Disease Overviews And Pharmacological Basis Of Drug Therapy Biology Essay


In the Health Survey for England 2006, the data shows that there are approximately 0.3% of men had recently diagnosed with myocardial infarction in the last 12 months, whereas in the case of women, there were 0.2% had experienced heart attack. In addition, from the combined aged-specific prevalence, the survey was also present with the estimation of 970000 of men and about 440000 of women who aged 35 or older have had experienced a heart attack giving a total of 1.4million of population diagnosed with myocardial infarction [Health Survey for England.2006].

Myocardial infarction is classified under acute coronary syndrome (ACS) which characterised with acute myocardial ischaemic attack, which commonly known as "heart attack" that attributable to the imbalance between blood oxygen supplies to and oxygen demand from myocardial cells. It can be further categorized based on the changes in electrocardiographic (ECG) as ST-segment-elevation myocardial infarction (STEMI) and non-ST-segment-elevation myocardial infarction (non-STEMI). Acute myocardial infarction often present with a diminished coronary blood supply to the myocardial cells. The cause of sudden reduction in coronary blood flow is primary due to the development atherosclerosis and complicated by thrombosis. Atherosclerosis is a progressive disease primarily initiated by the uptake of circulating low-density lipoproteins (LDLs) into blood vessels through transcytosis. This is followed by the infiltration of monocytes into the endothelium in response to hyperlipidaemia. The monocytes are transformed into macrophages and release free radicals for LDL oxidation. The oxidized LDL is uptake by macrophages and form lipid-laden foam cells in the extracellular space of endothelium. As the foam cells become larger, the lesion will be covered by the proliferated smooth muscle cells and deposited over the foam cell layer which eventually forms atheroma. The rupture of atherosclerotic plaque in coronary artery may expose the softer inner core of the plaque to the blood component in lumen. This results in setting off the aggregation of platelet and coagulation cascade around the damaged area. The blood clotting cascade is initiated with the formation of thrombus at the lesion area on the lumen of blood vessel accompanied with local vasoconstriction. In addition, the propensity of thrombosis due to atheromatous plaque development also impairs the antithromotin function of endothelium. As the thrombi have fully filled the remaining lumen, the blood supply to the myocardial cells will be obstructed, led to myocardial ischaemic attack. The myocardial necrosis will become detectable after 15-30 minutes of ischaemic attack due to the release of biochemical markers, primarily Troponin I or T and creatine kinase myocardial band from the necrotic myocytes into the bloodstream.

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There are several factors that have been identified to be increasing the risk of myocardial infarction, such as increasing age, male gender, and family history of ischaemic heart disease (heredity). Despite these non-modifiable risk factors, the disease management often intervene the modifiable risk factors, which consist of smoking, heavy alcohol consumption, hypertension, diabetes mellitus, hyperlipidaemia, obesity and sedentary lifestyle. The sign and symptoms of acute coronary heart disease are commonly present with acute central chest pain which last more than 20 minutes, often associated with nausea, sweatiness, dyspnoea and palpitation. In certain patients, it may present without chest pain (silent infarct) especially in elderly and diabetic patients. In addition, myocardial infarction may present along with syncope, pulmonary oedema, epigastric pain, stroke, increased or decreased pulse and blood pressure, present of 4th heart sound and may have signs of heart failure as well.

To diagnose a patient with STEMI, assessment though a 12 lead electrocardiogram and measurement of serum troponin I or T level should be carried out during admission and 12 hours after admission, or 12 hours after pain begins, depending on patient and the treatment facilities at the hospital. Other investigations should be initiated to established the appropriate treatment decisions, such as full blood count, urine and electrolyte, liver function, serum blood glucose, lipid profile, biochemical markers (cardiac enzymes: Creatine kinase-MB , Aspartate transaminase, lactate dehydrogenase).

The reperfusion therapies in management for patient with STEMI consist of primary percutaneous coronary intervention (PCI) and thrombolytic therapy. In spite of different type of interventions, a series of drug class is used in either adjuvant treatment to PCI or primary pharmacological treatment. This includes the antiplatelet agents (Aspirin,clopidogrel and GPllb/llla) and antithrombin agents (heparins, streptokinase and alteplase).

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Aspirin binds to the cyclooxygenase enzymes (COX-1 and COX-2) irreversibly which contribute to its antiplatelet effect. Inactivation COX-1 enzymes impedes the production of thromboxane A2, which under normal circumstances cause platelet aggregation over damage of the walls within blood vessels. However, due to its non-selectively binding to COX-1 and COX-2 enzymes, the potential adverse effect that might be encountered is dose-related gastrointestinal bleeding and neutropenia.

Clopidogrel is an adenosine diphosphate antagonist and it acts by inhibiting ADP-induced platelet aggregation. It works through irreversibly binds to P2 -receptor on platelets which decrease the expression of glycoprotein IIb/IIIa receptors and reduce the fibrinogen cross-linking of receptor. Its action also associated with side effects such as dyspepsia, diarrhoea, and abdominal pain, less commonly cause rash. 2

The rationale of using beta blockers in the treatment of myocardial infarction is mainly attributable to its blocking effect on beta1-receptor and hence reduces the catecholamines' positive inotropic and chronotropic effects. Eventually, they reduce the conduction and increase the refractory period of AV node which improve the left ventricular function and decrease the cardiac workload. Beta blockers are possesed with the side effects of fatigue, coldness of the extremities, bronchoconstriction, hypotension and gastrointestinal disturbance.

ACE-Inhibitors (captopril, enalapril, lisnopril) acts by blocking active site of angiotensin converting enzyme, in consequence, inhibit the conversion of angiotensin I to angiotensin II. The lost of strong vasoconstrictor angiotensin II resulting in vasodilation of blood vessel, decreased aldosterone secretion and increased circulating bradykinin, which also has vasodilating effect.As a result, they affect capacitance and resistance vessels, and reduce cardiac load as well as arterial pressure. In addition, the inhibition release of aldosterone into systemic circulation is followed with increased excretion of sodium and water. In terms of side effects, ACE-inhibitors often cause persistent dry cough, which is associated with the accumulation of bradykinin due to its bronchoconstrictor effect, first dose hypotension, taste disturbance, and neutropenia.

Low molecular weight heparins (LMWHs), such as enoxiparin, dalteparin and fondaparinux, are involved in inhibiting further blood coagulation or formation of thrombus in the affected area. They act by forming a heparin-antithrombin lll, thus activate the antithrombin lll. As a result, the complex enhances the action of antithrombin lll on factor Xa in the blood clotting cascade. The main side effect of administrating LMWHs is haemorrhage as its anticoagulant effect is not site-specific action. Moreover, although heparin-induced thrombocytopenia (HIT) was found to be an uncommon side effect, this immunologically mediated effect may lead to increased risk of spontaneous bruising and prolonged bleeding after injury. Heparins are administered through injection and this lead to higher risk of injection-site reaction.

Streptokinase is used a thrombolytic agent for its action on activating circulating plasminogen. The activated form plasmin can cleave the fibrin into small soluble products and hence remove a blood clot in the end. As product of bacteria streptococcus species, it has acquired antigenic and immunogenic effect which may cause other complications for patients who have developed antibody against it.

3-hydroxy-3-methylglutaryl-coenzyme A inhibitors (HMG-CoAR or Statins) is also used in the treatment of STEMI for its beneficial effect on reducing the circulating LDL concentration. This is done by competitively inhibit the HMG-CoAR enzymes which are responsible in synthesizing cholesterol. The reduction of LDL and cholesterol in turn decrease the potential risk contribute to acute coronary syndrome. However the use of statin drugs may rarely cause muscular side-effects but often significant. Other side effects also include gastrointestinal disturbances, headache, dizziness and altered liver function test results.

Evidence for treatment of the condition(s)

During the first 12 hours of pain onset or acute attack, the initial management for acute STEMI condition consists of oxygen therapy and pharmacology interventions such as opioid analgesics, antiplatelet drugs and beta blockers. Supplemental oxygen is recommended to be administered to patients with shortness of breath, continuing myocardial ischaemic or pulmonary oedema. In a systemic review on routine use of oxygen in MI treatment, it concluded that there is limited evidence to support the beneficial outcome from oxygen therapy [M Wijesinghe, et al. 2009]. Conversely there are few studies recommended that oxygen therapy may be indicated to relief hypoxia which often present during ischaemic attack [Wilson AT, et al.1997; Davidson, et al. 1973; Ribeiro LGT, et al. 1979]. In this current case, Mr T was given oxygen with air flow of 3 litres per minute via nasal prong system. This action was justified to be appropriate to aid his respiration and reduce myocardial ischaemia.

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In terms of antiplatelet therapy, aspirin and clopidogrel are most commonly used for acute myocardial infarction. In combined risk of cardiovascular death, non-fatal MI, and non-fatal stroke, administration of 300mg aspirin alone has an absolute risk reduction of 3.8% and relative risk reduction 30% in acute coronary syndrome in comparison to placebo effect [Antithrombotic Trialists' Collaboration. 2002]. On the other hand, the combination of aspirin and clopidogrel therapy was proved to be more effective in increasing the patency rate as well as reducing mortality rate and major vascular event [Sabatine MS, et al. 2003; COMMIT collaborative group. 2005 ]. In addition to this, a substudy of CLARITY-TIMI 28 trials have showed that administration of dual antiplatelet therapy (aspirin with clopidogrel) with a specific fibrinolytic agent is superior to aspirin alone in prehospital setting respecting to the increased patency rate of infarct artery and safety. The study have demonstrated that addition of clopidogrel to aspirin produce a 9% proportional risk reduction on death, reinfarction, or stroke in comparison to aspirin monotherapy during hospitalisation [COMMIT collaborative group. 2005]. On the other hand, a recent study involving 4203 patients with STEMI undergoing primary percutaneous coronary intervention had demonstrated that triple antiplatelet therapy, which comprised aspirin, clopidogrel and cilostazol, was more beneficial over dual antiplatelet therapy [K.Y.Chen, et al. 2009]. In comparison to dual therapy, the triple therapy group had showed a significantly lower risk of cardiac death (adjusted OR 0.52. 95% Cl 0.32 to 0.84) and total mortality rate (adjusted OR 0.60. 95% Cl 0.41 to 0.89). Other than that, triple antiplatelet therapy seems to have similar adverse event rate to dual therapy for major bleeding, however it has lower incidence of total major adverse cardiac event with adjusted odd ratio of 0.74 (95%Cl: 0.58 to 0.95) [K.Y.Chen, et al. 2009]. Although this study showed the potential benefit in terms of mortality rate and cardiac adverse rate, more trials, studies and meta-analysis are still required to support this method. Mr T was administered with both aspirin and clopidogrel tablets with strength of 300mg immediately during admission. This was considered to be appropriate as dual antiplatelet therapy was reported to have better effect than using either one only.

The recommended beta-blocker in the SIGN-93 guideline is metoprolol, administered via either 5-15mg intravenously or 50-100mg orally before proceeding to reperfusion therapy. In the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT) 2005, 45852 patients were involved in the randomised placebo controlled trial which in determining the outcome of additionally administration of up to 15mg injection and continuing the therapy with 200mg oral controlled-release tablets. The result was presented with no significant difference in mortality of any cause and co-primary end point (death, reinfarction or cardiac arrest) between the placebo group and allocated metoprolol group. However, the administration of additional metoprolol was found to have significantly lesser in reinfarction rate (absolute risk reduction 0.5%,p=0.001), ventricular fibrillation ( absolute risk reduction 0.5%; p=0·001) and arrhythmic death (absolute risk reduction 0.5%,p=0.002). However, it was reported administration of metoprolol in acute myocardial infarction was reported to be associated with higher risk of cardiogenic shock when comparing to placebo group (5·0% vs 3·9%; OR 1·30, 1·19-1·41; p_0·00001) [COMMIT collaborative group. 2005]. From the same study, a meta-analysis, which only involving 52411 patients with systolic blood pressure of more than 105mmHg, Killip class 1 (not diagnosed with heart failure), heart rate of more than 65 bpm, was carried out and established that the overall results of mortality from any cause, reinfarction rate, ventricular fibrillation or other cardiac arrest were found to significantly lower than the control group by 13%, 22%, and 15% respectively (p<0.002) [COMMIT collaborative group. 2005]. Whereas for beta blockers use in early pharmacological interventions, a systemic review of 25 randomised controlled trials showed that administration of beta blockers in long term therapy had decreased the odds of death by 23% (95% CI: 15% to 31%) and 42 patients is needed to treat for 2 years to prevent from death [Nick F., et al.1999]. In this case, Mr. T was not prescribed with any beta blocker for acute or chronic management of STEMI throughout the hospitalization. It is recommended in this case as to reduce the risk of reinfarction and arrhythmias occur during in-hospital management.

Based on the recommendation stated in SIGN-93 guideline, if primary PCI is not available, the primary management of STEMI should progress to thrombolytic therapy. Bolus administration of fibrin-specific thrombolytic agents such as tissue plasminogen activators was found to be more beneficial than fibrin-specific agents. In a systemic review on efficacy of thrombolytic agents involving a total number of patients of 142907, the results showed that there were no significant difference between alteplase and streptokinase in terms of mortality or reinfarction rate [DUNDAR, et al. 2003]. However, a meta-analysis presented in the same study showed that administration of alteplase was associated with significantly higher risk of haemorrhagic stroke and total stroke in comparison to streptokinase ( OR 1.29. 95%Cl: 1.31 to 1.46 for total stroke; OR 1.83. 95%Cl: 1.14 to 2.93 for haemorrhagic stroke). Conversely, another meta-analysis of eight studies demonstrated that there was significantly more incidence of major bleeding in patient using streptokinase [DUNDAR, et al. 2003]. In overall, although the use of streptokinase was reported to have higher risk of major bleeding, this was compensate with lower risk of stroke event and hence, streptokinase, which is a fibrin-specific thrombolytic agent, is recommended on practical ground [SIGN-93.2007]. Administration of streptokinase with 1.5 million units via intravenous infusion in this clinical case was found to appropriate as it is recommended in reperfusion therapy when primary PCI is not available.

Other agents used for reperfusion therapy through thrombolysis of STEMI also include the anticoagulants such as fondaparinux and bolus low molecular heparin. The oasis-6 randomised trial (n = 12092) had reported that subcutaneously administration of 2.5mg fondaparinux once daily up to eight days for patients not receiving primary PCI was superior to the placebo group. This was explained by the fondaparinux treated group had shown a significant reduction of death or reinfarction incidence rate at 30 days with hazard ratio of 0.86 (95% CI 0.77 to 0.96; P=.008). In patients underwent thrombolysis therapy, the study demonstrated that there were significant lower rates of death and myocardial infarction at 30 days than placebo or unfractionated heparin. However, there was no significant difference in rates of death and myocardial infarction between fondaparinux group and placebo group at 30 days of treatment (hazard ratio 1.2. 95%Cl: 0.91 to 1.57;p value of 0.19) [ The OASIS-6 Trial Group. 2006]. From this evidence, administration of fondaparinux seems to be beneficial in patients who are not eligible to PCI or when PCI is not available. As for heparins, a meta-analysis of randomized trial (n= 6069) was carried out to compare the effectiveness and safety profile between enoxaparin and unfractionated heparin as adjunctive therapy to streptokinase, t-PA or tenecteplase. From the presented results, the enoxaparin treated group had shown significant beneficial in triple end point combined of death, acute myocardial infarction and recurrent ischaemia over the unfractionated heparin treated group ( odd ratio 0.68; 95%Cl 0.58-0.80; p<0.001). Conversely, the adverse event of minor bleeding seems to favour the enoxaparin group with odd ratio of 1.29 (95%Cl 1.21-1.14; p<0.001) when compared to unfractionated heparin group [Pierre, et al. 2003]. Furthermore, in the OASIS-5 study, it had demonstrated there was no significant difference in terms hazard ratio of combined event of death, myocardial infarction or refractory ischaemic between enoxaparin and fondaparinux after nine days of treatment. However, fondaparinux had shown a better safety profile than enoxaparin as it has a lower risk of major bleeding (Hazard ratio 0.62; 95%Cl: 0.54-0.72; p<0.001). In this clinical case, both enoxaparin and fondaparinux were not initiated for reperfusion therapy and fondaparinux should be given along with streptokinase as this have been justified to be beneficial in reducing the death and reinfarction rate.

Perindopril oral tablet was initiated on day 3 of in-hospital management with the dose of 2mg daily. From a meta-analysis involving 100000 patients in 1998, patients allocated to ACE inhibitor therapy were found to have significant lower risk of thirty-day mortality compare to placebo group [ACE Inhibitor Myocardial Infarction Collaborative Group. 1998]. Administration of ACE in acute phase and for 4 to 6 weeks seems to have a 7% proportional reduction (95%Cl: 2% to 11%; p<0.004) in thirty-day mortality with avoidance of approximately 5 deaths per 1000 patients. The results from the study also demonstrated that ACE therapy also significantly lowered the incidence of nonfatal cardiac failure (14.6% versus 15.2%, p = 0.01). However, in terms of safety profile, the use of ACE inhibitors was found to have higher incidence of persistent hypotension (17.6% versus 9.3%, p<0.01) and renal dysfunction (1.3% versus 0.6%, p<0.01) comparing to placebo group [ACE Inhibitor Myocardial Infarction Collaborative Group. 1998].

A study based on data collected from 300,823 patients with acute myocardial infarction was conducted to assess the efficacy of early administration of statin in terms of early morbidity and mortality [Fonarow. 2005]. The results had shown a reduced risk of mortality in patients who were newly prescribed with statin or continuing statin therapy compared with patient group without statin therapy (4.0% and 5.3% versus 15.4% no statin). In addition, the increased in-hospital mortality rate was found to be significant in patients with STEMI who had discontinued the statin therapy during hospitalized (OR 1.25; 95%Cl: 1.07-1.45). On the other hand, the study also shown that early administration of statin was found to be associated with lower risk of cardiogenic shock, heart failure, ventricular fibrillation and rupture in comparison to patient group which never been administered with statin drugs (p<0.001) [Fonarow. 2005]. Simvastatin with a dose of 20mg was given throughout the four day of hospitalization and this decision was justified with the evidence shown.