Synthesis of Essential Drugs

Ruben Vardanyan, Victor Hruby

• Publisher: Elsevier Science
• Year: 2006
• ISBN:
  9780080462127
• Topic: Medicina
• Subtopic: Farmacología

Synthesis of Essential Drugs describes methods of synthesis, activity and implementation of diversity of all drug types and classes. With over 2300 references, mainly patent, for the methods of synthesis for over 700 drugs, along with the most widespread synonyms for these drugs, this book fills the gap that exists in the literature of drug synthesis. It provides the kind of information that will be of interest to those who work, or plan to begin work, in the areas of biologically active compounds and the synthesis of medicinal drugs.

This book presents the synthesis of various groups of drugs in an order similar to that traditionally presented in a pharmacology curriculum. This was done with a very specific goal in mind – to harmonize the chemical aspects with the pharmacology curriculum in a manner useful to chemists. Practically every chapter begins with an accepted brief definition and description of a particular group of drugs, proposes their classification, and briefly explains the present model of their action. This is followed by a detailed discussion of methods for their synthesis. Of the thousands of drugs existing on the pharmaceutical market, the book mainly covers generic drugs that are included in the WHO's Essential List of Drugs. For practically all of the 700+ drugs described in the book, references (around 2350) to the methods of their synthesis are given along with the most widespread synonyms.

Synthesis of Essential Drugs is an excellent handbook for chemists, biochemists, medicinal chemists, pharmacists, pharmacologists, scientists, professionals, students, university libraries, researchers, medical doctors and students, and professionals working in medicinal chemistry.

* Provides a brief description of methods of synthesis, activity and implementation of all drug types* Includes synonyms* Includes over 2300 references

1

General Anesthetics

Publisher Summary

In surgical practice, the term general anesthesia (narcosis) presently refers to the condition of an organism with a reversible loss of consciousness at a controlled level of nervous system suppression. It includes components such as analgesia (absence of pain), amnesia (absence of memory), and suppression of reflexes such as bradycardia, laryngospasm, and loss of skeletal muscle tonicity. In modern medical practice, general anesthesia is a complex procedure involving preanesthetic assessment, administration of general anesthetic drugs, cardiorespiratory monitoring, analgesia, airway management, and fluid management. General anesthetics are divided into two types such as inhalation anesthetics that include halothane, enflurane, isoflurane, methoxyflurane, and nitrous oxide, and noninhalation, intravenous such as barbiturates, ketamine, and etomidate. The objective of inhalation anesthetics is to obtain a concentration (partial pressure) of the drug in the brain sufficient to reach the desired level of anesthesia. In order to do this, anesthetic molecules must pass through the lungs into the brain through various biological phases. During noninhalation anesthesia, control and regulation during the procedure is significantly harder to accomplish than that with inhalation anesthesia.

In surgical practice, the term general anesthesia (narcosis) presently refers to the condition of an organism with a reversible loss of consciousness at a controlled level of nervous system suppression. It includes the following components: analgesia (absence of pain), amnesia (absence of memory), suppression of reflexes such as bradycardia, laryngospasm, and loss of skeletal muscle tonicity.

In modern medical practice, general anesthesia is a complex procedure involving preanesthetic assessment, administration of general anesthetic drugs, cardiorespiratory monitoring, analgesia, airway management, and fluid management.

Accordingly, general anesthetics are drugs that provide relief of pain, weaken the reflex and muscle activity, and ultimately result in loss of consciousness. The ideal anesthetic must include the aforementioned characteristics, as well as to have a wide range of therapeutic index and to have no significant side effects. Drugs used in anesthesiology, block or suppress neurological impulses mediated by the central nervous system, and permit surgical, obstetric, and diagnostic procedures to be completed painlessly. General anesthetics are divided into two types—inhalation (halothane, enflurane, isoflurane, methoxyflurane, and nitrous oxide), and noninhalation, intravenous (barbiturates, ketamine, and etomidate).

1.1 INHALATION ANESTHETICS

The object of inhalation anesthetics is to obtain a concentration (partial pressure) of the drug in the brain sufficient to reach the desired level of anesthesia. In order to do this, anesthetic molecules must pass through the lungs into the brain through various biological phases. Therefore, inhalation anesthetics must be soluble in blood and interstitial tissue.

The wide variation in structure, ranging from complex steroids to the inert monatomic gas xenon, led to several theories of anesthetic action. The mechanism by which inhalation anesthetics manifest their effect is not exactly known. Since they do not belong to one chemical class of compounds, the correlations between structure and activity are also not known. Inhalation anesthetics are nonspecific and therefore there are not specific antagonists. Interaction of inhalation anesthetics with cellular structures can only be described as van der Waals interactions. There are a number of hypotheses that have been advanced to explain the action of inhalation anesthetics; however, none of them can adequately describe the entire spectrum of effects caused by inhalation anesthetics.

The action of general anesthetics can be explained as a blockage of ion channels, or as specific changes in mechanisms of the release of neurotransmitters. Three of the proposed mechanisms are mentioned below.

1. Hydrate hypothesis: Anesthetic molecules can form hydrates with structured water, which can stop brain function in corresponding areas. However, the correlation between the ability to form hydrates and the activity of inhalation anesthetics is not known.

2. Ion channel hypothesis: Anesthetics block ion channels by interacting with cellular membranes and reducing the flow of Na⁺ ions and increasing the flow of K⁺ ions into the cell, which leads to the development of anesthesia.

3. Fluid membrane hypothesis: Anesthetics stabilize, or rather immobilize the cell membrane, hampering membrane fluidity, which produces changes in the ion channel action.

Selection of a specific anesthetic or combination of anesthetics is made depending on the type of medical intervention. For a long time, ether, chloroform, tricholoroethylene, ethyl chloride or chloretane, and also cyclopropane were widely used as inhalation anesthetics. Today, the following anesthetics are used most regularly in medicine: halothane, enflurane, isoflurane, metoxyflurane, and nitrous oxide. Researchers are also actively exploring the use of xenon as an anesthetic.

Halothane

Halothane, 2-bromo-2-chloro-1,1,1-trifluorethane (1.1.2), is made by the addition of hydrogen fluoride to tricholoroethylene and simultaneous substitution of chlorine atoms in the presence of antimony(III) chloride at 130 °C. The resulting 2-chloro-1,1,1-trifluorethane (1.1.1) undergoes further bromination at 450 °C to form halothane [1–3].

Halothane is a modern and widely used inhalation anesthetic. It begins to act very quickly, which is pleasing to patients, and it is very safe. The only drawback to using it is its hepatotoxicity. It is used in both short and long-lasting surgical operations. The most common synonym of halothane is fluothane.

Enflurane

Enflurane, 2-chloro-1,1,2-trifluoroethyldifluoromethyl ether (1.1.4), is synthesized by chlorinating in light 2-chloro-1,1,2-trifluoroethylmethyl ether to give 2-chloro-1,1,2-trifluoroethyldichloromethyl ether (1.1.3), followed by substitution of chlorine atoms by fluorine on the dichloromethyl group using hydrogen fluoride in the presence of antimony(III) chloride, or by using antimony(III) fluoride with antimony(V) chloride [4,5].

Enflurane has practically all the same characteristics as halothane and is used in the same situations. It is poorly absorbed. It is also prescribed under the name ethrane.

Isoflurane

Isoflurane, 2-chloro-2-(difluoromethoxy)-1,1,1-trifluorethane (1.1.8), is synthesized from 2,2,2-trifluoroethanol. 2,2,2-Trifluoroethanol is first methylated by dimethylsulfate. The resulting methyl ether (1.1.5) undergoes chlorination by molecular chlorine to give 2-(dichloromethoxy)-1,1,1-trifluoroethane (1.1.6). In the subsequent interaction (1.1.6) with hydrogen fluoride in the presence of antimony(V) chloride, chlorine atoms are ultimately replaced by fluorine atoms. The resulting ether (1.1.7) again undergoes chlorination by molecular chlorine to give isoflurane [6,7].

In terms of action, isoflurane is analogous to enflurane; howe...