Benziodiazepine Drugs:
Comparison of Diazepam, Clonazepam, & Lorazepam

Table of Content

Page 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Introduction
Page 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diazepam: History & Mechanism of Action
Page 5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diazepam: Pharmacokinetics
Page 6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diazepam: Comparison of Pharmacokinetics
Page 7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diazepam: Comparison of Pharmacokinetics
Page 8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diazepam: Comparison of Pharmacokinetics
Page 9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diazepam: Adverse Effect
Page 10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diazepam: Overdose
Page 11 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diazepam: Contradiction
Page 12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clonazepam: Information & Mechanism of Action
Page 13 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clonazepam: Pharmacokinetics
Page 14 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clonazepam: Comparison of Pharmacokinetics
Page 15 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clonazepam: Comparison of Pharmacokinetics
Page 16 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clonazepam: Comparison of Pharmacokinetics
Page 17 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clonazepam: Comparison of Pharmacokinetics
Page 18 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clonazepam: Adverse Effects
Page 19 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lorazepam: Information and Mechanism of Action
Page 20 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lorazepam: Pharmacokinetics
Page 21 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lorazepam: Comparison of Pharmacokinetics
Page 22 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lorazepam: Comparison of Pharmacokinetics
Page 23 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lorazepam: Adverse Effects
Page 24 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lorazepam: Overdose
Page 25 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion
Page 26 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References & Sources
Page 27 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References & Sources

Introduction: Abstract The purpose of this report is to expand the knowledge and idea about the effects and background of each drugs relating to benzodiazepine. To understand the mechanism of action, pharmacokinetics, adverse effects, and the comparison between drugs use to apply on patient and subjects that are being test for pharmacology reason. I will be reporting about 3 main drugs of benzodiazepines which are diazepam, clonazepam, and lorazepam.
Diazepam is lipophilic and is rapidly and completely absorbed after oral administration. Diazepam affects chemicals in the brain that may become unbalanced and cause anxiety. Diazepam is an oral medication that is used to treat anxiety. It belongs to the benzodiazepine family of drugs, the same family that includes alprazolam (Xanax), clonazepam (Klonopin), lorazepam (Ativan), flurazepam (Dalmane), and others. It is believed that excessive activity in the brain may lead to anxiety or other psychiatric disorders. The FDA approved diazepam in November 1963. Clonazepam is a chlorinated derivative of nitrazepam and therefore a chloro-nitrobenzodiazepine. Clonazepam has an intermediate onset of action, with a peak blood levels occurring one to four hours after oral administration. Long-term effects of benzodiazepines include tolerance, benzodiazepine dependence, and benzodiazepine withdrawal syndrome, which occurs in a third of people treated with clonazepam for longer than four weeks. Clonazepam is classified as a benzodiazepine. Lorazepam is a high-potency, intermediate-duration, 3-hydroxy benzodiazepine drug, often used to treat anxiety disorders. Lorazepam has all six intrinsic benzodiazepine effects: anxiolysis, anterograde amnesia, sedation/hypnosis, anticonvulsion, antiemesis and muscle relaxation. Lorazepam is used for the short-term treatment of anxiety, insomnia, acute seizures including status epilepticus, and sedation of hospitalized patients, as well as sedation of aggressive patients. Lorazepam is also the most common benzodiazepine used to decrease the likelihood of agitation and seizures in patients who have overdosed on stimulant drugs. As I mentioned about the definition and the basic information about these 3 drugs, it will make you understand and get the fundamental principle and will make your perceptive more easier.

Diazepam
Background and General Information Diazepam was created by Hoffmann-La Roche and is a benzodiazepine drug. It is commonly used to treat anxiety, panic attacks, insomnia, seizures (including status epilepticus), muscle spasms (such as in tetanus cases), restless legs syndrome, alcohol withdrawal, benzodiazepine withdrawal, opiate withdrawal syndrome and Ménière's disease. It may also be used before certain medical procedures (such as endoscopies) to reduce tension and anxiety, and in some surgical procedures to induce amnesia. It possesses anxiolytic, anticonvulsant, hypnotic, sedative, skeletal muscle relaxant, and amnestic properties. The pharmacological action of diazepam enhances the effect of the neurotransmitter GABA by binding to the benzodiazepine site on the GABAA receptor (via the constituent chlorine atom) leading to central nervous system depression.
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History
Diazepam was the second benzodiazepine invented by Dr. Leo Sternbach of Hoffmann-La Roche at the company's Nutley, New Jersey, facility following chlordiazepoxide (Librium), which was approved for use in 1960. Released in 1963 as an improved version of Librium, diazepam became incredibly popular, helping Roche to become a pharmaceutical industry giant. It is 2.5 times more potent than its predecessor, which it quickly surpassed in terms of sales. After this initial success, other pharmaceutical companies began to introduce other benzodiazepine derivatives.
Mechanism of Action
Diazepam binds to a specific subunit on the GABAA receptor at a site distinct from the binding site of the endogenous GABA molecule, known as an allosteric site. The GABAA receptor is an inhibitory channel which, when activated, decreases neuronal activity. Benzodiazepines do not supplement for the neurotransmitter GABA, rather benzodiazepines such as diazepam bind to a different location on the GABAA receptor, resulting in enhanced GABA effects.

Pharmacokinetics
Diazepam can be administered orally, intravenously (IV) (needs to be diluted, as it is painful and damaging to veins), intramuscularly (IM), or as a suppository. When administered orally, it is rapidly absorbed and has a fast onset of action. The onset of action is one to five minutes for IV administration and 15–30 minutes for IM administration. The duration of diazepam's peak pharmacological effects is 15 minutes to one hour for both routes of administration. The bioavailability after oral administration is 100% and 90% after rectal administration.
Diazepam is highly lipid-soluble, and is widely distributed throughout the body after administration. It easily crosses both the blood–brain barrier and the placenta, and is excreted into breast milk. After absorption, diazepam is redistributed into muscle and adipose tissue. Continual daily doses of diazepam quickly build to a high concentration in the body (mainly in adipose tissue), far in excess of the actual dose for any given day. Diazepam is stored preferentially in some organs, including the heart. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate, and withdrawal of diazepam during pregnancy and breast feeding is clinically justified.
The main active metabolite of diazepam is desmethyldiazepam (also known as nordazepam or nordiazepam). Its other active metabolites include the minor active metabolites temazepam and oxazepam. These metabolites are conjugated with glucuronide, and are excreted primarily in the urine. Because of these active metabolites, the serum values of diazepam alone are not useful in predicting the effects of the drug. Diazepam has a biphasic half-life of about one to three days, and two to seven days for the active metabolite desmethyldiazepam.

Figure [ 1 ] Biotransformation of Benzodiazepine
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Comparison of Pharmacokinetics in Different Biological State
Intramuscular Benzodiazepines: Use Midazolam & Diazepam

“The time to maximum plasma concentrations (Cmax) was shorter for midazolam (17.5 ± 6.5 min) than for diazepam (33.8 ±7.5 min). (P < 0.05, Table II) The IM absorption profiles for midazolam and diazepam demonstrate that there is more variability in the absorption rates of IM diazepam than those of IM midazolam (Figure 2). The mean time to peak absorption rate was shorter for midazolam (9 ±2 min) than for diazepam (13.8 ±7.5 min). The absorption of midazolam was almost complete within one hour following the im administration. However, for diazepam, considerable drug absorption continued, with larger variability, beyond one hour after the IM injection.” Analyze by Hung, Dyck, Varvel et al. Comparative absorption kinetics of intramuscular midazolam and diazepam. Can J Anaesth 1996;43:5 pp 450-5. We have found out that in every estimated pharmacokinetic parameter of each respective drugs, generally midazolam has more higher rate effect than diazepam. From what I understood, the plasma concentration of diazepam spends more time than the concentration of midazolam. Having mention it, that means midazolam is faster than diazepam in absorption and works more rapidly.

“Midazolam is the only benzodiazepine stable in aqueous solution and suitable for intramuscular injection. A delayed onset of action might be expected, as shown by Jawad et al., but this was not confirmed by Chamberlain et al. Intramuscular midazolam may be useful in patients when attempts to introduce an intravenous line are unsuccessful. It appeared to be well tolerated and rapidly effective for treatment of acute seizures.” The study was conducted by Wermeling, Archer, Manaligod et al. Bioavailability and pharmacokinetics of lorazepam after intranasal, intravenous, and intramuscular administration. J Clin Pharmacol 2001;41:1225-1231.

“We found that midazolam is superior to haloperidol and lorazepam in the sedation of violent and severely agitated patients (VSAPs) with respect to time to sedation and time to arousal. The use of midazolam in the control of VSAPs can facilitate patient care, rapidly ease the disruption to the ED, and hasten disposition.” Describe and concluded by Nobay, Simon, Levitt et al. A Prospective, Double-blind, Randomized Trial of Midazolam versus Haloperidol versus Lorazepam in the Chemical Restraint of Violent and Severely Agitated Patients. Acad Emerg Med 2004;11:744-749. As I discuss earlier between Diazepam vs Midazolam graph above this one, I finally conclude that Midazolam works as the fastest drug among both Diazepam and Lorazepam. From the research, it had mention “superior” therefore meaning that Midazolam has vast majority of affect compare to those 2 drugs. My thought on this graph indicates that Midazolam has the most effect on treating patients providing absolute easing process on the disruption to the ED.

Pharmacokinetics: Diazepam following renal administration from healthy patient
Pharmacokinetic information of diazepam following rectal administration was obtained from studies conducted in healthy adult subjects. No pharmacokinetic studies were conducted in pediatric patients. Therefore, information from the literature is used to define pharmacokinetic labeling in the pediatric population.
From the study of this graph, I summarize that by the use of Diastat conduct hepatically on impaired subjects, Diazepam after 7.5 mg IV holds the highest amount of mean plasma concentration in 550 ng/mL. While Diazepam after 15 mg Diastat shows that the line rises to 375 then initially decrease down to remain constant at 200 ng/mL. Desmethyldiazepam after 7.5 mg IV and Desmethyldiazepam after 15 mg Diastat increases slightly a bit but being constant at the extend of 8 hours. |
Metabolism and Elimination: It has been reported in the literature that diazepam is extensively metabolized to one major active metabolite (desmethyldiazepam) and two minor active metabolites, 3-hydroxydiazepam (temazepam) and 3-hydroxy-N-diazepam (oxazepam) in plasma. At therapeutic doses, desmethyldiazepam is found in plasma at concentrations equivalent to those of diazepam while oxazepam and temazepam are not usually detectable. The metabolism of diazepam is primarily hepatic and involves demethylation (involving primarily CYP2C19 and CYP3A4) and 3-hydroxylation (involving primarily CYP3A4), followed by glucuronidation. Adverse Effects
Adverse effects of benzodiazepines such as diazepam include anterograde amnesia and confusion (especially pronounced in higher doses) and sedation. The elderly are more prone to adverse effects of diazepam, such as confusion, amnesia, ataxia and hangover effects, as well as falls. Long-term use of benzodiazepines such as diazepam is associated with tolerance, benzodiazepine dependence and benzodiazepine withdrawal syndrome.

Adverse effects of benzodiazepines | Lack of tolerance produces : * sedation * memory impairment * lack of concentration * motor un-coordination * muscle weakness * acute confusional state | Physical dependence causes rebound withdrawal effects which include: * insomnia * anxiety * apprehension * irritability * palpitations, tremor, vertigo, sweating |
Diazepam has a range of side effects common to most benzodiazepines, including: Suppression of REM Sleep Impaired Motor Function

Overdose An individual who has consumed too much diazepam typically displays one or more of the following symptoms in a period of approximately four hours immediately following a suspected overdose: Mental Confusion Coma

Contraindications Use of diazepam should be avoided, when possible, in individuals with the following conditions: Hypoventilation

Clonazepam
Background and General Information
Clonazepam is a benzodiazepine drug having anxiolytic, anticonvulsant, muscle relaxant, sedative, and hypnotic properties. Clonazepam has an unusually long elimination half-life of 18–50 hours, making it generally considered to be among the long-acting benzodiazepines.
Benzodiazepines such as clonazepam have a fast onset of action and high effectiveness rate and low toxicity in overdose but, as most medications, it may have drawbacks due to adverse reactions including paradoxical effects and drowsiness. The benzodiazepine clorazepate may be an alternative to clonazepam due to a slow onset of tolerance and availability in slow-release formulation to counter fluctuations in blood levels. The pharmacological property of clonazepam as with other benzodiazepines is the enhancement of the neurotransmitter GABA via modulation of the GABAA receptor.
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Mechanism of Action
Clonazepam exerts its action by binding to the benzodiazepine site of the GABA receptors, which causes an enhancement of the electric effect of GABA binding on neurons, resulting in an increased influx of chloride ions into the neurons. This results in an inhibition of synaptic transmission across the central nervous system.
Benzodiazepines do not have any effect on the levels of GABA in the brain. Clonazepam has no effect on GABA levels and has no effect on gamma-aminobutyric acid transaminase. Clonazepam does however affect glutamate decarboxylase activity. It differs from other anticonvulsant drugs it was compared to in a study. Benzodiazepine receptors are found in the central nervous system but are also found in a wide range of peripheral tissues such as longitudinal smooth muscle-myenteric plexus layer, lung, liver and kidney as well as mast cells, platelets, lymphocytes, heart and numerous neuronal and non-neuronal cell lines.

Pharmacokinetics
Clonazepam is lipid soluble, and rapidly crosses the blood–brain barrier and penetrates the placenta. It is extensively metabolised into pharmacologically inactive metabolites. Clonazepam is metabolized extensively via nitroreduction by cytochrome P450 enzymes, particularly CYP2C19 and to a lesser extent CYP3A4. Erythromycin, clarithromycin, ritonavir, itraconazole, ketoconazole, nefazodone, and grapefruit juice are inhibitors of CYP3A4 and can affect the metabolism of benzodiazepines. It has an elimination half-life of 19–60 hours. Peak blood concentrations of 6.5–13.5 ng/mL were usually reached within 1–2 hours following a single 2 mg oral dose of micronized clonazepam in healthy adults. In some individuals, however, peak blood concentrations were reached at 4–8 hours.
Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum. Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients. Clonazepam is largely bound to plasma proteins. Clonazepam passes through the blood–brain barrier easily, with blood and brain levels corresponding equally with each other. The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam. Comparison of Pharmacokinetics in Different Biological State DOUBLE-BLIND CLONAZEPAM VS PLACEBO IN PANIC DISORDER TREATMENT American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4Ed (DSM-IV). Washington, DC: APA, 1994. To assess the effectiveness of clonazepam, in a fixed dose (2 mg/day), compared with placebo in the treatment of panic disorder patients. METHOD: 24 panic disorder patients with agoraphobia were randomly selected. The diagnosis was obtained using the structured clinical interview for DSM-IV . All twenty-four subjects were randomly assigned to either treatment with clonazepam (2 mg/day) or placebo, during 6 weeks. Efficacy assessments included: change from baseline in the number of panic attacks; CGI scores for panic disorder; Hamilton rating scale for anxiety; and panic associated symptoms scale. Clonazepam has some atypical features in comparison with other benzodiazepines, including the demonstration of elevated serotonin levels in the brain suggesting that this drug may also act by increasing the concentration of the neurotransmitter at synaptic receptor sites.

METHOD
To participate the subjects were required to be between the ages of 18 and 55, report at least three panic attacks in the last two consecutive weeks before the first challenge test day. They should be free of psychotropic drugs for at least one week and test negative for benzodiazepines and other medications. All patients underwent a physical examination and laboratory tests to ensure they were healthy enough to participate in the study. Exclusion criteria were the existence of any current mental disorder (other than panic disorder), history of psychosis or bipolar disorder, epilepsy, pregnancy, substance abuse within the prior 6 months and major medical disorders (uncontrolled thyroid, renal, hepatic, cadiac, pulmonary, or endocrinological diseases as determined by the physical examination, vital signs, or laboratory evaluations).
RESULTS
The patients were 14 women and 10 men with a mean age (±SD) of 37 (±6,9) years. In the clonazepam group were 9 women and 5 men (mean age±SD = 37,5±6,6 years) and in the placebo group were 5 women and 5 men (mean age±SD = 36,8±7,2 years).The difference of age between the two groups was not statiscally different (t test, p=0,780). One women of the clonazepam group was excluded because she had a major depression episode. Other woman of the placebo group was dropped out in the 2nd week because she was worse. At the endpoint, only one of 9 placebo patients (11,1%) were free of panic attacks, compared with 8 of 13 (61,5%) clonazepam patients(Fisher exact test , p=0,031) (Table 1).

In the placebo and clonazepam groups the CGI in first day ("baseline") were 4,7±0,8 and 4,4±0,7, respectively. After 6 weeks of treatment with placebo and clonazepam, this scores were 3,5±1,2 and 1,5±0,8 (two-way ANOVA with Tukey test, F=13,885, df=1, p<0,05). At the end of 6 weeks PGI (patient global impression) in the clonazepam group were 2±0,87. In the placebo group this score were 3,1±1,66 (t test, p= 0,108). It was also found an important reduction in anticipatory anxiety and phobias in the clonazepam group, when compared to placebo group. The percentage of waking hours in the clonazepam group at baseline and at endpoint were 55±32,9 x 14,7±7,6. In the placebo group these scores were 51±27,6 x 40,5±25,5 (t test, p=0,037, statiscally significant). In the placebo group 3 of 9 (33.3%) patients had reduction of 50% or more in the scores of Hamilton scale. In the clonazepam group 10 of 13(76,9%) patients had reduction of 50% or more in this score (Fisher exact test, p= 0,079) showing an important reduction of anxiety in clonazepam group compared to placebo, although not statiscally significant.

The most common adverse effects associated with the use of clonazepam were neuropsychiatric events: somnolence, reported by 7 (53,8%) and ataxia, reported by 4 (30,76%) patients. Other side effects that occurred with patients of the clonazepam group were memory problems (n=2, 15,38%), dizziness (n=3, 23%), irritability (n=1), depression (n=1) and libido decrease (n=1). Six (66,6%) of the placebo group and 2 (15,38%) of the clonazepam group reported no adverse events during the 6 weeks of the study (Table 2). The objective of this study was to assess the effectiveness of clonazepam, a fixed dose (2 mg/day) for 6 weeks , compared with placebo in the treatment of panic disorder patients.
The results of the current study suggest that the administration of clonazepam reduces panic attacks and anxiety in panic disorder patients. Clonazepam was greater over placebo in the study's efficacy outcomes (panic attacks, anticipatory anxiety and phobias). Although in a small sample the results of clonazepam reducing anxiety and panic attacks are striking and statically significant, when compared over placebo. From my critical analysis and understanding of placebo vs clonazepam graph shown in my report, I fully understand that these trials provide evidence for the efficacy of clonazepam in panic disorder. The results are supported by the evidence in the writing of the therapeutic effects of clonazepam in patients with panic disorder. Despite the controversies associated with dependence and adverse events clonazepam is a useful treatment option for panic disorder.

Comparison of Two Oral Symptom-triggered Pharmacological Inpatient Treatments of Acute Alcohol Withdrawal: Clomethiazole vs. Clonazepam
Prospective observational comparison within a quality improvement project. Because of a need for extra precautions against complications such as seizures and severe respiratory complaints, patients with a history of withdrawal seizures or complications with clomethiazole in their history were automatically assigned to the clonazepam group. The remaining patients were alternately assigned either to the clonazepam group (n = 38 altogether) or the clomethiazole group (n = 36). Rescue medication could consist of adding either extra clonazepam or clomethiazole. According to the protocol, 12 patients with withdrawal seizures in their history had to be automatically assigned to the clonazepam group. There were no patients reporting previous complications with clomethiazole. Pharmacological treatment duration was 3.9 ± 2.8 days in the clomethiazole and 4.3 ± 2.6 days in the clonazepam group (P = 0.55). The entire inpatient treatment duration was 11.5 ± 9.0 days in the clomethiazole and 10.2 ± 7.8 days in the clonazepam group (P = 0.51

Figure 1.
Primary effectiveness measures. From baseline to the end of the pharmacological treatment, both treatments reduced the scores to all times of measure (P < 0.001). There were no statistically significant differences between the groups (P > 0.05). Pharmacological treatment duration was 3.9 ± 2.8 days in the clomethiazole and 4.3 ± 2.6 days in the clonazepam group (day end). Day mid was at 2.3 ± 1.5 (clomethiazole) and 2.4 ± 1.2 days (clonazepam group) (both P > 0.5). The study also used the MAWS used in Germany so that a comparison with the international standard scale (CIWA-Ar) was possible.

Figure 2.
Secondary effectiveness measures. Autonomic parameter throughout the first 24 h of pharmacological treatment taken from the SAB-P protocols. Between the groups arose no relevant differences. There developed also no statistically relevant increase in each treatment group indicating smooth and balanced medication handling by nurse staff (all P > 0.1). Mean pulse pressure above 55 mmHg or an increase above 10% should increase the risk of cardiovascular complications * Udo Bonnet, Maresa Lensing, Michael Specka, Norbert Scherbau, Alcohol Alcohol. 2011;46(1):68-73. * Daeppen et al., 2002; Holbrook et al., 1999; Kumar et al., 2009; Mayo-Smith, 1997; Ntais et al., 2005

From what I comprehend and be fully aware of, there were no significant differences between the treatments with respect to primary and secondary effectiveness measures, safety or tolerability or duration of medication treatment. Both reduced the severity of initial withdrawal symptoms below 20% up to the ending of withdrawal medications. No withdrawal seizure or delirium occurred. Both score-driven treatments were equally effective, safe and well tolerated in this setting. This is the first study demonstrating the utility of clonazepam in the treatment of AWS syndrome. We hypothesize that this prospective comparative study shows that score-driven clomethiazole and clonazepam were (i) equally effective in the treatment of acute AWS and (ii) safe and well tolerated under simple precautions. If those patients with epileptic seizures under clomethiazole in their history were excluded in a second analysis, there are still no differences between the treatment groups Adverse Effects Drowsiness Euphoria

Anterograde Amnesia

Thrombocytopenia Ataxia

Lorazepam
Background and General Information
Lorazepam's effects are of intermediate duration. Similar to other benzodiazepines, it exerts its therapeutic effects via its interaction at benzodiazepine binding sites, which are located on GABAA receptors in the central nervous system. Although its half-life is shorter than that of other benzodiazepines, its affinity for its receptor translates to a longer duration of action relative to other benzodiazepines, but still shorter than those of diazepam and chlordiazepoxide following a single IV administration. Mechanism of Action
Lorazepam has strong sedative/hypnotic effects, and the duration of clinical effects from a single dose makes it an appropriate choice for the short-term treatment of insomnia, in particular in the presence of severe anxiety. It has a fairly short duration of action.[20] Withdrawal symptoms, including rebound insomnia and rebound anxiety, may occur after only seven days' administration of lorazepam. Lorazepam is sometimes used for individuals receiving mechanical ventilation. However, in critically ill patients, propofol has been found to be superior to lorazepam both in effectiveness and overall cost; as a result, the use of propofol for this indication is now encouraged, whereas the use of lorazepam is discouraged.
Its relatively potent amnesic effect, with its anxiolytic and sedative effects, makes lorazepam useful as premedication. It is given before a general anaesthetic to reduce the amount of anaesthetic agent required, or before unpleasant awake procedures, such as in dentistry or endoscopies, to reduce anxiety, to increase compliance, and to induce amnesia for the procedure. Oral lorazepam is given 90 to 120 minutes before procedures, and intravenous lorazepam as late as 10 minutes before procedures. Lorazepam is sometimes used as an alternative to midazolam in palliative sedation. In intensive care units lorazepam is sometimes used to produce anxiolysis, hypnosis, and amnesia. Intravenous diazepam or lorazepam are first-line treatments for convulsive status epilepticus. Lorazepam is more effective than diazepam in the treatment of status epilepticus. However, phenobarbital has a superior success rate compared to lorazepam and other drugs, at least in the elderly.

Pharmacokinetics Lorazepam is highly protein bound and is extensively metabolised into pharmacologically inactive metabolites. Due to its poor lipid solubility, lorazepam is absorbed relatively slowly by mouth and is unsuitable for rectal administration. However, its poor lipid solubility and high degree of protein binding (85-90%) mean its volume of distribution is mainly the vascular compartment, causing relatively prolonged peak effects. This contrasts with the highly lipid-soluble diazepam, which, although rapidly absorbed orally or rectally, soon redistributes from the serum to other parts of the body, in particular body fat. This explains why one lorazepam dose, despite its shorter serum half-life, has more prolonged peak effects than an equivalent diazepam dose. Ativan (lorazepam) is rapidly conjugated at its 3-hydroxy group into lorazepam glucuronide which is then excreted in the urine. Lorazepam glu-curonide has no demonstrable CNS activity in animals. The plasma levels of lorazepam are proportional to the dose given. There is no evidence of accumulation of lorazepam on administration up to six months. On regular administration, diazepam will accumulate, since it has a longer half-life and active metabolites, these metabolites also have long half-lives. Comparison of Pharmacokinetics in Different Biological State
Acute Tubular Necrosis Associated With Propylene Glycol From Concomitant Administration of Intravenous Lorazepam and Trimethoprim-Sulfamethoxazole Marybeth Hayman, Pharm.D., Edward C. Seidl, Pharm.D., Median Ali, M.D., Khalid Malik, M.D., FCCP
A 46-year-old obese (208 kg) Caucasian man with increasing shortness of breath was transferred directly from his primary care physician's office to the emergency department. Two days earlier, he began to experience a productive cough with yellow sputum, chest tightness, and wheezing. His medical history was notable for asthma, morbid obesity, and an unclear history of narcolepsy, perhaps associated with sleep apnea. He took no drugs and reported no known drug allergies. He did report smoking 1.5 packs of cigarettes/day.
On admission, the patient had a temperature of 38.5°C, heart rate 95 beats/minute, respiratory rate 20 breaths/minute, and blood pressure 146/59 mm Hg. Laboratory tests revealed a white blood cell count of 11 x 103/mm3 (normal range 4.4-11.3 x 103/mm3) with 77.5% neutrophils, 12.9% lymphocytes, 8.7% monocytes, 0.6% eosinophils, 0.3% basophils, and zero bands. Serum electrolytes were within normal limits, blood glucose was 182 mg/dl (70-110 mg/dl), and baseline blood urea nitrogen (BUN) and serum creatinine were 15 mg/dl (7-26 mg/dl) and 0.8 mg/dl (0.7-1.5 mg/dl), respectively. Breathing treatments with albuterol and ipratropium were administered, along with intravenous methylprednisolone 40 mg every 8 hours, and propofol was given for sedation. Clindamycin, azithromycin, and cefotaxime were administered to provide coverage for both community-acquired pneumonia and possible aspiration during intubation.
Over the next 5 days, the patient continued to deteriorate with increasing oxygen requirements. Blood, urine, and sputum cultures remained negative, and an angiographic study ruled out pulmonary embolism. The methylprednisolone dosage was increased to 125 mg every 8 hours. Despite aggressive medical management, there was no change in the patient's pulmonary examination.
On day 6, the patient still required a high fraction of inspired oxygen, and he developed diffuse pulmonary infiltrates consistent with acute respiratory distress syndrome. Despite fulminant respiratory failure, he remained hemodynamically stable with normal electrolytes and normal hepatic and renal function.
On day 7, tracheostomy and bronchoscopy were performed. On the evening of day 8, the patient was given an intravenous bolus of lorazepam 6 mg, along with continuous-infusion lorazepam at 4 mg/hour. The lorazepam dosage was titrated to a sedative effect, and propofol was titrated down. On day 9, an infectious diseases specialist was consulted. The patient's therapy was then changed from empiric antimicrobial therapy to scheduled imipenem and a single dose of tobramycin in order to cover ventilator-associated pneumonia pathogens. Over the next 3 days, the patient became increasingly febrile (temperature 40°C) and developed a white blood cell count of 20.5 x 103/mm3 (80% neutrophils, 1% bands). A bronchial wash specimen grew Stenotrophomonas maltophilia and Acinetobacter calcoaceticus. Laboratory data collected on day 13 revealed mild elevations in serum osmolality (312 mOsm/kg [normal range 270-290 mOsm/kg]), lactic acid 2.8 mmol/L (0.5-2.2 mmol/L), and serum glucose 334 mg/dl. Renal and hepatic functions were within normal limits, with serum creatinine 0.8 mg/dl and total bilirubin 0.8 mg/dl (0.2-1.2 mg/dl). On day 14, steroid therapy and an infectious process were thought to be contributing to the patient's hyperglycemia. To ensure tighter blood glucose control, continuous-infusion insulin was started with regular insulin at 5 U/hour, and antibiotic therapy was tailored to intravenous levofloxacin 500 mg/day plus intravenous trimethoprim 320 mg-sulfamethoxazole 1600 mg every 6 hours.
On day 17, 9 days after the start of continuous-infusion lorazepam and 3 days after the start of intravenous trimethoprim-sulfamethoxazole, laboratory tests revealed sudden, severe changes: a rise in serum creatinine to 3.1 mg/dl (Figure 1), nonoliguric renal failure, and marked metabolic acidosis. A nephrologist was consulted. The calculated fractional excretion of sodium was 0.47%. Urinalysis was negative for glucose, ketones, protein, nitrites, and leukocyte esterase. Renal sonography revealed a normal right kidney without hydronephrosis, echogenic stones, or perinephric collections. Figure 1: The amount of propylene glycol infused and the patient's serum creatinine levels during his hospital course after intravenous lorazepam was started on day 8. TMP-SMX = trimethoprim-sulfamethoxazole.
On day 18, trimethoprim-sulfamethoxazole was discontinued; continuous venovenous hemofiltration was started that evening. Morning laboratory data collected on day 19 revealed hyperosmolality, serum osmolality 346 mOsm/kg, sodium 140 mEq/L (normal range 135-145 mEq/L), BUN 128 mg/dl, glucose 284 mg/dl, mild hyperlactatemia (serum lactate 2.4 mmol/L), serum propylene glycol level 30 mg/dl, and an osmol gap of 15. These laboratory data were collected simultaneously, and the osmol gap (the difference between measured and estimated osmolalities) was calculated using the following equation: (1.86 x serum sodium [mEq/L]) + (glucose [mg/dl]/18) + (BUN [mg/dl]/2.8) + 9. Evidence suggests that patients with reduced renal function may be at heightened risk for propylene glycol-related toxicities. A prospective study addressed the influence of renal function on propylene glycol elimination. It found that impaired renal function seemed to exaggerate the toxic effects of propylene glycol. It is reasonable to assume that patients with intravascular depletion, diabetic nephropathy, or longstanding hypertension may be more sensitive than other patients to the microcellular tubule effects of propylene glycol.

Adverse Effects Adverse effects can include sedation and hypotension; the effects of lorazepam are increased in combination with other CNS depressant drugs. Other adverse effects include confusion, ataxia, anterograde amnesia and hangover effects. With long-term use of benzodiazepines, it is unclear whether cognitive impairments fully return to normal after cessation of therapy; cognitive deficits persist for at least six months after withdrawal, but longer than six months may be required for recovery of cognitive function. Lorazepam appears to have more profound adverse effects on memory than other benzodiazepines; it impairs both explicit and implicit memory. In the elderly, falls may occur as a result of benzodiazepines. Adverse effects are more common in the elderly, and they appear at lower doses than in younger patients. Benzodiazepines can cause or worsen depression. Paradoxical effects can also occur, such as worsening of seizures, or paradoxical excitement; paradoxical excitement is more likely to occur in the elderly, children, those with a history of alcohol abuse and in people with a history of aggression or anger problems. Lorazepam's effects are dose-dependent, meaning the higher the dose, the stronger the effects (and side effects) will be. Using the smallest dose needed to achieve desired effects lessens the risk of adverse effects. Any of the five intrinsic benzodiazepine effects possessed by lorazepam (sedative/hypnotic, muscle relaxant, anxiolytic, amnesic, and anticonvulsant) may be considered as adverse or side effects if unwanted: Sedative/Hypnotic Muscle Relaxant

Anxiolytic

Overdose In cases of a suspected lorazepam overdose, it is important to establish whether the patient is a regular user of lorazepam or other benzodiazepines, since regular use causes tolerance to develop. Also, one must ascertain whether other drugs were also ingested. Signs of overdose range through mental confusion, dysarthria, paradoxical reactions, drowsiness, hypotonia, ataxia, hypotension, hypnotic state, coma, cardiovascular depression, respiratory depression, and death.

Dysarthria

Heart Depression

Conclusion & Discussion After discussing about 3 drugs, we finally concluded that each drugs have respective effects on human body. Such results compelling to one other is something to consider as a matter of fact that it shows idea of the 3 drugs I mentioned above. We all know that each 3 drugs are all belong to benzodiazepine and all of it has their key important roles. In this discussion, I will summarize all 3 drugs and its comparison between healthy patients and result.
We all know that diazepam is a benzodiazepine drug that affects the chemical of the brain. It is used to relieve anxiety, muscle spasms, and seizures and to control agitation caused by alcohol withdrawal. The comparison I made for diazepam is between midazolam apply to intramuscular muscle. We found that midazolam spend less time absorbing plasma concentration than diazepam and also lorazepam. Another research I found is diazepam following renal administration in healthy patient. My analysis is that the use of Diastat shows that Diazepam with less amount of mg has the highest amount of plasma concentration with the extend of 8 hours.
Clonarazepam is the 2nd drug I have chosen for this research is used to treat seizure disorders or panic disorder. It works by decreasing abnormal electrical activity in the brain. In clonarazepam, I did 2 comparisons. The first is double-blinded clonarazepam vs placebo in panic disorder. Somnolence has the highest percentage 53.8% and ataxia with 30.76% in patients with treatment in panic disorder. The second one is Comparison of Two Oral Symptom-triggered Pharmacological Inpatient Treatments of Acute Alcohol Withdrawal: Clomethiazole vs. Clonazepam. From the looking of the graph, both treatment shows that they have such equivalent results. It may not be exactly the same but having a similar effect of AWS in patient is something to be consider about.
Lorazepam, the last benzodiazepine drug being selected in my research has the tendency to treat anxiety disorders. It works by slowing activity in the brain to allow for relaxation. The contrast and assessment of lorazepam research is Acute Tubular Necrosis Associated With Propylene Glycol From Concomitant Administration of Intravenous Lorazepam and Trimethoprim-Sulfamethoxazole. In this experiment, The lorazepam infusion was changed to continuous-infusion midazolam, and continuous venovenous hemofiltration was continued. Five days later, on day 24, the patient died from hypoxic respiratory failure. Renal biopsy showed disturbed brush borders of the proximal renal tubules, consistent with resolving ATN. I hope you will find this report intriguing and interesting for you to understand. I am grateful that you have given me this report so that I can further my knowledge on understanding about pharmacology. Thank you. References and Source 1. Cloyd JC, Lalonde RL, Beniak TE, Novack GD. A single-blind, crossover comparison of the pharmacokinetics and cognitive effects of a new diazepam rectal gel with intravenous diazepam.Epilepsia. 1998;39:520-526.

2. Moolenaar F, Bakker S, Visser J, Huizinga T. Biopharmaceutics of rectal administration of drugs in man IX. Comparative biopharmaceutics of diazepam after single rectal, oral, intramuscular and intravenous administration in man. Int J Pharmaceut. 1980;5:127-137.

3. DIASTAT AcuDial package insert. Aliso Viejo,Calif: Valeant Pharmaceuticals NA; Nov 2006.

4. Cereghino J, Cloyd J, Kuzniecky R; for the North American Diastat Study Group. Rectal Diazepam Gel for Treatment of Acute Repetitive Seizures in Adults. Arch Neurol. 2002; 59: 1915-1920.

5. Dreifuss FE,Rosman NP, Cloyd JC, et al. A comparison of rectal diazepam gel and placebo for acute repetitive seizures. N Engl J Med.1998;338:1869-1875.

6. Hung, Dyck, Varvel et al. Comparative absorption kinetics of intramuscular midazolam and diazepam. Can J Anaesth 1996;43:5 pp 450-5.

7. Wermeling, Archer, Manaligod et al. Bioavailability and pharmacokinetics of lorazepam after intranasal, intravenous, and intramuscular administration. J Clin Pharmacol 2001;41:1225-1231.

8. Nobay, Simon, Levitt et al. A Prospective, Double-blind, Randomized Trial of Midazolam versus Haloperidol versus Lorazepam in the Chemical Restraint of Violent and Severely Agitated Patients. Acad Emerg Med 2004;11:744-749.

9. Dreifuss FE; Penry JK, Rose SW, Kupferberg HJ, Dyken P, Sato S (March 1975). "Serum clonazepam concentrations in children with absence seizures". Neurology 25 (3): 255–8. doi:10.1212/WNL.25.3.255. PMID 1089913

10. Riss, J.; Cloyd, J.; Gates, J.; Collins, S. (Aug 2008). "Benzodiazepines in epilepsy: pharmacology and pharmacokinetics." (PDF). Acta Neurol Scand 118 (2): 69–86. doi:10.1111/j.1600-0404.2008.01004.x. PMID 18384456.

11. Curtin F, Schulz P (2004). "Clonazepam and lorazepam in acute mania: a Bayesian meta-analysis". J Affect Disord 78 (3): 201–8. doi:10.1016/S0165-0327(02)00317-8. PMID 15013244.

12. Adjeroud, S; Tonon, Mc; Leneveu, E; Lamacz, M; Danger, Jm; Gouteux, L; Cazin, L; Vaudry, H (May 1987). "The benzodiazepine agonist clonazepam potentiates the effects of gamma-aminobutyric acid on alpha-MSH release from neurointermediate lobes in vitro". Life Sciences 40 (19): 1881–7. doi:10.1016/0024-3205(87)90046-4. PMID 3033417

13. Greenblatt DJ, Shader RI, Franke K, Maclaughlin DS, Harmatz JS, Allen MD, Werner A, Woo E (1991). "Pharmacokinetics and bioavailability of intravenous, intramuscular, and oral lorazepam in humans". Journal of Pharmaceutical Sciences 68 (1): 57–63. doi:10.1002/jps.2600680119. PMID 31453.

14. Kemper N, Poser W, Poser S (1980). "Benzodiazepin-Abhängigkeit: Suchtpotential der Benzodiazepine grösser als bisher angenommen" [Benzodiazepine dependence: addiction potential of the benzodiazepines is greater than previously assumed]. Deutsche Medizinische Wochenschrift (in German) 105 (49): 1707–1712. doi:10.1055/s-2008-1070941. PMID 7439058.

15. http://en.wikipedia.org/wiki/Clonazepam

16. http://en.wikipedia.org/wiki/Diazepam

17. http://en.wikipedia.org/wiki/Lorazepam

18. http://www.medicinenet.com/diazepam/article.htm

19. http://www.everydayhealth.com/drugs/diazepam

20. http://www.netdoctor.co.uk/depression/medicines/diazepam.html

21. http://www.rxlist.com/diazepam-injection-drug/warnings-precautions.htm

22. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3016

23. http://www.rxlist.com/klonopin-drug.html

24. http://www.medicinenet.com/clonazepam/article.htm

25. http://www.rxlist.com/ativan-drug.htm

26. http://www.medicinenet.com/lorazepam/article.htm

27. http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682053.html

28. http://www.news-medical.net/drugs/APO-Lorazepam.aspx