Tetracaine

Mechanism of Action

Tetracaine primarily functions by blocking intracellular sodium channels. The drug travels across the lipid bilayer membrane in its non-ionized form and dissociates into its ionized form (cation/conjugate acid), which then acts on the α subunit of the Na⁺ channel. The drug functions as an allosteric inhibitor on the Na⁺ channel when it is in the open-activated state; it binds and activates more rapidly when a Na⁺/K⁺ channel for a particular nerve is in use. This blockade must occur at 3 successive nodes of Ranvier along an axon for nerve conduction to be impaired. Sodium influx is prevented during this process, thereby stopping cellular depolarization and any potential action potential from developing.[11][12]

Pharmacokinetics

Absorption: Tetracaine has a pKa of 8.46 at room temperature (25 °C), which is moderate. The drug has a relatively quick onset of action, especially when administered intrathecally. Lipid solubility for tetracaine is high, with a relative value of 80, making it among the most potent local anesthetics.

Distribution: The protein binding is moderate at 75%, allowing a relative duration of action of up to 200 minutes.

Metabolism: The drug undergoes hydrolysis primarily via plasma pseudocholinesterase (also known as butyrylcholinesterase) into an alcohol and para-aminobenzoic acid (PABA).[13] A small amount of metabolism is also performed by RBC cholinesterase.[14][15]

Elimination: A minimal amount of tetracaine is excreted unmetabolized in the urine.

Administration

Available Dosage Forms and Strengths

Tetracaine is commonly administered topically, subcutaneously, or via intrathecal injection.[16]

Adult Dosing

Ophthalmic formulation:

• Corneal foreign body removal: 1 to 2 drops in the affected eye every 5 to 10 minutes for 1 to 3 doses. This regimen can also be used for suture removal.
• Brief ophthalmic anesthesia (tonometry or short corneal/conjunctival procedures): 1 to 2 drops in the eye(s) prior to starting the procedure.
• Prolonged ophthalmic anesthesia (eg, cataract extraction or other extended procedures): 1 to 2 drops in the affected eye(s) every 5 to 10 minutes for 3 to 5 doses.

Topical formulation:

• Tetracaine is also available as a topical cream combined with lidocaine for local dermal anesthesia. This medication is applied to intact skin 20 to 60 minutes before superficial dermal procedures.

Spinal Anesthesia (1% tetracaine injection):

• For perineal procedures, including saddle block during vaginal delivery, 2 to 5 mg in dextrose or up to 5 mg (0.5 mL) of plain solution is usually enough. When the perineum and lower limbs need to be covered, 10 mg (1.0 mL) is typically injected at the L3 or L4 level. To reach the costal margin, 15 to 20 mg (1.5 to 2.0 mL) may be given, usually at the L2 to L4 interspace. Doses exceeding 15 mg are rarely necessary and should only be used in exceptional circumstances. The injection should be given slowly, at about 1 mL every 5 seconds.

Specific Patient Populations

Hepatic impairment: As mentioned earlier, metabolism occurs primarily through plasma cholinesterase, which is produced mainly in the liver. Therefore, dosing should be administered cautiously in patients with liver disease, neonates, and those with atypical homozygous pseudocholinesterase deficiency.[17]

Renal impairment: No dose adjustments are provided in the product labeling. 

Pregnancy considerations: There is a lack of preclinical data and animal studies. Systemic administration should be performed carefully and only after a thorough risk-benefit evaluation and discussion with the patient.

Breastfeeding considerations: No specific data are available regarding the use of tetracaine while breastfeeding. However, since other local anesthetics tend to appear in breastmilk in minimal amounts, a one-time injected dose of tetracaine—such as for a dental procedure—is not expected to harm a breastfeeding infant. Clinicians are advised to select an alternative anesthetic, particularly if the baby is a newborn or premature. If tetracaine is applied to the skin, it is unlikely to affect the baby as long as it’s not used on or near the breast. When applying any topical product to the breast, only use water-based creams or gels. Ointments should be avoided, as they can lead to the infant ingesting excessive levels of mineral paraffins through contact.[18]

Pediatric patients: The safety of ophthalmic tetracaine administration in the pediatric population has been demonstrated.

Older patients: Clinicians are advised to administer the lowest effective dose possible, taking into account the concomitant medications.

Adverse Effects

When dosing based on weight, clinicians should not exceed 1.5 to 3 mg/kg of the patient's actual weight. The 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 near a large vascular supply and adding local vasoconstrictors to the solution (epinephrine or phenylephrine).[19]

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. This condition may then present with hyperexcitability of the patient due to the blockade of CNS inhibitory pathways before progressing to depressive phenomena, seizures, and a comatose state before hemodynamic collapse. Tetracaine does exhibit vasodilatory properties when given in toxic doses and exerts dose-dependent decreases in cardiac contractility. Additionally, it may prolong the duration of PR and QRS intervals, potentially leading to sinus bradycardia and ultimately asystole. Ventricular arrhythmia is a possibility, but it is more common with bupivacaine.[20]

Direct neural toxicity has been noted with chloroprocaine and lidocaine, although it is rare with tetracaine. These may manifest after neuraxial administration as cauda equina syndrome (lumbosacral radiculopathy, saddle anesthesia, loss of bowel/bladder tone). Neural toxicity may also manifest after a 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 the neuraxial technique and avoiding preservatives, including sulfites and EDTA (which have been implicated in CES and TNS when used).[21]

Allergic reactions to tetracaine can occur. While allergy to local anesthetics is rare, it is more common with aminoesters than aminoamides. This reaction appears primarily to be due to para-aminobenzoic acid (PABA). Additionally, it is essential to review the drug label for the presence of preservatives, particularly methylparaben, which metabolizes to PABA.[22]

Drug-Drug Interactions

• Tetracaine should be avoided in patients receiving sulfonamide therapy, as its metabolite PABA can inhibit the antibacterial activity of sulfonamides.

• Local anesthetics, including tetracaine, may increase the risk of methemoglobinemia, particularly when administered concurrently with oxidizing agents such as nitroglycerin, nitroprusside, and nitrous oxide. Other drugs that should be avoided are cyclophosphamide, ifosfamide, dapsone, sulfonamides, nitrofurantoin, chloroquine, primaquine, phenytoin, sodium valproate, and phenobarbital.

Contraindications

Tetracaine is contraindicated for patients with a known history of severe allergic reactions to the drug. Additional contraindications include infection at the site of administration and uncontrolled hypotension.

Warning and Precautions

One relative contraindication to administering tetracaine is the previous administration of a local anesthetic. Clinicians should carefully note when a patient has received such medications, such as in cases of postoperative pain relief and when local anesthetic infiltrate has been used, concerning the duration of the effect of different agents. Since the advent of liposomal bupivacaine, which may exercise its effect for up to 72 hours, it bears mention that concurrently administered local anesthetics may combine to precipitate toxic symptoms.[23]

With ophthalmic tetracaine, corneal injury and damage to epithelial cells have been noted following intracameral administration. Corneal toxicity/toxic keratopathy with permanent corneal damage can develop due to prolonged use.[7][24]

Monitoring

The American Society of Anesthesiology, in addition to international standard conventions, recommends continuous ECG and pulse oximetry, intermittent blood pressure monitoring with concomitant inspection of respiratory rate, or ETCO₂ during any regional or neuraxial anesthetic administration.[25]

Toxicity

Signs and Symptoms of Overdose

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.

Management of Overdose

Care is necessary to quickly secure the patient’s airway and breathing and support hemodynamics. 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 when administering 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, the recommendation is to begin lipid rescue therapy immediately. Intravascular administration of concentrated lipids theoretically acts as a sump to freely circulating local anesthetics, allowing for rapid clearance of the drug from systemic circulation. A 20% lipid emulsion should be immediately started at 1.5 mL/kg, followed by infusion at 0.25 mL/kg/min. The bolus dose may be repeated, and the infusion increased if the patient persists with hemodynamic compromise or arrhythmia.[26] According to the American Society of Regional Anesthesia (ASRA), LAST resuscitation differs from standard ACLS protocols, but a delay in resuscitation is not recommended. ASRA recommends a smaller initial dose of epinephrine (≤1 μg/kg). Clinicians should avoid administering calcium channel blockers, β-blockers, or vasopressin.[27]

Enhancing Healthcare Team Outcomes

Tetracaine is rarely used today, except in topical applications for brief ENT and ophthalmologic procedures. This medication has been studied in rat models and found to function via a dose-dependent inhibition of intracellular calcium release through ryanodine receptors. Tetracaine's pharmacology has not been studied in humans; however, it may be of interest, as its mechanism is similar to that of dantrolene in treating malignant hyperthermia.[28]

For a successful outcome, the interprofessional healthcare team should work in a coordinated manner to safely administer tetracaine and monitor for potential adverse effects. This will result in more effective anesthesia, fewer adverse events, and better patient outcomes.