Analytical Study of Some Drugs Used in Treatment of Cns Disorders
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ANALYTICAL STUDY OF SOME DRUGS USED IN TREATMENT OF CNS DISORDERS Thesis Presented For the Partial Fulfillment of the Degree of Master in Pharmaceutical Sciences "Analytical Chemistry” By Rowayda Mohamed Fouad Department of Raw Materials National Organization for Drug Control and Research (NODCAR) B. Pharm. Sci. Cairo University (2005) Under the Supervision of Prof. Dr. Azza Aziz Mohamed Mostafa Professor of analytical chemistry Faculty of Pharmacy, Cairo University Dr. Nesrin Khamis Ramadan Selim Ass. Prof. of analytical chemistry Faculty of Pharmacy, Cairo University Dr. Afaf Osman Mohamed Osman Ass. Prof. of Analytical Chemistry National Organization for Drug Control and Research (NODCAR) Department of Analytical Chemistry Faculty of Pharmacy Cairo University 2012 ACKNOWLEDGMENT First and foremost, thanks to ALLAH. I wish to express my sincere gratitude and profound thanks to Prof. Dr. Azza Aziz Mohamed Mostafa, Professor of Analytical Chemistry, Faculty of Pharmacy, Cairo University, for her supervision, beneficial discussion, kind guidance and continuous encouragement. My great pleasure and deep thanks to Dr. Nesrin Khamis Ramadan Selim, Associate Professor of Analytical Chemistry, Faculty of Pharmacy, Cairo university, for her kind and keen supervision, fruitful help, generous assistance, valuable advises, beneficial discussions and stimulating directions. I am deeply grateful to Dr. Afaf Osman Mohamed Osman, Associate Professor of Analytical Chemistry, National Organization for Drug Control and Research (NODCAR) for her kind guidance, valuable advices, generous assistance and continuous encouragement. My special thank and sincere appreciation and gratitude to Prof. Dr. Bothaina Abd EL-Fattah Moussa, Professor of Organic Chemistry, Faculty of Pharmacy, Cairo University, for her great effort in interpretation the I.R. and mass spectra and suggesting the expected pathway of formation of degradation products . I would to thanks all the staff members in Analytical Chemistry Department, Cairo University and Raw Material Department, NODCAR I am indebted profoundly to my husband, father, mother and Yousif my son. Rowayda Mohamed fouad . I.0. Introduction The central nervous system (CNS) directs the functions of all organs of the body. The peripheral nervous system (PNS) receives thousands of sensory inputs and transmits them to the brain via the spinal cord. After sensory information has been evaluated, selected areas of the central nervous system initiate nerve impulses to organs or tissue to make an appropriate response. Any change in the CNS, PNS or brain response cause disorder in this region. Chemical influences are capable of producing a myriad of effects on the activity and function of the CNS. Since our knowledge of different regions of brain function and the neurotransmitters in the brain is limited, the explanations for the mechanisms of drug action may be vague. The known neurotransmitters are, acetylcholine which is involved with memory and learning, norepinephrine which is involved with mania-depression and emotions and serotonin which is involved with biological rhythms, sleep, emotion, and pain (1). 1-CNS Stimulants: Stimulants are drugs that exert their action through excitation of the CNS. Psychic stimulants include caffeine, cocaine, and various amphetamines. These drugs are used to enhance mental alertness and reduce drowsiness and fatigue. However, increasing the dosage of caffeine above 200 mg (about 2 cups of coffee) does not increase mental performance but may increase nervousness, irritability, tremors, and headache. Heavy coffee drinkers become psychically dependent upon caffeine (2). 1.1. Caffeine and the chemically related xanthines, theophylline and theobromine: The action of caffeine is to block adenosine receptors as an antagonist, as caffeine has a similar structure to the adenosine group. This means that caffeine will fit adenosine receptors as well as adenosine itself. It inhibits the release of neurotransmitters from presynaptic sites but works in concert with norepinephrine or angiotensin to augment their actions. 1.2. Amphetamines: The stimulation caused by amphetamines is caused by excessive release of norepinephrine from storage sites in the peripheral nervous system. It is not known whether the same action occurs in the CNS. Two other theories for their action are that they are degraded slower than norepinephrine or that they could act on serotonin receptor sites. 1 Therapeutic doses of amphetamine elevate mood, reduce feelings of fatigue and hunger, facilitate powers of concentration, and increase the desire and capacity to carry out work. They induce exhilarating feelings of power, strength, energy, self-assertion, focus and enhanced motivation. 1.3. Cocaine: Biologically, cocaine acts as aserotonin–norepinephrine–dopamine reuptake inhibitor, also known as a triple reuptake inhibitor (TRI). The widespread recreational use of cocaine has created serious social problems. In order to achieve its effects, cocaine must cross the so-called blood-brain barrier. If antibodies are bound to the cocaine molecule, it cannot cross. This has raised the possibility of immunizing people against cocaine. 2. CNS Depressants: CNS depression refers to physiological depression of CNS that can result in decreased rate of breathing, decreased heart rate, and loss of consciousness possibly leading to coma or death. Depressants are drugs that can be used to slow down brain activity. CNS depression can also be caused by the accidental or intentional inhaling of certain volatile chemicals such as Butanone. CNS depressants may be prescribed to treat anxiety, muscle tension, pain, insomnia, acute stress reactions, panic attacks, and seizure disorders. In higher doses, some CNS depressants may be used as general anesthetics (3). There are different classes of CNS depressant drugs as antidepressant, sedative hypnotic drugs, analgesics drugs, hallucinogenic drugs and local anesthetics. 2.1. Antidepressant: Antidepressant drugs are used to restore mentally depressed patients to an improved mental status. Depression results from a deficiency of norepinephrine at receptors in the brain. Mechanisms that increase their effective concentration at the receptor sites should alleviate depression (4). Antidepressant drugs act by one or more of the following stimulation type mechanisms: Increase release of norepinephrine: Amphetamines and electroconvulsive therapy act by this mechanism. Amphetamines mimic norepinephrine. Prevent inactivation of norepinephrine: Monoamine oxidase (MAO) inhibitors are thought to act as antidepressant agents in part by preventing the breakdown and inactivation of norepinephrine. 2 Prevent the reuptake of norepinephrine: The action of norepinephrine at the receptor site is terminated by the reuptake of norepinephrine by the neuron from which it was originally released. 2.1.1. Tricyclic Antidepressants: They are the most effective drugs presently available for the treatment of depression. These act by increasing the release of norepinephrine. Amphetamine and cocaine can also act in this manner. imipramine (Tofranil) , desipramine (Norpramin) , and other closely related drugs are among the drugs currently most widely used for the treatment of major depression. All tricyclic antidepressants block the re-uptake of norepinephrine at nerve terminals. 2.1.2. Selective Serotonin re-uptake Inhibitors Serotonin (5-hydroxytryptamine or 5-HT) is a monoamine neurotransmitter found in cardiovascular tissue, in endothelial cells, in blood cells, and in CNS. The role of serotonin in neurological function is diverse, and there is little doubt that serotonin is an important CNS neurotransmitter. In recent years, selective serotonins re uptake inhibitors have been introduced for the treatment of depression. Prozac is the most famous drug in this class. 3 2.1.3. Monoamine Oxidase (MAO) Inhibitors Monoamine oxidase (MAO) causes the oxidative deamination of norephinephrine, serotonin, and other amines and reducing the concentration of the neurotransmitter after it has sent the signal at the receptor site. Most MAO inhibitors are hydrazine derivatives. Hydrazine is highly reactive and may form a strong covalent bond with MAO with consequent inhibition for up to 5 days. These drugs are less effective and produce more side effects than the tricyclic antidepressants. Thus, MAOIs are used most often when tricyclic antidepressants give unsatisfactory results. Phenelzine is the hydrazine analog of phenylethylamine, a substrate of MAO. This and several other MAOIs as isocarboxazide are structurally related to amphetamine. 2.2. Hypnotic and sedative Drugs: Hypnotic and sedative drugs are non-selective, general depressants of CNS. If the dose is relatively low, a sedative action results in a reduction in restlessness and emotional tension. A larger dose of the same drug produces a hypnotic sleep inducing effect. As the dosage is increased, the result is anesthesia or death if the dosage is sufficiently high (5). 2.2.1. Barbiturates The barbiturates once enjoyed a long period of extensive use as sedative-hypnotic drugs; however, except for a few specialized uses, they have been largely replaced by the much safer benzodiazepines. Barbiturates are CNS depressants and are similar to the depressant effects of alcohol. The original use of barbiturates was to replace drugs such as opiates, bromides, and alcohol to induce sleep. Various theories for the action of barbiturates include: changes in ion movements across the cell membrane;