Prilocaine toxicity

Methemoglobinemia has been reported with benzocaine, Cetacaine (a mixture of benzocaine, butyl aminobenzo-ate, and tetracaine), cocaine, lidocaine, novocaine, and prUocaine. Acquired methemoglobinemia can result from exposure to chemicals that contain an aniline group, such as benzocaine and procaine, or to those that are transformed to metabolites that contain an aniline group, such as lidocaine and prilocaine. Toxic blood concentrations of local anesthetics, aberrant hemoglobin, and NADH-methemoglobin reductase deficiency are critical... 

Machado HS, Bastos RS. Inadequate tourniquet inflation associated with a case of prilocaine toxicity. Eur J Anaesthesiol 1998 15(2) 234-6. 

Touma S, Jackson JB. Lidocaine and prilocaine toxicity in a patient receiving treatment for mollusca contagiosa. J Am Acad Dermatol 2001 44(Suppl 2) 399 00. 

Prilocaine hydrochloride [1786-81-8] is also similar in profile to Hdocaine, although prilocaine has significantly less vasodilator activity. Prilocaine is the least toxic of the amino amide local anesthetics. However, its tendency to cause methemoglobinemia, especially in newborns, has eliminated its use in obstetric surgery. 

Q74 Prilocaine should be avoided in patients receiving co-amoxiclav. Prilocaine may cause ocular toxicity v/hen used for ophthalmic procedures. 

Prilocaine is a local anaesthetic of low toxicity, which should be avoided in severe or untreated hypertension, severe heart disease and in patients using drugs that may cause methaemoglobinaemia. Prilocaine may cause ocular toxicity, which has been reported with the use of the product in excessively high doses during ophthalmic procedures. 

In terms of pharmacological parameters, prilocaine is comparable to lidocaine however, because of a number of toxic manifestations, it is rarely used in medical practice. Citanest and xylonest are well-known synonyms for prilocaine. 

Percutaneous drug absorption can present special problems in newborns, especially in preterm infants. While the skin of a newborn term infant may have the same protective capacity as the skin of an adult, a preterm infant will not have this protective barrier until after 2 to 3 weeks of life. Excessive percutaneous absorption has caused significant toxicity to preterm babies. Absorption of hexachlorophene soap used to bathe newborns has resulted in brain damage and death. Aniline dyes on hospital linen have caused cyanosis secondary to methemoglobinemia, and EMLA (lidocaine/prilocaine) cream may cause methemoglobinemia when administered to infants less than 3 months of age. 

EMLA cream (lidocaine 2.5% and prilocaine 2.5%) consists of a eutectic mixture of focal anesthetics. It is used to provide topical anesthetic to intact skin. Other topical preparations are effective only on mucosal surfaces. EMLA has been shown to reduce pain on venipuncture and provide substantial anesthesia for skin graft donor sites. No significant local or systemic toxicity has been demonstrated. 

The earliest signs of CNS toxicity are circumoral and tongue numbness, tinnitus, tremor, and dizziness. These appear at plasma lidocaine (lignocaine) concentrations of about 5 pg-mL-1. The value for prilocaine is similar to lidocaine but bupivacaine toxicity appears at about half those of lidocaine. Further progression is evidenced by drowsiness, visual disturbances, or muscle twitching (plasma lidocaine of 5-10 pg-mL-1). Over 10 p-mL-1 grand mal convulsions, coma and respiratory arrest are likely. Serious CNS toxicity is indicative of imminent and potentially fatal cardiac toxicity since lidocaine is associated with direct cardiac depression at plasma concentrations in excess of 20 pg-mL-1. 

Prilocaine is suitable for most types of local anaesthetic block but is not suitable for epidural use in obstetrics because of the need for repeat administration. Its main uses are for infiltration anaesthesia and intravenous regional anaesthesia where its low toxicity makes it the drug of choice. Levobupivacaine... 

Prilocaine is an amide-type LA with a rapid onset and an intermediate duration of action associated with a low toxicity. However, metabolism to ortho-toluidine can cause oxidation of the ferric form of hemoglobin to the ferrous form, creating methemoglobin. In most cases the methemoglobuniemia is benign, but sometimes tissue hypoxia is observed (Eriksson, 1966). 

Prilocaine, which is equal in potency to lidocaine, has a longer duration of action. It is metabolized to o-toluidine, which in toxic doses may cause methemoglobinemia. 

Prilocaine is used similarly to lidocaine (t,i 1.5 h), but it is slightly less toxic. It used to be the preferred drug for intravenous regional anaesthesia but it is... 

Injection directly into the cerebrospinal fluid (CFS) ensures complete CNS bioavailability for drugs that cannot cross the blood-brain barrier. This dosage route is used to treat serious CNS infections such as meningitis and ventriculitis, and with such agents as mepivacaine and prilocaine for spinal anesthesia. Drugs injected intrathecally initially distribute into approximately 140 ml of CSF, thus producing high concentrations in the CNS with low risk of systemic toxicity. 

Lidocaine is the most widely used aminoamide local anesthetic agent, with a low toxic potential its effects are mostly typical for this class of drug. It can be given by injection or topically and is also combined with prilocaine in Emla for topical administration. It is also used as an antidysrhythmic drug and has occasionally been used in other conditions, such as multiple sclerosis, chronic daily headache, migraine and cluster headaches, and neuropathic pain, such as postherpetic neuralgia. 

Some distinction must be made between the main groups of local anesthetics as to the frequency of complications. Hypersensitivity reactions, for example, are relatively less common with the aminoamides, such as bupivacaine, cinchocaine, etidocaine, lidocaine, mepivacaine, prilocaine, and ropivacaine, than with the amino-esters. However, the systemic toxic effects of individual local anesthetics differ bupivacaine, cinchocaine, and tetracaine are the most toxic. Furthermore, the individual characteristics of the patient (for example age, sex, body weight, and cardiac, renal, and hepatic function) are important (SEDA-17,134). 

In eight episodes of toxic methemoglobinemia in seven premature infants after the combination of caudal anesthesia (prilocaine 5.4—6.7 mg/kg) and Emla cream (prilocaine 12.5 mg) for herniotomy, the highest methe-moglobin concentration 5.5 hours after anesthesia was 31% (86). All the infants were sjmptomatic, with mottled skin, pallor, cyanosis, and poor peripheral perfusion. The most severe symptoms occurred at 3-8 hours and disappeared within 10-20 hours. The authors stressed the importance of recognizing the poor tolerance of premature infants to methemoglobinemia and that whereas topical prilocaine is relatively safe, caudal administration is not. 

Systemic toxic reactions are the most common complications of intravenous regional anesthesia, and they occur soon after the tourniquet is released. In cases of early accidental tourniquet release or rupture, deaths have resulted prilocaine seems to be the safest agent for this technique (271). 

A 74-year-old woman was given prilocaine 400 mg for carpal tunnel surgery. Within 3 minutes, she developed signs of central nervous system toxicity, sweating, and tachycardia. Twenty minutes later, her symptoms had resolved and the cause was found to be a leak in the tourniquet. 

The endothelial toxicity of local anesthetics has been assessed in pigs, as this might be relevant to the safety of agents given by intracameral injection (335). Lidocaine, mepivacaine, and prilocaine were safe, while bupivacaine in clinically effective concentrations resulted in significant cell reduction. 

Animal No mutagenic or carcinogenic potential was found in preclinical testing of lidocaine or prilocaine. The 2,6-xylidine metabolite of lidocaine did display carcinogenicity in a 2 year oral toxicity study in rats 60, but not 30 times the single administration dose. The procaine metabolite o-toluidine has been carcinogenic in mice at 60-960 and 60-320 times standard dosing levels. 

Prilocaine is an amide-type LA, with a very low allergenic potential and low toxicity" and is non-vasodilating. Unfortunately, prilocaine is metabolized into ortho-toluidine, a chemical that can induce methemoglobinemia. In doses higher than 500 mg, it can cause cyanosis and reduce the oxygen-carrying capacity of the blood. 

Mixing lidocaine base and prilocaine base in equal parts, at room temperature, gives a eutectic mixture. This mixture is emulsified in a base that consists mainly of water and polyoxyethylene castor oil, and the anesthetics are added to the oily phase. Phenol has an excellent oil/water partition coelEcient. The oils lower the toxicity of phenol, but also slow down its rate of penetration as well as absorption of the local anesthetics. There is a competition between the phenol solution and the EMLA, which changes the activity and penetration of the combined molecules. 

On the other hand the ( )-isomer of deprenyl is a much more potent MAO-B inhibitor than the (+)-isomer. For these reasons racemic deprenyl has been replaced by ( )-deprenyl in clinical practice. In the racemic local anesthetic prilocaine (Figure 26.6) only the R-( )-isomer is metabolized to an aniline derivative (ortho-tolnidine) and to the corresponding para- and ortho-aminophenols that are highly toxic and responsible for met hemoglobinemia. ... 

Prilocaine is similar to lidocaine but has a longer duration of action and is less toxic. It can be used in combination with felypressin (a vasoconstrictor), but not by podiatrists. 

Prilocaine (No. 10) represents an interesting situation in that the presence of only one o-methyl group has two consequences. A predictably shorter duration of action because of more facile amide hydrolysis, as compared with lidocaine, and a significant likelihood of methemoglobinemia at higher doses being produced by o-toluidine that results from this amide hydrolysis. The much lower levels of 2,6-xylidine produced from lidocaine (Fig. 13-8) do not produce this hematological toxicity. However, because of more rapid metabolism and the resultant shorter duration of action, overall toxicity of prilocaine is about 40% less than lidocaine. 

The introduction of a eutectic mixture of lidocaine (2.5%) and prilocaine (2.5%) (EMLa) bridges the gap between topical and infiltration anesthesia. The efficacy of this combination lies in the fact that the mixture of prilocaine and lidocaine has a melting point less than that of either compound alone, existing at room temperature as an oil that can penetrate intact skin. EMLA cream produces anesthesia to a maximum depth of 5 mm and is applied as a cream on intact skin under an occlusive dressing, for procedures involving skin and superficial subcutaneous structures (e.g., venipuncture and skin graft harvesting). EMLA must not be used on mucous membranes or abraded skin, as rapid absorption across these surfaces may result in systemic toxicity. 

---