Fundamentals of Pharmacology - Assignment Example

PHARMACOLOGY SCH3236 SEMESTER ONE 2016 ASSIGNMENT TWO Name: Student Number: Date: 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) (a) aminoglycosides (b) quinolones (c) carbapenems (d) polymyxins 2. State the mechanisms of action of each of these agents. (4 marks) Aminoglycosides – Act by inhibiting protein synthesis. Quinolones – Act by inhibiting topoisomerase II, which defragments the DNA of the bacterial cell. Carbapenems – Act by inhibiting call wall synthesis Polymyxins – Act by binding to lipopolysaccharide to disrupt the outer and inner membrane of bacteria. 3. Outline the pathophysiology underlying Mr BT’s hypersensitivity to penicillin (4 marks) Hypersensitivity to pencillin occurs when the immune system reacts to the drug, mistaking it for a harmful substance. The hypersensitivity occurs when at first, the immune system detects the drug as an infection and develops antibodies against the type of penicillin taken. When you take the drug for the second time, the antibodies initially formed will be produced to fight the drug as if it were a bacterial or viral infection. The chemicals released as a result of this allergic reaction results to the symptoms that are associated with the hypersensitivity reaction (Pichler, 2007). 4. Given the fact that Mr BT is allergic to penicillins, is cephalexin therapy contraindicated here? (3 marks) Cephalexin can be used as an alternative in Mr BT’s case. However, caution must be taken when administering cephalexin, because sometimes a cross sensitivity may occur if he is using beta-lactam drugs, an observation that has been made with penicillin-allergy patients. 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 act by binding to steroid intracellular receptors in the cytoplasm, which then modulate the transcription of genes in the target tissues. This controls protein synthesis, including enzymes that are involved in the regulation of vital cell activities. Corticosteroids form a protein that inhibits the action of the enzyme phospholipase A2 required for availability of arachidonic acid. The latter is vital in forming inflammatory mediators. Corticosteroids also act by altering the ion permeability of the cell membranes, and also alter neurohormones production (Bullock & Manias, 2013). Adverse effects requiring monitoring during treatment include: Adrenal suppression especially in infants, HPA axis suppression, convulsions and raised ICP, immunosuppression, and blood hyper-coagulation. 2. To which cytotoxic drug groups do each of the drugs in the case study belong? (5 marks) Vincristine – mitotic poison L-asparaginase – Enzyme Daunorubicin - Cytotoxic anthracycline antibiotic Methotrexate – Antimetabolite Cytarabine - Antimetabolite 3. Describe the mechanism of action of each of the drug groups identified in question Antibiotic Type Cytotoxic Agent (5 marks) Mitotic poison acts by partially attaching to the tubulin protein, thereby hindering separation of cell chromosomes during metaphase. Enzymes (L-asparaginase) acts by breaking down asparagine that is required by the cells to survive. Cytotoxic antibiotics act by contact inhibition to limit cell division. Antimetabolites act by conversion to cytosine arabinoside triphosphate, which interferes with DNA synthesis (Galbraith, Bullock, Manias, Hunt, & Richards, 2015). 4. What are the common immediate and delayed adverse reactions associated with cytotoxic drugs? (4 marks) Immediate adverse reactions include, vomiting, nausea, reversible alopecia, bone marrow suppression and skin rashes. Delayed adverse effects reactions include delayed emesis, neurotoxicity, cardiovascular toxicity and effect on gonadal function and fertility. 5. Describe the clinical management of a client with increased susceptibility to infection. (5 marks) Increased susceptibility can be clinically managed using three major ways: Bacteriotherapy, preventing overgrowth of the disease causing micro-organisms, and using combined or improved treatments. Bacteriotherapy is a natural way of using a harmless bacteria to displace the disease causing microorganisms. Overgrowth of the microorganisms can be controlled through intermittent therapy. Some infections are better managed by using combined treatments or using latest treatment options if available. 6. To which antimicrobial drug group does doxycycline belong? Is it considered a bactericidal or bacteriostatic agent? Explain. (3 marks) Doxycycline belongs to tetracycline antibiotics group and is considered as a bacteriostatic agent. Doxycycline acts by inhibiting synthesis of bacterial protein. The drug binds onto the ribosomal sub-unit, interfering with the production of bacterial protein. Thus, limiting the growth of bacteria. 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) Every antimicrobial drug is characterized by precisely determined natural spectrum of antimicrobial activity, which is the range of microbe strains that can be inhibited by the antimicrobial. The strains of microbes that can be affected by the antibiotic are determined in the initial phases of the drug study, before its introduction into clinical practice. Doxycycline has anti-microbial spectrum of activity over a broad range of gram-positive and gram-negative microorganisms. A drug with this spectrum of activity is preferred because it can treat a wide range of infections caused by protozoa and bacteria. 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 drug therapy can be administered to patients with no constraints and have the appropriate indications. The indications for this drugs include symptoms of myocardial ischaemia in a duration of < 12 hours, within 12 hours of chest pain that lasts for at least half an hour, and changes in ECG of ST elevation or left bundle branch block. Patients who do not have these changes in ECG are not supposed to be administered with fibrinolytic drug therapy. The constraints regarding the timing of administration include: major trauma (including surgery) within 30 days, cerebral event in 6 months, uncontrolled hypertension, bleeding peptic ulcer in a duration of 2 months, and non-compressible vascular puncture.   2. Compare and contrast the mechanisms of action of the fibrinolytic drugs streptokinase and aspirin. (3 marks) Streptokinase mechanism of action is by activation of conversion of plasminogen into plasmin. Plasmin, a proteolytic enzyme, has the capability to break the cross-links between molecules of fibrin and provide the required structural integrity to promote clot lysis. Aspirin acts by the mechanism of inactivating cyclo-oxygenase activity required for the synthesis of enzyme prostaglandin and thromboxane. Both streptokinase and aspirin have an inhibitory effect on activation of platelet aggregation and activation (Ritter, Lewis, Mant, & Ferro, 2008). 3. What adverse reactions should be monitored during and after fibrinolytic drug therapy? (3 marks) Adverse reactions Bleeding complications Anaphylactoid reaction Cardiac arrhythmias Intracraneal hemorrhage 4. Describe the mechanism of action of the antidysrhythmic agent amiodarone.  To which Vaughan Williams antidysrhythmic drug class does it belong? (4 marks) The mechanism of action of amiodarone is by sodium, calcium and potassium channel blocking effects on the AV and SA nodes, which increases the refractory duration and lengthens the potential of cardiac action. The antisympathetic blocking action of sodium, potassium and calcium channels are accountable for the dromotropic effects on the SA and prolonged refractoriness in the AV node. The vasodilatory action of amiodarone can reduce cardiac load and myocardial O2 consumption (Lilley, Collins, Snyder, & Savoca, 2014). Amiodarone belongs to class III antiarrhythmic agent. 5. Compare and contrast the actions of heparin and streptokinase (3 marks) Streptokinase acts by forming a plasminogen complex which converts plasminogen into active plasmin by exposing the plasminogen-active site, i.e. it promotes thrombolysis. Active plasmin degrades clots of fibrin and plasma proteins that in turn causes degradation of clots. Heparin on the other hand favors the activity of AT-III (Antithrombin III) by binding on the AT-III, inactivating thrombin and causing a conformational change. AT-III inhibits Thrombin clotting factors Xa and IXa, and the resulting complex is stable. Both heparin and streptokinase bind on the AT-III and both have anticoagulant effect. 6. Outline the pathophysiology of heart failure (4 marks) Heart failure occurs when the heart is incapable of providing sufficient blood flow that meets all the body’s metabolic requirements. Changes in cardiac function – The cardiac output decreases due to reduction in stroke volume which results from diastolic dysfunction or systolic dysfunction or both. The ventricle may become weak due to overloading with blood during diastole. This triggers increased contraction in the muscles to increase cardiac output. Systemic Vascular function – In order to compensate for this lower cardiac output, the heart increases the pump rate. This worsens the condition as more nutrients are required by the heart muscles which pump the blood at increased rates. The feedback mechanisms try to keep normal arterial pressure by activating sympathetic adrenergic nervous system to constrict arterial resistance vessels. This increases systemic vascular resistance. Blood volume – There is a compensatory feedback that serves to raise ventricular preload, thereby increasing stroke volume. Stroke volume declines as the diastole or systole contractions begin to fail. An increase in the volume of blood in the ventricle during systole is an indication that lesser blood is pumped out of the heart. A decreased volume of blood during diastole is an indication of less blood flowing into the heart. Cardiac reserve – The cardiac reserve is lowered. The heart requires the capability to maintain normal metabolic demands, and also elevated demands, for example, in the event of exertion or exercise (Hosenpud & Greenberg, 2013). After sometime, the heart begins to enlarge, a condition called hypertrophy. The muscle fibres enlarge to enhance contractility, but become stiff and unyielding with time, becoming unbeneficial. The arterial pressure fall and the flow of blood into the kidneys reduces. 7. Describe the mechanism of action of ACE inhibitors and indicate why they are a drug of choice in heart failure (4 marks) ACE inhibitors act by competitively inhibiting the formation of angiotensin-II (active octapeptide) from angiotensin-I (inactive decapeptide). Angiotensin-II is a vasoconstrictor which promotes the formation of aldosterone, and facilitates sympathetic activity. The latter promotes the retention of water and sodium. By inhibiting the formation of angiotensin-II form angiotensin-I, ACE-inhibitors result in vasodilation and inhibit increases in volume due to aldosterone. ACE inhibitors are powerful vasoconstrictors and are very important in managing heart failure. They can relieve symptoms of heart failure, such as swelling and fluid build-up. They make blood vessels relax and reduce blood pressure, which enhances blood flow. As a result, the pump can easily supply blood to all tissues in the body without hard work.   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 a condition where fluid builds up in the lungs. It occurs when the heart is not able to pump blood through the arteries at a faster rate as the veins return the blood to the heart. Failure of the left ventricle causes accumulation of blood in the pulmonary veins, producing an elevated blood pressure in the veins. Increase in pressure in the left ventricle forces the plasma fluid to move from the capillaries into surrounding interstitial spaces and air sacs or alveoli (Bullock & Manias, 2013). As the alveoli gets filled up with fluid, their ability to supply oxygen to the body becomes limited, resulting to pulmonary edema. 9. Compare and contrast the actions of the loop and thiazide diuretics (4 marks) Diuretics works to decrease the quantity of fluid flowing in the blood vessels and the amount of salt in the blood, thus, reducing the arterial pressure. Thiazides act by interfering with salt and water transportation across certain kidney cells. Loop diuretics act by inhibiting the reabsorption of sodium, potassium and chloride. They compete for the binding site of these salt ions. Thiazides have a weaker action in the kidneys and have a smaller effect in the amount of urine produced compared to loop diuretics. The two diuretics have opposing effects on calcium balance. Thiazides promote calcium balance while loop diuretics promote urinary calcium loss. 10. At what stages do the diuretics and the peripheral vasodilators interrupt the pathophysiology of heart failure? (3 marks) Diuretics are an integral component for treating both acute and chronic heart conditions. They have been effective in improving hemodynamics as well as symptoms of heart failure, such as edema and dyspnea in the early stages. Peripheral vasodilators act on the venules and arterials by dilating these vessels to reduce the blood pressure (Galbraith, Bullock, Manias, Hunt, & Richards, 2015). They are used when there is acute myocardial infarction and hypertension resulting from heart failure. PART D - (Total 10 marks) Compare and contrast the general characteristics of the following drug groups: a. the TCAs and the SSRIs Both SSRIs and TCAs are equally effective when it comes to treating depression. However, SSRIs have improved safety and tolerability, and that is why they have replaced TCAs. TCAs work by increasing the levels of norepinephrine and neurotransmitters serotonin in the brain by lowering reabsorption rate by the nerve cells. TCAs act by strongly inhibiting the reabsorption of both serotonin and norepinephrine. SSRIs, on the other hand, they are extremely selective. SSRIs acts as weak inhibitors during the reabsorption of non-serotonergic neurotransmitters, like norepinephrine, but are strong inhibitors in the reabsorption of serotonin. It is because of this EERIs selectivity that they have fewer side-effects compared to TCAs. TCAs have a similar structure, unlike SSRIs that have varying molecular structures. SSRIs do not affect as many sites of action as TCAs do, and because of this, SSRIs result to fewer adverse effects. The overall tolerability of SSRIs in acute and long-term therapy is better than that of TCAs. SSRIs induce notably less cardiotixic, anticholinergic and antihistaminergic side-effects in comparison to TCAs. SSRIs prevent the blocking of alpha1-adrenergic receptor, and as a result, they are not potential effects of antihypertensive medications, as opposed to TCAs. TCAs present safety and toxicity problems as a result of the effects they have on multiple action mechanisms. In contrast, SSRIs have a lower toxicity. SSRIs and TCAs are equally effective in the treatment of panic disord b. the non-selective MAOIs and the RIMAs Generally, MAOIs and the RIMAs share several properties, with differences being selectivity and reversibility. MAOIs bind on the monoamine oxidase enzyme permanently, thereby preventing the breakdown of monoamine neurotransmitters. Non-selective RIMAs bind with enzymes reversibly and can detach to reactivate the enzyme. When it comes to effectiveness, RIMAs are comparatively weaker than non-selective MAOIs, although they can be more effective than other drugs from the antidepressant family. When under treatment using RIMA drugs, it is not necessary to have dietry restrictions as in the case with non-selective MAOI antidepressants. c. the TCAs and the tetracyclic antidepressants TCAs and tetracyclic antidepressants are used to treat depression as an option where other drug options have failed. However, TCAs are more effective in treating depression than tetracyclic class of drugs. Only Remeron from the tetracyclic drugs is still highly effective. Both drugs act by affecting reabsorption of neurotransmitters serotonin used for communication between the brain cells. TCAs have a high affinity as both antagonists and agonists, which may contribute to the effectiveness of the drug, or its side effects (Walsh & Schwartz-Bloom, 2004). TCAs also act as anticholinergics and potent antihistamines, properties that provide a sedative effect. Tetracycline antidepressants act as antagonists depending on the binding site. d. the TCAs and the non-selective MAOIs Both TCAs and non-selective MAOIs are effective antidepressants and work by altering neurotransmitters in the brain cells. However, TCAs are have more side effects compared to MAOIs (Bodkin & Gören, 2007). Use of MAIOIs require diet restrictions to avoid high blood pressure, unlike non-selective MAOIs that do not diet restrictions. e. the SSRIs and the SNRIs SSRIs and SNRIs are reuptake-inhibitor antidepressants. On the mode of action, SSRIs work by affecting the neurotransmitters in the brain cells to send and receive chemical messages, while SNRIs act by blocking the reabsorption of both norepinephrine and serotonin to relieve depression. SSRIs are selective and only affect serotonin, SNRIs affect both serotonin and norepinephrine neurotransmitters. (2 marks each) References Read More