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.
Part A: Three short answer questions (10 marks, ~ 150 - 200 words each) that will require you to integrate and apply knowledge from the three modules of this course. Phenylephrine is a drug that is found in many decongestant nasal sprays. A. Describe the mechanism of action for phenylephrine, including the intracellular signalling and second messengers involved. (4 marks) B. Identify ONE drug that will interfere with the actions of phenylephrine and explain why this occurs. (1 mark) C. Briefly discuss whether the nasal route of administration is subject to first-pass metabolism (2 marks) D. The half-life of phenylephrine is around 3 hours. 1. I. Briefly discuss whether this half-life is specific to nasal administration. (1 mark) II. Calculate how long it would take to reach a steady-state concentration with repeated dosing every 3 hours. Provide the equation used. (2 marks) Benzodiazepines are positive allosteric modulators at the GABA-A receptor. A. Explain the different ways that positive AND negative allosteric modulators can affect receptor function. (4 marks) B. Discuss the mechanism of action of benzodiazepines and their effect on central nervous system (CNS) activity. (4 marks) C. Identify ONE advantage that a positive allosteric modulator may have compared to an agonist drug for the same receptor, and explain why this is the case. (2 marks) A. Compare and contrast the two main types of non-steroidal anti-inflammatory drugs (NSAIDs). Include in your answer the mechanisms of action for these drugs and their major adverse effects. (5 marks) B. Pharmacokinetic studies showed that less than 1% of a single dose of diclofenac is excreted unchanged in urine. Briefly explain the following: (5 marks) I. Whether diclofenac is a drug with high hepatic or renal elimination ratio; II. How you would adjust diclofenac dosage in a patient with hepatic impairment; III. How you would adjust diclofenac dosage in a patient with renal impairment. Part B: A structured extended response (500 - 600 words). Tramadol (That is the drug I have been given) These drugs are all listed as “CYP3A4 substrates” in the Australian Medicines Handbook (AMH). Click on this page to access a copy of the TGA Product Information statement for a medication that contains your drug. 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. (I attached the copy of TGA as a attachment) 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: 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. 1 AUSTRALIAN PRODUCT INFORMATION APO- TRAMADOL (TRAMADOL HYDROCHLORIDE) CAPSULES WARNINGS Limitations of use Because of the risks associated with the use of opioids, APO-Tramadol should only be used in patients for whom other treatment options, including non-opioid analgesics, are ineffective, not tolerated or otherwise inadequate to provide appropriate management of pain (see section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE). Hazardous and harmful use APO-Tramadol poses risks of hazardous and harmful use which can lead to overdose and death. Assess the patient’s risk of hazardous and harmful use before prescribing and monitor the patient regularly during treatment (see section 4.4. SPECIAL WARNINGS AND PRECAUTIONS FOR USE). Life threatening respiratory depression Serious, life-threatening or fatal respiratory depression may occur with the use of APO- Tramadol. Be aware of situations which increase the risk of respiratory depression, modify dosing in patients at risk and monitor patients closely, especially on initiation or following a dose increase (see section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE). Concomitant use of benzodiazepines and other central nervous system (CNS) depressants, including alcohol Concomitant use of opioids with benzodiazepines, gabapentinoids, antihistamines, tricyclic antidepressants, antipsychotics, cannabis or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Limit dosages and durations to the minimum required; and monitor patients for signs and symptoms of respiratory depression and sedation. Caution patients not to drink alcohol while taking APO-Tramadol. 1 NAME OF THE MEDICINE Tramadol hydrochloride 2 QUALITATIVE AND QUANTITATIVE COMPOSITION The capsules contain 50 mg tramadol hydrochloride as the active ingredient. Excipients with known effect Methyl hydroxybenzoate (E218), propyl hydroxybenzoate (E216), gelatin 2 For the full list of excipients see section 6.1 List of excipients. 3 PHARMACEUTICAL FORM Hard gelatin capsules having green cap and yellow body filled with a homogeneous white to off-white powder. 4 CLINICAL PARTICULARS 4.1 THERAPEUTIC INDICATIONS APO-Tramadol for the short-term management of severe pain for which other treatment options have failed, are contraindicated, not tolerated or are otherwise inappropriate to provide sufficient management of pain. 4.2 DOSE AND METHOD OF ADMINISTRATION The dose of tramadol should be titrated according to the severity of the pain and the clinical response of the individual patient. Tramadol is approved for use in adults and adolescents over the age of 12 years. The recommended dosage of APO- Tramadol capsules is as follows: 50 – 100 mg administered two or three times daily may be sufficient. Tramadol 50 mg may be adequate as the initial dose for less severe pain. Otherwise, 50 – 100 mg as needed for relief, every four to six hours may be administered. For more severe pain, an initial dose of 100 mg is usually more effective. The maximum daily dose should not exceed 400 mg per day. Paediatric Use See section 4.3 CONTRAINDICATIONS and section 4.5 SPECIAL WARNINGS AND PRECAUTIONS FOR USE- Paediatric use). Use in the Elderly See section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE. Dose adjustment in renal impairment In patients with renal insufficiency the elimination of tramadol is delayed. In these patients prolongation of the dosage intervals should be carefully considered according to the patient's requirements. Since only 7% of an administered dose is removed by haemodialysis, dialysis patients can receive their regular dose on the day of dialysis. Dose adjustment in hepatic impairment Slow release tramadol products should not be used in patients with severe hepatic insufficiency. In these patients, the immediate release (IR) form of oral tramadol (capsule) may be administered if appropriate. In hepatic impairment, the initial oral dose of tramadol is 50 mg of the immediate release formulation. Depending on the severity of impairment and individual clinical response, the recommended dosage interval (4 to 6 hours) may require to be extended, and/or the dose level titrated as required (see section 4.4 - SPECIAL WARNINGS AND PRECAUTIONS FOR USE). 3 4.3 CONTRAINDICATIONS Tramadol is contraindicated in: • individuals with known hypersensitivity to tramadol or any excipients • acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic drugs • Patients with severe respiratory disease, acute respiratory disease and respiratory depression • All children younger than 12 years of age (see section 4.4- Special warnings and precautions for use) • Postoperative management of children younger than 18 years of age following tonsillectomy and/or adenoidectomy (see section 4.4- SPECIAL WARNINGS AND PRECAUTIONS FOR USE) • patients who are receiving monoamine oxidase (MAO) inhibitors or who have taken them within the last 14 days • known sensitivity to opioids • patients with uncontrolled epilepsy or epilepsy not adequately controlled by treatment. Tramadol must not be used for narcotic withdrawal treatment. 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE Hazardous and harmful use APO-Tramadol contains the opioid tramadol hydrochloride and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Tramadol at recommended doses. The risk of addiction is increased in patients with a personal or family history of substance abuse (including alcohol and prescription and illicit drugs) or mental illness. The risk also increases the longer the drug is used and with higher doses. Patients should be assessed for their risks for opioid abuse or addiction prior to being prescribed Tramadol. All patients receiving opioids should be routinely monitored for signs of misuse and abuse. Opioids are sought by people with addiction and may be subject to diversion. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the safe storage and proper disposal of any unused drug (see section 6.4 Special precautions for storage and section 6.6 Special precautions for disposal). Caution patients that abuse of oral or transdermal forms of opioids by parenteral administration can result in serious adverse events, which may be fatal. Patients should be advised not to share APO-Tramadol with anyone else. Acute Abdominal Conditions The administration of tramadol may complicate the clinical assessment of patients with acute abdominal conditions. Respiratory Depression Serious, life-threatening or fatal respiratory depression can occur with the use of opioids even when used as recommended. It can occur at any time during the use of Tramadol but 4 the risk is greatest during initiation of therapy or following an increase in dose. Patients should be monitored closely for respiratory depression at these times. The risk of life-threatening respiratory depression is also higher in elderly, frail, or debilitated patients and in patients with existing impairment of respiratory function (e.g. chronic obstructive pulmonary disease; asthma), hepatic or renal impairment (see section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE). Opioids should be used with caution