Pharmacology: the Bioavailability of Lignocaine - Essay Example

? Lignocaine Section Drug absorption the oral bioavailability The bioavailability of lignocaine is 35% following an oral administration (Kwan, 2001). Discuss whether the bioavailabilty is influenced by first pass hepatic extraction, gastrointestinal absorption, or both The bioavailability of lignocaine is dependent upon the absorption and hepatic biotransformation of the drug. Absorption of the drug is dependent upon the dose total, duration of exposure, concentration of the dose and the site of exposure (Kwan, 2001). The drug absorbed well in the gastrointestinal system but undergoes extensive first pass hepatic transformation. In the liver, lignocaine biotransformation involves oxidative N-dealkylation, cleavage of the amide linkage, ring hydroxylation and conjugation (Bennett, 1992). The oxidative N-dealkylation process is the major pathway in biotransformation of the drug in the liver. The oxidative N-dealkylation pathway produces glycinexylidide and monoethylglycinexylidide metabolites that have less potent pharmacologic effects than lignocaine (Kwan, 2001). In addition, these metabolites are less toxic than the primary drug. Section 2. Drug formulation and administration routes List all the formulations and doses available in Australia In Australia, Lignocaine is available as a lignocaine injection, Xylocaine, Xylocaine with adrenaline, Xylocard, Xyloproct suppositories. In addition, it is also sold as Gravocain, Leostesin, Maricaine, Cappicaine, Esracaine, Lidoderm and Anestacon. Many ointments, lotions, creams and gels used topically, contain lignocaine. Lidoderm contains 5% of lignocaine and is used for the treatment of neuropathic pain. Lignocaine injection is approved for administration of 200-300mg for adults and 100mg for children in the treatment of cardiac arrhythmias. Topical ointments and gels contain 5% of lignocaine. Some other formulation have been added to adrenaline and are used for cardiac arrest with arrhythmias. Discuss any administration issues that are followed for safe and efficacious use The loading dose of the drug is usually administered as an infusion dose or a slow infusion so as to avoid the toxic effects of the drugs. When given as rapid bolus, lignocaine causes hypotension due to depression of the myocardial contractility as well as CNS related effects (Grover, 2009). The side effects following rapid bolus infusion are seen more commonly in the elderly. They are also seen in patients with pre-existing heart conditions. In order to achieve the plasma therapeutic dose, the loading dose is followed by a maintenance dose. When the drug is used as a local anaesthetic agent via infiltration method, blood vessels should be avoided (Donald & Henry, 2003). Discuss the reasons why the drug is not available as an oral formulation Lignocaine is well absorbed in the gastrointestinal system. However, due to its extensive hepatic biotransformation, it is administered as parenterally (Bennett, 1992). It is available as topical, mucosal, intravenous, intratracheal and intramuscular formulation so as to avoid the extensive first pass hepatic extraction. The drug is not available as an oral formulation because it provides low concentration of the unchanged drug in plasma. Section 3. Drug distribution State the percent bound to plasma proteins The plasma binding ability of lignocaine is dependent on the concentration of the drug (Kwan, 2001). This implies that the higher the concentration of the drug, the less it is bound to plasma. About 60-80% of the drug is protein bound in a concentration of about 1-4 mcg of free base in every millilitre (Kwan, 2001). In some condition, the binding of the drug is increased or decreased. In case of myocardial infarction and other acute illness, the binding of lignocaine to plasma proteins is increased. This is because of increase the concentration of plasma alpha-1 glycoprotein. Plasma alpha-1 glycoprotein is an acute phase reactant protein. It binds lignocaine thus reducing the concentration of the free drug available to exert its pharmacological effects. In these diseases, higher doses of the drug are recommended to exert it effects (Sophie & Rogers, 2008). In addition to binding to plasma, the drug is lipophillic thus has high affinity for fat and adipose tissue. State the volume of distribution (V) in either L/kg or Litres The volume of distribution of the drug is 0.6- 4.5 L/ Kg (Toutan, 2004). Is this small or large relative to blood volume In relation to blood, the drug has a relatively high volume of distribution. What does the volume of distribution tell you about the drug This is a measure of the proportion of drug in the body and plasma at a certain time. It is employed in calculating the loading dose of a drug that is necessary to achieve the targeted therapeutic dose of the drug. Lignocaine is rapidly distributed from plasma into the highly perfused organs in the body. These include the liver, brain, heart and kidney. It is calculated as the quantity of drug within the body at a specific period of time divided by the drug concentration in plasma at the stated time. The apparent volume of distribution reflects the balance between binding to plasma protein, which tends to increase the plasma concentration of the drug, and binding to plasma which decreases the plasma concentration. Lignocaine is highly lipophillic and the plasma binding ability of the drug dependent on the concentration of alpha-1 acid glycoprotein. This implies that the concentration of the drug in plasma is reduced in patients who have low levels of the acute phase protein (Toutan, 2004). Section 4. Clearance Concepts Determine the systemic and hepatic clearance Liver metabolism is the primary clearance for Lignocaine. Systemic clearance is a total of all clearances of the drug in the body. Hepatic clearance of the drug is the rate of elimination in the liver divided by the concentration of the drug. Lignocaine has a systemic clearance of 38.4 L/h/70kg (Kwan, 2001). The renal system contributes less in the clearance of lignocaine. Does the drug have a low, intermediate of high hepatic clearance Lignocaine has a high hepatic clearance. It has an extensive first pass hepatic metabolism. After oral administration, only a small fraction of the drug appears in plasma: less than 3%. This means that lignocaine must be given intravenously to avoid this high first pass extraction. What effect would hepatic enzyme inhibition or induction have on the hepatic clearance of your drug? Hepatic enzyme induction would lead to increased hepatic metabolism of the drug. This will lead to increased drug clearance. Hepatic enzyme inhibition will decrease hepatic metabolism of the drug. This will translate to decreased hepatic clearance of the drug. Section 5. Half-life State the half-life (hours) Half-life is the time taken for the amount of drug in the plasma or in the body to be eliminated from the body. The time course of lignocaine in the body depends on the clearance and the volume of distribution. Half-life of lignocaine can be calculated by multiplying 0.7 by its volume of distribution then dividing this by the clearance. This translates to 0.7 * 77 (volume of distribution). This equals 53.9 which is divided by 38.4 (clearance) which results to approximately 1.5 hrs (hence, 1-2 hrs). How long will it take for the drug to reach steady-state after commencing oral administration? Steady state can be estimated by the time taken to attain five half lives. This estimates the steady state of lignocaine as 8-10 hrs after parenteral administration (Broek, Marcel & Alwin, 2011). If the systemic clearance of your drug decreased by 50%, calculate the new half-life and time to steady state If the systemic clearance of lignocaine is decreased by 50%, the half-life will alter accordingly. From the above calculation, the new half-life will be 0.7 multiplied by 77 (Volume of distribution) divided by 50% of clearance (50 % of 38.4). This equals to 53.9 divided by 19.2. This translates to a new half-life of approximately 3 hrs. This means that the half-life will increase by twice its normal value. The new time to steady state will also increase by twice. This will translate to a steady state of 16 to 20 hrs. Section 6. Life stages as a factor in variability Determine whether dose adjustment is required for age and indicate the change in dosage Dose adjustment is required for age. Children should be given lower doses that are commensurate to their weight, age and physical condition. However, lignocaine should be used with caution in those below two years of age (Morgan et al., 2006). There lacks sufficient data, which supports the efficacy and safety of lignocaine in this age bracket. Dose adjustment is also required for the elderly. Elderly patients should be given lower doses commensurate with their physical condition and age (Morgan et al., 2006). Explain the rational for the age related dose adjustment Dose adjustment is required in the elderly due age related changes in body composition and body function. Aging is characterized by an increasing loss of organ functional capacities. Receptor stimulation response is also decreased (Heavner, 2008). In addition, there is an increase in body fat amount and a consequent decrease in water content as the age progresses. The kidney excretory capacity also decreases in the elderly. In view of the above changes, normal lignocaine doses given to the elderly would lead to increased plasma concentration and decreased clearance. This would potentiate incidences of adverse effects of lignocaine. These include neurologic effects such as tremors, paresthesia, nausea, speech and auditory disturbances and convulsions. Thus, lignocaine doses should be reduced for the elderly. The young ones also exhibit decreased drug metabolism and elimination rates compared to the adults (Berde, 1993). Therefore, there is a need to lower the dose in the paediatric age group. Section 7. Impact of disease states Is dose adjustment required in individuals with hepatic disease? The hepatic system plays a pertinent role in the pharmacokinetics of lignocaine. Therefore, dose reduction is necessary pertaining to hepatic diseases. Liver dysfunction decrease clearance by hepatic metabolism (Verbeeck, 2008). In patients with liver diseases, lignocaine plasma clearance is significantly reduced. The volume of distribution becomes elevated. In such a situation, the elimination half-life may increase more than three times the normal value. Steady state concentrations in such patients will be achieved after 24 to 36 hrs compared to the normal 8 to 10 hrs. This will potentiate the adverse effects of the drug. Therefore, the maintenance dose needs to be reduced. However, the loading dose can be given in the usual amount (Verbeeck, 2008). References Berde, C 1993, ‘Toxicity of local anaesthetics in infants and children’, J Paediatric Pharm, vol. 122, no. 5, pp. 14–20. Bennett, N 1992, ‘Pharmacokinetics of Lidocaine and its de-ethylated metabolites: dose and time dependency studies in Man’, Journal of Pharmacokinetics and Bio pharmacology, vol. 3, pp. 265-281. Broek, V, Marcel, P & Alwin, D 2011, ‘Lidocaine (Lignocaine) Dosing Regimen Based upon a Population Pharmacokinetic Model for Preterm and Term Neonates with Seizures’, Clinical Pharmacokinetics, Vol. 50, no. 7, pp. 461-469. 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