The Mechanism of Interaction of Midazolam - Essay Example

? Midazolam Midazolam is an imidazobenzodiazepine soluble in water at acid formulation and also highly lipid soluble. The main advantage of Midazolamis the rapid onset and the high metabolic clearance of the compound. The other pharmacological advantages are, they cause no irritation, has anxiolytic, amnestic properties and the induction is non-painful and rapid. (Reves et al. 1985). 1. The chemical name of the drug is 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine. 2. The approved indications of the drug a) Intravenous administration along with an opoid is done for sedation and for the induction of the general anaesthesia and for ventilation of the sedated patients. b) Oral administration is also done for short term treatment. This is done mainly for the insomnia patients. c) Midazolam is also indicted for the management of schizopernia. 3. Midazolam is found to interact with many drugs. The drug interaction is found to either increase the activity or decrease the activity of Midazoalm. The drug interaction occurs mainly with the antipsychotic medications, barbiturates, antibiotics and antifungal, cimetidine, Diltiazem, Narcotics, Seizure and Sleep medications, alcohol and antidepressant medicines such as Antipsychotic drugs include: Aripipraxole , asenapine, chlorpromazine, clozapine, fluphenazine, haloperidol, Iloperidone, loxapine, lurasidone, molindone, olanzapine, paliperidone and perphenazine and pimozide. Barbutarates include: Amobarbital, Butalbital, Pentobarbital and Secobarbital. Antibiotics such as Clarithomycin, Erythromycin, Isoniazid, Itraconazole , ketoconazole and Telithromycin. Narcotics such as morphine and oxycodone are used in combination with Midazolam. (drugs.emedtv.com) The pharmacokinetic drug interactions are found to occur based on the enzymes involved in the metabolism. The drug interaction with the CNS depressants such as alcohols, opioids and barbiturates are found to have lethal, clinical and forensic consequences with midazolam. Many studies have found that this interaction results in death. (Mozayani and Raymon 2004). Similarly when analgesics are used along with the midazolam, they are found to have greater sedative effects. The gastrointestinal agents when combined with midazolam are found to increase the rate of absorption of the drug. Cimetidine when used along with Midazolam is found to increase the retention time of Midazolam in the body. Similarly the antifungal agents are also found to inhibit the movement of Midazolam from the body. 4. a) The mechanism of interaction of Midozolam is understood well. The main target of Midazolam is the GABAa receptor. This is an ionotropic receptor with gamma amino butyric acid as the endogenous ligand. When GABAa receptor is activated then it transmits Chloride ions through their pores and polarizes the neurons. This polarization results in the inhibition of the neurotransmission. The benzodiazepines binds to the receptor found between the alpha and gamma receptor subunits. The five subunits of GABA receptor are sensitive to benzodiazepine. When benzodiazepine binds to the alpha and the gamma subunits of the GABA receptor, and brings the receptor into its control. The binding brings out a change in the conformation of the GABA – alpha and makes them to open the chloride ion channel and this polarizes the membrane. This process inhibits the signal transduction pathway by arresting the GABA molecules and creating sedatory and anxiolytic effects to the human. (Sigel 2002). b. Midozolam is the substrate for the receptor GABA only. This is very specific in nature. It binds to the GABA receptors that are having only alpha and gamma subunits. The binding of benzodiazepine modifies the GABAs response by the receptor. As these receptors are found in the cerebral cortex region, limbic system, cerebellar cortex and spinal cord, its effect can be felt in many parts of the body. The two compartmental model enables the specificity of the molecule and increases the sensitivity. (Stoelting and Miller 2007) c. Clinical Efficacy: Intravenous midozoalm is very effective in treating refractory status epilepticus in children. Continuous intravenous injection was very effective for the treatment. Midozolam was able to control the seizures very effectively. (Pellock 2008). The Midozolam is used along with Fentanyl for the endoscopy sedation in Cirrhotic patients. (clinicaltrials.gov 2009). Midozolam is also used for children who are having malaria and convulsions. (Muchochi et al. 2008). The intranasal and buccal Midozolam are used for the treatment of seizures. Electroencephalography confirmed this effect in the patients. They had similar speed and safety as that of intravenous and rectal diazepam. (Armijo et al. 2004). 5. Midozolam is metabolized in the liver and hardly 1% is excreted in the urine. The Midozolam is excreted as conjugated metabolites in the urine. In urine, methyl and glucuronide conjugates are excreted. Midozolam is found to be metabolized only by the enzyme cytochrome P450 3A4. (Wheeler, Wong and Shanley 2010). 6. The hydroxylation of the methyl group of the imidazole ring occurs in Midazolam and they are eliminated from the body following hydroxylation.1-hydroxy- Midozolam is the primary urinary excretory product. The 4-hydroxy-midozolam and dihydroxy-midozolam are also found at smaller concentration in the urine. It is also found that 45-57% of the drugs are excreted as these conjugates in the urine. 20% of the Midozolam is converted into 1-hydroxy- Midozolam and 7% of the Midozolam is converted into 4-hydroxy-midozolam. Cytochrome P450 3A4 and cytochrome P450 3A5 are the major enzymes that are involved in the drug metabolism. The Midozolam elimination from the body occurs through the gastrointestinal and hepatic cytochrome P450 3A4 metabolism only. 7. When Midazolam binds to the CYP2C19 enzyme, it was found that Midazolam was considered as the CYP3A4/5 substrate and was found to follow the Michaelis-Menten Kinetics. The inhibition of Midozolam and the enzyme was because of the (+)-N-3-benzylnirvanol and S-mephenytoin. The inhibitory effect was very good for CYP3A4/5 enzyme and was not the same for CYP2C19 enzyme. (Emoto and Iwaski 2007) 8. The Midazolam is found to interact with analgesics, antiasthma medications, antimicrobials, cardiovascular drugs, CNS drugs, gastrointestinal tract drugs, local anaesthetics and muscle relaxants. Analgesics: Aspirin and diclofenac when combined with Midozolam are found to increase the sedatory effect. Antiasthma medications: Aminophylline reduces the effectiveness of Midozolam. Antimicrobials: ciprofloxacin decreases the activity of Midozolam whereas rifampycin increases the effect. Combined therapy of Midozolam and erythromycin found to create sedation. Most of the antifungal drugs are found to increase the effect of Midozolam. Cardiovascular drugs: Diltiazem and verapamil are found to increase the effect of Midozolam and beta-adrenergic blocking drugs decrease the effect of Midozolam. CNS Drugs: The antidepressant drugs such as fluoxentine and fluvoxamine increases the effect of Midozolam. GI Tract drugs: Omeprazole and cimetidine are found to increase the effect of Midozolam. Local anesthetics and muscle relaxants activities are increased by the addition of Midozolam with them. (Greenwood, Seymour and Meechan 2009). 9. a). The bioavailability of Midozolam by oral administration is 0.3. After oral administration of the drug, there is incomplete absorption and as a result good excretion of the drug occurs. Because of this property, large doses of the drug must be administered for better results and at frequent intervals. Children may require a dose of 0.25 – 0.75 mg /kg for oral administration and 0.025-0.1 mg/ kg for intravenous administration. (Cote, Lerman and Todres 2009). b). The bioavailability of the Midozolam is influenced by the absorption rate of the liver and small intestine. The elimination of Midozolam is influenced both by the gastrointestinal and hepatic CYP3A mediated metabolism. The oral Midozolam bioavailability was 50% less than that expected and it brings out the conclusion that only liver does the metabolism. (Thummel et al. 1996). c). gastrointestinal tract absorption is very rapid for the oral administration of Midazolam. The drug is given as Midazolam hydrochloride. Parenteral administration of the drug has a very good on set of action and good local tolerance. The half life is only two hours. The plasma level and clinical effects are very good and fast. (Kanto 1985). 10. a). Brand names: Midazolam hydrochloride, Midazolam hydrochloride Novaplus and Versed Strength: Midazolam injection 1mg/ml, 2mg/ml, 5mg/ml and Midazolam tablet 15 mg are the standard dosage forms available. (imb.ie, 2007) Dose form: Solutions and syrup. Route of administration: IV, IM, oral. 11. a). Midazolam is 97% bound to plasma protein. b). The unbound fraction is 0.04. 12. The volume of distribution of Midazolam is 0.8-1.2 L/kg. (imb.ie 2007) a) The volume of distribution is very large when compared to the blood volume. b) Midazolam has a great affinity towards the plasma proteins. Hence the binding is very high. The percentage of binding reflects the volume of distribution. If the plasma bound Midazolam is high then the volume of distribution will be high. This is the relationship. (imb.ie 2007) 13. The loading dose of Midazolam is 200 micrograms/kg. The loading dose is given at small increments at particular intervals of time. (imb.ie, 2007) 14. Liver: a) The systemic clearance of Midazolam from the liver is around 0.157l/min. b) The hepatic clearance is found to be high in the children who are ventilated. c) The first pass metabolism of midozolam is the general phenomenon for the high-turnover of CYP3A4 substrates and thus it concludes that the drug has high extraction. (Paine et al. 1996). d) The hepatic enzyme induction is found in the hepatic clearance. (Paine, 1996). Kidney: a) The clearance of Midozolam in the kidney was found to be around 15% of the total concentration. The renal excretion of the drug is very negligible. (Sennesael et al. 1991). b) In the renal patients, the unbound fractions were higher than the normal persons. The volume of distribution and the renal clearance were found to be reduced in the renal patients. (Sennesael et al. 1991). c) As the volume of distribution, systemic availability and renal clearance varies for the renal dysfunction patients, change in the dosage level is necessary with respect to the individual patients. (Sennesael et al. 1991). 15. a). The half life of Midazolam varies from 5 to 7 hours depending upon the drug administration alone or in combination with other drugs. When given as oral administration, the half life of the drug is 1.5 to 2.5 hours. (Sennesael et al. 1991). b) The tissue distribution is very rapid after the oral administration of Midazolam. The steady state is attained within 2 hours after the administration. The steady state value is found to be 0.7-1.21/kg and about 98% of the oral Midazolam is bound to the plasma proteins. (Sennesael et al. 1991). c) The systemic clearance of Midazolam occurs is about 28 +/- 9 hours. 16. For the pediatrics, it was found that there is no relationship between the pharmacokinetic and pharmacodynamic relationship. When the sedation levels were found for the pediatrics using comfort scale, plasma concentrations and metabolites concentration in the blood, no evident PK-PD relationship was found. Thus it is concluded that the dosage level should be recommended based on the clinical information. (de Wildt et al. 2005). The response to the drug is measured in terms of total plasma concentration and beta band EEG activity. Beta band EEG activity is measured using exponential PK-PD model. The mean bioavailability, mean systemic clearance, harmonic mean in initial and terminal half lives are also measured accordingly. This will give an idea about the pharmacodynamic value. If a drug is administered intranasally, then its effect on the healthy volunteers is identified using the pharmaco response. This is easily identified using the pre-hospital monitoring. (Knoester et al. 2002). 17. Midazolam is found to achieve the hypnotic endpoint very less in elders than the young people. A negative correlation occurs between the age and intravenous administration of midazolam. This was confirmed through a study on the effect of Midazolam in the patients of age between 45 and 85 years. Over dosage produced very less effect for the elderly patients because their requirement was very small and the overdose could not be taken up by them. The half life of Midazolam was higher in the elderly patients. The total clearance was highly reduced in the elderly patients. The total body clearance is the only pharmacokinetic parameter that was found to be the same in the elderly patients irrespective of sex; the clearance was 40% less than the young patients. For the women, there was no significant difference in the body clearance and dosage level. This was agreed in many studies. The distribution volume was also found to be high in all the elder patients. Age created very less change in the plasma protein binding, central compartmental volume and volume of distribution. Thus it concludes that the age could not give a significant role in the dosage selection at the elderly patients. The pharmacokinetic parameters were not affected. (Sieber 2006). The PK-PD (pharmacokinetic and pharmacodynamic) effect of Midazolam was studied in elderly and the younger patients. It was found that a 50% dose reduction is required for the elder patients to attain the hypnotic end point when compared with the elders. Thus it proves that the concentration response was very high in the elderly patients at a concentration range of 0.5mg for the extreme conditions. (Sieber 2006). 18. Midazolam is a potent sedative agent and this should be administered slowly and dosage should be individualized. Hepatic metabolism of Midazolam occurs through oxidation and conjugation of glucuronide. Severe liver diseases reduce the binding of the Midazolam with its receptor. In the elderly patients the systemic clearance is reduced and the half life of the drug is prolonged to 75 – 150 hours. The hepatic clearance rate of Midazolam is 5 times greater than the lorazepam and 10 times greater than the diazepam. The blood flow at the liver determines the metabolic rate of Midazolam drug. The age factor is found to associate very less with that of the drug metabolism. The half life of Midazolam is similar in the people of varying age. (Barash et al. 2009). The hepatic metabolism is impaired by age, and the co administration of other drugs. Conscious sedation limits vary for adults and children. 1 to 2.5 mg of drug can be given at a single time with a dilution rate of 1ml/min. The maximum dosage level is 5 mg for the Intravenous administration of Midazolam. If the patient has CNS depressions, then a lesser amount can be administered. For children, the intramuscular administration should be practiced with a dose concentration of 0.15 to 0.1 mg/kg. For infants Intravenous titrations with very smaller amounts at regular intervals can be given. For children between 6 months to 5 years , intravenous injection with a maximum concentration of 0.1mg/ kg and a maximum dosage level of 0.6 mg can be given. For children greater than 6 years the high dose level is 10 mg. for the hepatic function impaired patients the doses should be titrated because of the decreased clearance rate and the increased half life of the drug. High retention time of the drug is possible for the hepatic patients hence dilution and titration are very essential. (drugs.com). 19. Midazolam over dosage results in impaired coordination, confusion, coma, diminished reflexes, sedation and somnolence. There was no proven specific organ toxicity for the over dosage of Midazolam. If over dosage of Midazolam is given for the patients then the pulse rate, respiration rate and the blood pressure should be monitored and general measures should be employed. Airway should be maintained with proper administration of oxygen. Peritoneal dialysis, forced diuresis, or hemodialysis can be performed for the treatment of overdose of Midazolam. Flumazenil is a specific benzodiazepine –receptor antagonist. (Aronson 2008). This can be used for the complete removal of Midazolam form the body. The anecdotal effects are good for flumazenil. The patients administered with flumazenil should be monitored for respiratory depression and other residual benzodiazepine effects. (Rajeswari 2008). If Midazolam is given as over dose then acute intoxication is found from the blood sample analysis and High performance liquid chromatography (HPLC) test. (Rajeswari 2008). For high risk patients, the onsets of seizures are possible. Hence the patients who are exposed to cyclic antidepressant drugs and those who are long term users of Midazolam must be taken greater care. Hence proper dose adjustment of flumazenil is required. Rapid Midazolam withdrawal is also a big risk for the patients like the seizures. Panic anxiety can also occur because of flumazenil replacement for Midazolam. (Rajeswari 2008). References: Aronson, JK 2008, Meyler's Side Effects of Psychiatric Drugs, Elsevier. Armijo, JA., Herranz, JL., Pena Pardo, MA and Adin 2004, “Intranasal and buccal midazolam in the treatment of acute seizures”, Revista de neurologia, Vol.38, No.5, pp. 458-468. Barash, PG., Cullen, BF., Stoelting, RK and Cahalan, M 2009, Clinical anesthesia, Lippincott Williams and Wilkins. 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Wheeler, DS., Wong, HR Shanley, TP 2010, Pediatric Critical Care Medicine: Basic Science and Clinical Evidence, Springer. . Read More