CLEVELAND CLINIC FOUNDATION

Department of General Anesthesiology


AMINO ESTER LOCAL ANESTHETICS


Contents:

PROCAINE

Procaine is a short acting amino ester local anesthetic with pKa of 8.9. Commercially prepared solutions have a pH 5.5 to 6.0, slow onset, very short blood half-life due to rapid hydrolysis by plasma cholinesterase. The plasma half-life is thought to be approximately 20 seconds. Hence, there is very little toxicity associated with this agent. Due to its extremely poor protein binding, it has a very short duration of action in all the situations where it is used. The toxic dose is thought to be in the range of 1000 mg., but reports of toxicity associated with procaine use are extremely rare.

Clinical uses of procaine at the present time are extremely limited. It is effective for skin infiltration in limited areas. It is used in combination with tetracaine for spinal anesthesia in certain circumstances and has a particular favor at the Brigham and Womens Hospital in Boston for obstetric spinal anesthesia for Cesarean-section. It is used in that circumstance in combination with tetracaine to increase the duration of the block associated with tetracaine as well as perhaps increasing the intensity of the block by combination of synergistic effect. It is also used in the context of pain therapy for differential blockade with increasing concentrations. One aspect associated with toxicity in the use of procaine is the production of the metabolite para-amino-benzoic acid, discussed earlier, which is associated with an increased rate of allergy.


CHLOROPROCAINE

Chloroprocaine (a chemical modification of procaine) is an short duration amino ester local anesthetic with pKa of 8.9, prepared in solution with a pH of 2.5 to 4.0. It is characterized by rapid onset of action despite a high pKa. Due to its extremely low toxicity relatively high concentration is used. It also has an extremely short plasma half-life because it is metabolized by cholinesterase and reports of CNS toxicity are extremely unusual. Toxic dose is thought to be in the range of 800 to 1,000 mg. or more with epinephrine. It is thought to be the least toxic in the CNS and/or cardiovascular system of all agents in current use.

The most relevant clinical use presently is epidural anesthesia. It is also used in peripheral blocks with short duration; as well as combined with other long acting, slow onset local anesthetics for the combined effect of rapid onset with prolonged duration. Examples of these agents are: bupivacaine and tetracaine. In obstetrics, there is epidural chloroprocaine that is used in situations where epidural anesthesia must be rapidly converted to high level for Cesarean-section or, rapidly providing anesthesia to the perineum for application of forceps. Another advantage in obstetrics is limited or no transmission to the fetus.

Controversy exists with the use of chloroprocaine. It is related to reports of persistent, serious neurological deficits associated with accidental massive subarachnoid injection of chloroprocaine in attempted epidural anesthesia. First, it should be noted that incremental dosing was almost invariably not utilized in the cases reported and, hence, in addition, to agents specific controversy there is probably a technical error associated with these cases. Initially, the agent itself was felt to be implicated; subsequent evaluation suggest that the preservative, anti-oxidant, bisulfite, may by itself produce the phenomenon. In one study involving rabbits, the intrathecal injection of bisulfite was associated with the same persistent neurological deficits that the combination of the chloroprocaine, and bisulfite were associated. It should be noted, however, that in cell culture, chloroprocaine at supra-clinical doses is associated with cytotoxicity. It is unclear if it is clinically relevant. It has not been reported since the reformulation of chloroprocaine, without bisulfite.

The second controversy is more recent. In the context of outpatient anesthesia, epidural anesthesia with chloroprocaine has been reported to be associated with persistent severe lumbar muscle spasm. This may be associated with the acid pH of chloroprocaine. This is felt to be a relative clinical contra-indication to the use of chloroprocaine for epidural anesthesia in outpatients at this time and further investigation is pending.


TETRACAINE

Tetracaine is an amino ester with a pKa of 8.6, a commercial preparation in a liquid form with a pH between 4.5 and 6.5. It is a slow onset, very short plasma half-life, long duration local anesthetic with limited systemic toxicity. Systemic toxicity is reported to be considerably higher than procaine and two-chloroprocaine, but case reports are rare. The plasma half-life is in a 2-1/2 to 4 minute range. The toxic dose is thought to be in the 2 mg/kg range or, 120 total mg, total. This may be greater when used in conjunction with epinephrine.

Clinical uses of tetracaine are principally related to spinal anesthesia with and without the use of epinephrine resulting in a fairly reliable, long onset spinal anesthetic. It is also used in combination with other agents for conduction block. Examples of this would include the combination with lidocaine or chloroprocaine for axillary, interscalene, femoral, sciatic or ankle blockade. It is also used by ophthalmologists for topical anesthesia of the eye and by pulmonologists and other endoscopists for topical anesthesia of the airway.


COCAINE

Cocaine is an amino ester local anesthetic with the pKa of 8.5 and a pH in commercial preparation which is extremely variable. It is a slow onset, short duration local anesthetic which has the unique characteristic of being a vasoconstrictor. All other local anesthetics are associated with vasodilation. CNS toxicity is related to both the local anesthetic properties of the agent as well as its influence on re-uptake of catecholamines. Impaired re-uptake of can be associated with adrenergic phenomenon to include hypertension, tachycardia, arrhythmia and other serious cardiac effects.


BENZOCAINE

Benzocaine is an amino ester with a pKa 8.5 and pH in preparation between 4.5 and 6.0. It has a slow onset, short duration and moderate toxicity. The estimated toxic doses is in the 200-300 mg. range. Its clinical use is limited to topical anesthesia for which it is uniquely suited and in particular situations where it is supplied by aerosol to mucous membranes and in inaccessible areas of the airway. Excessive use of benzocaine in pediatric cases is associated with met-hemoglobinemia.


Written by Dr John E Tetzlaff