Fundamentals of Pharmacology - Assignment Example

PHARMACOLOGY SCH3236 SEMESTER ONE 2017 ASSIGNMENT TWO PART A - (Total 15 marks) Chapter 81 - page 1085 - Fundamentals of Pharmacology (7th Edition) Mr BT is 47-year-old man admitted to hospital with prostate hypertrophy requiring a transurethral resection of the prostate (TURP). The procedure is completed without complication and Mr BT returns to the ward with an indwelling catheter in place, it remains in situ for three days. After the catheter is removed, Mr BT experiences urinary frequency and a burning sensation during micturition. A urine sample is taken and sent to the microbiology laboratory for analysis. The microbiology report shows the following: Microscopy: white blood cells ++, Gram-negative rods Culture: Pseudomonas aeruginosa Sensitivity: amoxicillin-resistant, cephalexin-sensitive, trimethoprim-resistant, gentamicin-sensitive His medical history indicates hypersensitivity to penicillin. Answer the following questions: 1. Which antibacterial agent(s) would be effective in the therapy of Mr BT’s urinary tract infection? (4 marks) Aminoglycosides and quinolones, though aminoglycosides are preferred. Pseudomonas aeruginosa always infects individuals after long periods of hospitalization. The most common environment for infection is hospital setup whereby there are strains that have developed resistant to the common antibiotics. Carbapenems can also be used in the treatment of urinary tract infections of Pseudomonas aeruginosa. To treat the nosocomial infections they cause especially to the urinary tract, aminoglycosides remain the most preferable therapeutic agent (Clark, 2012). 2. State the mechanisms of action of each of these agents. (4 marks) Aminoglycosides are indicated in mycobacterial, gram-negative and gram-positive bacterial infections (Katzung and Trevor, 2015). Gentamicin and kanamycin are classical examples. They disrupt the synthesis of proteins by binding to the 30s ribosomal subunit in the bacteria. They also interfere with the normal linkage of lipopolysaccharides on the bacterial cell wall hence cell wall damage. Carbapenems are β lactams that do not diffuse easily through bacterial wall. They do so through burrowing through the porins. They then transverse periplasmic space and acylate the peptidoglycan binding proteins. These proteins include transglycolases, carboxypeptidases and transpeptidases. These proteins catalys the formation of bacterial cell wall; their acylation interferes with cell wall synthesis. Quinolones are bactericidal antibiotics that are preferred for resistant strains bacterial infections and are more precisely indicated for genitourinary infections. Drugs in this class inhibit bacterial replication by inhibiting DNA synthesis. This is by preventing the activity of the enzyme that unwinds the DNA material to allow for replication – topoisomerase II (Walsh, Schwartz-Bloom and Levine, 2010). 3. Outline the pathophysiology underlying Mr BT’s hypersensitivity to penicillin (4 marks) Penicillins do share the common core ring in their chemical structure but their side chains are different. In normal circumstances, the ring is metabolized into penicilloyl penicillin itself. This penicillin comprises penilloate and penicilloate that can trigger an IgE dependent immune response (Apley and Smith, 2015). The symptoms that characterize penicillin hypersensitivity after IgE response includes itchiness on the skin surfaces, swelling of the throat that resembles rhinitis, swelling of other mucosal surfaces. These lead to difficulty in breathing. In such hypersensitivity reactions, other antibiotics are explored. 4. Given the fact that Mr BT is allergic to penicillins, is cephalexin therapy contraindicated here? (3 marks) Cefalexin is an example of drugs in the class of cephalosporins. These drugs, for a long time, have been contraindicated in patients with penicillin allergy. This is because when they are administered, they cause profound manifestations of penicillin hypersensitivity. It must, however, be noted that this cross-reactivity is unique to specific cephalosporins such as cephalothin, cefazolin, cephalexin and cefadroxil. Ceftriaxone and cefuroxime are not associated with any worsening of hypersensitivity reactions of penicillin. From the foregoing illustration, it is easily appreciated that cephalexin administration be contraindicated in patients with penicillin allergy (Clark, 2012). PART B: (Total 30 marks) Chapter 81 - page 1085 - Fundamentals of Pharmacology (7th Edition) KY is a 12-year-old boy who has been diagnosed recently with acute lymphoblastic leukaemia (ALL). He has been admitted to hospital for treatment. KY’s initial therapy will comprise the corticosteroid dexamethasone, as well as the cytotoxic agent’s vincristine, L-asparaginase, daunorubicin, methotrexate and cytarabine. He experiences gastrointestinal upset but responds well to therapy; however, he does require close monitoring of his condition. KY receives adjunct therapy with the colony stimulating factor filgrastim. KY’s four siblings are tissue-typed for bone marrow transplant. One of the children is considered a good match. While awaiting transplantation, KY develops a fever. He receives intravenous therapy with doxycycline to reduce the risk of sepsis. This crisis passes. After bone marrow transplant, KY makes good progress and moves into remission. Answer the following questions: 1. Describe the mechanism of action of the corticosteroids and indicate the adverse effects that require monitoring during treatment with these drugs. (6 marks) Corticosteroids are drugs synthesized to mimic the role of the glucocorticoids and mineralocorticoids produced by the adrenal cortex. They majorly have an anti-inflammatory role and the ability to suppress immunity. However, some are involved in regulation of salt in the body. In the process of inflammation, prostaglandins and inflammatory mediators such as leukotrienes play a key role. The process of their release to effect inflammation is initiated by the conversion of phospholipids to arachidonic acid (Apley and Smith, 2015). Corticosterioids enhance the role of phospholipase A2 inhibitor 2. Inflammatory mediators are therefore controlled by inhibiting release of arachidonic acid. This effect can be reached by using topical, systemic or ocular formulations. The major adverse effects of corticosteroids that require monitoring include an increase in risk of infections, gastrointestinal bleeding and ulcers and platelet disorders that may result into poor wound healing and easy bruising (Aley and Smith, 2015). 2. To which cytotoxic drug groups do each of the drugs in the case study belong? (5 marks) Vincristine belongs to vinca alkaloids which are microtubule damaging agents L-asparaginase belongs to the miscellaneous antineoplastic agents Daunorubicin belongs to the antitumor antibiotics drug class which are anthracyclines Methotrexate is an antimetabolite which is a folic acid analogue Cytarabine is also an antimetabolite which is a pyrimidine analogue (Katzung and Trevor, 2015). These antineoplastic drugs have a similar gross effects though they have different chemical structures and diverse mechanisms of action. 3. Describe the mechanism of action of each of the drug groups identified in question Antibiotic Type Cytotoxic Agent (5 marks) Vinca alkaloids are derivatives of the Vinca rosea plant and they inhibit the polymerization of tubulin hence they damage and disrupt the assembly of microtubules. This consequently interferes with the formation of spindle fibres used in the process of mitosis. Cells are therefore arrested in the metaphase stage as the cells are subjected to aptosis. When the cells are arrested in this stage, cell division and replication is blocked and the neoplastic ability of the cells is compromised. The lymbhoblastic cells will not be able to increase in number (Katzung and Trevor, 2015). L-asparaginase depletes L-asparigeine in tumor cells. The L-asparagine amidihydrolase is essential in hydrolysis of L-aparagine to aspartate and ammonia. On its depletion, this process cannot take place. Aspartic acid is an essential amino acid that is involved in cell development and division. L-asparaginase prevents both division and may act on the tumor cells by destroying them (In Clark and In Kumar, 2017). Antitumor antibiotics interfere with the synthesis of nucleic acids. They have an effect on DNA synthesis, RNA synthesis or both. Daunorubicin for instance inhibits thev synthesis of both DNA and RNA. In general, they are referred to as antitumor antibiotics due to their ability to prevent protein synthesis and nucleic acid formation as seen in the case of tetracyclines as well as antibacterials such as erythromycin (Hilal-Dandan, Brunton and Goodman, 2014). Antimetabolites inhibit cell replication in regions such as bone marrow by either resembling normal subtrates, inhibiting synthesis inhibiting the function or synthesis of RNA. They are always specific to a given stage in the cell cycle. When they resemble the normal subtrates, the cells of the reticuloendothelial system act on them but there is inability to form blood cells despite the involvement of cytokines and stimulating factors. Similar to antitumor antibiotics, there is incapability of the cells to synthesize RNA that will be used to form protein in ribosomes as well as in the DNA replication stages (In Clark and In Kumar, 2017). Folic acid analogues bind strongly to dihydrofolate reductase enzyme leading to the depletion of tetrahydrofolate. This reduces the 1-carbon transfer involved in purine synthesis and also in the process of methionine and serine synthesis. This consequently decreases the synthesis of nucleic acid and that of important cellular proteins. Folate is known as a requirement for cell division as well as DNA synthesis since its procedural processes in the cells involve components of the nucleus that will develop into the nucleic acid. By binding to the enzyme that aids the processes, formation of new blood cells is crippled and the burden of tumor cells will be handled. (Katzung and Trevor, 2015). A study by Al-Snafi (2017) observed that pyrimidine analogues inhibit DNA synthesis by inhibiting thymidylate synthase that aids the synthesis of DNA. It may also incorporate into RNA to interfere with its processing. This, in turn, slows the growing of tumors (In Clark and In Kumar, 2017). 4. What are the common immediate and delayed adverse reactions associated with cytotoxic drugs? (4 marks) Cytotoxic drugs tend to cause serious injuries to highly proliferating cells such as those of the bone marrow, reproductive organs, the gastrointestinal tract and the hair follicles. This property leads to the drug toxicity that leads to loss of hair (alopecia), loss of bone marrow (myelosuppression), disruption to the gastric cells which increases the emetic potential and the tendency to have nausea and vomiting as well as a reduction in immunity that is evident in low white blood cell count. With long term use, patients can develop resistance to the drugs through a set of mechanisms or may develop treatment-induced tumours due to the mutagenic properties of these drugs. This is a delayed adverse reaction and may take around 10 years (Al-Snafi, 2017). 5. Describe the clinical management of a client with increased susceptibility to infection. (5 marks) Increased susceptibility to infections is caused by the immunosuppressive cytotoxic drugs. Apart from infections, they may also develop malignancies and cytopenias. In cases where a patient has an increased risk of developing infections, vaccines can be given – in this case live attenuated should be avoided. The vaccines are able to prevent infections from specific microorganisms. According to Hashilkar et al. (2017) immunostimulants can also be used to elevate the functionality of the immune system. This can be used alongside cytotoxic drugs or can serve as an alternative for the cytotoxic drugs (Nagahisa & Okumura, 2017). On stimulation of the immunity, the cells of the immune system will effectively distinguish healthy cells from cancer cells hence effect the T-cell mediated cytotoxicity. Antibodies and other antimicrobial agents can be used on detection of specific infections. Alternatively, a bone marrow transplant can provide a long lasting solution by enhancing production of functional leukocytes that can take place in immune processes (Pazdernik and Kerecsen, 2011). 6. To which antimicrobial drug group does doxycycline belong? Is it considered a bactericidal or bacteriostatic agent? Explain. (3 marks) Doxycycline is an antibiotic. It is used to treat bacterial infections. It falls under the drug class Tetracyclines. Their mechanism of action is based on their binding of 30s ribosomal subunit A-site. This prevents the binding of t-RNA to the A-site. Tetracyclines are bacteriostatic (Katzung and Trevor, 2015). This is because they inhibit protein synthesis and prevent bacteria from reproducing. They, therefore, are not killed and cannot replicate at the same time since they need proteins to be able to make new cells (Hilal-Dandan, Brunton and Goodman, 2014). 7. Define the term ‘antimicrobial drug spectrum of activity’. What is the spectrum of activity of doxycycline? Why choose a drug with this spectrum of activity? (2 marks) Antimicrobial drug spectrum of activity is a measure of the range of microorganisms to which an antimicrobial agent can act on. Doxycycline is a broad spectrum antimicrobial that can act on gram positive and gram negative bacteria as well as helminths and some protozoa and malaria (Clark, 2012). PART C - (Total 35 marks) Chapter 55 - page 693 - Fundamentals of Pharmacology (7th Edition) In the ambulance, a paramedic initiates oxygen therapy and administers morphine to SA (patient) for pain relief, as well as a low dose of aspirin. After SA arrives at the hospital, investigations confirm that he is suffering from an acute myocardial infarction. SA receives an intravenous infusion of the fibrinolytic agent streptokinase, as well as the anti-dysrhythmic amiodarone for ventricular tachycardia. Cardiac enzyme level test indicate that the damage to the myocardium is extensive. During his hospital stay he receives treatment with subcutaneous heparin and the B-blocker atenolol. Acute heart failure develops, which requires treatment with the ACE inhibitor enalapril and the loop diuretic frusemide. The diuretic is for the treatment of SA’s pulmonary oedema. After prolonged hospital stay, SA is discharged. He goes on to develop chronic heart failure, which is managed with an ACE inhibitor, a diuretic and a peripheral vasodilator. 1. What is the rationale for the use of fibrinolytic drugs in acute myocardial infarction (AMI)?  Are there any constraints regarding the timing of administration of these drugs in AMI? (4 marks) Fibrinolytic drugs are used to enhance reperfusion in the ischemic tissues by breaking down the clots. This is made possible by activating plasminogen to its active form. The active form (plasmin enzyme) breaks the links between fibrin molecules. This eliminates obstruction of cardiac vessels hence corrects perfusion. The cardiac myocytes can consequently receive adequate perfusion that allows them to enable pumping of blood to lungs for oxygenation and to the body systems where required. In the management of acute myocardial infarction, there are no limitations for using fibrinolytic agents since they are considered the first line drug for treating AMI (Edmunds, 2016). 2. Compare and contrast the mechanisms of action of the fibrinolytic drugs streptokinase and aspirin. (3 marks) Fibrinolytics activate fibrinolysis by activating the proenzyme plasminogen to its active form plasmin. Plasmin degrades clots formed by fibrin mesh by degrading the links that form the meshwork. The clot is broken down and eliminated by further degradation in liver and kidney. Aspirin on the other hand inhibits platelet aggregation at different sites and platelet adhesion becomes compromised. No clot cannot form consequently. Prostacyclin production by aspirin is responsible for this role (Galbraith et al, 2015) 3. What adverse reactions should be monitored during and after fibrinolytic drug therapy? (3 marks) Fibrinolytic drugs are associated with major bleedings that results from the initiation of the fibrinolysis process. It is therefore possible for excessive bleeding to occur at various sites whereby drug action is not intended. If this is not controlled, excessive bleeding can result into hemolytic shock (Galbraith et al, 2015). Some patients are hypersensitive to various fibrinolytic agents. They have a formed allergy to the drug and on therapeutic use, they have a high chance of developing anaphylactoid reaction. Fibrinolytic drugs can cause cerebrovascular accidents when degraded clots in the coronary vessels are embolized to cerebral vessels. The eboli cause obstruction of cerebral arteries and microvasculature and this is responsible for the cerebrovascular accidents. The same mechanism is similar in the development of cholesterol embolus syndrome. This occurs when the degraded clot had cholesterol components. Cardiac arrhythmias and intracranial hemorrhage also result as adverse effects of using fibrinolytic agents for therapy. 4. Describe the mechanism of action of the antidysrhythmic agent amiodarone.  To which Vaughan Williams antidysrhythmic drug class does it belong? (4 marks) Amiodarone is a K+ channel blocker. It causes a delay in repolarization as it plolongs the refractory period. Its mechanism of action is the prolongation of action potential by delaying the K+ reflux (Katzung and Trevor, 2015). Apart from its role as a drug in this group, it has other mechanisms of action that resemble that of other classes. According to Vaughan Williams’ classification, it falls under Class III Antiarrhythmic agents (Clark, 2012). 5. Compare and contrast the actions of heparin and streptokinase (3 marks) Heparin has an anticoagulant activity that is produced by inactivating thrombin as well as factor Xa to its inactive form factor X. this mechanism is antithrombin independent. It then binds to antithrombin through a high affinity pentasaccharide. Streptokinase creates an active complex which enhances the cleavage of Arginine-Valine bond present in plasminogen molecule and form plasmin which is a proteolytic enzyme. This plasmin has the role of degrading fibrin matrix of thrombi. This is its antithrombotic role (Clark, 2012). One unique action that heparin possesses is that it can prevent the formation of fresh clots but it cannot dissolved clots that are already formed. Streptokinase, considering its mechanism of action, can participate in both circumstances. 6. Outline the pathophysiology of heart failure (4 marks) Heart failure is initiated by injury to the myocardium that is caused by either hypertension, ischemic heart disease or diabetes mellitus. Other causes may be infection, myocarditis, cardiomyopathies, systemic infections and valvular disease. The injury is preceded by dyspnea that results from pulmonary congestion, ascites and peripheral edema. Many compensatory mechanisms begin in order to normalize the ventilation-perfusion ratio. These mechanisms can be characterized by increasing cardiac output increasing the ventricular volume and increasing the thickness of the wall. With time, these compensatory feature worsens the heart failure. 7. Describe the mechanism of action of ACE inhibitors and indicate why they are a drug of choice in heart failure (4 marks) Angiotensin Converting Enzyme prevents the RAAS mediated progressive worsening of Myocardial infarction. ACEs therefore reduces Angiotensin II and aldosterone slowing down the harmful effects associated with this hormone. The harmful effects include myocardial fibrosis, cardiac hypertrophy, remodeling and vasoconstriction. They also improve survival rates by 20-30% and patients treated by ACEs respond best to therapy. This is why it is the drug of choice for heart failure (Galbraith et al, 2015). 8. Pulmonary oedema is caused by alterations in fluid distribution between pulmonary blood vessels and the lung tissue.  Using fluid dynamics and changes in fluid pressure, explain the link between heart failure and pulmonary oedema. (3 marks) Pulmonary edema is highly associated with heart failure. Each of the conditions has the ability of resulting to the other. Pulmonary edema occurs following an increased venous pressure. This results into an increase in capillary permeability as the colloid osmotic pressure decreases. Pulmonary edema that results from heart failure is due to activation of humoral and neurohumoral mechanisms promoting the expansion of extracellular fluid through a promotion of Sodium and Water retention. Abnormal Starling forces that occur include an increase in venous capillary pressure and reduced plasma oncotic pressure. Extravasation of fluid follows leading to edema formation (Clark, 2012). In general, when the heart weakens and loses its effectiveness in pumping blood, fluid buildup occurs at various points ranging from the extremities to lungs. It is mostly associated with left sided heart failure. 9. Compare and contrast the actions of the loop and thiazide diuretics (4 marks) Loop diuretics acts on the thick ascending loop of Henle by inhibiting the Na+, K+, Cl- co-transporter. Sodium, potassium and chloride ions are not reabsorbed; therefore, they are excreted in urine to reduce blood volume. Thiazide diuretics, on the other hand, blocks the Na+, Cl- hence inhibit the reabsorption of both sodium and chloride ions. This mechanism leads to reduced blood volume since it is also characterized by fluid loss (Katzung and Trevor, 2015). 10. At what stages do the diuretics and the peripheral vasodilators interrupt the pathophysiology of heart failure? (3 marks) Diuretics have a common role of reducing blood volume by increasing the elimination of fluid as urine. Diuretics act at different points in the kidney. Carbonic anhydrase inhibitors act on the proximal convoluted tubule, loop diuretics act on the thick ascending Loop of Henle, thiazide diuretics in the distal convoluted tubule and some act on the collecting duct. Unnecessary water and salts are excreted through the urine. This then makes it simpler for the heart to control blood pressure. By reducing the blood volume, the work load of the heart reduces consequently and heart failure gets mildly simplified. The diuresis property of these drugs also reduces the incidences of fluid accumulation in tissues – edema (Apley and Smith, 2015). PART D - (Total 10 marks) Compare and contrast the general characteristics of the following drug groups: a. the TCAs and the SSRIs Contrast TCAs are poorly tolerated whereas SSRIs are well tolerated SSRI elicit their actions by binding to serotonin transporter to inhibit it while TCAs inhibit transport of serotonin and other transporters eg. Norepinephrine transporter (Bullock and Manias, 2013). Comparison Both have an effect on serotonin receptors and both cause weight gain as a side effect (Katzung and Trevor, 2015). b. the non-selective MAOIs and the RIMAs MAOIs undergo a significant first pass metabolism and are well absorbed orally whereas RIMAs do not undergo first pass metabolism. RIMAs, unlike MAOIs, does not result into hepatotoxicity and they have a reduced hypertensive action and toxicities associated with tyramine (Bullock and Manias, 2013). c. the TCAs and the tetracyclic antidepressants Apart from the inhibitory effects at the serotonin, norepinephrine and histamine receptors, TCAs have effects on adrenergic and muscarinic receptors. TCAs have a three ringed structure whereas Tetracyclic Antidepressants have a four ringed structure (Bullock and Manias, 2013). d. the TCAs and the non-selective MAOIs TCAs are used for melancholic depression and are not effective in reactive depression whereas MAO inhibitors are used for atypical and refractory conditions with poor response to other medications. Both cause dry mouth as a side effect (Bullock and Manias, 2013). e. the SSRIs and the SNRIs SSRIs inhibit serotonin transporter whereas SNRIs inhibits the transporters of both serotonin and Norepinephrine. Unlike SSRIs, SNRIs result into increase in blood pressure as well as pulse rate (Bullock and Manias, 2013). References Al-Snafi, A. E. (2017). Pharmacology and therapeutic potential of Euphorbia hirta (Syn: Euphorbia pilulifera)-A review. IOSR Journal of Pharmacy, 7(3), 7-20. Al-Snafi, A. E. (2017). The pharmacology and medical importance of Dolichos lablab (Lablab purpureus)-A review. IOSR Journal of Pharmacy, 7(2), 22-30. Al-Snafi, A. E. (2017). The pharmacology of Equisetum arvense-A review. IOSR Journal of Pharmacy, 7(2), 31-42. Apley, M. D., & Smith, R. A. (2015). Bovine clinical pharmacology. Philadelphia, Pennsylvania: Elsevier. Bullock, S., & Manias, E. (2013). Fundamentals of Pharmacology VS. Sydney: Pearson Education Australia. Clark, M. A. (2012). Lippincott's illustrated reviews: Pharmacology. Philadelphia etc: Lipincott Williams and Wilkins. Galbraith, A., Bullock, S., Manias, E., Hunt, B., & Richards, A. (2015). Fundamentals of pharmacology: An applied approach for nursing and health. Hashilkar, N. K., Gelula, M. H., & Angadi, N. B. (2017). Effectiveness and student perspective of a pilot effort in team based learning in pharmacology for medical undergraduate. International Journal of Basic & Clinical Pharmacology, 5(4), 1413-1416. Hilal-Dandan, R., Brunton, L. L., & Goodman, L. S. (2014). Goodman and Gilman's manual of pharmacology and therapeutics. New York: Mcgraw-Hill. In Clark, M. L., & In Kumar, P. J. (2017). Kumar and Clark's Clinical medicine. Katzung, B. G., & Trevor, A. J. (2015). Basic & clinical pharmacology. New York [etc.: McGraw-Hill Education. Nagahisa, A., & Okumura, T. (2017). Pharmacology of grapiprant, a novel EP4 antagonist: receptor binding, efficacy in a rodent postoperative pain model, and a dose estimation for controlling pain in dogs. Journal of veterinary pharmacology and therapeutics, 40(3), 285-292. Pazdernik, T., & Kerecsen, L. (2011). Rapid review pharmacology. Philadelphia, PA: Mosby/Elsevier. Walsh, C. T., Schwartz-Bloom, R. D., & Levine, R. R. (2010). Levine's pharmacology: Drug actions and reactions. London: Informa Healthcare. Read More