Ain Shams University, Faculty of Pharmacy

Department of Clinical Pharmacy…………….

DO NOT WRITE YOUR NAME OR ID
Degree: …Bachelor of Pharmacy………….
Year/Level: Third-year………….
Course Title: …Pharmacokinetics…………
Course Code: …452/2………….
Academic Year: Second Semester 2019-2020
Topic Title:……Lidocaine………………………………..

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Abstract:

Lidocaine is a class 1B anti-arrthymatic drug used in the treatment of ventricular arrhythmias.

It is also used as a local anesthetic in dental complications[1]. Based on our study to the pharmacological
action of Lidocaine, its structure-activity relationship characteristics[2] and the way it interacts inside the
body from the moment it is administrated till it is excreted out of the body which is called
pharmacokinetics[1], we could determine the proper dose for different ages and multiple conditions.
Although it has a very complicated modeling mechanism, with a high ability to cause toxicity, we can
study its path through the body and also provide safer ways and methods to use Lidocaine on a wider
range and spectrum without any human intervention[1].

By using different (TDM) methods we could specify the drug’s half life[3], we could also know the
elimination ratio, the proper dosage form and the possible effective route of administration[1]. We could
assess its efficacy in treating different populations of people with hard conditions like chronic liver
diseases or renal diseases, the condition of pregnancy, and the possible ways to administer Lidocaine
either in heart problems or in Dental anesthetizing[4].

Keywords:

(TDM) means Therapeutic drug monitoring

(ADME) absorption-distribution-Metabolism,

Introduction:

Pharmacology is the field of knowledge that aims to study the drugs used in the treatment and the support
of the body defense mechanisms against different diseases. It has major two branches that explain the
ability of the drug to interact within body systems to give its effect; Pharmacodynamics which is the
branch related to the effect and Pharmacokinetics which is the branch concerned with the interaction of
the body with the drug upon administration a given dose[5].

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Pharmacokinetics of the drug describes the effect of the route the drug will take since the dose has
approached the body cavity, its passage from the site of administration to the body circulation which is
termed as absorption, its specific accumulation in a certain organ rather than others. This behavior is
known as distribution and the factors concerning its occurrence, its conversion from the active form that
may cause toxicity into the less active form of more hydrophilicity (or vice versa) which is called
Metabolism and finally the method it makes its way out of the body in a process called Excretion[5].

Absorption can occur from different routes of administrations; the Enteral route for example, which
includes oral route which is characterized by its liability to lose a number of its active ingredients due to
the first-pass metabolism, and the sublingual route which bypass the first-pass metabolism and is limited
to some drugs like nitroglycerine. There is also the parenteral route which includes three subtypes: the
(IV) route in which no absorption takes place as the site of administration is the systemic circulation
itself. There is also the (IM) and the (SC) routes and all of them are not affected by the first-pass
metabolism.

Absorption is affected by the blood flow, the suitable contact surface, and duration for absorption. That’s
why the small intestine is better as an absorption site than the stomach. Also, the ratio between the ionized
and the unionized form affect the amount absorbed, as the uncharged form of the weak acids and bases of
different drugs is the absorbed form, so the environment of the drug controlled by its pH and the PKa of
the medium must be adjusted to increase the uncharged form. Theoretically, weak acidic drugs would be
better absorbed in acidic medium while weak basic drugs are better absorbed in the basic medium[5].

Distribution is the affinity of the drug to be concentrated in some areas rather than other areas inside the
body. This affinity depends on many factors like the Blood flow which varies as it is high in some areas
like the brain, kidney, and liver, these organs are highly perfused not like the adipose tissue so distribution
differs according to the site[5]. Distribution is also affected by the capillary permeability as BBB is
characterized by providing the brain great security against wide ranges of drugs, it may become
permeable due to meningitis[6].

Some of the drugs remain free in the plasma and able to do its pharmacological effect or can be
metabolized or excreted, while the rest is bound to plasma proteins like albumin. The binding depends on
the intrinsic capacity of albumin as it prefers to bind to the anionic hydrophobic drugs. also, the

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competition between drugs on the binding with the plasma protein concerning their affinity plays an
important role in the distribution of the drug[5].

Metabolism is the process in which is the drug or any foreign material in the body is changed from a form
to another form easily excreted by the body[6]. It occurs through two phases. The first phase aims to
increase the hydrophilicity of the drug to be a substrate useful to enter the second phase which includes
the addition of large groups by Glucuronidation or acetylation. In some cases, the drug starts with the
second phase which includes acetylation like isoniazid then proceeds to the first one[5]. This sequence
produces a drug easily excreted out of the body. Usually, the result of this process is an inactive drug.
However, there are some exceptions; procainamide when metabolized yields N-acetyl procainamide
which is active[6].

Excretion is the process in which the body gets rid of the toxic wastes and the different products of
metabolism. It has a product of certain hydrophilicity enough to be excreted and can’t be reabsorbed again
as lipophilic drugs. It includes three steps: Glomerular filtration with the help of the hydrostatic pressure
in the glomeruli, all drugs, and substances that can pass, they pass based on their size independent of other
factors like pH or solubility. The second phase is the reabsorption. The drugs of high lipophilicity and
also useful materials like amino acids or glucose can be reabsorbed through this phase. If the drug remains
uncharged, it can be reabsorbed and cause toxicity, so Manipulation of the urine depending on the nature
of the drug will help to prevent this type of toxicity in a process called ion trapping Where alkalinization
of urine would be useful to get rid of acidic drugs while acidification of the urine will be useful to get rid
of basic drugs.

We can observe here that we made the contrary to the absorption case, as we here want the drug in the
ionized form to get rid of it. The secretion phase which includes the transfer of materials by active
transport to the tubules to be excreted depending on two active transport systems: anionic and cationic
systems. One of the most famous applications is the mixture of penicillin and probenecid, in which the
latter increases the half-life of penicillin contributing to its high binding affinity to the anionic carriers so
penicillin stays longer in the systemic circulation[5]

Studying (ADME) gives us the knowledge about the drug that we use, which will help in modeling
diagrams explaining the concentration of blood in plasma and urine to interpret the equations That we can

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calculate from them the half-life,(Cmax) and many other parameters like the volume of distribution and
Elimination constant[6].

The action of the drug inside the body and all the possible information will be useful to take from this
general knowledge what suits every case to provide our patient with the suitable medical care to help in
curing him based on his health and the condition he has. This application is called clinical
pharmacokinetics, so for each case, we can calculate the dose regimen of the patient, expected side
effects, duration, and possible adverse effects[6].

Figure 1 showing the structure of Lidocaine (Xylocaine)[7]

Lidocaine has three main parts; a lipophilic center which is important for the anesthetic activity as it is
responsible for the binding with the channel proteins (the two methyl substitutions protect the drug
against amidase activity, an intermediate chain formed of an amide linkage which is more resistant than

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the ester bond with a bridge and finally the hydrophobic center which is formed of secondary amine
which is responsible for making salt of Lidocaine[2].

Lidocaine is an antiarrhythmic drug class IB that also serves as a local anesthetic. The cardiac
physiological effects of lidocaine in standard serum concentrations are generally restricted to the His-
Purkinje system and the ventricular myocardium. It has a small impact on the autonomic nervous system.
Lidocaine is most commonly used in the treatment of indicative or life-threatening ventricular
arrhythmias as an alternative to other antiarrhythmic drugs. However, it is not recommended for treating
supraventricular arrhythmias. Many years ago, lidocaine was prescribed as the primary treatment of
isolated premature ventricular beats but was later no longer used[1].

Newly revised protocols for advanced cardiac life support (ACLS) strongly advise that lidocaine be
included in the treatment of defibrillation-resistant tachycardia/fibrillation (VT / VF) that will not respond
to amiodarone[1].

Lidocaine can be administrated by (I.V) infusion, (I.M) injection which is preferred to be in the Deltoid
muscle for better bioavailability, via an endotracheal tube or by Intraosseous infusion due to a cardiac
arrest. When it is taken orally it suffers large variability due to the first-pass metabolism. Lidocaine
accompanied by epinephrine (targeted for anesthesia) can not be used for cardiac or anticonvulsant
purposes
Only those lidocaine parenteral preparations are obtainable as the hydrochloride salt and contain 86 %
.lidocaine base (S = 0.86)[1]

After Intravenous injection, Lidocaine is widely spread in body tissues[1].

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Figure 2 presents a table showing distribution volume (V) for diverse patient populations after the
administration of a dose of lidocaine[1].

Lidocaine is predominantly metabolized by multiple cytochrome P450 isozymes by simultaneous de-

ethylation steps: CYP3A5, CYP3A4, and CYP1A2. CYP1A2 may be mainly accountable for the
lidocaine biotransformation in individuals with the normal liver at clinically relevant concentrations of
lidocaine. The ratio of liver extraction is high, ranging from 0.62 to 0.81 of the dose given[1].

As for other heavily absorbed products, the biggest factor of clearance appears to be the hepatic blood
flow. However, alterations in lidocaine clearance may also result from activation or suppression of hepatic
enzymes. Therefore, changes in either intrinsic hepatic metabolic capacity or hepatic blood flow may
affect lidocaine elimination. Lidocaine metabolism results in the development of two metabolites,

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(MEGX) and glycinexylidide (GX). MEGX may lead to both pharmacological and toxic effects whereas
GX may lead to toxicity[1].

Lidocaine's attitude is generally portrayed by an open, two-compartment model[1]. Drugs with two
compartments model will have a central compartment and a peripheral compartment not like drugs of the
one-compartment model that have instantaneous distribution and only have a central compartment[8]. The
central compartment includes the highly perfused tissues which are: liver, kidney and in the case of our
drug the heart is considered as a central compartment as it takes no time for lidocaine to reach the heart
and start its action[9]. In this case, no instantaneous distribution takes place as in the one-compartment
model drugs as the drug takes time to diffuse through different tissues in the body. Although elimination
occurs during the distribution phase that’s why there is a rapid decline in the first part of the model. At the
end of this phase which is called the alpha or the distribution phase, The rate of decline starts to decrease
because the effect of distribution becomes negligible as there is a state of equilibrium that has been
reached between the central and the peripheral compartments. The second phase is called the elimination
phase[8].

Figure 3 showing the two-

compartment model of
Lidocaine drug which is
taken intravenously[1].

Lidocaine plasma protein

binding relies on many
factors, including the dosage
of drugs, plasma protein sort
and dosage, sample
processing method, pH, and method of quantification. Lidocaine shows binding depending on
concentration; the degree of binding decreases as the overall concentration. While lidocaine links to
albumin (~25 %), the dominant amount about (~50%) is bonded to alpha-1-acid glycoprotein (AAG).

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Health conditions change (AAG) concentration. Reduced AAG concentrations lead to a higher unbound
lidocaine fraction and greatly increased therapeutic and toxic effects for any concentration. In
comparison, elevated concentration of AAG decreases the number of active drugs and may reduce the
pharmacological impact at any given overall concentration of lidocaine[1].

Factors causing drug-drug interactions concerning lidocaine administration are the free form of the drug
and the intrinsic clearance. These factors cause a mild to moderate effect on the dose to be taken to the
patient if there is another drug that causes any of these factors, but the most important factor that may
induce a large impact on the actual dose is the effect on the hepatic blood flow[1].

Amiodarone and Erythromycin cause a state of CYP3A4 inhibition, so it causes an increase in the
duration of action of lidocaine. This effect is usually mild to moderate, so we should decrease the
Lidocaine dose with a ratio ranging from 10% to 20%. Beta-adrenergic receptors cause a decrease in the
hepatic blood flow and a decrease in the intrinsic clearance causing a major effect, so patients taking
Metoprolol should decrease the Lidocaine dose by 30%, and if propranolol was the drug taken he should
decrease the Lidocaine dose by 40% to 50%.

Cimetidine causes a decrease in the hepatic blood flow but the interaction occurs only upon oral
administration, so it has a minor to moderate effect causing a decrease in lidocaine infusion rate by 15%
to 25%. Fluvoxamine is an exception of drugs affecting Lidocaine as it doesn’t decrease the hepatic blood
flow, but it is a potent inhibitor to CYP1A2- causing a major impact leading to a decrease in the infusion
rate of Lidocaine by 40% to 60%[1].

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 Figure four showing the different drug-drug interactions caused by the different doses of Lidocaine.

Cytochrome P450 3A4 is the most plentiful isozyme of the CP450 class. Lidocaine is the main substrate
that is metabolized by it. There was a study done to inspect the genetic variability that may occur due to
the presence of 23 CYP3A4 alleles of this isoform. The study also aims to assess its catalytic impact if the
case has a certain allele more abundant than other isoforms[10].

CYP3A4*1 and other 22 CYP3A4 forms were produced in Spodoptera frugiperda 21 insect cells.
Lidocaine was then added to the microsomes. The experiment was accomplished with 50–3,000 µM for
60 min at 37°C. UPLC technology was used to analyze the results. The results showed that there 2
inactive alleles with no activity (variants number seventeen and thirty). 5 alleles (variants number two,
five, nine, sixteen, and twenty-four) were found to cause a decrease in the intrinsic clearance when being
compared to the wild type (variant number one)[10].

The two-compartment model representing Lidocaine, The carriable pharmacokinetics due to extensive
metabolism and the limited safety of its dosing are the reasons causing dosing strategies of Lidocaine to
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be difficult and require care. So, arrhythmia should be treated by loading doses for the first time to
provide an acceptable distribution within the central compartment. The Lidocaine is rapidly distributed to
the peripheral compartment causing a decrease in the concentration in the blood to a sub-therapeutic level,
so the (IV) bolus should be maintained continuously according to the suitable age taking the
medication[1].

Figure five showing the different strategies based on the dosage form type to treat Ventricular
arrythmia[1]

However, there must be continued maintenance to the rate of the dose administered as the condition may
change during administration. Many methods were carried out to adjust a continuous dose which is
effective to treat in proper time at proper concentration with least human intervention as shown below in
figure 6. Methods number three and four are considered to require some human intervention but it doesn’t

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need a special delivery system. While in the case of method 5 it needs a special delivery system but it is
characterized by the absence of the need for human intervention[1].

Figure six showing how to maintain and manage the administration of Lidocaine infusion[1].

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Diseases in the liver which are chronic typically reduce the removal of lidocaine. Regardless of the
expected decrease in protein-bound for this patient, a sustained infusion at 1.3 mg/kg/hr for concentrations
of 3 mg / L will be introduced. The severity of hepatic dysfunction according to Child-Pugh can affect the
selection of the starting infusion dose. The added concern for those prescribed to take lidocaine with
hepatic dysfunction is the possible retention of the activated MEGX metabolite. Given these drug
levels, this aggregation can increase the chance of developing toxicity[1].

Since lidocaine is almost entirely removed in healthy individuals, it is commonly believed that renal
disease does not affect its existence and removal. This research indicates that loading doses of lidocaine
do not require adjustment in patients with chronic kidney disease. Nonetheless, patients receiving long-
term dialysis with severe renal disease were included in the last researches. Another study showed that
lidocaine clearance decreases significantly in patients with severe chronic renal insufficiency (i.e., CrCl <
30 mL / min/1.73 m2) who do not make hemodialysis. So we can conclude that the initial doses of
Lidocaine should be reduced for a patient suffering from chronic kidney diseases[1].

Ideal body weight (IBW) must be used to measure the proper dose, and ABW will be used to determine
the continuous dose of IV infusion. At present, lidocaine is classifieds class B drug. Even if lidocaine
quickly traverses the placenta to the fetus, interpretative research studies in which lidocaine was
prescribed to the mother at any stage of pregnancy showed no evidence of a link between the use of
lidocaine in large categories with the occurrence of birth defects. Also when it is used as a local
anesthetic, The addition of epinephrine causes a delayed passage to the placenta so it is considered to be
safe during pregnancy[4]. Although minor levels of lidocaine are released into breast milk at
concentrations of ~40 %, The American Academy of Pediatrics finds no harm to use it with breast
feeding[1].

The (TDM) methods are used to adjust the therapeutic ranges of many drugs, but the most important
contribution is in the detection of the effective and toxic concentrations of class 1 antiarrhythmic drugs
due to the narrow therapeutic range of these drugs[3]. As for Lidocaine, effective concentration is as
important as the toxic concentration[1]. It is important to determine the concentration of the drug in the
plasma with no interference with the metabolites produced from Lidocaine which was achieved by
Enzyme Immune Assay (EIA) method[3].

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The widely agreed dosage range is 1.5–5 μg / ml with a distribution half-life of about 8 minutes as it
takes a small time to cross to the peripheral compartment and approximately 2 hours of elimination half-
life. Some patients may witness some side effects at therapeutic doses higher than 3 μg / mL, such as
dizziness, drowsiness, euphoria, or parrhesia. Concentrations of lidocaine serum outside the therapeutic
limit can induce twitching of the body, anxiety, agitation, dysarthria, paranoia, seizures, or coma. In
lidocaine concentrations higher than 6 μg / mL, cardiac negative impacts such as hypotension,
atrioventricular block, and circulatory collapse have been reported but are not highly linked with
particular serum concentrations. Seizures triggered by lidocaine are not as difficult to diagnose as seizures
caused by theophylline and usually treated by common antiseizure medication therapy. Lidocaine
derivatives (MEGX and GX) are probably responsible for the central nervous system adverse effects
related to lidocaine treatment[1].

Figure 7 showing the effect of different concentrations and their possible adverse effects[1].

Lidocaine is usually intravenously administered but may also be administered intramuscularly. Upon
intramuscular injection, absorption is fast, with optimum concentrations occurring approximately 1 hour
upon administration and 100 percent bioactivity. The medication of intramuscular administration may
boost creatine kinase (CK) levels due to muscle injury caused by the injection, and this enzyme is
evaluated in patients who would have had a myocardial infarction. So the comparatively heart-specific
creatine kinase isozyme (CK-MB) needs to be assessed in patients with myocardial infarction that have
given intramuscular injections[9].

In the ordinary population, plasma protein binding is about 70 percent. For this amount, roughly 30
percent is due to albumin-binding medication, while 70 percent is due to α1-acid glycoprotein (AGP-
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binding lidocaine).AGP is known as an acute-phase reactant protein that is found in lower concentrations
in all persons but is secreted in high quantities in response to some diseases such as myocardial
infarction. Lidocaine's attachment to AGP is even greater in patients with these disorders, resulting in a
free drug amount as low as 10–15 percent[9].

AGP levels rise steadily over the first 12–72 hours after myocardial infarction, resulting in a drop in the
unbound lidocaine fraction from around 30 percent to 20 percent over this time. The rapid rise in protein
binding due to AGP production in patients with myocardial infarction induces a significant decrease in
lidocaine clearance, and amounts of lidocaine will rise to unusually high levels in patients taking the drug
for more than 24 hours. Owing to competing for hepatic metabolism between parent drug and derivatives,
patients suffering from myocardial infarction may experience accumulation of lidocaine during long-term
(> 24 hours) infusions. Tracking for toxic complications in patients undergoing long-term infusions of
lidocaine is also necessary, and concentrations of lidocaine serum can be related insights to avoid toxicity
to lidocaine[9].

Patients with atrial fibrillation or ventricular tachycardia should examine their electrocardiogram (ECG or
EKG) to assess the reaction to lidocaine. The treatment purpose is to reduce ventricular arrhythmias and
to prevent adverse drug reactions. Lidocaine injection is mostly stopped within 6–24 hours and it is
possible to reassess if long-term use of antiarrhythmic medications is needed or not, while prolonged
infusions can be required in patients with chronic tachyarrhythmias[9].

Serum concentration control may assist in stepping up or diminish the dosage of lidocaine. For example,
if the ventricular arrhythmia resurfaces and the concentration of lidocaine serum is < 5 μg / mL, The
solution is to increase the dose of lidocaine. After all, if the concentration of the lidocaine serum
exceeds 5 μg / mL, a dose rise is unlikely to be efficient in preventing arrhythmia, and there is an
additional chance that drug side effects may occur[9].

Conclusion:

We can finally state a fact about Lidocaine, which is that Lidocaine maybe not widely used now against
cardiac complications as before due to the great role that other safer, better pharmacokinetics and as
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effective as Lidocaine classes can perform, like the beta-adrenergic antagonists[3]. But its
pharmacological importance remains effective by utilizing modern applications and drug delivery systems
to improve its action based on our study to its unique pharmacokinetics[1].

List of references:

[1] J. E. Murphy, Clinical Pharmacokinetics.

[2] G. (Department of P. C. Kayal, “Chemistry And SAR of Local Anesthetics |authorSTREAM.”
http://www.authorstream.com/Presentation/gauravkayal-2024846-chemistry-local-anesthetics/
(accessed May 28, 2020).
[3] G. Jürgens, N. A. Graudal, and J. P. Kampmann, “Therapeutic drug monitoring of antiarrhythmic
drugs,” Clin. Pharmacokinet., vol. 42, no. 7, pp. 647–664, 2003, doi: 10.2165/00003088-
200342070-00004.
[4] J. M. Lee and T. J. Shin, “Use of local anesthetics for dental treatment during pregnancy; safety for
parturient,” J. Dent. Anesth. Pain Med., vol. 17, no. 2, p. 81, 2017, doi:
10.17245/jdapm.2017.17.2.81.
[5] M. T. P. and T. Department), “General Pharmacology 1 lecture(1),” 2018.
[6] S. S. ( D. of C. Pharmacy), “Introduction to Pharmacokinetics lecture 1.”
[7] “Lidocaine | C14H22N2O - PubChem.” https://pubchem.ncbi.nlm.nih.gov/compound/Lidocaine
(accessed Jun. 01, 2020).
[8] A. Elkhouly, “Two Compartment Model lecture 8,” 2020.
[9] L. Bauer, Applied Clinical Pharmacokinetics.
[10] P. Fang et al., “Functional assessment of CYP3A4 allelic variants on lidocaine metabolism in
vitro,” Drug Des. Devel. Ther., vol. 11, pp. 3503–3510, 2017, doi: 10.2147/DDDT.S152366.

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