An update on the chemistry, pharmacology and dose calculations of mepivacaine hydrochloride for Podiatrists in the United Kingdom

43 Local anaesthetic agents suppress action potentials in excitable tissues by blocking 44 voltage-gated sodium channels. In doing so they inhibit the depolarisation of nociceptive 45 nerve fibres and so prevent the transmission of pain impulses. UK legislation allows 46 HCPC-registered Podiatrists with POM-A annotation access to six local anaesthetic drugs 47 and two of these with the addition of adrenaline. The use of local anaesthetia has 48 transformed the treatment of nail pathology by Podiatrists. In the UK, the drug of choice 49 in podiatric practice is 3% mepivacaine hydrochloride: it is a good choice of drug for 50 digital anaesthesia. This paper will review the chemistry, pharmacology and dose 51 calculation of mepivacaine, and challenge some of the orthodoxy over the rigid 52 calculation of maximum safe dosages. 53 54 Level of clinical evidence: 5 (review). 55 56


Introduction 61
Local anaesthesia (LA) is defined as any technique that renders part of the body 62 insensitive to pain or sensation without affecting consciousness (Khan, 2017). LA drugs 63 do this by interrupting neural conduction via the inhibition sodium ion influx through 64 ionophores within neuronal membranes (Malamed, 2019). Their key application is to 65 facilitate pain free treatment (Pope and Brown, 2020). Clinical experience and 66 pharmacological discoveries have allowed the development of safe and efficient practice 67 using a range of different drugs since Halstead's first peripheral nerve block in 1885 68 (Calatayud, 2003). The history of LA is a fascinating subject in its own right. For those 69 that want to know more about the origins and advancement of this branch of medicine, 70 refer to the chapter by Chuan and Harrop-Griffiths in Hadzic's Textbook of Regional 71 Anesthesia and Acute Pain Management (Chuan and Harrop-Griffiths, 2017), and work by 72 Borthwick (Borthwick, 2001/05) who details the Podiatric history of access to these 73 drugs. given as a digital block prior to nail surgery (Maher, 2020). Lidocaine hydrochloride is 81 the most widely used anaesthetic in medicine and dentistry worldwide (Becker, 2012) 82 but mepivacaine hydrochloride (M.HCl) appears to be* the most commonly used agent in 83 UK podiatric practice (*based on the senior author's experience of teaching under-and 84 post-graduate LA theory and practice).

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The aim of this paper is to give colleagues an update on the chemistry and pharmacology 87 of M.HCl, to give an overview of the variability in dose calculations and to challenge some 88 of the orthodoxy over the rigid calculation of maximum safe dosages. It will be provided 89 as a preprint to obtain wider professional feedback before the next iteration of this work.

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Persons exempted Prescription only medicines to which the exemption applies Conditions 1. Registered chiropodists or podiatrists against whose names are recorded in the relevant register annotations signifying that they are qualified to use the medicines specified in column 2.   Histology and Physiology of Action Potentials

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The sodium-potassium pump is an electrogenic transmembrane ATPase structure that 126 pumps three sodium ions out of the cell and two potassium ions into the cell, for every 127 single ATP consumed (Pirahanchi et al, 2020 properties to the molecule (see fig 1). The intermediate linkage provides a basis for 152 classification and also determines the pattern of biotransformation: amino-esters are 153 hydrolysed by plasma esterases, whereas amino-amides are bio transformed hepatically.

154
The terminal amine may exist in a lipid-soluble tertiary form (3 bonds) or as a positively 155 charged, water-soluble quaternary form (4 bonds) (Becker, 2006). anaesthesia is predicated on the proportion of molecules that convert to the tertiary, 171 lipid-soluble structure when exposed to physiologic pH (7.4) (Becker 2006).

173
The pKa of a molecule represents the pH at which 50% of the molecules exist in the 174 tertiary, lipid-soluble form and 50% in the quaternary, water-soluble form. The 175 Henderson-Hasselbalch equation (Log [non-ionized drug]/[ionized drug] = pH -pKa) 176 allows us to calculate the ratio of those two states (Tsuchiya, 2007). The acidic 177 environment of inflamed tissues favours the quaternary, water-soluble configuration f 178 and accounts for difficulty in anesthetising inflamed or infected tissues as fewer 179 molecules exist as tertiary lipid-soluble form that penetrates nerves. In these situations, 180 M.HCl with pKa of 7.6 (this pH value varies in different sources) -compared to 181 bupivacaine with a pKa of 8.1 -is more likely to provide effective anaesthesia (Becker,182 2006).

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The aromatic ring improves the lipid solubility of the compound. Greater lipid solubility 185 enhances diffusion through nerve sheaths and neural membranes: this correlates with 186 drug potency because a greater portion of an administered dose can enter neurons 187 (Becker, 2006). Circulating LA is bound by plasma proteins (α1-acid glycoproteins). The 188 duration of action of each LA agent depends on plasma protein binding and correlates 189 with a compound's affinity for the protein of the sodium channels. Bupivacaine exhibits 190 95% protein binding compared to 55% or 77% (references vary) for M.HCl, hence the 191 difference in their duration of neural blockade (Becker, 2012). Both potency and 192 duration of action also correlate with increasing molecular weight but also with an 193 The addition of a vasoconstrictor, such as epinephrine (adrenaline) prolongs the 203 anaesthetic effect by reducing the systemic distribution of the agent. Multiple sources 204 state that vasoconstrictors must not be used to produce ring-block of an extremity (e.g. a 205 finger or toe) because they may cause prolonged ischaemia and gangrene (Broomhead, 206 2020). The senior author regularly adds 2% lidocaine with 1/200,000 epinephrine to 207 long acting LA agents such as levo-bupivacaine and ropivacaine for peripheral nerve 208 blocks. This is interesting topic and worthy of a further commentary in another paper 209 (spoiler alert: the risks are likely exaggerated). The chapter by Broomhead (2002) properties are summarised in table 2. This is a summary from product monographs, 224 Patient Information Leaflets (PILs, e.g., www.drugs.com) and Summary of Product 225 Characteristics (SPCs) found through the literature search. As noted below, the primary 226 evidence source is often missing or unclear in such documentation. PILs and product data 227 are supported by the pharmaceutical industry. In communication with the Chief 228 Executive Officer of one of these companies, it was stated that these guidelines are for 229 educational purposes only and are not intended for medical advice, diagnosis and 230 treatment (unreferenced on request). 231 232

Chemistry
Mepivacaine was the second amide local anaesthetic to be clinically introduced.
C15H22N2O.HCl: 1-methyl-2', 6'-pipecoloxylidide monohydrochloride is a tertiary amide salt. The hydrochloride is easily soluble in water, stable in solution, very resistant to acid and alkaline hydrolysis, and can be repeatedly boiled without decomposition.
Brand names Scandonest (UK), Carbocaine (US) Available concentrations 1%, 1.5%, 2% with epinephrine 1:100,000, 3% solutions Dose mg/kg and total Adults: 4.4, 5, 6, or 6.6 (varies on the reference) The MSD for healthy adults should not exceed 400mg at one treatment Children 3 or 5/6 (varies on the reference) Concentrations of less than 2% for those under 3 years of age

Contra-indications and precautions
Mepivacaine has been shown to be less toxic (systemic and neural tissue) than lidocaine in adults and provides a somewhat longer duration of action than lidocaine because of a less pronounced vasodilatory effect. Injection of repeated doses of mepivacaine may cause significant increase in blood levels with each repeated dose due to slow accumulation of the drug or its metabolites, or due to slower metabolic degradation than normal. Tolerance varies with the status of the patient. Debilitated, elderly patients, acutely ill patients, and children should be given reduced doses commensurate with their weight and physical status. Mepivacaine should be used with caution in patients with a history of severe disturbances of cardiac rhythm or heart block. Young children should be given minimal doses of each agent. Changes in sensorium such as excitation, disorientation, drowsiness, may be early indications of a high blood level of the drug and may occur following inadvertent intravascular administration or rapid absorption of mepivacaine. Mepivacaine is contraindicated in patients with a known hypersensitivity to amide-type local anaesthetics. The binding affinity of mepivacaine in serum is reduced in the presence of bupivacaine. Displacement of mepivacaine by bupivacaine was observed when an α1 acid glycoprotein solution was studied via classic competitive inhibition. Allergic-type reactions are rare and may occur as a result of sensitivity to the local anaesthetic or to other formulation ingredients. These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic oedema (including laryngeal oedema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly, anaphylactic-like symptoms (including severe hypotension). Patients allergic to methylparaben or para aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc. have not shown cross-sensitivity to amino-amides agents. Mepivacaine crosses the placenta: there is considerable transfer of mepivacaine across the placenta after maternal doses and the ratio of foetal to maternal concentrations is about 0.7. Although neonates have a very limited capacity to metabolise mepivacaine it appears they are able to eliminate the drug. On the basis of long usage, anaesthetics of the mepivacaine type are considered to be reasonably safe for use on pregnant women. Retrospective studies of pregnant women receiving local anaesthetics for emergency surgery early in pregnancy have not shown that local anaesthetics cause birth defects. However, no controlled studies have been carried out in pregnant women. Moreover, no animal reproduction studies have been performed with mepivacaine. Therefore, caution should be taken before administering this anaesthetic during early pregnancy. The mutagenic potential of mepivacaine has not been evaluated. It is not known whether local anaesthetics are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when mepivacaine is administered to a nursing woman.  impossible to expel all the solution via a dental syringe (see fig 2). 300 301 302 Figure 2: the last 0.2ml of a 2.2 ml Scandonest cartridge extracted via a Luer syringe 303 304 The maximal adult doses for M.HCl, and the dose per body weight, vary widely from 305 source to source for both total dose and dose by weight (see   An alternative method is to use the drug concentration in a one-step method (Williams 330 and least 20 kg). Note that this is half of the oft-quoted adult dose. One must also remember 379 the physiological discrepancy between a would-be prop forward 10-year-old and a 15-380 year-old that needs to run around in the shower to get wet.

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The College of Podiatry Nail Surgery guidelines (Gohil, 2019) quote an earlier statement 383 from the then Director of Education, Ashcroft in 2003 and notes that M.HCl is not licenced 384 for podiatric use in children because the manufactures did not apply for such a licence. 385 Ashcroft went on to reassure members that "The Society would consider the 386 administration of Scandonest, suitably dose adjusted for children, to be acceptable 387 professional practice." 388 389

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A brief overview of LA theory has been presented together with a more detail update on 391 the drug mepivacaine. It was surprising to see the discrepancies in the literature over the 392 various chemo-physical properties of the drug, as well as variability is MSD values. This 393 cuts across the traditional way LA theory is taught in UK podiatric practice.

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Malamed (2019) -in a key dental anaesthetic text -suggests that the properties of an LA 396 include: 397 1. It should not be irritating to the tissue to which it is applied 398 2. It should not cause any permanent alteration of nerve structure 399 3. Its systemic toxicity should be low 400 4. It must be effective regardless of whether it is injected into the tissue or is applied 401 topically to mucous membranes 402 5. The time of onset of anaesthesia should be as short as possible 403 6. The duration of action must be long enough to permit completion of the 404 procedure yet not so long as to require an extended recovery 405 The choice of LA in peripheral nerve blockade is (or should be) determined by desired 406 speed of onset, block intensity, and duration of anaesthesia and analgesia (Eng, 2014) and 407 therefore Podiatrists should consider the use other agents where indicated (Uddin and 408 Reilly, 2008). It might be argued that this is less important for the humble digital block 409 and therefore in this, 3%M,HCl is a good choice. hours -an overall dosage of 4800mg -without evident signs of central nervous system or 433 cardiovascular toxicity. Most LAs will not produce CV toxicity until the blood 434 concentration exceeds three times that necessary to produce seizures. 435 436 Rosenberg et al (2004)  concluded that students should be made aware that there is more than one standard, and 460 that teaching should emphasize sound medical and pharmacologic principles, a concern 461 echoed in this paper. In the UK, the podiatric LA drug of choice is mepivacaine hydrochloride. It is a good 491 choice for digital anaesthesia, and its use has transformed the treatment of nail pathology. 492 It is almost equally popular in Dentistry but less so in the world of (medical) anaesthesia 493 where less cardio-toxic agents such as levo-bupivacaine and ropivacaine are the first line 494 agents for peripheral nerve block because of their reduced cardiotoxicity.