Information pertaining to the pharmacokinetics and pharmacodynamics of lignocaine was examined by performing a literature search of PubMed, Embase and MEDLINE (via Ovid), pharmacology textbooks and online sources. Only articles in the English language and human studies were considered. There were no date restrictions applied to the MEDLINE and Central searches. The last search update was in November 2014. The online databases were searched for the following terms: “lidocaine”, “lignocaine”, “humans”, “pharmacokinetics”, “pharmacodynamics”, “adult”. Specifically, clinical information relevant to the pharmacokinetics and pharmacodynamics of lignocaine was included in this literature review.

Using a combined search strategy, a total of 7311 articles were revealed. A further search confining the results to “humans” and “English language” revealed 216 information sources and titles, of which 81 references were examined for analysis. A detailed review was undertaken that included the screening of manuscript or abstract titles against the key search criterion. A total of 120 articles were included in this review.

Similar to other local anesthetics, the mechanism of action of lignocaine for local or regional anesthesia is by reversible blockade of nerve fibre impulse propagation[7]. Some local anesthetic is removed by tissue binding and circulation when lignocaine is infiltrated near a nerve[8]. The remaining anesthetic enters the nerve cells by diffusion through membranes. Lignocaine then binds to sodium channels, causing a conformational change that prevents the transient influx of sodium, therefore depolarisation[9]. All potentially excitable membranes are affected, however sensory fibres are blocked preferentially because they are thinner, unmyelinated and more easily penetrated[10]. Lignocaine’s onset of action is rapid, and blockade, whilst dependent of dose given, concentration used, nerves blocked and status of the patient, may last for up to 5 h when administered as a peripheral nerve block[7].

An important indication for lignocaine is prophylaxis or treatment of life-threatening ventricular arrhythmias. The mechanism of action of lignocaine for its antiarrhythmic action is by direct effect on mammalian Purkinje fibres. By decreasing the slope of phase 4 and changing the excitability threshold, lignocaine reduces automaticity[9]. This results in a decrease of both the action potential length and the refractory period duration of the Purkinje fibres[11]. The PR interval, QRS and QT durations are not commonly effected by lignocaine[9]. There is no evidence of any important interactions between lignocaine and the autonomic nervous system, thus lignocaine has minimal effect on autonomic tone[11].

The antinociceptive effects of lignocaine are thought to be attributable to the blockade of neuronal sodium channels and potassium currents[12,13], and the blockade of presynaptic muscarinic and dopamine receptors[14,15]. Local anesthetics have also been shown to block sodium and potassium currents centrally at a spinal cord level, specifically targeting the spinal dorsal horn neurons, in addition to their generally accepted peripheral nerve blockade[13]. The mechanisms of these actions at the molecular level are complex and further characterization will be integral in our understanding of central neuraxial anesthesia.

Lignocaine has potential utility as a potent anti-inflammatory agent, although to date well-designed studies are lacking to substantiate its use in most clinical settings. A variety of lignocaine’s actions on inflammatory cells have been described. Accumulating data suggests that lignocaine’s powerful anti-inflammatory properties may be superior in many ways to nonsteroidal anti-inflammatory drugs and steroids, the traditional anti-inflammatory agents[16,17]. However lignocaine is not approved for this specific indication and potential risks of toxicity (see below), particularly in unmonitored patients, may negate its beneficial antiflammatory effects. Unfortunately, the specific molecular mechanisms involved in the migration of polymorphonuclear granulocytes and free radicals are not well known. Sodium channel blockade can be however excluded. Firstly, because in vivo local anesthetic solutions are active at lower concentrations than those required for blockade of the sodium channel, and secondly because sodium channels in vitro are often not even detectable in the cell lines that are being investigated[17].

Whilst lignocaine’s antinociceptive effects are thought to be secondary to the blockade of neuronal sodium channels and potassium currents[12,13], and the blockade of presynaptic muscarinic and dopamine receptors[14,15], its anti-inflammatory effects are complex and multifactorial. In vitro pre-incubation of human polymorphonuclear granulocytes or monocytes with varying concentrations of lignocaine have been reported to inhibit leukotriene B4 release[18], Both leukotriene B4 and prostaglandin E2 can induce edema; therefore the blockade of these cells may explain lignocaine’s beneficial effects on tissue inflammation and edema prevention[19]. In these studies, the treatment of the peritoneum with intravenous local anesthetic solutions resulted in a reduction of the amount of Evans blue-albumen extravasated from areas of inflammation, with histological examinations supporting these clinical findings. However, in the perioperative setting, development of edema is complex and multifactorial. To evaluate the effects of intravenous lignocaine on the development of edema in this setting, further clinical studies are required.

Lignocaine has been documented to block the release of interleukin-1 (IL-1), an inflammatory mediator acting on polymorphonuclear granulocytes, which in turn activates phagocytosis, respiratory burst, degranulation and chemotaxis[16,17]. This reduction in the release of interleukins may also contribute to lignocaine’s anti-inflammatory effects. In vitro, lignocaine, at concentrations of 0.2-20.0 mmol/L, has been shown to inhibit IL-1 production in peripheral blood mononuclear cells[18]. In vivo studies have shown that at high micromolar concentrations, lignocaine can inhibit histamine release from human leukocytes, mast cells, and cultured basophils[20]. Accordingly, the anti-inflammatory actions of lignocaine are thought to be attributable to lignocaine’s direct effects on macrophage and polymorphonuclear granulocyte function, in addition to its inhibition of the release of several critical markers of the inflammation cascade.

Arachidonic acid (released from phospholipids) and the subsequent generation of bioactive eicosanoids have a critical function in the regulation of tissue preservation and the patho-physiological response to organ injury and ischemia[21]. This critical sequence of biological processes is modified by lignocaine’s action on the enzymes phospholipase A2, cyclooxygenase and lipoxygenase. Lignocaine interacts in a dual manner with phospholipase A2; causing inhibition of its activity at high concentrations and stimulating activity at lower concentrations[22,23]. Lignocaine has been shown to inhibit spontaneous prostaglandin biosynthesis, in early in vitro studies[24,25]. Lignocaine administration significantly inhibited prostanoid release and biosynthesis from human gastric mucosa in response to experimental damage[26-28]. In dogs with cardiac arrhythmias the release of prostaglandin was seen to be inhibited during systemic administration of lignocaine[29]. Lastly, topical lignocaine has been shown to inhibit prostaglandin release when used clinically for the treatment of burns in an animal model[30], confirming other studies that report reduced prostaglandin release from gastric mucosa as a result of lignocaine intervention[26]. These inhibitory effects on prostaglandin release may explain some of the powerful antinociceptive and anti-inflammatory effects of intravenous lignocaine described in patients with severe burns[31,32].

Numerous in vivo and in vitro studies demonstrate the effects that lignocaine have on thromboxane B2 release[26,28,33]. Lignocaine has an inhibitory effect on thromboxane induced platelet aggregation, which may contribute to reduced incidence of venous thrombosis[34,35]. In addition, early studies demonstrate that lignocaine at low concentrations can powerfully inhibit the release of histamine from activated mast cells[36,37]. Lignocaine also has important effects on oxygen free radical production. The inhibition of free oxygen radical formation (such as superoxide anions) by lignocaine has been eloquently demonstrated in clinical trials[38,39]. The mechanism of action of this direct scavenging effect is due to lignocaine’s interaction with protein and phospholipid membranes, the interference with mitochondrial radical formation[40], and the prevention of free radical production[41].

Lignocaine has also been shown to possess antibacterial activity[16]. The potent effects of lignocaine on antimicrobial activity are related to lignocaine’s concentration and pharmacological structure. Structure is of lesser importance as both amide and ester type local anaesthetics can inhibit bacteria in high enough concentrations[42]. Lignocaine has been shown to have important inhibitory actions on various strains of bacterium, including important Gram-positive cocci such as Staphylococcus aureus and Streptococcus pneumonia, and Gram-negative bacteria such as Haemophilus influenza and Pseudomonas aeruginosa[16,43-46]. Lignocaine’s anti-bactericidal effects are poorly understood, however complex interactions between the local anesthetic solutions and the bacterial wall[47] or with macromolecules at the surface of the bacterium[44] have been implicated. Functional changes, which include the alterations in the membrane proteins and reductions of membrane fluidity that may be induced by electrostatic interactions between anionic membrane components and cationic local anesthetics, have been implicated mechanisms[45,48,49]. Consequently, various cell and membrane functions such as the DNA binding properties of the cell and membrane-bound ATPase activity may be inhibited[50,51]. The immuno-modulating and anti-inflammatory effects of lignocaine are summarized in Table 1.

One of the earliest studies evaluating the pharmacokinetic properties of lignocaine was by Friden[52] in 1965. It was observed that lignocaine displayed a rapid onset of action, but of very short duration (between 10-20 min) after the intravenous administration of either 50 or 100 mg boluses doses. In the same year, Beckett et al[53,54] reported that lignocaine had a half-life of approximately 10 to 20 min one hour after the administration of an intravenous bolus. Two years later, Gianelly et al[55] reported that patients with occlusive coronary artery disease who were administered a continuous intravenous lignocaine infusion, without an initial loading dose, achieved acceptable plateau plasma concentrations within a 30 to 60 min period, suggestive of a 10 to 20 min half-life. Rowland et al[56] studied the ability of intravenous lignocaine to control ventricular arrhythmias in order to understand its disposition kinetics, and thus was able to establish safe and effective dosage regimens. Rowland reported a rapid early fall in lignocaine plasma levels after the administration a 50 mg bolus dose. The mean half-life was 7 min. However, they also reported a significantly slower phase (a mean half-life of 108 min), related to the drug’s elimination. After a 4-h lignocaine infusion, the average elimination time of 108 min was similar to the elimination half-life of 96 to 108 min reported by Beckett et al[54]. Rowland found that lignocaine was primarily eliminated by metabolism, since urine collected 24 h after the bolus contained less than 4% of unchanged lignocaine. The range of elimination half-life was relatively narrow (73 to 133 min) among the subjects evaluated[56]. Beckett et al[54] also put forward that de-ethylation of lignocaine to monoethylglycine xylidide was the drug’s primary metabolic pathway.

Lignocaine’s pharmacokinetics have been studied in a variety of clinical models, which include healthy volunteers, subjects with chronic pain syndromes, and patients with cardiac failure[56-59]. The speed of onset of lignocaine is 1 to 5 min after local infiltration, and 5 to 15 min after peripheral nerve blockade. Lignocaine’s absorption is dependent upon the total dose administered, the route by which it is delivered, and blood supply to the site of injection[7]. In 1972, Scott et al[57] found that upon injection of lignocaine 400 mg, serum levels were highest following infiltration of vaginal mucosa and lowest following subcutaneous abdominal infiltration. Major nerve blocks and epidurals result in intermediate peak plasma levels. Irrespective of the administration site, peak serum levels occurred 20 to 30 min following injection. The addition of adrenalin (1:200000) to the local anesthetic solution reduced peak levels and delayed the rate of absorption.

When lignocaine is given intravenously to normal subjects, the volume of distribution is 0.6-4.5 L/kg[60]. The plasma binding of lignocaine is inversely proportional to the drug concentration. It is 60% to 80% protein-bound at concentrations of between 1 and 4 mcg/mL[7]. Binding fraction also depends on the plasma levels of the acute phase reactant alpha-1-glycoprotein[9]. Lignocaine has been shown to cross the placenta and blood-brain barrier by simple passive diffusion. Given that proportion of maternal protein binding is greater than that foetal protein binding, the maternal total plasma concentration will be higher, however free lignocaine concentrations will remain the similar in both mother and fetus[7]. Fetal lignocaine concentration may be increased by transmembrane pH gradients, such as fetal acidosis, and associated ion trapping[9]. Lignocaine may exist in ionised or unionised form depending on the pH of the environment. As a weak basic drug, lignocaine tends to be more unionised and able to cross cell membranes in basic media[10]. In fetal acidosis lignocaine crosses the placenta in unionised form, becomes ionised given the acidic environment of the fetal circulation and becomes “trapped”, thus increasing fetal lignocaine concentration.

Lignocaine is dealkylated in the liver by the cytochrome P450 system forming numerous metabolites. Monoethylglycine xylidide and glycine xylidide are the key active metabolites, both of which have reduced potency but have comparable pharmacologic activity to lignocaine[9]. The only reported metabolite of lignocaine found to be carcinogenic in a rat model is 2, 6-xylidine[61]. Its pharmacologic activity is unknown. After the intravenous administration of lignocaine, monoethylglycine xylidide and glycine xylidide concentrations equate to approximate 11% to 36%, and 5% to 11%, respectively, of the total plasma lignocaine concentrations[62].

Hepatic blood flow appears to be a limiting factor in lignocaine’s metabolism. The rate of metabolism is slower reduced in patients with congestive cardiac failure, chronic liver disease and hepatic insufficiency, and after acute myocardial infarction[63]. Lignocaine and its metabolites are predominantly renally excreted. Less than 10% of lignocaine is excreted without being metabolised[53,64].

The total body plasma clearance of lignocaine in healthy volunteers has been reported to be approximately 10-20 mL/min per kilogram[62]. The majority of lignocaine elimination occurs in the liver, and since the total body plasma clearance of lignocaine is about 800 mL/min and hepatic blood flow is about 1.38 L/min[65,66], up to 60% of an oral dose is metabolised before entry into the systemic circulation. This accounts for the low plasma lignocaine concentrations observed following a the oral administration of 500 mg lignocaine hydrochloride[67].

Elimination half-life is defined as the rate at which a local anesthetic is removed from the blood. Therefore, the time necessary for 50% reduction in lignocaine blood level is one half-life; two half-lives equates to a 75% reduction, three half-lives to an 87.5% reduction, four half-lives to a 94% reduction, five half-lives to a 97% reduction and six half-lives to a 98.5% reduction. The half-life of lignocaine has been shown to be approximately 100 min following either an infusion lasting less than 12 h or a bolus injection. In this setting lignocaine demonstrates linear pharmacokinetics[56]. However, following an intravenous infusion greater than 12 h, lignocaine exhibits nonlinear, or time-dependent pharmacokinetics. Patients who received prolonged lignocaine infusions following a myocardial infarction, were found to have lignocaine concentrations that continued to rise for approximately 48 h, with the half-life extending up to 4 h[68].

The maximum doses for lignocaine is based primarily on manufacturer recommendations and animal studies. Animal studies are frequently used to calculate a drug’s therapeutic index. This is derived or calculated from the median toxic dose and median effective dose ratio. It is important to note that the complexities found within human populations are not replicated in animal studies. General recommendations based on site of administration, use of vasoconstrictors, and patient factors such as age, hepatic, renal, cardiac diseases, and pregnancy have been attempted. However due to the lack of quality data, specific recommendations regarding generic maximum doses cannot be definitively made. Furthermore, recommended doses from manufacturers vary between countries. The intrathecal ED50 of lignocaine for a motor block (defined as the development any motor block in either leg within a five-minute-period) has been shown to be approximately 13.7 mg (95%CI: 13.1-14.4 mg)[69]. According to most manufacturers recommendations, the maximum dose of lignocaine for infiltration and regional nerve block techniques is 300 mg (approximately 4.5 mg/kg) or 500 mg (7 mg/kg) with 1:200000 adrenalin (based on a 70 kg patient). However, for neuropathic pain treatment in human subjects, the ED50 and ED90 of lignocaine has been reported as 372 mg and 416 mg respectively, although the resulting plasma levels were not evaluated[70]. Generally, however, from animal data, the ED50 of intravenous lignocaine for CNS toxicity is approximately 19.5 mg/kg (95%CI: 17.7-21.3 mg/kg) and 21 mg/kg (95%CI: 19.0-23.4 mg/kg) for electrocardiographic evidence of cardiac toxicity[71].

As discussed above, plasma concentrations of lignocaine differ widely, depending on the total dose administered, the method and route of delivery, and the vascularity of the site where it is injected. Plasma levels of between 0.5 and 5.0 mcg/mL (2-20 μmol/L) are required for many of reported clinical effects after both intravenous or subcutaneous administration[72]. A infusion of intravenous lignocaine administered at a dose of 2 to 4 mg/min results in plasma levels of between 1 and 3 mcg/mL after 150 min[73]. After 15 min of the same infusion, a 2 mg/kg intravenous bolus of lignocaine leads to peak plasma levels of 1.5 to 1.9 mcg/mL[74]. Subcutaneous lignocaine infusions may be advantageous over intravenous drug delivery methods because plasma levels are more stable, and therapeutic benefit may be achieved whilst avoiding the toxic effects of peaks and troughs associated with episodic drug administration or a prolonged continuous intravenous infusion[75].

The aim of an intravenous lignocaine infusion is to achieve a therapeutic steady-state concentration while minimising systemic toxicity. The pharmacokinetic implication of using a lignocaine bolus dose prior to a continuous infusion is important. This technique increases plasma concentrations allowing therapeutic ranges to be achieved more quickly. Hsu et al[59] evaluated the lignocaine’s pharmacokinetics during 2-d infusion in patients who underwent cardiac surgery. These researchers concluded that lignocaine plasma concentrations are more accurately described using a two-compartment pharmacokinetic model, and advocated that lignocaine infusions should be dosed by body weight, with the infusion dose reduced after 24 h to avoid toxicity. The authors advocated that the ideal lignocaine continuous infusion protocol is a bolus/loading dose of 1 mg/kg, then an infusion at 50 mcg/kg per minute infusion for the first hour, then 25 mcg/kg per minute for the second hour, then 12 mcg/kg per minute for the following 22 h, and finally 10 mcg/kg per minute for the remaining 24 h. The pharmacokinetics of lignocaine are summarised in Figure 1.

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Figure 1 Summary of the pharmacokinetics of lignocaine.