination: Elimination half life of Diazepam is larger than greatly exceeds that of midazolam—-> CNS effect of diazepam is prolonged in comparison to the midazolam, esp in elderly. Context sensitive half life of Midazolam is short —> only benzo suitable for continuos infusion
Note About Midazolam’s pharmacokintics:
Midazolam is highly lipid soluble and enters the brain fast however it takes 3-5 min for midazolam to equilibrate in brain (longer effect site equilibrium than propofol ad thiopental). —> when you use midazolam pace it sufficiently to permit peak effect to be recognized before repeat dose
what is pharmacodynamics? and what is the pharmacodynamics of benzodiazepines?
pharmacodynamics describes the relationship between plasma drug concentration andd the pharmacologic effect. ( how does the drug work in the body).
Benozos bind to post synaptic GABAa receptors in CNS, with highest density in cerebral cortext. They bind to y subunit of GABAa and midazolam has more affinity for it than diazepam.
Once bound to GABAa receptor it enhanced GABAa mediated Cl- current which leads to hyperpolarization and reduced excitability.
bc most of GABAa receptors which benozs work on are on post synaptic neurons in CNS the effect of benzos outside CNS is minimal compared to barbiturates.
What is the spectrum of effect of benzodiazepines?
- sedative
- hypnotic
- anxiolytic
- anterograde amnestic
- anticonsulsant
- Muscle relaxation
All these different effects are produced by different doses of benzos.
1.amnestic, sedative and anxiolytic states are produced by 1-2 mg of midazolam
2. Hypnotic effect is produced when you use Midazolam
for induction and the dose for that is 0.1-0.3 mg/kg
3. Anticonvulsive affect is usually by Diazepam 0.1 mg/kg IV and it used for ppl who are undergoing alcohol withdrawals, status epilepticus and local anesthesia induced
4.Muscle relaxation can occur at higher doses and the GABAa receptors effected by it are in spinal cord
How safe are benzodiazepines?
Benzos ALONE, have minimal depression of ventilation and cardiovascular system—> relatively safe to use in large doses when admin alone.
Also if you screw up and give too much benzo you can always reverse your CNS effect with Flumazenil.
What are the effects of benzos on CNS, respiratory and cardiovascular system?
CNS: decreases blood flow and o2 consumption (cerebral metabolism of O2) does NOT decrease ICP, it is NOT Neuroprotective
CVS: When you use Midazolam for induction (0.1-0.3 mg/kg) (Note: not when you use it for anxiolysis, sedation of amnesia 1-2mg) produces a decrease in your BP (SVR X CO) Midazolam does not effect your cardiac output, it effects your SVR by causing vasodilatation.
Note: Cardiac output is the amount of blood (L/min) pumped by heart every min. It is Defined by CO: HRXSV
The chance of causing Midazolam induced hypotension is more likely in hopovolemic patients
Respiratory system:
Generally when you use it for anxiolysis, amnesia and sedation there is minimal depression of ventilation (1-2 mg)
When you use it for induction (0.1-0.3 mg/kg) a rapid intravenous injection and give you apnea especially if you have opioids on board
NOTE: Benzos decrease the ventilatory response to carbon dioxide, this is usually minimal unless you have opioids on board
why do we use Midazolam more than Diazepam?
Bc it has a more rapid onset, more amnesia, less post op sedation
What r the clinical uses of midazolam?!
- anxyolitic, amnestic, sedative 1-2 mg
- induction: 0.1-0.3 mg, induction facilitated when small doses of opioid (fentanyl 50-100 Mcg) is injected 1-3 min before Midazolam injection ( really no reason to use it for induction unless someone is sensitive to propofol, bc it has a slower onset and slower awakening)
- Anti-seizure: diazepam 0.1 mg/kg for seizure induced by local anesthesia, alcohol withdrawal and status epilepticus
General dosage notes:
General dosage notes: Vial: 2 mg in 2 ml Dose: 1-2 mg Onset: 1-5 min Peak: 5-7 min Duration: 20-30 min Metabolized: in the liver Excreted: kidneys
General dosage notes:
General dosage notes: Vial: 2 mg in 2 ml Dose: 1-2 mg Onset: 1-5 min Peak: 5-7 min Duration: 20-30 min Metabolized: in the liver Excreted: kidneys
