Anesthetics development

Kharasch ED, Schroeder JL, Liggitt EID, Park SB, Whittington D, Sheffels P. New insights into the mechanism of methoxyflurane nephrotoxicity and implications for anesthetic development (part 1) Identification of the nephrotoxic metabolic pathway. Anesthesiology 2006 105(4) 726-36. 

Ziconotide, a novel non-opioid, non-local anesthetic, developed for the treatment of severe chronic pain. Ziconotide CK GKGAKCSR LMYDCCTGSC RSGKCa (disulfide bonds C -C, C -C , also previously referred to as Prialt , Cl 1009, or SNX-111, is the synthetic equivalent of the cone snail peptide... 

Procaine (its hydrochloride is marketed as Novocaine ) was one of the first local anesthetics developed for infiltration and regional anesthesia. It is synthesized by the following Fischer esterification ... 

Nitrous Oxide. Nitrous oxide, described by Priesdy in 1772, was first used to reHeve severe dental pain in the latter part of the 18th century. Sometime in the mid-1800s N2O was successfully used as an anesthetic, and its widespread usage coincided with the development of anesthesia machines. Nitrous oxide is a nonflammable, colorless, odorless, and tasteless gas that can exist as a Hquid under pressure at room temperature. It is normally stored in cylinders. However, it supports combustion. 

Anesthetic Agents Under Development. Ropivacaine (AL-381) (22, R = similar in stmcture to mepivacaine and bupivacaine, has... 

The NF and reagent grades are employed in the pharmaceutical industry which makes use of benzyl alcohol s local anesthetic, antiseptic, and solvent properties (17—20). It also finds use in cough symps and drops ophthalmic solutions bum, dental (21), and insect repeUant solutions and ointments and dermatological aerosol sprays. It is used in nail lacquers and as a color developer in hair dyes by the cosmetics industry (22), and in acne treatment preparations (23). 

The Class I antiarrhythmic agents inactivate the fast sodium channel, thereby slowing the movement of Na" across the cell membrane (1,2). This is reflected as a decrease in the rate of development of phase 0 (upstroke) depolarization of the action potential (1,2). The Class I agents have potent local anesthetic effects. These compounds have been further subdivided into Classes lA, IB, and IC based on recovery time from blockade of sodium channels (11). Class IB agents have the shortest recovery times (t1 ) Class lA compounds have moderate recovery times (t 2 usually <9 s) and Class IC have the longest recovery times (t 2 usually >9 s). 

Special containers have been developed for anesthetic ether to prevent deterioration before use. Their effectiveness as stabHizers usuaHy depends on the presence of a lower oxide of a metal having more than one oxidation state. Thus the sides and the bottoms of tin-plate containers are electroplated with copper, which contains a smaH amount of cuprous oxide. Staimous oxide is also used in the linings for tin containers. Instead of using special containers, iron wire or certain other metals and aHoys or organic compounds have been added to ether to stabHize it. 

The line of reasoning that leads from morphine to the 4-phenyl-piperidines is so clear—if unhistoric—as to demand exposition in an integral chapter. The chronologically oriented chapter on the development of the local anesthetics is included specifically to give the reader some appreciation of one of the first approaches to drug development. 

Not all MH susceptible patients experience a crisis with their first anesthetic. A susceptible patient can have one or more uneventful anesthetics and develop the MH crises during subsequent anesthetics. Mortality from MH was 90% in the early years, came down to 70% n 1975 and it was estimated to be 7% in 1980 and has remained relatively stable through the 1980s. 

Phencyclidine (l-[l-phenylcyclohexyl] piperidine, PCP) was originally developed as an intravenous anesthetic in the 1950s. Used for this indication, it causes a trance-like state without loss of consciousness and was hence classified as a dissociative anesthetic. However, it was soon withdrawn from human use because it produced unpleasant hallucinations, agitation, and delirium. The product was later used in veterinary medicine. Ketamine, a chemically closely related substance, was developed to replace PCP and is stiU in use as a dissociative anesthetic in children. Ketamine is less potent than PCP, and its effects are of shorter duration. However, it may also cause hallucinations (see the section on ketamine in Chapter 7, Club Drugs ). Much of the ketamine sold on the street (special K, cat Valium) has been diverted from veterinarians offices. 

Ketamine is a cyclohexane human and veterinary injectable anesthetic that is also known by the slang names K, special K, vitamin K, and cat Valium (Bobo and Miller 2002). It is produced in a liquid form or as a white powder and is usually ingested orally or intranasally but is occasionally administered intramuscularly. Ketamine is a phencyclidine (PCP) analog that was first developed in 1962. 

Studies of the intoxicating effects of toluene showed that the inhalation of its vapor at a concentration of 200 ppm was associated with the development of mild-to-moderate intoxication, characterized by sedation, paresthesias, and hyporeflexia. Toluene vapor concentrations of 600-800 ppm induced a confusional state, whereas greater concentrations produced an intense euphoria (Benignus 1981 Press and Done 1967). In humans, plasma concentrations of toluene of 10-100 pM have been reported to be intoxicating these concentrations are close to the intoxicating concentrations of alcohol and in-halational anesthetics (Miller 1985). 

Is the development of ultrashort-acting (less abused) PCP derivatives that are good anesthetics and analgesics with very little respiratory depression possible ... 

Although PCP was developed as an anesthetic, its profile as an anesthetic is very different from typical general anesthetics of the CNS-depressant class (Domino 1964). Nonetheless, PCP has a number of behavioral and pharmacological effects similar to those of depressants such as the barbiturates (Balster and Wessinger 1983). PCP has profound motor effects, as evidenced by effects on rotorod performance and similar measures (Kalir et al. 1969 ... 

Phencyclidine (PCP), one of the arylcyclohexylamines. was developed and originally used as a general anesthetic for humans. Due to psychotic and hallucinogenic reactions, use of the drug for humans was discontinued. It is now used legally only in veterinary medicine as an animal immobilizing agent. 

Examples abound regarding the role of serendipity in the discovery of new therapeutic approaches, which on closer examination usually turned out to be the result of clinicians paying attention to unexpected clinical effects rather than discounting them. For example, lithium was tried first for hypertension, chlorpro-mazine was initially developed as an anesthetic, and imipramine was originally regarded as an antihistamine and an antipsychotic agent. Without astute clinical observations, these drugs would not have found their niche, nor would clozapine have been revived for the benefit of millions of the most difficult to treat schizophrenic patients. Other examples include the expanded indications of newer... 

Very few injectable dosage forms have been specifically developed and approved by FDA for intraocular use. However, the ophthalmologist uses available parenteral dosage forms to deliver antiinfectives, corti-costerioids, and anesthetic products to achieve higher therapeutic concentrations intraocularly than can ordinarily be achieved by topical or systemic administration. These unapproved or off-label uses have developed over time as part of the physician s practice of medicine. However, these drugs are usually administered by subconjunctival or retrobulbar injection and rarely are they injected directly in the eye [301]. 

The ion-channel blocking mechanism has been widely tested and found to be important in both pharmacology and physiology. Examples are the block of nerve and cardiac sodium channels by local anesthetics, or block of NMDA receptor channels by Mg2+ and the anesthetic ketamine. The channel-block mechanism was first used quantitatively to describe block of the squid axon K+ current by tetraethylammonium (TEA) ions. The effects of channel blockers on synaptic potentials and synaptic currents were investigated, particularly at the neuromuscular junction, and the development of the single-channel recording technique allowed channel blockages to be observed directly for the first time. 

One of the first pharmacological classes to be studied by medicinal chemists was local anesthetics. Many of the guiding principles which are used to this day, for example, molecular dissection, side chain substitution and inversion, and the like, were first developed in the course of those early researches. 

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