Drug Discovery And Development: The Development Of Diazepam As An Anxiolytic - Essay Example

Drug Discovery and Development: The Development of diazepam as an anxiolytic” How the drug was developed and stages of development Leo Sternbach a worker at Hoffmann-La Roche synthesized benzodiazepine, chlordiazepoxide (Librium) in 1955 while working for the formulation of tranquilizers. In the initial stages the pharmacological properties of the compounds were unsatisfactory and the project was stopped by Sternbach. After around two years, in April 1957, Earl Reeder one of the co-workers noticed a “crystalline” compound left over from the ceased project when he was cleaning spring in the laboratory. The “crystalline” compound was called chlordiazepoxide. The compound when tested showed various effects like strong sedative, anticonvulsant and muscle relaxant. Later, diazepam was marketed in 1963 by Hoffmann–La Roche under the trade name Valium. Thus two drugs emerged as the most successful commercially available drugs revolutionizing the science of anti-anxiolytic drugs. By the year 1970s they potentially replaced older drugs for sedative and hypnotic uses (Shorter, 2005). Sites and mechanism of Action Diazepam belongs to benzodiazepine group. Diazepam acts on ascending reticular formation (responsible for wakefulness) in midbrain and on limbic system (responsible for thought). Muscle relaxation is produced by primary medullary site of action and ataxia is due to action on cerebellum (Tripathi, 2008; Rang & Dale, 2007; Brunton, 2005). Diazepam binds to benzodiazepine binding site on GABAA receptor Cl- channel complex. GABAA receptor is a pentameric structure (like a lily flower). It contains many sub-units and encloses Cl- channel. The opening of Cl- channel is modulated by GABA. Diazepam by binding to benzodiazepine binding site (α/γ subunit interface) facilitates GABA action (more amount of GABA will bind to GABAA receptor). It is not a GABA mimetic, it only facilitates GABA mediated Cl- channel opening. Opening of Cl- channel causes influx of Cl- ions and causes hyperpolarization. This decreases the firing rate of neurons. Therefore it possesses hypnotic action- induction of sleep- reticular activating system- depresses CNS- decreases the spread of epileptic discharge, therefore possesses anticonvulsant action (Tripathi, 2008; Rang & Dale, 2007; Brunton, 2005). It is therefore a DOC (Drug of Choice) in status epilepticus and other convulsive disorders. By acting on limbic system it induces anxiolytic action. A diagram depicting GABAA-benzodiazepine receptor-chloride channel complex The chloride channel is gated by the primary ligand GABA acting on GABAA receptor located on the β- subunit. The benzodiazepine (BZD) receptor located on the interface of α and γ subunits modulates GABAA receptor in either direction (Tripathi, 2008). Pharmacokinetics of the drug Oral absorption of Diazepam is good. Diazepam is widely distributed in body; absorption from intramuscular site of administration is irregular. It is 99% bound to plasma proteins. Being lipid soluble it enters blood brain barrier. It has a half life of 30- 60 hrs. It undergoes redistribution. Diazepam is metabolized in liver by dealkylation, hydroxylation to many metabolites, some of which may be active (methyl-diazepam, oxazepam). The biological half life of diazepam may be much longer than plasma half-life. Diazepam undergoes entero-hepatic circulation. Its phase I metabolites are excreted in urine as glucuronide conjugates. It crosses placenta and is secreted in milk (Depression; Tripathi, 2008). Diazepam on daily use cumulates in body and its action may be extended to next day. Diazepam has a slow elimination but marked redistribution. It is less likely to cause rebound insomnia on discontinuation of chronic use. Withdrawal phenomenon is mild. Preparation and doses- VALIUM TABLET 2, 5, 10 mg. Injection: 10 mg/ 2ml inj. (Tripathi, 2008) What does it treat and how? It is used as: Hypnotic: A hypnotic should not be casually prescribed for every case of insomnia. Understanding the cause of insomnia and use of non-pharmacological measures is initially advocated. When non-pharmacological measures fail then drugs like diazepam are used. Anxiolytic and for day time sedation. As anti-convulsion especially emergency control of status epilepticus, febrile convulsions, tetanus. Centrally acting muscle relaxant. For pre-anesthetic medication, inducing agent in IV anesthesia. Before electro-convulsive therapy, as it is muscle relaxant, it minimizes the injury. Before electrical cardio-version of arrhythmias. Before cardiac catheterization, endoscopies, in obstetrics and in many minor procedures. Diazepam IV has gained popularity because of its calming- amnesic- analgesic and muscle relaxant properties and high margin of safety. Alcohol withdrawal in dependent subjects. Along with analgesics, non-steroidal anti-inflammatory drugs, spasmolytics, anti-ulcer and many other drugs (Rang & Dale, 2007; Harvey, 2008). Side effects Diazepam is relatively a safe drug. Side effects of hypnotic doses are: Dizziness Vertigo Ataxia Disorientation Amnesia Prolonged reaction time- impairment of psycho-motor skills, should not drive. Hangover if large doses are used. Weakness Blurring of vision Dry mouth Urinary incontinence Older individuals are more susceptible to psychomotor side effects. Paradoxical stimulation Irritability and sweating Night mares Diazepam has low dependence producing liabilities Withdrawal symptoms are mild Administration during labor may cause flaccidity and respiratory depression in the neonate. Cross tolerance to alcohol and other CNS depressant drugs (Rang & Dale, 2007; Brunton, 2005). Where the drug is derived from? In the early part of 1954 at the laboratories of Hoffmann-LaRoche in Nutley, new Jersey, one of the workers Leo Sternbach thought of reinvestigating a few of the tricyclic compounds that he synthesized around 20 years back at University of Cracow during his post-doctoral findings on dyestuffs. He correlated the chlorpromazine, then discovered compound with the compounds he got during his post-doctoral years. By addition of basic side chains to his compounds he primed 40 new compounds. He submitted these compounds to Lowell Randall for screening them for a role as muscle relaxant, sedative and anti-convulsant properties. None of them were found to be active (Sneader, 2005). When investigated it was found that tricyclic system of the key synthetic intermediate was not of benhepatodiazine as was thought earlier rather of a quinazoline- 3-oxide. It is because of this a lack of biological activity was observed in the compounds derived from the intermediate. The last compound remained untested until one of his colleague found it while cleaning the laboratory after around 18 months. Sternbach agreed to get the compound tested for the activity of chlorpromazine as a tranquillizer (Sneader, 2005). The compound was found to possess low toxicity and was free from side effects. Thus this compound was biologically active. On testing its chemistry, it was found that by using primary amine methylamine in the last step of synthesis, the reaction showed a different pathway of ring enlargement. The product that resulted was benzodiazepine. Sternbach then filed a US patent for this compound in 1958. The compound was tested on 16000 patients and was then approved by US Food and Drug Administration in 1960. Since then many benzodiazepines came in existence and are used as anti-anxiety agents and hypnotics (Sneader, 2005). Structure of Diazepam Advantages and disadvantages of usage: In comparison to barbiturates: Barbiturates Diazepam 1. Low margin of safety 2. High abuse liabilities 3. Depress REM sleep so cause nightmares. Sleep is not refreshing. 4. They induce hepatic microsomal enzymes and have lot of drug- drug interaction. 5. If toxicity occurs, there is no specific antidote available 1. High margin of safety 2. Low abuse liabilities 3. REM sleep is not impaired so incidence of nightmares is less. Sleep is refreshing. 4. They do not induce microsomal enzymes. Less drug- drug interaction. 5. If toxicity occurs due to overdose a specific antidote Flumazenil is available which antagonizes the action of diazepam. (Sharma, 2008) References Brunton, L. L., Lazo, J. S., Parker, K. L. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. Publisher: McGraw- Hill Professional, 11h edition. 2005. Depression. Available at http://www.sncese.com/antianxiety-or-anxiolytic.html [Accessed on 18th March 2010]. Harvey, R. A., Champe, P. C., Finkel, R., Cubeddu, L, X., Clarke, M. A. Lippincott’s Illustrated Reviews: Pharmacology 4th Edition. Publisher: Lippincott Williams & Wilkins. 2008. Rang, H. P., Dale, M. M. Rang & Dale’s Pharmacology. Churchill Livingstone, 6th edition. 2007. Sharma, H. L., Sharma, K. K. Principle of Pharmacology. Publisher: Misc. 2008. Shorter, E. Benzodiazepines. A Historical Dictionary of Psychiatry. Oxford University Press. pp. 41–2, 2005. Sneader, W. Drug discovery: a history. Publisher: Wiley- Interscience, 1 edition. 2005. Tripathi, K. D. Essentials of Medical Pharmacology. Publisher Jaypee. 6th edition. 2008. Read More