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A structured extended response (500 - 600 words). You will be allocated a drug and will need to write a structured extended response (500 – 600 words) discussing this drug and some key aspects of its pharmacology. Drug allocations will be published at the start of the assessment time, they will not be available prior to this time. You must write about your allocated drug. A series of structured questions to guide your response will be made available in the assignment instructions at the same time – please use these to guide your response. Your allocated drug is Lidocaine, which is listed as a “CYP3A4 substrate” in the Australian Medicines Handbook (AMH). A copy of the TGA Product Information statement for a medication that contains your drug (this will be provided as a PDF). These Product Information PDFs contain the pharmacokinetic data that you will need to answer the questions below. If your drug has a range of values for any of the pharmacokinetic data, then please use the average of these values for your calculations. 1. Briefly discuss whether the value of the volume of distribution applies to all routes of administration and comment on the distribution of your allocated drug. 2. Calculate how long it takes to a) eliminate 95% of a single dose after absorption, and b) to reach a steady-state blood concentration after repeated dosing at regular half-life interval. Provide the equations used. 3. Calculate the systemic clearance of your allocated drug. Provide the equation used. Discuss whether this clearance value applies to all routes of administration. 4. Briefly discuss how administering your allocated drug with each of the medicines/foods below would affect the pharmacokinetics and risks of administering your allocated drug: 5. a) the antibiotic rifampicin, classified as a “potent inducer of CYP3A4” in the AMH; b) the antibiotic ketonazole, classified as a “potent inhibitor of CYP3A4” in the AMH. c) the herbal medicine St John’s wort, classified as an “inducer of CYP3A4” in the AMH; d) grapefruit juice, classified as an “inhibitor of CYP3A4” in the AMH. PI template Lidocaine-Baxter (Lidocaine (Lignocaine) hydrochloride (as monohydrate)) Version 1.0 1 of 17 AUSTRALIAN PRODUCT INFORMATION LIDOCAINE-BAXTER (LIDOCAINE (LIGNOCAINE) HYDROCHLORIDE) SOLUTION FOR INJECTION 1 NAME OF THE MEDICINE Lidocaine (Lignocaine) hydrochloride (as monohydrate) 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Lidocaine (Lignocaine) hydrochloride (as monohydrate) 10 mg/mL or 20 mg/mL, solution for injection Lidocaine (Lignocaine) hydrochloride (as monohydrate) is a fast acting local anaesthetic and antiarrhythmic drug. Lidocaine-Baxter is a clear, colourless to almost colourless, sterile, isotonic, preservative-free solution containing Lidocaine (Lignocaine) hydrochloride (as monohydrate) 1% or 2%. For the full list of excipients, see Section 6.1 List of excipients. 3 PHARMACEUTICAL FORM Solution for Injection. 4 CLINICAL PARTICULARS 4.1 Therapeutic indications For production of local or regional anaesthesia by nerve block, infiltration injection, caudal or other epidural blocks. Treatment or prophylaxis of life-threatening ventricular arrhythmias, including those associated with myocardial infarction, general anaesthesia in patients predisposed to ventricular arrhythmias, digitalis intoxication, or following resuscitation from cardiac arrest. 4.2 Dose and method of administration Lidocaine (Lignocaine) Injection is for one dose in one patient only. Discard any remaining contents. As a local anaesthetic for infiltration and nerve block The dosage varies and depends upon the area to be anaesthetised, vascularity of the tissues, number of neuronal segments to be blocked, individual tolerance and the technique of anaesthesia. The lowest dose needed to provide effective anaesthesia should be administered. For specific techniques and procedures, refer to standard textbooks. Lidocaine-Baxter (Lidocaine (Lignocaine) hydrochloride (as monohydrate)) Version 1.0 2 of 17 It is recommended that the dose of lidocaine (lignocaine) at any one time should not exceed 3mg/kg. However, the dose administered must be tailored to the individual patient and procedure, and the maximum doses here quoted should be used as a guide only. The normal recommended dose of lidocaine (lignocaine) for various anaesthetic procedures in an average, healthy 70kg adult patient are as follows: Procedure Concentration (%) Volume (mL) Dose (mg) Infiltration 1.0 20 200 Peripheral Nerve Blocks - Paravertebral - Pudenal (each side) - Paracervical 1.0 1.0 1.0 3 - 5 10 10 30 – 50 100 100 Sympathetic Nerve Block - Cervical (stellate ganglion) - Lumbar 1.0 1.0 5 10 50 100 Epidural Blocks (2 – 3 mL per segment) - Thoracic - Lumbar - analgesia - anaesthesia - Caudal – obstetric analgesia 1.0 1.0 2.0 1.0 10 – 20 10 – 20 5 – 10 10 - 20 100 – 200 100 – 200 100 – 200 100 - 200 The doses suggested above are only a guide. Toxic levels vary widely between patients so doses should be individualised and blood levels should be monitored. Epidural injections should be administered slowly with frequent aspirations. Subarachnoid and intravascular injections are two of the most serious complications of this technique. If blood or spinal fluid become manifest during aspiration, the needle must be withdrawn and relocated. The technique of epidural anaesthesia should only be attempted by physicians skilled in this area and readiness for emergencies must be ensured. During spinal anaesthesia the positioning of the patient is very important and the patient's pulse and blood pressure should be monitored. During thoracic, lumbar and caudal epidural anaesthesia, a marked fall in blood pressure and/or intercostal paralysis may be seen, possibly due to the use of excessive doses, improper positioning of the patient or accidental disposition of the anaesthetic within the subarachnoid space. Hypotension and bradycardia may occur as a result of sympathetic blockade. For continuous epidural or caudal anaesthesia and paracervical block for obstetric analgesia the maximum dose should not be repeated at intervals of less than 1.5 hours. Lidocaine-Baxter (Lidocaine (Lignocaine) hydrochloride (as monohydrate)) Version 1.0 3 of 17 Adults The dose should not exceed 200 mg. For spinal anaesthesia, the dose should not exceed 100 mg. Children For children, a reduced dosage based on body weight or surface area should be used. The dosage should be calculated for each patient individually and modified in accordance with the physician’s experience and knowledge of the patient. Early signs of local anaesthetic toxicity may be difficult to detect in cases where the block is given during general anaesthesia. In order to minimise the possibility of toxic effects, the use of Lidocaine (Lignocaine) Injection 1 % solution is recommended for most anaesthetic procedures involving paediatric patients. The dose should not exceed 3 mg/kg. For intravenous use in cardiac arrhythmias Patients with congestive heart failure or cardiogenic shock may require smaller bolus doses. Adults The usual dose is lidocaine (lignocaine) 50 to 100 mg administered intravenously under ECG monitoring. The dose may be injected at a rate of approximately 25 to 50 mg (2.5 to 5.0 mL of the lidocaine (lignocaine) 1% solution or 1.25 to 2.5 mL of the 2% solution) per minute. A sufficient period of time should be allowed to enable a slow circulation to carry the drug to the site of action. If the initial dose of 50 to 100 mg does not produce the desired response, a second dose may be given after five minutes. No more than 200 to 300 mg of lidocaine (lignocaine) should be administered during a one hour period. Following a single injection in those patients in whom arrhythmia tends to recur and who are incapable of receiving oral antiarrhythmic therapy, intravenous infusions of lidocaine (lignocaine) may be administered at a rate of 1 to 4 mg/minute (20 to 50 mcg/kg/minute). Intravenous infusions must be given under ECG monitoring to avoid potential overdosage and toxicity. The infusion should be terminated as soon as the patient's cardiac rhythm appears to be stable or at the earliest signs of toxicity. It should rarely be necessary to continue the infusion beyond 24 hours. As soon as possible, patients should be changed to an oral antiarrhythmic agent for maintenance therapy. Paediatrics For children, a reduced dose based on body weight or surface area should be used. It is recommended that the 1% solution be used to minimise the possibility of toxic effects. Experience with lidocaine (lignocaine) is limited. A suggested paediatric dose is a loading dose of 0.5 to 1 mg/kg repeated if necessary up to 3-5 mg/kg, followed by continuous infusions of 10 to 50 micrograms/kg/min. Lidocaine-Baxter (Lidocaine (Lignocaine) hydrochloride (as monohydrate)) Version 1.0 4 of 17 Geriatrics A reduction in dosage may be necessary for elderly patients, particularly those with compromised cardiovascular and/or hepatic function. Impaired hepatic function Although lidocaine (lignocaine) is metabolised by the liver, dosage reduction for local anaesthesia is probably not warranted. However, caution should be exercised with repeated doses or prolonged infusion. Impaired renal function Impairment of renal function is unlikely to affect lidocaine (lignocaine) clearance in the short term (up to 24 hours). However, toxicity due to accumulation may develop with prolonged or repeated administration. 4.3 Contraindications • Known hypersensitivity to local anaesthetics of the amide type. • Inflammation or sepsis at the proposed site of injection and in the presence of septicaemia. • Patients with myasthenia gravis, severe shock or impaired cardiac conduction. • Epidural or spinal anaesthesia in patients with - uncorrected hypotension or - coagulation disorders or receiving anticoagulants or - serious diseases of the central nervous system or spinal cord such as meningitis, spinal fluid block, cranial or spinal haemorrhage, tumours, poliomyelitis, syphilis, tuberculosis or metastatic lesions of the spinal cord. • Antiarrhythmic use in patients with - supraventricular arrhythmia or - Stokes-Adams Syndrome or severe degrees of sinoatrial, atrioventricular or intraventricular block unless the patient has an artificial pacemaker. • Lidocaine (Lignocaine) suppresses ventricular pacemaker activity and may cause ventricular standstill in such patients • General contraindications related to epidural anaesthesia, regardless of the local anaesthetic used, should be taken into account. 4.4 Special warnings and precautions for use General precautions • When any local anaesthetic agent is used, resuscitative equipment