Synthesis of Best-Seller Drugs

Ruben Vardanyan, Victor Hruby

• Publisher: Academic Press
• Year: 2016
• ISBN:
  9780124115248
• Topic: Medicine
• Subtopic: Pharmacology

Synthesis of Best-Seller Drugs is a key reference guide for all those involved with the design, development, and use of the best-selling drugs. Designed for ease of use, this book provides detailed information on the most popular drugs, using a practical layout arranged according to drug type.

Each chapter reviews the main drugs in each of nearly 40 key therapeutic areas, also examining their classification, novel structural features, models of action, and synthesis. Of high interest to all those who work in the captivating areas of biologically active compounds and medicinal drug synthesis, in particular medicinal chemists, biochemists, and pharmacologists, the book aims to support current research efforts, while also encouraging future developments in this important field.

• Describes methods of synthesis, bioactivity and related drugs in key therapeutic areas
• Reviews the main drugs in each of nearly 40 key therapeutic areas, also examining their classification, novel structural features, models of action, and more
• Presents a practical layout designed for use as a quick reference tool by those working in drug design, development and implementation

Chapter 1

General Anesthetics

Abstract

This chapter discusses those drugs that are used in general anesthesia, which is the state of controlled, reversible unconsciousness and loss of protective reflexes, controlled level of nervous system suppression to allow adequate surgical access, obstetric, and diagnostic procedures to be completed painlessly.

General anesthetic pharmacology is unique because so many types of molecules possess this activity, including, haloalkanes, ethers, barbiturates, quaternary ammonium salts, steroids, simple gases, and other organic compounds. General anesthetics produce a widespread neurodepression in the central nervous system by enhancing inhibitory neurotransmission and reducing excitatory neurotransmission.

Keywords

General anesthetics; Tranquilizers; Central nervous system depressants (barbiturates and hypnotic agents); Opioid analgesics; Ketamine; Muscle relaxants; Reversible acetylcholinesterase inhibitors; Inhalation anesthetics

The use of inhaled ether for surgical anesthesia was first demonstrated in 1846. Since then, the development of new safe anesthetics has contributed greatly to the advancement of surgery and other invasive procedures.

General anesthesia is the state of controlled, reversible unconsciousness and loss of protective reflexes, controlled level of nervous system suppression to allow adequate surgical access, obstetric, and diagnostic procedures to be completed painlessly. The patient receives medications for amnesia, analgesia, muscle paralysis, and sedation. Anesthesia 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 medical practice, general anesthesia is a complex procedure involving: preanesthetic assessment, administration of general anaesthetic drugs, cardiorespiratory monitoring, analgesia, airway management, and fluid management.

In a typical clinical procedure, the patient is premedicated with a sedative intended to relieve anxiety and facilitate the induction of anesthesia itself. For this purpose it is accepted to use tranquilizers, such as diazepam, lorazepam, or midazolam, or a central nervous system depressant-barbiturate such as thiopental, methohexital, or the hypnotic agent propofol. Sedation is followed by intravenous injection of an opioid analgesic such as morphine, fentanyl, alfentanil, or ketamine, which has a wide range of effects in humans, including analgesia and anesthesia. In addition, a nondepolarizing curare-like derivative like vecuronium or d-tubocurarine, or a depolarizing drug such as succinylcholine, is administered to induce muscle paralysis. After connection to artificial respiration, general anesthesia is maintained by a mixture of oxygen and nitrous oxide, often in combination with a volatile agent such as halothane, enflurane, or isoflurane. At the conclusion of the surgery, muscle relaxation is reversed by neostigmine or other anticholinesterase, and normal breathing is restored.

The ideal general anesthesia must include the aforementioned characteristics, as well as have a wide therapeutic index and no significant side effects.

The underlying neurocellular mechanisms by which the state of general anesthesia is achieved are only just beginning to be understood.

Components of general anesthesia formally are divided into two groups: noninhalation, (barbiturates, ketamine, and etomidate), and inhalation (halothane, enflurane, isoflurane, desflurane and nitrous oxide). Since the publication of our first book [1] in 2006 where the synthesis of all above mentioned drugs are described, no novel entities that address fundamentally new general anesthesia approaches have entered the clinic. That is the reason we limit discussion to the structural formulas of anesthetic agents in current clinical use.

1.1. Noninhalation Components for General Anesthesia

Tranquilizers

Benzodiazepines—diazepam (1.1.1), lorazepam (1.1.2), and midazolam (1.1.3)—which have anxiolytic, sedative, and anticonvulsant effects, and cause amnesia and muscle relaxation, are frequently used to relieve patient’s anxiety during anesthesia. (Fig. 1.1.)

Fig. 1.1 Benzodiazepines used during anesthesia.

Central Nervous System Depressants (Barbiturates and Hypnotic Agents)

Two barbiturates primarily used in surgical practice are thiopental (1.1.4) and methohexital (1.1.5). Barbiturates are hypnotics, and at therapeutic doses have a very weak analgesic and muscle relaxant effect. Intravenous injection of a therapeutic dose of propofol (1.1.6) produces hypnosis rapidly with minimal excitation, usually within 40 seconds from the start of an injection. Etomidate (1.1.7) classified as a sedative hypnotic drug because of the quick loss of consciousness upon intravenous administration. It has an anticonvulsant activity and does not display analgesic characteristics. Duration of its action depends on the administered dose. (Fig. 1.2.)

Fig. 1.2 Barbiturates and hypnotic agents used during anesthesia.

Fig. 1.3 Opioid analgesics used during anesthesia.

Opioid Analgesics

Opioid analgesics, in particular morphine (1.1.8), fentanyl (1.1.9), alfentanil (1.1.10), and sufentanil (1.1.11), are widely used in the practice of anesthesiology as adjuncts. Recently, remifentanil (1.1.12) became popular for the mainten...