Lidocaine vs. Lidocaine HCl in Pharmacy Compounding

By Andrew Glasnapp, PharmD, PCCA Senior Clinical Compounding Pharmacist

Swedish chemists Nils Löfgren and Bengt Lundqvist discovered lidocaine in 1942. Pharmaceutical manufacturer Astra AB (which later joined with Zeneca Group PLC to form AstraZeneca) subsequently acquired the rights to it and secured a U.S. patent in 1948. They then started manufacturing it in Worcester, Massachusetts, in 1951. Lidocaine was already in very high demand by that point, and demand remains very high in our compounding world. PCCA currently has over 300 formulations containing lidocaine, and nearly 5% of our Clinical Services inquiries are to discuss lidocaine in some manner. Many inquiries we receive at PCCA are focused on patient safety and knowing when to use each form of lidocaine. To compound appropriately with this active pharmaceutical ingredient (API), it is beneficial to understand its chemical and physical properties, clinical considerations of some common uses, and the safety and toxicity profiles.

Chemical and Physical Properties of Lidocaine and Lidocaine HCl

PCCA currently sells two forms of lidocaine: Lidocaine Hydrochloride USP Monohydrate (PCCA #30-1213) and Lidocaine USP (PCCA #30-1031).

Lidocaine Hydrochloride USP Monohydrate has a molecular weight of 288.81. The molecular structure contains one molecule each of chloride and water. The term “hydrate” refers to “water of hydration.” Water of hydration is water that is stoichiometrically bound into a crystal. You could consider Lidocaine Hydrochloride USP Monohydrate to be the ionized form of lidocaine.

Lidocaine Hydrochloride USP Monohydrate is very water soluble. The pH of an aqueous solution is acidic, often in the range of 4-5. It has a pKa of approximately 7.8. Remember, pKa is the acid dissociation constant, where a molecule exists half in ionized form and half nonionized. What that means to a compounder is that, in an aqueous vehicle, Lidocaine Hydrochloride USP Monohydrate will be half precipitated at a pH of 7.8. As a practical matter, you should be concerned with any pH above 7 since precipitation may start below the pKa value.

Lidocaine USP, sometimes referred to as lidocaine “free base” because it is not bound with chloride and water, has a molecular weight of 234.34. By comparing the molecular weights, you can see a salt ratio of free base to HCl monohydrate salt of 1:1.23. Lidocaine USP is not soluble in water; however, it is soluble in ethyl alcohol and oils. You could consider Lidocaine USP to be the nonionized form of the chemical.

Clinical Considerations for Lidocaine and Lidocaine HCl

Choosing the correct form of lidocaine to use can be challenging. You can gain more insight into this choice by examining lidocaine’s mechanism of action as well as the location of its receptor site on neurons.

Lidocaine acts mainly by inhibiting sodium influx through sodium-specific ion channels in the neuronal cell membrane — in particular, the so-called voltage-gated sodium channels. When the influx of sodium is interrupted, an action potential cannot arise, and the neuron cannot conduct the signal. The receptor site is thought to be located at the cytoplasmic (inner) portion of the sodium channel. Lidocaine Hydrochloride USP Monohydrate binds more readily to sodium channels in an activated state; thus, it tends to take effect faster in rapidly firing neurons. This is referred to as state-dependent blockade. When a patient is in pain, the sodium channels are in an activated state, and the ionized form of lidocaine (Lidocaine Hydrochloride USP Monohydrate) is the best choice.

Conversely, when a patient is not in pain, and you wish to provide anesthesia prior to a pain stimulus, the nonionized form of lidocaine (Lidocaine USP) is the best choice. Since lidocaine’s receptor site is thought to be on the internal surface of the cell membrane, the drug must penetrate the membrane, which is achieved best in the nonionized form. This is most important when applying lidocaine to the surface of skin but not important when applying to mucous membranes.

When to Use Lidocaine and Lidocaine HCl

The information in the table above does not reflect absolute rules. There may be exceptions in certain situations.

Tip for More Effective Topical Anesthesia Prior to Pain Stimulus

Many physicians will prescribe higher and higher concentrations of lidocaine when they wish to achieve more effective topical anesthesia prior to a pain stimulus. In theory, this makes sense, but the limiting factor is the solubility of lidocaine in the vehicle chosen. Absorption rate through the skin is limited by the concentration gradient, which in turn is limited by the solubility of lidocaine in the vehicle. Therefore, no gain in effectiveness is achieved by exceeding the solubility in the vehicle.

A consideration for topical anesthesia prior to a pain stimulus is to focus on the application procedure. A technique called “stripping the skin” removes the top layers of dead skin cells as well as some sebum and triglycerides on the surface and, if done correctly, can dramatically increase onset of anesthesia. The first step is to scrub the skin vigorously with ethyl alcohol. Next, apply the compound to the surface followed by occlusion. Some prescribers recommend occlusion for 30 minutes, depending on the situation. This technique is only necessary when applying anesthesia prior to a pain stimulus.

Common Lidocaine Uses and Dosages

Lidocaine Hydrochloride USP Monohydrate is commonly used in many aqueous dosage forms. Some examples are in the table below.

Lidocaine USP is commonly used in anhydrous dosage forms. Some examples are included in the table below.

Safety and Toxicity Considerations for Lidocaine and Lidocaine HCl

Lidocaine is classified as a IB antiarrhythmic. Its antiarrhythmic effects result from its ability to inhibit the influx of sodium through the "fast" channels of the myocardial cell membrane, thereby increasing the recovery period after repolarization. Lidocaine suppresses automaticity and decreases the effective refractory period and the action potential duration in the His-Purkinje system at concentrations that do not suppress automaticity at the sinoatrial node. The drug suppresses spontaneous depolarizations in the ventricles by inhibiting reentry mechanisms, and it appears to act preferentially on ischemic tissue.

Lidocaine can cause adverse cardiovascular effects such as myocardial depression, sinus bradycardia, hypotension, cardiovascular collapse and cardiac arrest. These effects typically occur with high plasma drug concentrations but have occurred with smaller doses in rare instances.

The maximum intravenous dosage for regional anesthesia is 300 mg of lidocaine in 10-60 mL of a 0.5% solution. The intravenous route presumes 100% absorption and immediate distribution. Therefore, compounded lidocaine in routes that have less than 100% absorption and dosages under 300 mg provide a theoretical margin of safety. Pharmacists should always consider the milligram strength of lidocaine and not just the percentage strength. For example, a 10% lidocaine compound contains 100 mg of lidocaine per gram. The theoretical safety margin would then be an application of no more than 3 Gm, which would contain 300 mg of lidocaine. Another safety factor is the volume of the preparation dispensed to a patient. Compounders can provide a margin of safety by limiting the quantity dispensed and therefore reduce the risk of an accidental toxic dose. PCCA members can access PCCA Document #97181, Topical Anesthetics — Dosing and Safety, which is a helpful resource for learning more about dosing considerations. Below is a table from that document.

The information in this table is based on data from the package inserts of commercial products, which are listed in the references at the end of this article.

Allergic and anaphylactic reactions have been associated with lidocaine administration. Allergic reactions may manifest as cutaneous lesions, urticaria, edema, angioedema, bronchospasm, dermatitis, dyspnea, laryngospasm, pruritus or anaphylactic shock. Allergic reactions may occur as a result of sensitivity either to local anesthetic agents or to other components in the formulation. Since lidocaine is an amide-type anesthetic, the recommendation would be to avoid any other amide-type anesthetic agents like bupivacaine (Marcaine^®) and ropivacaine for patients with an allergy to lidocaine. There have been no reports of cross-sensitivity between lidocaine and the ester-type anesthetics like procaine, tetracaine and benzocaine.

Lidocaine was discovered almost 80 years ago, but its demand hasn’t diminished since then. It’s imperative to understand its chemical and physical properties, clinical considerations of some common uses, and the toxicity profiles in order to compound appropriately with this essential API.

Andrew Glasnapp, PharmD, FAPC, PCCA Senior Clinical Compounding Pharmacist, has been a registered pharmacist since 1990 and completed the University of Arkansas’ nontraditional PharmD program in 1999. After serving two years as corporate director of compounding for Pharmacy Associates Limited in Marshalltown, Iowa, Andrew moved to Houston in 1993 to work for PCCA. In the past, he has served as a clinical instructor in drug information for both the University of Houston and the University of Arizona colleges of pharmacy. Andrew is also a past member of the compounding task force of the Iowa Pharmacists Association and the compounding section of the Texas Pharmacy Association’s executive committee. Andrew is the recipient of the University of Houston Clinical Preceptor of the Year Award for 2000 as well as the Eagle Award in 2005, one of the most prestigious awards presented by PCCA.

A version of this article originally appeared in PCCA’s members-only magazine, the Apothagram.

References

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These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The information contained herein is not intended to replace or substitute for conventional medical care, or encourage its abandonment.