Applications of Pharmacokinetic Principles - Assignment Example

1 Define the terms 'pharmacokinetics' and 'pharmacodynamics'. Include in your answer an example of at least one drug. Pharmacodynamics is the study of therapeutic or toxic effects of a drug in the body whereas pharmacokinetics is the study of the movement of drugs in the body and encompasses absorption, distribution, metabolism and excretion. E.g. magnesium hydroxide, a component of antacid drugs, neutralizes HCl in the stomach during treatment of indigestion and other gastrointestinal ailments giving magnesium chloride. The pharmacokinetics of magnesium hydroxide is quite simple as it does not need to be absorbed into the body because it is taken orally and exerts its effects in the gut by neutralizing hydrochloric acid. 2 What is meant by 'plasma protein binding'? In your answer, explain the effects that plasma protein binding has on the metabolism and elimination of protein bound drugs. Plasma proteins binding refers to drug molecules binding to plasma proteins, albumin and globulin. Plasma protein bound drugs are pharmacologically inert because they cannot leave the bloodstream and therefore they cannot be metabolized nor eliminated. This is because a drug to act on the body, it needs to enter into the tissues and plasma bound drugs do not. (Bullock & Manias, 2013) 3 Why should aspirin not normally be administered to a patient who is taking a course of the anticoagulant drug, warfarin? Warfarin depletes the amount of active vitamin K from the liver via inhibiting epoxide reductase, and this can be altered by administration of vitamin K whereas aspirin is a non-competitive inhibitor of COX which is required for platelet synthesis. Aspirin increases the activity of Warfarin via its antiplatelet activity and displacement from albumin. Administering both can cause adverse anticoagulant activity in a patient leading to severe hemorrhage because of the increased activity of warfarin. (Bullock & Manias, 2013) 4 Explain the 'hepatic first pass effect'. Why is it important to consider this effect when administering drugs orally? Hepatic first-pass effect refers to metabolism of a drug in the liver before distribution to the body. It is an important fact to consider when administering drugs orally because, depending on metabolism in the liver, the correct dosage can be formulated to obtain the therapeutic effects intended. Some drugs are formulated as pro-drugs for oral administration so that they can undergo first pass metabolism in the liver to transform them into active compounds. Other drugs undergo extensive metabolism in the liver that they cannot be administered orally. Understanding hepatic first-pass metabolism leads one to formulate the correct dosage for in oral administration for effective therapeutic effects (Bullock & Manias, 2013) 5 Morphine, a narcotic analgesic, has a half-life of about 2 –3 hours. The half-life of naloxone (Narcan), the “antidote” for narcotic overdose, is approximately 1 hour. What does the term 'half-life' mean, and what implications does this information have for the prescribers of these drugs? Half-life refers to the length of time required for the concentration of a drug to decrease by half after it has been administered. The above information means that naloxone, which has a much stronger affinity for opiate receptors than morphine, has to be administered frequently to alter the effects of morphine overdose. Observation of the patient is important for the prescribers due to the longer half-life of morphine to ensure toxic effects do not return. (Bullock & Manias, 2013) 6 What is meant by 'steady state' concentrations of a drug? Explain how and when a steady state is achieved. Steady-state concentration refers to when the minimum effective concentration of a drug is attained which is therapeutically beneficial. Steady-state concentration is attained after approximately five half-lives of a drug have passed. (Bullock & Manias, 2013) 7. Describe the characteristics and properties of enzymes. What is the difference between competitive and non-competitive enzyme inhibition? Give one example for each. Enzymes are catalysts involved in biological reactions but remains unaltered by the reactions. They require a substrate to act and some are substrate specific whereas others can act on different substrates. Competitive enzyme inhibition is when another substrate can displace the bound substrate from an enzyme e.g. sulfonamides that compete for the active sites of the enzymes that uses 4-aminobenzoic acid in the synthesis of folic acid in bacteria since they cannot use preformed folic acid hence preventing the synthesis of folic acid in bacteria. Non-competitive inhibition occurs when a substrate cannot be displaced by another substrate and hence the enzyme is rendered non-functional, e.g. aspirin, in its antiplatelet activity, renders cyclo-oxygenase enzyme inactive since it cannot synthesize platelets again. (Bullock & Manias, 2013) 8. What happens when a drug acts as an 'antagonist'? Explain how atropine, an anticholinergic, acts as an antagonist at cholinergic receptors. What are the effects of atropine on the human body? A drug blocks a receptor and prevents natural chemicals acting on the receptor when it acts as an antagonist. Atropine is a competitive antagonist to acetylcholine. The synaptic activity of atropine is prolonged by acetylcholinesterase inhibitors Atropine blocks muscarinic receptors in the nerves thereby blocking the release of acetylcholine from the nerve peripherals. The effects of atropine on the human body include tachycardia, dry mouth, blurred vision, tachycardia, urinary retention and constipation. (Bullock & Manias, 2013) 9. Describe the drug interactions which may occur when the following drugs and/or other substances are administered concurrently: a phenelzine and broad beans or cheddar cheese Phenelzine is a monoamine oxidase inhibitor. Administering phenelzine concurrently with broad beans or cheese would lead to an increase in amines such as tyramine in the bloodstream leading to an increase in the blood pressure. This is because the enzyme required for the chemical alteration of such amines, monoamine oxidase, is inhibited leading to an increase in the blood levels of amines. (Bullock & Manias, 2013) b Tetracyclines and antacids Tetracyclines form insoluble or poorly absorbable chelates with metallic ions such as magnesium found in antacids. This interferes with the absorption of tetracycline and hence its bioavailability (Bullock & Manias, 2013) c Alcohol and diazepam Administering both simultaneously can lead to enhanced effects of diazepam causing severe drowsiness, decreased motor skills and sedation. This is because alcohol enhances the effects of sedatives since it is a nervous system depressant and diazepam is a sedative. (Bullock & Manias, 2013) PART B (Total 20 marks) The treatment of pain and inflammation is a cornerstone of pharmacology research. a) Describe the actions and possible adverse effects of two analgesics, one narcotic and one non-narcotic and a (different) anti-inflammatory drug (10 marks). Morphine is a narcotic analgesic that acts via inhibition of neurotransmitter release from afferent terminals of the spinal cord. It also activates descending inhibitory controls in the midbrain. It does this by inhibiting calcium entry, increasing the outward potassium current and inhibiting adenylate cyclase. It was the first narcotic analgesic and is the one that is used presently. The possible adverse effects of morphine include tolerance and dependence. They are induced by chronic exposure to morphine or any other opioids. This is a problem because tolerance dictates that higher doses are required to exert an effect due to receptor desensitization caused by functional uncoupling of opioid receptors from G-proteins hence uncoupling receptors from their effector systems. Another adverse effect of tolerance is that when it high, the maximum attainable response with morphine is reduced. Withdrawal effects due to dependence are only realized after the drug is removed. (Aperheim & Favaro, 2012) Acetaminophen is a non-narcotic analgesic. Its mode of action has not been fully defined but it is believed that it causes its analgesic effect via inhibition of cyclooxygenase (COX) and predominantly COX-2. This prevents prostaglandin H2 formation via metabolism of arachidonic acid. This is an unstable intermediate byproduct that forms pro-inflammatory compounds. Inhibition of COX enzymes in the CNS lowers the concentration of prostaglandin E2 and produces analgesia via activating the descending inhibitory serotogenic pathways. Commonly observed side effects of acetaminophen include nausea, constipation, vomiting and injection site pain for IV administration. (Aperheim & Favaro, 2012) Ibuprofen is an anti-inflammatory drug that is a non-selective inhibitor of COX enzyme responsible for the synthesis of the pro-inflammatory prostaglandin from arachidonic acid. its adverse effects include irritation of the gut due to the protective role of prostaglandins in the gut lining. It is however safe when used the correct dosage is administered. b) Provide examples of conditions/diseases that each drug could be used for and explain why they are effective for the treatment of that condition (10 marks). Morphine can be used to treat extreme traumatic cases such as injuries in the battlefield because it acts on the nervous system in alleviating pain. It is effective because it is fast acting and in such cases, pain relief is a priority. Morphine patch and slow releasing tablets have been developed and this acts in management of chronic pain conditions such as back pain and spinal cord injuries, where the release of slow doses of morphine is required to alleviate recurring pain. It should, however, be used at appropriate doses to prevent dependence or tolerance build up. Acetaminophen on the other hand should be used as a common painkiller for pain relief in conditions such as ulcers. It is advantageous because it does not lead to cardiovascular problems that are associated with other nonsteroidal anti-inflammatory drugs and does not cause gut irritation. It is also a great alternative for the elderly and those at risk of heart disease or stomach problems. Ibuprofen is ideal for easing pain after surgical operations, treating arthritis and dental pain. This is because it reduces the concentration of prostaglandins at the site of injury and hence produces the intended therapeutic effects, i.e. pain relief. (Aperheim & Favaro, 2012) PART C (Total 35 marks) Chapter 55, page 694 - Fundamentals of Pharmacology (7th Edition) BB, a 5-year-old boy with a history of chronic asthma, has been admitted to hospital suffering a moderately severe asthma attack. Over a period of time his condition has been well managed using daily inhalation of the corticosteroid beclomethasone, coupled with inhalation of the Beta2 agonist salbutamol when required. His parents think that this particular attack was brought on by a mild respiratory infection that has been affecting the other members of the family. Treatment begins with oxygen therapy and a dose of the Beta2 agonist salbutamol via an inhaler and spacer. A dose of hydrocortisone is administered intramuscularly soon after. Inhaler treatment is repeated hourly. After eight hours the acute attack is easing and by 12 hours post admission BB is ready for discharge. 1. Briefly outline the long-term aims of asthma management, the first-line therapy and the preferred treatment of an acute attack according to the National Asthma Campaign. (7 marks) Long term aims involve maintaining the best lung function possible, abolishing symptoms, preventing development of permanent lung impairment, avoiding unnecessary drug effects and reducing mortality due to acute attack. The first line therapy is preventive. It stabilizes and reduces chronic inflammation of the airways using corticosteroids and/or asthma prophylactic agents. The preferred treatment in an acute attack involves a combination of bronchodilators via a nebuliser which allows deeper penetration of the drug into the bronchial tree. Dose and frequency is determined by severity of the attack. In children, due to distress caused by an asthma attack, hypoxia is corrected using supplemental oxygen and reversal of airway obstruction using inhaled β2 agonists and oral or parenteral corticosteroids. (Bullock & Manias, 2013) 2. Explain why the mild respiratory infection would be considered a trigger for BB’s asthma attack. (3 marks) When there is an infection, foreign antibodies cause mast cells to rapture. The cytoplasm of mast cells contains granules full of inflammatory mediators and hence when degranulation occurs, widespread release of chemical mediators leads to bronchoconstriction, edema and elevated mucus production hence the attack. 3. What is the rationale for the use of inhaled corticosteroids in the long-term management of BB’s chronic asthma? (3 marks) Inhaled corticosteroids are fast acting bronchodilators and thereby when inhaled they give rise to therapeutic effects faster than when administered orally as it is a case of chronic asthma. They also prevent rupturing of Mast cells hence are preventative. 4. a. What short-term adverse effects would you expect to see with inhaled corticosteroids? (2 marks) Inhalation of corticosteroids is associated with some short-term toxicities. They include hyperglycemia, hypertension and immunosuppression that is often marked with candidiasis. There are also adverse psychotic reactions such as affective disorders and sleep disturbances. Whereas these reactions may manifest with the first several doses, discontinuation or reduction of dosage will reverse the short-term effects. In view of this, it is necessary to keep the dosage to lowest effective dose. b. What short-term adverse effects would you expect to see associated with inhaled B2 agonists? (5 marks) Hypertension, headache, palpitations and fine muscle tremors are some of the adverse effects of B2 agonists. Hypertension and headache is commonly due to peripheral vasodilation. 5. What problem may be associated with the long-term use of inhaled corticosteroid therapy in young children? (4 marks) Long term corticosteroid therapy may result in stunted growth, osteoporosis, diabetes, hypertension, cataracts and repeated infections, bruising and atrophy. 6. Why has the health team managing BB’s acute attack used an inhaler and spacer to administer the bronchodilator therapy rather than a nebuliser? (2 marks) An inhaler and a spacer allowed for fast action of the drug due to a faster drug delivery process. Nebulizer treatment takes a bit longer and this is time one does not have with a 5-year-old in an acute attack. Children also lack the coordination required to inhale a drug as is the case using a nebulizer due to distress. (Bullock & Manias, 2013). A spacer also has a one-way valve that allows drug particles to move into the chamber during inhalation and holds them in the chamber during exhalation hence providing efficient drug delivery. 7. How does the systemic administration of the corticosteroid hydrocortisone assist in the recovery after an acute asthma attack? (4 marks) Systemic administration reduces recurrence of attacks since they are anti-inflammatory agents and when in the system, a recurrent attack can be mediated by the corticosteroid hence preventing a relapse. They also decrease the mucus produced in the lungs and prevent inflammation in aerial ways. They are useful in controlling symptoms when starting long-term treatment of asthma. (Bullock & Manias, 2013) 8. What aspects of your client’s condition would you monitor during this combined therapy? Why? (5 marks) I would monitor the client’s oxygen levels to ensure that hypoxia does not set in. I would also monitor the breathing rhythm of the client to ensure the treatment is working. PART D - (Total 15 marks) Eva Bernstein, aged 58, comments how relieved she is now that her doctor has started her on the thiazide hydrochlorothiazide as part of her antihypertensive therapy. “Now I won’t have to worry about having food without salt. The water tablet will take care of it,” she explains. What would be your response to her? What other lifestyle issues will you explore with Ms Bernstein? The prolonged effects of thiazide hydrochlorothiazide makes it ideal for her because it is cost effective and reduces morbidity and mortality especially in conjunction with beta-blockers. She should use the drug plus a beta-blocker to enjoy the full benefits from her treatment and she should continue taking food with salt occasionally because dehydration is a potential side effect of using diuretics. The tablet will take care of it to some extent but she should not discontinue using salt. However, it is important that her doctor monitors her for hypokalaemia, hyponatraemia and dehydration. She should also administer her water tablet on a once-daily dose, preferably in the morning to prevent the diuresis affecting her sleep. If another dose is required, she should take it in the early afternoon or midday. Another lifestyle advice would be to eat foods rich in potassium because hypokalaemia is associated with weakness, dizziness, and nausea. Potassium supplements are also encouraged. She should also take precautions in the sun because thiazide diuretics can cause photosensitivity due to a sulphonamide group present in their structure. Taking water is also another lifestyle issue she should embrace because of the effect of dehydration. Dose-related hyperglycemia can be caused by diuretics and hence she should use a low-dose thiazide to avoid such an effect (Bullock & Manias, 2013) References Asperheim, M. K., & Favaro, J. (2012). Introduction to pharmacology. St. Louis, Mo: Elsevier/Saunders. Bullock, S., & Manias, E. (2013). Fundamentals of Pharmacology VS. Sydney: Pearson Education Australia. .Hilal-Dandan, R., Brunton, L. L., & Goodman, L. S. (2014). Goodman and Gilman's manual of pharmacology and therapeutics, editors Randa Hilal- Dandan, Laurence L. Brunton. New York: McGraw-Hill. Krishna, R. (2004). Applications of Pharmacokinetic Principles in Drug Development. Boston, MA: Springer US. Macheras, P., & Iliadis, A. (2016). Modeling in biopharmaceutics, pharmacokinetics, and pharmacodynamics: Homogeneous and heterogeneous approaches. Moini, J. (2009). Fundamental pharmacology for pharmacy technicians. Clifton Park, NY: Delmar Cengage Learning Pazdernik, T., & Kerecsen, L. (2011). Rapid review pharmacology. Philadelphia, PA: Mosby/Elsevier. Pea, F. (2012). Pharmacokinetics in everyday clinical practice. Torino: SEEd srl. Pharmaceutical Society of Australia. (2013). Australian medicines handbook. Adelaide, S. Aust: Australian Medicines Handbook. Top of Form Rosenbaum, S. (2011). Basic pharmacokinetics and pharmacodynamics: An integrated textbook and computer simulations. Hoboken, N.J: John Wiley & Sons . Top of Form Bottom of Form Top of Form Bottom of Form Top of Form Bottom of Form Top of Form Top of Form Bottom of Form Bottom of Form Bottom of Form Read More