The Drug Diazepam in Pharmacology - Essay Example

The Drug Diazepam in Pharmacology Section 1: Introductory Concepts 1. Drug Profile Chemical name: 7-chloro-1-methyl- 5-phenyl- 1, 3-dihydro-2H- 1,4-benzodiazepin-2-one Generic Name: Diazepam Australian Trade Names: Ranzepam, Antenex, Valium, Valpam, Diazepam, Diazepam Elixir, Diazepam Rectal Solution. 2. A. List the approved indications for your drug. Diazepam is used for the management of anxiety disorders. Diazepam can also be used for acute alcohol withdrawal, the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis. Diazepam can also be used to treat trauma (injury, inflammation) to muscles, bones and joints. It combats spasticity due to upper motor neuron lesions such as cerebral palsy and paraplegia, as well as in athetosis and stiff man syndrome (Aschenbrenner & Venable 342). Indications: Short-term management of anxiety, agitation Acute alcohol withdrawal Muscle spasm Premedication Conscious sedation Status epilepticus Benzodiazepine withdrawal: Acute behavioral disturbance, Parasomnias (night terrors, sleepwalking). Indications from Benzodiazepines: Anxiety, Panic disorder, Sleep disorders, Seizures, Acute behavioral disturbance. Acute alcohol, barbiturate or benzodiazepine withdrawal Muscle spasm Premedication and sedation for procedures and in intensive care units (Australian Medicine Handbook 2011). B. Determine whether your drug is approved for paramedic use in South Australia, and if it is, identify the approved paramedic indications for your drug in South Australia. In South Australian Ambulance Services the most common drug in use with patient is Midazolam. Only paramedics are allowed to use in the management of “psychostimulant induced behavioral disturbances” in times of emergency (National Drug Strategy). Section 4: Over-The-Counter & Complementary and Alternative Medicines 3. Add to your drug profile: a. A list of conventional over-the-counter (OTC) medicines, complementary alternative medicines (CAMs) and prescription medicines that are known or suspected to undergo clinically relevant interactions with your profile drug in humans. b. List the source(s) of information you have used and indicate the strength of the evidence (e.g. anecdotal report, clinical case, clinical trial, etc) for each of the interactions that you have identified. fluconazole + diazepam Fluconazole is an antifungal that belongs to a group of drugs known as azoles that increases the effects of Diazepam by increasing the levels of Diazepam available in the plasma at any given time. A study conducted by Saari established that Fluconazole increased the level of Diazepam two and a half times thereby increasing the sedative effects of Diazepam. However, the peak plasma concentrations and the pharmacodynamics of Diazepam were not affected (941-999). rifampicin + diazepam Rifampicin may substantially increase the metabolism of diazepam, decreasing its concentration and clinical effect. A diazepam dose should be increased or an alternative used, e.g. temazepam. voriconazole + diazepam Voriconazole may inhibit Diazepam's metabolism, increasing the risk of adverse effects. In essence, Voriconazole acts the same way as Fluconazole by increasing the levels of Diazepam that are available in the plasma at any given time (Saari 941-999). Therefore, a Diazepam dose should be decreased. Diazepam + phenytoin Diazepam may possibly increase or decrease phenytoin concentration. The phenytoin concentration should be monitored in case of toxicity and the phenytoin dose should be adjusted as necessary (Australian Medicine Handbook 2011). Interactions Enhanced sedation or respiratory and cardiovascular depression may occur if diazepam or other benzodiazepines are combined with drugs that have CNS-depressant properties such as alcohol, antidepressants, sedative antihistamines, antipsychotics, general anaesthetics, other hypnotics or sedatives and opioid analgesics. The metabolism of most benzodiazepines is controlled by the isoenzymes CYP2C19 and CYP3A4. Hence, adverse effects may also be produced by using drugs that negatively interact with these isoenzymes. Diazepam is metabolized mainly by hepatic microsomal oxidation and is therefore more susceptible to pharmacokinetic changes than lorazepam, oxazepam, and temazepam (Sweetman 18 Nov 2011). Morphine or pethidine decreases the rate of oral absorption of diazepam. This is because of the effect of opioid analgesics on gastrointestinal motility (Gamble 1976). In one test, dextropropoxyphene prolonged the half-life and reduced the clearance of alprazolam, but diazepam and lorazepam did not have similar effect (Abernethy 1985). Ciprofloxacin has been reported to reduce diazepam clearance and prolong its terminal half-life, but diazepam's pharmacodynamics were not affected (Kamali 1993). Isoniazid has been reported to increase the half-life of a single dose of diazepam in healthy subjects (Ochs 1981). In contrast, rifampicin has decreased the half-life of diazepam, but the same effect does not work with ethambutol (Ohnhaus 1987). Plasma binding of diazepam was reduced, and free concentrations increased, immediately after heparin was injected into a patient (Routledge 1980). Since plasma concentrations of Diazepam appear to be affected by fluvoxamine, the best thing to do is to give fluvoxamine patients lorazepam, which has a different metabolic pathway (Perucca 1994). Fluoxetine appears to have a similar effect on diazepam but it decreases plasma concentrations of diazepam's active metabolite desmethyldiazepam (nordazepam) and its effect is minor (Lemberger 1988). Although lithium has been reported to interact with diazepam resulting in hypothermic episodes, this is more an idiosyncratic response, not a true drug interaction. Using lithium with benzodiazepines is safe (Ross 1987). Sodium valproate displaces diazepam from plasma-protein binding sites (Dhillon & Richens 1982). Propranolol and metoprolol both inhibit the metabolism of diazepam, although not to too much overall effect. No pharmacokinetic interaction has been seen between atenolol and diazepam (Klotz & Reimann 1984). According to a study conducted by Treasaden established that in the management of anxiety, the use of diazepam and propanolol together was better than the use of propanolol or diazepam alone (417-412). Raised serum-digoxin concentrations have been reported in patients also taking diazepam. The use of benzodiazepines reduces digoxin (Castillo-Ferrando 1980). Chronic use of disulfiram can inhibit the metabolism of diazepam leading to a prolonged half-life and reduced clearance in both healthy patients and alcoholics (MacLeod 1978). Several studies involving giving diazepam to healthy subjects have shown that cimetidine inhibits the hepatic metabolism of diazepam. The clearance of diazepam decreases and the half-life is prolonged. Oral diazepam was absorbed more rapidly after metoclopramide was given by needle. Studies of continuous omeprazole dosage on the pharmacokinetics of a single intravenous dose of diazepam in healthy subjects indicate inhibition of diazepam metabolism in a similar manner to cimetidine (Andersson 1990). Study with Diazepam has supported suggestions that oral contraceptives may inhibit the biotransformation of benzodiazepines metabolised by oxidation (Abernethy 1982). Phlebitis associated with intravenous diazepam resolved with local heat but recurred on two separate occasions after oral penicillamine (Brandstetter 1981). There are reports of aminophylline given by needle reversing intravenous diazepam sedation (Niemand, 1984). Drug Profile activities for Module 2 Section 3: Signal Transduction Mechanisms for Receptors 4. For your drug: A) Discuss in detail the mechanism of action. Your answer should: o Identify how the interaction of the drug with its molecular target(s) accounts for the major therapeutic effect (i.e. the effect you want the drug to cause in clinical practice; e.g. for paracetamol - pain relief) o Include a description of how the drug alters function at the cellular level. o Include a description of how the altered cellular function manifests as a change in body system function, and the eventual major therapeutic response Mechanism of Action: The exact sites and mode of action of the benzodiazepines have not been fully described but the drugs work via the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Benzodiazepines work by binding to GABA thereby increasing the physiological effect of GABA. They affect the limbic, thalamic, and hypothalamic levels of the CNS, producing anxiolytic, sedative, hypnotic, skeletal muscle relaxant, and anticonvulsant effects. Benzodiazepines can influence all types of CNS depression such as mild sedation, hypnosis and coma because GABA has a general inhibitory effect on the millions of nerves in the brain. In essence, GABA works as a natural down regulator of the actions of nerves. Therefore, by increasing the action of GABA benzodiazepine increases the down regulatory effects of the nerves. Specific binding sites that work well with benzodiazepines have been detected in the CNS, and the affinity of these sites for the drugs is enhanced by using GABA and chloride. The sites and actions of benzodiazepines within the CNS appear to include GABAA receptors (GABA recognition sites), high-affinity benzodiazepine receptors, and chloride channels, but not enough is known of the sites of action of benzodiazepines and GABA-regulated (-gated) chloride channels) (Aschenbrenner). Benzodiazepines like diazepam produce skeletal muscle relaxation predominantly by inhibiting spinal polysynaptic afferent pathways, although they can also inhibit monosynaptic afferent pathways. As explained earlier by Aschenbrenner, Benzodiazepine acts by increasing the down regulatory effects of GABA and the fact that GABA has effects on these nerves explains the muscle relaxation aspect. The drugs can act as inhibitors of neuronal transmitters and excitatory Benzodiazepines can help epileptics by suppressing the spread of seizure activity through the same mechanism. These types of drugs have very little effect on the autonomic nervous system, respiration, or the cardiovascular system (Bethesda accessed 18 Nov 2011). The sites and actions of benzodiazepines within the CNS appear to include GABAA receptors (GABA recognition sites), high-affinity benzodiazepine receptors, and chloride channels, but not enough is known of the sites of action of benzodiazepines and GABA-regulated (-gated) chloride channels. Beonzodiazepines function by binding to the “gamma sub-unit of GABA-A receptor.” Binding of Benzodiazepines causes a modification of the receptor in the alpha sub-unit thereby increasing the “activity” in the chloride channels in the sub-unit (Lundbeck Institute). According to Lundbeck Institute Benzodiazepines like diazepam produce skeletal muscle relaxation predominantly by inhibiting spinal polysynaptic afferent pathways, although they can also inhibit monosynaptic afferent pathways. The drugs can act as inhibitors of neuronal transmitters and excitatory synaptic transmission. Diazepam may also directly depress motor nerve and muscle function. B ) Using 4 journal articles, critically review the evidence for the clinical effectiveness of your drug in humans. Your answer should identify and critique the: Type of study Comparator agent (e.g. placebo, current gold standard therapy, etc) Sample size Measures of effectiveness In a studies conducted by Dreifuss et al (1998) and Cereghino et al (1998), there was the realization that Diazepam positively reduced seizures as compared to a placebo The two randomized, double-blind, parallel-group, placebo-controlled clinical studies establishing how efficient rectal diazepam is for the management of acute repetitive seizures in adults and children 2 years of age and older, 125 and 158 patients were used respectively. In these studies in adult and pediatric patients, seizure occurrence was lessened in diazepam-treated patients as opposed to the placebo. About 55– 62% of patients were seizure-free during the 12-hour observation period versus 20–34% for placebo recipients (Dreifuss, et al. 1998; Cereghino, et al. 1998). In a clinical study to establish the effects of diazepam when administered orally and rectally it was established that the oral administration led to higher serum levels after sixty minutes as compared to rectal administration. The study used 12 drug resistant epileptic patients over a period of 24 hours and the general realization was that for rectal administration the mean serum levels after 60 minutes was 170ng/ml while for oral administration was 270ng/ml. According to the study, oral administration is more effective than rectal administration. The findings of the study are important in determining the most effective route of administration of diazepam (Institute of Neurology London). In a study to compare the effectiveness of diazepam in humans in reducing neural anxiety, diazepam was compared with a placebo. The stud involved 17 Japanese subjects and the general realization was that diazepam was 95% more effective than the placebo and that the effective dose was 12 to 18 mg per day. The study also established that a dose of 6mg per day had no difference with the placebo (Inada). In a clinical double-blind trial to compare the effectiveness of diazepam and buspirone in a 60 patients diagnosed with anxiety disorders according to DSM-III manual. Diazepam and buspirone were administered equally in a period of four weeks and the general realization was that diazepam had an earlier effect during the first two weeks as compared to buspirone although diazepam demonstrated higher adverse drug reactions as compared to buspirone (Dominiquez). Drug Profile activities for Module 3 Section 1. Renal Excretion of Drugs and their Metabolites 5. Determine whether your drug is: - Primarily excreted unchanged (as the parent drug) in the urine (renally cleared). - Excreted in the urine principally as metabolites (metabolised; hepatically cleared) - Using a diagram (if possible) as an aid discuss its metabolism noting the types of reactions, that is either fictionalization or conjugation reactions, and identify the involvement of any CYP, UGT or other drug metabolizing enzymes. - Identify the main metabolites (note those on your figure), and state the percent of the parent compound metabolized to the specific metabolite. Benzodiazepine is metabolized via the liver microsomal P450 system and the conjugation system to increase the solubility and subsequently elimination of the drug. All benzodiazepines are lipid soluble and are able to cross the blood brain barrier and placental barrier. Benzodiazepines are principally metabolized in the liver and eliminate via the urine as glucoronide conjugates. Figure 1 shows the pathway for the metabolism of diazepam. Figure 1 courtesy of Tox Lab The first step in the metabolism of diazepam is de-alkylation. Diazepam is metabolized by the CYPC19 & CYP3A4 enzyme system. Diazepam is principally eliminated via urine. 7. In relation to the metabolism of your drug discuss the influence of host (e.g. disease states) and environmental factors in terms of enzyme induction and/or inhibition on the metabolism of your drug. The plasma elimination half-life of diazepam and/or its metabolites works longer for neonates, in the elderly, and in patients who have hepatic or renal impairment. The elderly and the neonates do not have effective liver systems for the elimination of diazepam. Diazepam and its metabolites can cross the blood-brain barrier and the placental barrier. Section 4. Drug-Drug Interactions 8. For your drug: i. List all known drug-drug interactions involving the metabolism of your drug. ii. Explain the mechanism of each of the interactions (i.e. Drug A inhibits the metabolism of Drug B by Enzyme X). iii. Note the clinical consequences of each of the interactions (e.g. increases the plasma concentration of Drug B leading to an enhanced pharmacological effect and toxicity). 9. For your drug: a. Determine and state the oral bioavailability b. Discuss whether the bioavailability is influenced by gastrointestinal absorption, first pass hepatic extraction or both? c. If your drug is only available as a parenteral formulation discuss whether that is principally due to problems with gastrointestinal absorption or excessive first pass metabolism. Diazepam is readily and completely absorbed from the gastrointestinal tract. The peak plasma concentrations take place from between 30 to 90 minutes after oral doses. Section 2. Drug formulation and routes of administration 10. For your drug: a. List all of the dose forms and strengths available in Australia. (Identify brand names only if they are important for distinguishing between dose forms or they describe combination products) tab, 2 mg (white), 50, Ranzepam tab, 2 mg (scored, white), 50, Antenex , Valium, Valpam tab, 5 mg (yellow), 50, Diazepam tab, 5 mg (scored, yellow), 50, Antenex, Valium, Valpam tab, 5 mg (scored, white), 50, Ranzepam oral liquid, 1 mg/mL, 100 mL, Diazepam Elixir supp, 10 mg, 20, Diazepama (ON) Rectal solution, 1 mg/mL, 5 mL, 10 mL, Diazepam Rectal Solution Inj, 5 mg/mL, 2 mL, 5, 50, Diazepam (Australian Medicine Handbook, 2011) b. Discuss any administration issues that are followed for safe efficacious use. Diazepam can be given orally, rectally and parenterally, although there is a risk of dependence. Doses should be as low as possible to control symptoms and courses of treatment should be short, not normally exceeding 4 weeks. Diazepam is withdrawn gradually. Elderly and debilitated patients receive half the usual adult dose. Dosage reduction may also be required in patients with hepatic or renal problems. The intramuscular route is usually only used when oral or intravenous dosage cannot be given. An injection should be carried out slowly into a large vein of the antecubital fossa at a recommended rate of no more than 1 mL of a 0.5% solution (5 mg) per minute. The patient would be in the supine position and under medical supervision for at least an hour after the dose. Diazepam may be given by continuous intravenous infusion; to prevent precipitation, solutions should be freshly prepared following directions regarding diluent and concentration of diazepam as stated in the licensed product information (Sweetman, accessed 18 Nov 2011). Section 3. Drug distribution 11. For your drug determine from the primary literature whether it is bound to plasma proteins a. State the percent bound Diazepam is 98 to 99% bound to plasma proteins. b. Calculate the unbound fraction Unbound fraction of diazepam equal 1 to 2 % of total (Ibid) 12 For your drug, determine from the primary literature its volume of distribution (VD) in either litres per kilogram (L/kg) or litres (L): a. Is your drug’s VD small or large relative to blood volume? b. What does the volume of distribution tell you about the way your drug is distributed throughout the body? (Discuss in terms of plasma protein and tissue binding, distribution into adipose tissue, etc). Benzodiazepines are widely distributed into body tissues and cross the blood-brain barrier. When diazepam is given intravenously, there is an early, rapid decline in plasma concentrations of the drug with regards to the distribution into the tissues. The concentration of diazepam in the fetal circulation has been reported to be equal to or greater than maternal plasma drug concentrations. The drug and its metabolites can be found in bodily milk (Bethseda, accessed 18 Nov 2011). Diazepam has a biphasic half-life with an initial rapid distribution phase and a prolonged terminal elimination phase of 1 or 2 days; its main metabolite, desmethyldiazepam, has a half-life of 2 to 5 days. Diazepam and desmethyldiazepam accumulate when more is given and the relative proportion of desmethyldiazepam in the body increases when used regularly over time (Sweetman, accessed 18 Nov 2011). 13. For your drug (Answer 13a OR 13b): a. If given as a loading dose, indicate the usual loading dose. OR b. If never given as a loading dose, explain why not. (e.g. toxic if given as a loading dose, unacceptable adverse effects from loading dose etc). Loading dose is used for some drugs to reach a desired therapeutic concentration in the blood in short period of time. Diazepam has no loading dose. It is readily and completely absorbed from the gastrointestinal tract, peak plasma concentrations occurring within about 30 to 90 minutes of oral doses. Diazepam is absorbed more rapidly as a rectal solution. Section 4. Clearance Concepts 14. For your drug (Answer 14a OR 14b): a. If primarily metabolised by the liver (i.e. if fe is < 0.5): 1. Determine systemic (total) clearance. 2. Does it have low, intermediate or high hepatic clearance? 3. Would you predict that your drug has low, intermediate of high first pass extraction? 4. What effect would hepatic enzyme induction or inhibition have on the hepatic clearance of your drug? Diazepam is oxidised in the liver to N1-desalkyl derivatives. It is extensively metabolized by hepatic cytochrome P450 2C19 and 3A4 isoenzymes to N-desmethyldiazepam, 3 – hydroxydiazepam and oxazepam as well as glucuronidation. The metabolites of diazepam should combine with glucuronic and/or sulfuric acid before being urinated out as inactive conjugates. Their renal clearance is 20-30 mL/min 2C19 or 3A4 enzyme inducers (e.g. carbamazepine, rifampicin and St John's wort) are expected to increase diazepam metabolism and decrease its plasma concentration. In the same way, enzyme inhibitors (e.g. cimetidine, clarithromycin, fluoxetine, fluvoxamine, ketoconazole, omeprazole, topiramate, grapefruit juice) will decrease diazepam metabolism and increase its plasma concentration and activity (Australian Medicine Handbook, 2011). Section 5. Half-life Mansour Alkahtani - 2056535 20 15. For your chosen drug: a. State the half-life. b. How long will it take (in hours) to reach steady-state after commencing oral administration? c. If the systemic clearance of your drug decreased by 40% calculate the new half-life and time to steady state. Half-life of diazepam is 20-50 hours. Section 6. Therapeutic Drug Monitoring 16. How is the response to your drug monitored pharmacodynamically when administered in the hospital setting? If your drug is used in the pre-hospital setting does the monitoring differ from the hospital setting? Or, if your drug is used in a community setting how this does differ from the other settings? When using diazepam, patients with panic disorders should be monitored for the number ofspontaneous and situational panic attacks and associated anxiety, as well as the symptoms ofbehavior, phobic fears, somatic manifestations, and secondary disability (e.g., interference with normal work or social activities) (Bethseda, accessed 18 Nov 2011). For recovering alcoholics using diazepam, alcohol withdrawal symptoms should be monitored. Alcohol symptom withdrawal assessment scales (available from specialist alcohol treatment centres are used for hospitalized patients, enabling doses of diazepam to be given according to the severity of symptoms. Alternatively, diazepam may be given in repeated doses (eg 10–20 mg every 2 hours) until symptoms subside (Australian Medicines Handbook. 2011). Drug Profile activities for Module 5 Section 1: Life stages as a factor in variability 17. For your drug: a. Ascertain if dosage is adjusted for age and indicate the change in dosage (e.g. higher or lower in young or elderly etc.) b. If the dosage is adjusted for age is the change due to altered pharmacokinetic orpharmacodynamic factors? (only answer part b if the dosage is adjusted for age) The plasma elimination half-life of diazepam and/or its metabolites is prolonged in neonates and in the elderly. For example in the management of anxiety diazepam can be dosed in pediatrics as 1 to 2.5 mg orally 3 to 4 times daily and increased gradually as needed and in geriatrics from 2 to 2.5 mg orally 1- 2 times a day and increased gradually as needed and tolerated. In adults 2 to 10 mg orally 2 to 4 times a day would be given, depending on symptom severity (Ibid). Section 2: Impact of disease states 18. For your drug: a. Ascertain if dosage adjustment is required in individuals with hepatic disease Mansour Alkahtani - 2056535 22 b. If your drug is adjusted in hepatic disease is the change due to altered pharmacokinetic or pharmacodynamic factors? (only answer part b if the dosage is adjusted in hepatic disease) (Oxidative metabolism of diazepam is apparently for those with hepatic impairment) does not make sense; this causes a longer half-life and reduced clearance (Ochs, 1983) . In cases of mild-to-moderate impairment, low doses of diazepam would be given to reduce risk of precipitating coma (Australian Medicines Handbook, 2011). Section 3: Drug dependence, misuse and abuse 19. For your drug; a. Describe the potential for overdose (intentional or accidental) associated with your drug, the clinical signs and symptoms expected and the patient treatment plan. b. If your drug is used to treat overdose conditions, describe how you would incorporate its use into the patient treatment plan (only answer part b if your drug is used to treat overdose conditions) Benzodiazepine overdoses will cause somnolence, impaired coordination, slurred speech, confusion, coma, diminished reflexes, hypotension, seizures, respiratory depression, and apnea. Death from an overdose of benzodiazepines without alcohol is rare. Most patients recover rapidly (Sweetman, accessed 18 Nov 2011).  Treatment of benzodiazepine intoxication consists of general supportive therapy. Flumazenil, a benzodiazepine antagonist, normally deals with benzodiazepine overdoses, but the benefits as opposed to the risks should be considered. If ingestion of the benzodiazepine is recent and the patient is fully conscious, emesis should be brought on. If the patient is comatose, Gastric Mansour Alkahtani - 2056535 23 lavage would be used for a comatose patient. Pulse, respiration, and blood pressure should be monitored when the patient is recovering, plus the patient should be closely observed. IV fluids should be administered and an adequate airway maintained. Hypotension may be controlled intravenously with norepinephrine or metaraminol. Although some manufacturers recommend use of caffeine and sodium benzoate to combat CNS depression, most authorities believe caffeine and other analeptic agents cannot be relied on. Flumazenil is better (Ibid). Benzodiazepines can be addictive even if used short-term. Symptoms of benzodiazepine dependence include drowsiness, ataxia, slurred speech, and vertigo. Nevertheless, sudden discontinuance of benzodiazepines in physically dependent patients causes anxiety, agitation, tension, dysphoria, anorexia, insomnia, sweating, vomiting, diarrhea, blurred vision, irritability, memory impairment, impaired concentrating ability, clouded sensorium, paresthesias, ataxia, tremors, muscle and abdominal cramps, heightened sensory perception, hallucinations, acute psychosis, decreased appetite/weight loss, and seizures which are clinically indistinguishable from tonic-clonic seizures. It may be hard to tell withdrawal symptoms apart from illness return or rebound. Because some benzodiazepines and their metabolites have long elimination half-lives, withdrawal symptoms may not occur until several days after the drugs have been discontinued (Ibid). Treatment of benzodiazepine takes time. Gradual dosage tapering is particularly important for those who may have a seizure (Ibid). Works Cited Aschenbrenner, Diane S. Drug Therapy in Nursing. Philadelphia: Lippincott Williams & Wilkins, 2009. Dominiquez, Jacobson. "Comparison of Bupirone and Diazepam in Genralized Anxiety Disorder." PubMed (1985): 290-296. Inada, Nozaki. "Efficacy of Diazepam as an Anti-Anxiety Agent: Meta-Analysis of Double Blind Randomized Controlled Trials Carriedout in Japan." PubMed (2008): 483-487. Institute of Neurology London. "Comparison of the Rectal Dose against Oral Dose in the Administration of Diazepam." Journal of Neurology, Neurosurgery, and Psychiatry (2008): 1674-1678. Lundbeck Institute. "Mechanism of Action of Benzodiazepines." 2011. CNS Forum. 23 December 2011 . National Drug Strategy. "Management of Patients with Psychostimulant Toxicity: Guidelines for Emergency Departments." May 2006. National Drug Strategy. 20 December 2011 . TI, Saari. "Voriconazole and fluconazole increase the exposure to oral diazepam." PubMed (2007): 941-999. Tox Lab. Metabolism of Diazepam. 2011. 24 December 2011 . Treasaden, Hallstrom. "Diazepam and Propanolol in the Management of Anxiety." British Journal of Psychiatry (1981): 417-421. Zimmerman, Christa. "A Comparison of the Clinical and Psychological Effects of Diazepam and Amylobarbitone Sodium on Anxiety in Patients." British Journal of Clinical Pharmacology (1977): 605-611. Read More