Tetracaine is an amino-ester class local anesthetic. It has been in use for a variety of purposes since the early 1930s, but its most common use today is as a topical ophthalmic anesthetic for short procedures on the surface of the eye, as well as the ears and nose. Spinal anesthesia is also another indication. The World Health Organization (WHO) lists tetracaine as an essential medicine and is relatively inexpensive in comparison to other local anesthetic agents.
Tetracaine functions primarily via blockade of intracellular sodium channels. The drug travels in non-ionized form across the lipid bilayer membrane and dissociates into its ionized form (cation/conjugate acid) which then acts on the alpha-subunit of the Na-channel. The drug functions as an allosteric inhibitor on the Na-channel when it is in the open-activated state; thus, the drug binds and activates faster when a Na/K channel for a particular nerve is in use. This blockade must occur at three successive nodes of Ranvier along an axon for nerve conduction to be impaired. During this process sodium influx is prevented, thereby stopping cellular depolarization and any potential action potential developing.
Tetracaine has a pKa of 8.46 at room temperature (25C) which is moderate although the drug has a relatively quick onset of action, especially for intrathecal administration. Lipid solubility for tetracaine is high at a relative value of 80; thus, it is amongst the most potent of any local anesthetic. Its protein binding is moderate at 75% allowing a relative duration of action up to 200 minutes. The drug undergoes hydrolysis primarily via plasma cholinesterase (butyrylcholinesterase), produced in the liver, into an alcohol and para-aminobenzoic acid (PABA). There is also a small amount of metabolism by RBC cholinesterase. There is a minimal amount of tetracaine excreted unmetabolized in the urine. It has a pH of 4.5-6.5 in plain solution. It is commonly administered topically, subcutaneously, or via intrathecal injection.
On a weight basis, it is recommended not to exceed 1.5-3mg/kg of actual patient weight for dosing. Toxicity of the drug is affected by the site of administration. Tetracaine undergoes absorption (from fastest to slowest) in the following order: IV > intercostal > caudal > epidural > brachial plexus > subcutaneous. Absorption speed may be mitigated by avoiding areas with high vascular supply nearby and/or by adding local vasoconstrictors to the solution (epinephrine or phenylephrine). As alluded to earlier, metabolism occurs via plasma cholinesterase primarily produced from the liver, so dosing should cautious in patients with liver disease, neonates, and patients with atypical homozygous pseudocholinesterase deficiency.
One of the primary concerns with tetracaine as with other local anesthetics is CNS toxicity. Toxicity may manifest initially as circumoral numbness, tinnitus, blurry vision, and dizziness. It may then present with hyperexcitability of the patient due to the blockade of CNS inhibitory pathways before progressing to depressive phenomena, seizures, and comatose state before hemodynamic collapse. Tetracaine does exhibit vasodilatory properties when given in toxic doses and exerts dose-dependent decreases on cardiac contractility. In addition to this, it may increase the duration of PR and QRS intervals progressing to sinus bradycardia then to asystole. Ventricular arrhythmia is a possibility but is more common with bupivacaine.
Direct neural toxicity has been noted with chloroprocaine and lidocaine, although rare with tetracaine. These may manifest after neuraxial administration as cauda equina syndrome (lumbosacral radiculopathy, saddle anesthesia, loss of bowel/bladder tone). It may also manifest after neuraxial technique as transient neurologic symptoms (painful lumbosacral radiculopathy lasting up to 10 days); this may be particularly more common in patients undergoing surgery in the lithotomy position, who are or will be non-ambulatory for prolonged periods, and those who are obese. Some degree of risk may be mitigated by using lower doses of local anesthetic for neuraxial technique and by avoiding preservatives including sulfites and/or EDTA (which have been implicated for CES and TNS when used).
Allergic reactions to tetracaine can occur. While allergy to local anesthetic is rare, it is more common with aminoesters than aminoamides. This reaction is thought primarily to be due to para-aminobenzoic acid (PABA). In addition to this, care should be taken to review the drug label for any addition of preservatives, especially methylparaben which metabolizes to PABA.
No absolute contraindications exist to the use of tetracaine aside from prior evidence of serious allergic response. Relative contraindication to use is previous administration of local anesthetic. Care should be taken to note when a patient has received such medications as in the case of postoperative pain relief when local anesthetic infiltrate has been used, concerning the duration of effect of different agents. Since the advent of liposomal bupivacaine, which may exercise its effect for up to 72 hours, it should be noted that concurrently administered local anesthetics may combine to precipitate toxic symptoms.
The American Society of Anesthesiology, in addition to international standard conventions, recommends continuous ECG and pulse oximetry, blood pressure monitoring intermittently with concomitant inspection of respiratory rate or ETCO2 during any regional or neuraxial anesthetic administration.
The most feared complication of tetracaine toxicity is the progression to local anesthetic systemic toxicity (LAST) syndrome marked by all previously mentioned features of CNS and cardiovascular toxicity. The provider administering the medication must exercise prompt recognition of the progression of this syndrome.
Care should be taken to quickly secure the patient’s airway and breathing and support hemodynamics. It is important to note that hypoxia, hypercarbia, and acidosis can worsen cardiac contractility, exacerbate arrhythmia, and lower the seizure threshold. Controlled ventilation can attenuate hypoxia and hypercarbia mitigating such effects. Additionally, benzodiazepines may be prudent during the administration of high doses of tetracaine as they raise the seizure threshold and have the added benefit of anxiolysis during a nerve block or surgical procedure.
While there is no direct reversal agent or treatment for tetracaine toxicity, it is recommended to begin lipid rescue therapy immediately. Intravascular administration of concentrated lipid is theorized to act as a sump to freely circulating local anesthetic allowing for rapid clearance of the drug from systemic circulation. 20% lipid emulsion should be started at 1.5mL/kg immediately followed by infusion at 0.25mL/kg/min. The bolus dose may be repeated, and the infusion increased if the patient persists with hemodynamic compromise or arrhythmia.
Tetracaine is rarely used today outside of topical application for short ENT and ophthalmologic procedures. It has been studied on rat models and found to additionally function via a dose-dependent inhibition of intracellular calcium release through ryanodine receptors. This pharmacology has not been studied in humans but may be of some interest as this mechanism is similar to that of dantrolene for use in treating malignant hyperthermia.
For successful a successful outcome, the entire team including nurses, pharmacists, and other clinicians should work in a coordinated fashion to safely use tetracaine and monitor for side effects.
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