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Pharmacotherapeutic group: Local anaesthetics. ATC code: N01B B02.
Pharmacology: Polyamp: Lignocaine, like other local anaesthetics, causes a reversible blockade of impulse propagation along nerve fibres by preventing the inward movement of sodium ions through the nerve membrane. Local anaesthetics of the amide type are thought to act within the sodium channels of the nerve membrane.
Local anaesthetic drugs may have similar effects on excitable membranes in the brain and myocardium. If excessive amounts of drug reach the systemic circulation rapidly, symptoms and signs of toxicity will appear, emanating mainly from the central nervous system and cardiovascular systems.
Central nervous system toxicity usually precedes the cardiovascular effects as it occurs at lower plasma concentrations. Direct effects of local anaesthetics on the heart include slow conduction, negative inotropism and eventually cardiac arrest.
Indirect cardiovascular effects, e.g. hypotension and bradycardia, may occur after epidural or spinal administration depending on the extent of the concomitant sympathetic block.
Pharmacodynamics: MDV: Xylocaine contains lidocaine, which is a local anaesthetic of the amide type. Lidocaine reversibly blocks impulse conduction in the nerve fibres by inhibiting the transport of sodium ions through the nerve membrane. Similar effects can also be seen on excitatory membranes in the brain and myocardium.
Lidocaine has a rapid onset of effect, a high anaesthetic frequency and low toxicity. Lower concentrations of lidocaine have less effect on motor nerve fibres.
Pharmacokinetics: MDV: The rate of absorption is dependent on dose, route of administration and perfusion at the injection site.
Intercostal blockades produce the highest plasma concentrations (approx. 1.5 micrograms/ml per 100 mg injected), while subcutaneous injections in the abdomen produce the lowest plasma concentrations (approx. 0.5 micrograms/ml per 100 mg injected). The volume of distribution in steady state is 91 litres, and plasma protein binding, which is predominantly to alpha-1-acid glycoprotein, is 65%.
Absorption is total and bi-phasic from the epidural space with half-lives of about 9.3 minutes and 82 minutes. The slow absorption is the time-limiting factor in the elimination of lidocaine, which explains the slower elimination after epidural injection, compared with intravenous injection.
Lidocaine is eliminated predominantly through metabolism. Dealkylation to monoethyl-glycinexylidide (MEGX) is mediated mainly by cytochrome P450 3A4. MEGX is metabolised to 2,6-xylidine and glycinexylidide (GX) 2,6-dimethylaniline is metabolised further by CYP2A6 to 4-hydroxy-2,6-dimethylaniline, which is the major metabolite in the urine (80%) and is excreted as conjugate. MEGX has a convulsant activity equivalent to that of lidocaine, while GX is devoid of convulsant activity. MEGX appears to occur in similar plasma concentrations as the parent substance. The elimination rates of lidocaine and MEGX after an intravenous bolus dose are approx. 1.5-2 and 2.5 hours, respectively.
On account of the rapid hepatic metabolism, the kinetics are sensitive to all alterations in liver function.
The half-life can be more than doubled in patients with impaired liver function. Impaired renal function does not affect the kinetics, but can increase the accumulation of metabolites.
Lidocaine crosses the placenta and the concentration of free lidocaine is the same in the mother and the foetus. However, the total plasma concentration is lower in the foetus, which has a lower degree of protein binding.
Polyamp: Lignocaine has a rapid onset and a medium duration of action. The onset of action is 1 - 5 minutes following infiltration and 5 to 15 minutes following other types of administration.
The rate of absorption depends upon the dose, the route of administration and the vascularity of the injection site. Intercostal blocks give the highest peak plasma concentrations (approximately 1.5 μg/mL for every 100 mg injected), while abdominal subcutaneous injections give the lowest (approx. 0.5 μg/mL per 100 mg injected). Epidural and major nerve block produce peak plasma levels intermediate between these.
Absorption of lignocaine from the epidural space occurs in 2 phases; the first phase is in the order of 9 minutes and the second is approximately 82 minutes. The slow absorption is the rate-limiting step in the elimination of lignocaine, which also explains the apparent elimination half-life following epidural injection is longer than after intravenous administration.
The plasma binding of lignocaine is dependent on drug concentration, and the fraction bound decreases with increasing concentration. At concentrations of 1 to 4 μg of free base/mL, 60 - 80% of lignocaine is protein bound. Binding is also dependent on the plasma concentration of the α1-acid glycoprotein.
Lignocaine crosses the blood-brain and placental barriers by passive diffusion. Since the degree of plasma protein binding in the foetus is less than in the mother, although free lignocaine concentrations will be the same, the total plasma concentration will be greater in the mother.
Lignocaine has a total plasma clearance of 0.95 L/min, a volume of distribution at steady state of 91 L, an elimination half-life of 1.6 hr and an estimated hepatic extraction ratio of 0.65. Approximately 90% of a parenteral dose of lignocaine is rapidly metabolised in the liver by de-ethylation to form monoethylglycinexylidide (MEGX) and glycinexylidide (GX) followed by cleavage of the amide bond to form xylidine and 4-hydroxyxylidine which are excreted in the urine. Less than 10% of a dose is excreted unchanged in the urine.
The principal metabolites, MEGX and GX also possess pharmacological activity. The rate of metabolism of lignocaine appears to be limited by liver blood flow which may be reduced in patients after acute myocardial infarction and/or congestive heart failure. The rate of lignocaine metabolism may also be reduced in patients with liver or hepatic tissue necrosis, possibly because of altered perfusion.
The duration of action depends upon the concentration used, the dose given, the nerves to be blocked and the status of the patient. The 2% solution will produce an effect for 1½ - 2 hrs when given epidurally, and up to 5 hrs when given as a peripheral nerve block.
