History, Pharmacology und Toxicity of Localanesthetics Masterthese eingereicht bei Prof. Dr. Dr. med. Hüseyin Nazlikul vorgelegt von Krassimir Shelev Unterseestrasse 11 CH-Kreuzlingen Kreuzlingen, 20.05.2015 Table of contents Page 1. Summary 3 2. Introduction 5 2.1 Origin of local anesthetics 5 2.2 Develoment of local anesthetics 8 2.3 Pharmakologie of local anesthetics 13 3. Toxicity von local anesthetics 20 3.1 Toxicity of cocain 20 3.2 Toxicity of other local anesthetics 22 4. Case reports 27 4.1 Case 1 : Bupivacain toxicity 27 4.2 Case 2 : Ropivacain toxicity 30 5. Discussion 32 5.1 Bupivacain intoxication case 32 5.2 Ropivacain intoxication case 35 6. Conclusions 37 7. References 38 2 1 . Summary Local and regional anesthesia, as we know it today, results from the development of both suitable drugs and application techniques. The present work describes a survey oft he historical, pharmacological and clinical knowledge oft the toxicyty of local anesthetics, with particular attention paid to long-acting amino amid drugs. The part 1 of this thesis ( Introduction ) describes the history of local and regional anesthesia from the discovery of cocaine in 1859 to the introduction of modern long-acting local anesthetics between 1963 and 1998. After the conquens of Peru in 1530 by Pizzaro, the coca plant was discovered, and its general effects were described. The active substance was isolated in 1860 by Niemann and called cocaine. The first clinical use of cocaine is attributed to Koller in 1884, as he used it for topic anesthesia in ophtalmic surgery. The use of cocaine became popular at once but, unfortunately, the frequency of central nervous system (CNS) and cardiovascular (CV) toxic reactions increased at ist use spread. The medical community and the industry were stimulated for the search of new drugs with local anesthetic properties and less toxicity. After a first quest for other plants with similar properties, the strategy changed to chemical synthesis of new substances. Following the synthesis of cocaine in 1891, numerous amino ester derivates were produced between 1891 and 1930. Unfortunately, much of these substances showed more or less toxicity and suffered from a tendency to trigger allergic reactions. Futhermore, the duration of the effects remained a major concern, so that the industry began to explore the features of amino amides in particular. In 1944, lidocaine was the first amino amid local anesthetic introduces in a clinical setting. The search for new drugs led in 1963 to the introduction of bupivacaine, the first long-acting amino amid local anesthetic used on a wide clinical basis. Like earlier for cocaine, the popularity of bupivacaine led from 1979 onwards to an increasing amount of CV toxicity casualties. This repetition oft the history led the pharmaceutical industry to the discovery oft the less cardias toxicity oft he S(-)- form of the bupivacaine enantiomer and to search fort he synthesis of a pure S(-)- form long-acting amino amid local anesthetic. After chemical development in 1988, ropivacain, a pure S(-)-form local anesthetic, was clinically introduced in 1996. The survey ot the historical develoment of local anesthetic is followed by a description of the pharmacology oft these drugs. The chemical structure (intermediate chain with aromatic and 3 amine ends) and the physico-chemical properties (lipophilia, ionisation, protein binding, molecular weight) of local anesthetics are discussed, as well as their mechanism of action and their pharmocokunetics. The diffusion of local anesthetics from the application site to the action site, and their interactions with the sodium and potassium channels in the cell membrane are described, as well as their resorption, distribution, metabolism and elimination. In part 2 of this work ( Toxicity of local anesthetics ) the toxicity of cocaine and of the other substances are discussed with particular empasis on their CNS and CV toxicity. The mehanisms of toxicity of local anesthetics associated directly with their effect in blocking the ion channels in the cell membrane are described. Their interactions with the gama- aminobutric acid (GABA) receptor complex are described as they play a key role in the CNS toxicity of local anesthetics. The depressant effects of local anesthetics on both nerve and cardiac tissue is due to their blocking effects on the sodium, potassium and calcium channels. The particularly high CV toxicity of bupivacaine is discussed, as well as evidences fort he lower toxicity of ropivaciane. In part 3 ( Case reports ), two clinical casualties with CNS and CV toxicity of long-acting amino amid local anesthetics are presented in detail. The first case is a failed axillary plexus block with bupivaciane leading to cardiac arrest. The second case is a particular intravascular injection of ropivacaine for an intended sciatic block leading to major CV toxicity. The resuscitation of the bupivaciane case was difficult and led to death after a prolonged coma; the resuscitation of the ropivaciane case was relatively easy and led to early complete recovery. In both cases, blood concentrations of the drugs were determined. In part 4 ( Discussion ) , a review of the published experience with bupivacaine and ropivaciane CNS and CV toxicity is presented, discussed and compared with the clinical experience and the measured blood content of the drugs in the two reported cases. There are very few published cases with enough detailed information such as blood levels to draw real conclusions about the blood concentration leading to CNS or CV toxicity for bupivacaine or ropivaciane. The review of the published literature confirms that the dose-effect curves of CNS and CV toxicity overlap and that different factors can influence the appearance or the absence of symptoms of CNS or CV toxicity for a given blood concentartion of local anesthetic. 4 Part 5, (Conclusions), summarizes the actual knowledge about bupivacaine and ropivacaine blood concentrations during CNS and/or CV toxicity casualities and states that there are actually insufficient data to draw absolute conclusions. However, when compared with bupivacaine, and further to the recently experimentally demonstrated greater safety margin of ropivacaine, the clinical experience to date strongly supports that acute ropivacaine CV toxicity is less severe, shorter, and easier to treat. For peripheral nerve blocks, when large doses of local anesthetics are needed, it seems that ropivacaine should be preferred to bupivacaine. 5 2. Introduction 2.1 Origin of local anesthetic Local anesthesia as we know it today, emerged through the development oft wo entities: the discovery of suitable drugs and the invention of a convenient syringe to deliver the former. 2.1.1 The invention of the syringe In 1850, the idea of the syringe was not new. Indeed, the principle of a barrel with piston onside was known and extensively used as a clyster pump during Moliere`s time (1622- 1673). As they were large devices, it was impossible to deliver only a few drops of a solution at a precise location. In 1852 in Lyon, the Frenchman Pravaz invented a silver hollow needle that he attached to a plass syringe (1). He miniaturised this syringe to a volume of about 1.5 milliliter. In 1853, the Scotsmann Wood also developed a metallic hollow needle silimar to Pravaz`s. This invention enabled a liquid, or a solution of drugs, to be brought in close contact with nervous tissue, in order to have a targeted and precise effect on them. Wood utilised his syringe to first inject morphine or opiate solutions in the neighbourhood of nerves. This led only to partial success because, as discovered later, the observed effects were due tot he general effect oft he injected substances. 2.1.2 Cocaine, the first local anesthetic The years following the conquest of Peru by Francisco Pizzaro in 1530, brought to light the properties of a wonderful plant, whose leaves were remarcably stimulating when chewed. The native Indians regarded this plant as divine, and stressing its importance in their economy, called it in their language khoka, meaning the plant. This name was later europeanized to coca. 6 After the european authors had described the general and stimulating effects of coca (3), the Austrian von Scherzer brought a sufficient amount of coca leaves to Europa and gave this material tot he German chemists Niemann and Lossen (4). Betwen 1859 and 1860, Niemann isolated and described the main alcaloid of the coca plant, which he called cocaine (5). The chemical empirical formula was C17H21O4N. His work in this field was completed in 1862 by Lossen (6), who isolated cocainum muraticum, an acid salt of cocaine. In Vienna, the Austrian pharmacologist von Schroff was the first to view cocaine as a narcotic, like opium. He described a skin insensibility as an effect of cocaine application, but thougt this to be of central nervous origin. In 1856, Percy was the first to propose the use of coca leaves as an anesthetic. The Italian physician Mantegazza described the calming properties of cocaine on the stomach mucous membrane in 1859 (7). Despite these observations, it took another 25 years to use cocaine as a medical drug. In 1862, Schraff demonstrated a mydriasis in the eye oft he rabbit, while in 1864, Bennett reported an analgetic effect on mucous membranes. In 1880, in an experiment on himself, van Anrep described the local anesthetic property of cocaine when subcutaneously infiltrated, making the skin insensible top in stimulus (8). However, the real impulse given to local anesthetic came from the demonstration of analgesia of the eye by Koller in 1884(9). The Austrian physician Freud, who later became famous as a psychiatrist, was at the Vienna General Hospital at the time when, in an historical controversy, he first suggested the use of cocaine for its local anesthetic properties and mentioned this possibility to his colleague and friend Koller(3).