Lidocaine Pharmacology: Local Anesthetics, Mechanism and Uses PDF

PM 716 Pharmacology Chapter 26 Local Anesthetics Seven Things (ST) Document fort **Lidocaine** \(1) Drug Class and Stem: Lidocaine is an amide local anesthetic Stem is "caine" because all local anesthetics were derived from cocaine (but cocaine is an ester local anesthetic). Examples of amide...

PM 716 Pharmacology Chapter 26 Local Anesthetics Seven Things (ST) Document fort **Lidocaine** \(1) Drug Class and Stem: Lidocaine is an amide local anesthetic Stem is "caine" because all local anesthetics were derived from cocaine (but cocaine is an ester local anesthetic). Examples of amide local anesthetics, lidocaine, mepivacaine, ropivacaine, articaine etc. One "i" = ester local anesthetic Two "i" = amide local anesthetic They are called amides because they are destroyed by an amidase enzyme found in the liver. Some are called esters because they are destroyed by an esterase enzyme which is in every tissue in the body. Which local will act longer, esters or amides? Inject lidocaine into the toe and it will not be destroyed until it reaches the liver which gives the podiatrist time to complete the surgery. \(2) Primary Use: Anesthetize a local area of the body. \(3) Site of Action: The sodium channel on neurons Remember the issue: charged molecules are water soluble and do not cross membranes uncharged (neutral) molecules are readily soluble in lipid The problem is lidocaine must be uncharged (neutral) to pass through lipid membranes to reach the neuron. However, the charged (water soluble) form is required for binding to the inner vestibule of the sodium channel. More on this to come below. Lidocaine (and all others in the amide class) exist when injected are in an equilibrium between charged and uncharged forms. \(4) Mechanism of Action: Block voltage gated sodium channels in neurons When a voltage signal arrives at the axon terminal the sodium channel opens and sodium flows in (Na outside the axon 150 mm/L, Na inside 5 mmol/L). Think of this as the flow of an electrical signal repeated a billion times down the Lidocaine (and all others) block the sodium channel and prevent it from opening to allow sodium to flow into the axon. The signal that tells the brain, "You feel this pain," never arrives. (The phone has gone dead.) \(5) Physiological Effects The pain signal from the toe never arrives in the brain to be detected by the patient. \(6) Major ADRs: \(a) Major dangerous systemic effects due to inadvertent injection into the vascular system. May cause sedation, light-headedness, visual and auditory disturbance, tongue numbness and a metallic taste. Seizures and cardiac death can occur at high doses. \(b) Neurotoxicity from local effects produced by direct contact with neuronal elements. Found mostly with spinal and epidural application of the local anesthetics. \(7) Anything Unique About Administration: The t ½ of lidocaine is about 10 min, other amides run from 5 to as much as 28 min. Liquid for injection with or without an added vasoconstrictor (epinephrine) used to cause vasoconstriction and slow down the removal of the drug from the site of injection. Topical patches, and topical creams of lidocaine available OTC. \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ \(1) **Lidocaine (Xylocaine^^)** \(a) pH of the injectable solution is pH 6.5 \(b) pH of the injectable solution with added epinephrine is pH 4.5 (REF: Xylocaine product insert, APP Pharmaceuticals, LLC, Schaumberg, IL 60173, Product Insert \# 451175A, date, Feb 2010). \(2) **Lidocaine pKa** \(a) The pKa of lidocaine is 7.86 At pH 7.86, lidocaine is 50% ionized (water soluble) and 50% (REF: Osol, A., ed, Remington's Pharmaceutical Sciences, 16^th^ edition, 1980, pg 994). \(3) All pharmaceutical companies prepare their final lidocaine with and without epinephrine in a controlled buffer solution. The pH of the buffer solution is chosen to provide the greatest stability of the drug (to give the longest possible shelf life). This pH "may" not be the best pH for clinical efficacy, lack of pain etc. But rather it is a compromise between shelf stability and maximum efficacy. \(4) The fastest onset of action of a drug is often the drug that is mostly in the lipid soluble unionized form. The drug must cross membranes to reach the sodium receptor on the axon, bind and block that sodium channel. \(5) Acidic injectable drugs are more painful compared to neutral or alkaline drugs (from what the medical books teach) Several articles on the subject of pH adjustment of lidocaine were brought to my attention by students in a previous class. These may have been mentioned in the student's other classes. They asked me for comment and I will share this with you. \(1) Sinnott, C.J. et al., *Anesthesiology* 93:1045-1052 (2000) \(a) Commercial lidocaine 1% adjusted to pH 7.99 with sodium bicarbonate resulted \(b) The rest of the article was too confusing, had too many variables, diluted commercial lidocaine in water to various percentages without regard to the fact that the buffer in the commercial preparation was not designed to be diluted, did not describe the buffer in the commercial preparation etc. etc. \(2) Frank, S.G., *Canadian J Plastic Surgery* 20:71-73 (2012) \(a) 1% and 2% lidocaine were found to have a pH of about 6.09. With epinephrine the pH was about 4.2 (same as the Product Insert data show above). \(b) The target for pH adjustment was 7.38 to 7.62. The authors then describe how to make the buffer adjustment. A well done, simple, clean paper with well defined objectives. \(3) Parham, S.M., *Can J Surgery* 39:31-35 (1996) \(a) Double blind randomized clinical trial on lidocaine, lidocaine adjusted with sod bicarbonate, or saline injections sc to determine which is more painful. \(b) RESULTS: Lidocaine pH 6.79 (no adjustment) pain score \~ 20 Lidocaine pH 7.82 (sod bicarb adjusted) pain score \~ 10.5 Saline pH 6.5 pain score \~ 30 \(c) Authors conclusions are that adjusted lidocaine is better than unadjusted lidocaine regarding pain but no difference with regard to onset or duration of action. \(d) Comments by RMR: \(1) Saline at 6.5 is more painful than lidocaine at 6.7, must be the effect of the anesthetic and nothing to do with the pH (?). \(2) OK, raise pH of lidocaine and pain is less. Could this be due to the fact that a pH further away from the pKa makes the drug penetrate better? \(3) IV saline has a pH of 6.5 and patients do not report pain. Why? I am not sure. \(4) Gosteli, P., *Anesth Analg* 81:104-109 (1995) \(a) Control: 2% lidocaine with epinephrine at pH 4.58 Test 1 2% lidocaine with epinephrine adjusted with sod bicarb to pH 6.47 Test 2 1.73% lidocaine with epi adjusted with sod bicarb to pH 6.42 \(b) Results, onset time , no difference surgical anesthesia better in pH adjusted lidocaine complete block better in pH adjusted lidocaine \(c) Comments RMR, OK same as other reports. Good study because it is focused on foot and ankle surgery. Same issues of confusion on my part with regard to pH, ionization, pKa etc. \(5) Zahl, K. Ophthalmology 98:239-242 (1991) \(a) 2% lidocaine 2% lidocaine with sod bicarb 2% lidocaine with epinephrine 2% lidocaine with epinephrine pH adjusted \(b) Results: buffered lidocaine had the fastest onset of action \(6) Chow, MY, Anesth Analg 86:566-568 (1998) \(a) No comments. \(7) Sinnott, C. J., Anesthesiology 93:1045-1052 (2000) \(a) A study in rats may or may not apply to humans. \(b) Lidocaine pH adjusted from 6.58 to 7.99 with sod bicarb decreased the degree and duration of block. \(c) Lidocaine with epi and pH adjusted hastened onset, without effecting degree or duration. \(d) OK, not sure of the importance. Epi causes vasoconstriction, drug stays at injection site longer etc. etc.