Mr AR is a 41 years old male. His calculated BMI was 20.9kg/m2. His presenting complaint was chest pain which has lasted for three days before being admitted into the hospital. His chest pain was of pressing type, it occurred even at rest and lasted for 5-10 minutes each time. It was relieved slightly by rest and it was always accompanied by numbness on his left hand. He had shortness of breath, orthopnea, headache and low effort tolerance. He complained of abdominal discomfort also. He had stopped taking all his medications for the past three days. He had a pacemaker fixed 16 years ago for his atrial fibrillation (AF), but the pacemaker stopped functioning 3 years ago. Due to financial constraint, he did not go for a new pacemaker replacement. He underwent an angiogram last year and was found that he has 2 blocked vessels. He has a history of hypertension too.
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Before being admitted into the hospital, he has been taking frusemide 40mg twice daily, hydrochlorothiazide 25mg once daily, perindopril 8mg once a day and amlodipine 10mg once a day for his hypertension. For his AF, he has been taking warfarin 5mg once daily and digoxin 125microgram once daily. In addition, he took simvastatin 40mg at night for the prevention of cardiovascular events. Mr AR was found to have poor compliance. He always missed the dose, took the medications at the wrong time and was unsure the reason behind taking all his medications.
He was first admitted to the acute and emergency department. ECG was carried out and there was no ST-elevation. His blood pressure was found to be high, 172/126mmHg. No troponin test was done on Mr AR, the only available test results on cardiac enzymes were that of creatine kinase (CK), aspartate amino transferase (AST) and lactate dehydrogenase (LDH). All three were not elevated. Hence, he was diagnosed with unstable angina, gastritis and hypertensive urgency. He was given nifedipine 10mg, aspirin 300mg, Sublingual GTN and plavix 300mg in the acute and emergency department. His management plans were to monitor his vital signs every hourly for two hours followed by every two hourly and to carry out dextrostix test three times daily. He was given 60mg enoxaparin subcutaneously immediately and twice daily thereafter, intravenous ranitidine 50mg three times daily, sublingual glyceryl trinitrate (GTN) one tablet when required and IV frusemide 20mg twice daily. He was restricted to fliud intake of 800mL per day and started on fliud input and output monitoring. He will also be started on low salt diet for the management of his hypertension.
On day 2, he no longer complained of chest pain. His potassium level was found to be slightly lower than normal range (3.3mmol/L). His BP was still high throughout the day, fluctuating at around 150/120mmHg. He was started on tablet clopidogrel 75mg once daily. On day 3, IV frusemide was changed to oral frusemide. On day 4 his blood pressure has already dropped to around 120/90 mmHg. He was planned for discharge and enoxaparin was to be stopped on that day.
Disease overview and pharmacological basis of drug therapy
Mr AR was diagnosed with 3 diseases. Only unstable angina will be discussed. Unstable angina (UA) is categorized under acute coronary syndrome (ACS) which is very common in the UK. According to the hospital episode statistic year 2002-2003, there were 83842 cases of UA in England and 4421 cases in Wales.1 UA happened when there is insufficient myocardial oxygen supply to meet the oxygen demand of the heart. The reduction in the oxygen supply is due to the disruption of artherosclerotic plaque, causing the formation of intracoronary thrombus and hence narrowing of artery. Abnormal vasospasm of the coronary arteries or coronary dissection may also lead to UA. UA is closely related to non-ST elevated myocardial infarction (NSTEMI) as they have the same pathogenesis and both are presented as chest pain. The only difference between them is that in NSTEMI, there is a rise in the cardiac biomarkers such as cardiac troponin or the MB isoenzyme of creatine phospokinase (CK-MB), which indicates myocardial injury. In UA, the ischemia is not severe enough to cause damage to the myocardial cells and thus releasing these biomarkers in detectible amount.
For the diagnosis of unstable, the patient’s history of anginal symptoms should be obtained. Physical examination like cardiac examination and vital signs monitoring may also be done. Patient with ongoing chest discomfort should have a 12-lead ECG performed within 10 minutes of onset to check if there is any ST-elevation or depression. If there is no ST elevation, STEMI will be ruled out and the level of serum cardiac biomarkers will be used to determine if the patient has UA or NSTEMI. Troponin I or T are normally the biomarker chosen for detecting myocardial cell death as it is detectable in the serum 3-6 hours after a myocardial infarction and remained raised for 14 days. If the serum troponin level is less than 0.01g/L, then the patient will be diagnosed to have unstable angina. CK-MB may also be used when troponin test is not available. In Mr AR case, the results on the cardiac enzymes available, namely AST, CK and LDH are all non specific cardiac biomarkers as those enzymes can also be elevated in skeletal muscle injury or liver disease.
The treatment of UA can be divided into emergency treatment and secondary prevention treatment.2,3 Patients must rest in bed and ECG monitoring should be continued during the early phase of hospital stay. Sublingual glyceryl trinitrate (GTN) tablet or spray should be given for the relief of angina symptoms. GTN is a fast acting coronary vasodilators. Dilatation of veins going to the heart reduces ventricular volume and preload, while dilatation of systemic conductive arteries together with the decrease in ventricular volume causes a reduction in afterload. These effects will all reduce the myocardial oxygen demand.4 GTN also found to dilate collateral vessels, thus the areas of ischemia will receive a higher blood flow. If the chest pain is not relieved by GTN, intravenous morphine sulphate can be given to ensure patient comfort. Patient with ongoing chest pain or high risk patients should be given inravenous beta-blockers followed by oral route if there is no contraindication. Intermediate or low risk patients can be given oral beta-blockers. If beta-blocker is contraindicated such as the in presence of uncontrolled heart failure, or the chest pain is not relieved by GTN and beta-blocker, nondihydropyridine calcium channel blocker can be given.
Antiplatelet therapy should be given immediately by giving aspirin 300mg initially, followed by 75mg once daily for long term secondary prevention. In addition, clopidogrel 300mg should be given initially and 75mg daily thereafter for 3 months. Aspirin works by inhibiting the cyclooxygenase (COX) 1 enzyme on the platelet, thus preventing the production of thromboxane which stimulates platelet aggregation.5 Clopidogrel is an antiplatelet which acts by inhibiting adenosine diphosphate (ADP) from binding to its receptor, hence blocking the activation of ADP-mediated glycoprotein GPIIb/IIIa complex, a step involved in aggregation of platelets.6 Unfractionated heparin (UH) or low molecular weight heparin (LMWH) is an important antithrombotic agent in the management of UA. LMWH is normally preferred over UH as it can be given subcutaneously and no coagulation monitoring is needed. LMWH like enoxaparin should be given for 2-8 days. Heparin binds to antithrombin and the complex formed deactivates a series of enzymes involved in the coagulation process. Thus thrombus formation will be inhibited.7 Patients with high risk of MI or death should also be given glycoprotein IIb/IIIa antagonist such as eptifibatide, tirofiban or abciximab.
For the secondary prevention treatment, in addition to aspirin and clopidogrel, beta-blockers should be continued indefinitely. Statins can be started regardless of the patient’s cholesterol level for the preventing cardiovascular events. Statins are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, which act by inhibiting the biosynthesis of cholesterol.8 Angiotensin converting enzyme (ACE) inhibitors are useful in patients with UA also. They work by inhibiting the production of angiotensin II which is a potent vasoconstrictor and reducing the breakdown of bradykinin which is a potent vasodilator.9
Evidence for the treatment of the conditions
When the patient was admitted to the acute and emergency department, he was given clopidogrel 300mg, aspirin 300mg immediately and was then continued with long term treatment of 75mg of clopidogrel. The use of clopidogrel for the long term treatment of unstable angina was supported by two large trials. First, the CAPRIE trial which compare the beneficial effect of clopidogrel versus aspirin in patients at high risk of ischaemic event.10 In this trial, patients were either given 75mg clopidogrel once daily or 325mg of aspirin once daily. The clopidogrel group has a marginally lower risk of ischaemic stroke, myocardial infarction, or vascular death (5.32%) compared to the aspirin group (5.83%). The side effects reported were similar in both groups, indicating that clopidogrel has a comparable safety profile to that of aspirin.
The second trial is the CURE Trial which investigate the beneficial effect of adding clopidogrel to aspirin therapy in patients with non-ST elevation acute coronary syndrome.11 In this trial, 12,562 patients were given either 300 mg clopidogrel innitially, then 75 mg once daily or placebo plus aspirin for 3 months to a year. It was found that there was a lower rate of death from cardiovascular causes, nonfatal MI or stroke in the clopidogrel group. However, the risk of major bleeding was significantly higher in clopidogrel group. Hence, it can be concluded that long term clopidogrel should be used in patients with acute coronary syndrome in addition to aspirin.
In addition, according to a meta-analysis done by the Antithrombotic Trialists’ Collaboration, long term treatment of aspirin in the range of 75-150mg was found to be beneficial in patients with acute coronary syndrome. In cases where antithrombotic effect is needed immediately such as during acute attack of MI or UA, aspirin at a dose of 300mg should be given.12 In Mr AR case, only 300mg of aspirin was given in the acute and emergency department, no long term treatment of aspirin was given. This might be due to his newly diagnosed gastritis. NSAIDs were found to cause or worsen gastritis.13 According to the AHA/ACC guideline, clopidogrel will be the alternative for patients intolerant to aspirin due to gastrointestinal problems. According to a study done by Harker LA et al. where the tolerability and side effects of aspirin and clopidogrel were compared using the results from the CAPRIE trial, it was found that the group of patients receiving clopidogrel has a lower percentage of gastrointestinal side effects, with a rate 27.1% compared to 29.8% in those taking aspirin (p < 0.001).14 This finding support the reason behind clopidogrel being the only antiplatelet given to Mr AR. However, The difference in the incidence of side effects between the two treatment group was small and higher rate of occurrence of gastrointestinal problem in aspirin group might be due to the high dose of aspirin used (325mg).
The policy of the ACC/AHA guideline of using clopidogrel instead of aspirin in patient with a history of GI complication was also refuted by Chan and colleagues.15 In this study, 320 patients who had recovered from aspirin-induced upper GI bleeding were given either 75 mg of clopidogrel daily or 80 mg of aspirin daily together 20mg of proton-pump inhibitor esomeprazole twice daily. When the patients were followed up after one year, it was found that patients in the aspirin group has a lower rate of recurrent upper GI bleeding compared to those receiving clopidogrel plus esomeprazole (8.6% versus 0.7%, P=0.001). No protective effect was conferred by esomeprazole in aspirin-induced lower GI bleeding. Hence, low dose aspirin is still deemed appropriate in Mr AR’s case if given with a proton pump inhibitor or H2-antagonist like ranitidine.
On day 1 Mr AR was given 60mg of enoxaparin immediately and twice daily thereafter. A comparison between the efficacy of UH and LMWH was carried out in the ESSENCE trial.16 In this trial, patients were allocated either subcutaneous enoxaparin plus placebo bolus and infusion or bolus and infusion unfractionated heparin plus placebo subcutaneous injection. In addition, they were all given oral aspirin. It was found that the enoxaparin group has a lower rate of recurrent angina, MI or death and also the need of revascularization process. Hence it was concluded that enoxaparin is more advantageous than UH, as there is little protein binding, longer plasma half life and more resistant to neutralisation by platelet factor IV as compared to UH. The dose given to Mr AR is justified according to a trial where the dose of enoxaparin was adjusted according to the weight of the patients. 17 It was found that giving 1mg/kg of enoxaparin to patients with UA or non-Q wave MI resulted in a lower risk of major bleeding compared to giving a dose of 1.25mg/kg (6.5% versus 1.9%). Mr AR’s weight was 59kg, thus a dose of 60mg is appropriate and evidence based.
Sublingual GTN was given to Mr AR for the relief of his chest pain. According to the British Medical Journal evidence centre, no good evidence was found on the angina. There is one randomized placebo controlled study done by Karlberg et al. where they compared the effectiveness of intravenous GTN versus placebo in reducing ischaemic attack in unstable angina.18 In this trial, they found that patients given GTN have a fewer new onset of chest pain compared to placebo group. No trial was done to investigate the effectiveness of sublingual GTN in preventing ischaemic attack. However, according to a methodological study done by G Nyberg to determine the time of onset of sublingual GTN, it was found there was a significant reduction in the intensity of exercise induced chest pain and an improvement in the ST-depression when 0.5mg of GTN was given sublingually at the onset of chest pain.19 Hence, there is a consensus that sublingual GTN can be used for symptomatic control of unstable angina.
Mr AR’s previous medications were continued during the hospital stay. Among those medications, perindopril, an ace-inhibitor, is also proved to be beneficial in the prevention of MI. There are two well known studies done on the effect of ace-inhibitors in preventing cardiovascular event in patients with cardiovascular disease, namely the HOPE trial and the EUROPA trial.20,21 In the HOPE trial, ramipril was chosen as the treatment drug. As for the EUROPA trial, perindopril was chosen to investigate if there is any beneficial effect in preventing MI, cardiac arrest or mortality in patients with stable coronary disease. It was found out that in the group of patients receiving perindopril, there was a 20% relative risk reduction in the primary end point as compared to the placebo group. Hence, it was concluded that perindopril should be given to all patients with coronary heart disease, including Mr AR who has unstable angina.
In addition, Mr AR was continued with 40mg simvastatin once daily at night. According to a trial on simvastatin, it was found that giving simvastatin to high risk patients lowers their cholesterol level and reduces the incidence of cardiovascular events.22 In this trial, 20536 adults in the UK with high risk of getting cardiovascular event were given simavastatin 40mg daily or placebo. It was found that the simvastatin group has a lower percentage of all cause of death (12.9%) and major vascular event (19.8%) compared to the placebo group (14.7% and 25.2% respectively). There was a difference of about 1.0mmol/L in the LDL cholesterol level between the two groups after treatment regardless of the initial cholesterol level. This indicates that there is a reduction in the LDL cholesterol level in the simvastatin group which is independent on the initial cholesterol level. For patient given simvastatin, the risk reduction of the first major vascular event is similar no matter the patients were taking ace inhibitors, aspirin, beta blockers or antihypertensive drugs or not. This shows that simvastatin provides additional benefits when added to the existing treatment with these drugs. Thus, it can be concluded that simvastatin will be beneficial to Mr AR who was taking ace inhibitor and antihypertensive drugs concurrently.
Mr Ar was newly diagnosed with gastritis and was commenced on IV ranitidine. In a double blind clinical study, patients diagnosed with gastritis were given 300mg ranitidine daily for 4 weeks or placebo only.23 It was found that patients from the ranitidine group improved significantly faster than the placebo group and 80% of the patients had their symptoms completely resolved. Only 45% of the patients from placebo group achieved improvement in their symptoms while the remaining showed no change in their gastritis. Hence, it was concluded that ranitidine is an effective treatment option for gastritis. However, this trial only involved 52 patients and this small sample size renders the finding from trial inconclusive. In another trial where the effectiveness of ranitidine and sucrafate was compared, it was found out that both have a similar activity in relieving the symptoms of gastritis.24 77.6% of the patients receiving sucralfate and 79.4% from the ranitidine group had their symptoms completely resolved at the end of the study period (8 weeks). However, ranitidine was found to act faster in relieving pain compared to sucralfate. Hence, it can be concluded that the management of Mr AR’s gastritis with ranitidine is justified.
Mr AR was given nifedipine 10mg for the treatment of his hypertensive urgency. Even though nifedipine was found to be effective in reducing blood pressure within 20 minutes, this fast release, short-acting calcium channel blocker are not recommended in this case as Mr AR did not receive any beta-blocker before. According to the results obtained from the Holland Interuniversity Nifedipine/metoprolol Trial (HINT), monotherapy with nifedipine in patients with unstable angina naïve to beta blockers was associated with a higher risk of recurrence ischaemic attack or MI.25 The event rate ratio compared to placebo for beta blocker naïve, nifedipine only group was 1.15. As for the group receiving both nifedipine and metoprolol, the ratio was lower (0.80). Patients who were already receiving beta blockers and were added with nifedipine also showed lower rate ratio (0.68). Hence, it was concluded that nifedipine was only beneficial in patients who were treated with beta blocker at the same time. Moreover, it was found from the Trent study that nifedipine does not show any beneficial effect in patients with MI.26 In this trial, the death rate for patients receiving nifedipine 10mg four times daily and placebo was similar. When the number of death and MI were compared among patients taking beta blocker and not taking beta blocker among admission, it was found that the latter group has a higher rate of death and MI. This result is comparable to those from the HINT trial. Hence, the use of nifedipine in treating Mr AR’s hypertensive urgency is not justified, other drug should be chosen.
Conclusion
The immediate treatment of UA with high dose of antiplatelet agent aspirin and clopidogrel together with the antithrombotic agent LMWH are justified as they help preventing the progression of UA to MI. Sublingual GTN on the other hand helps relieving his chest pain. As for his previous perindopril and simvastatin that were continued, these help in preventing recurrent angina also. Choosing clopidogrel for the long term prevention treatment of UA due to the presence of gastritis might not be the best option for Mr AR. Once his gastritis has resolved, life-long aspirin at the dose of 75mg should be added in with oral ranitidine 300mg twice daily prescribed as prophylaxis against NSAID induced gastritis. However, the use of nifedipine in the management of his hypertensive urgency is not justified. Instead, he should be given labetalol, atenolol or clonidine which were found to be better alternatives to nifedipine in treating hypertensive urgency.27
PATIENT MEDICATION PROFILE
Patient details
Name: AG
Consultant: –
General Practitioner: –
Address: –
Gender: Male
Weight: 59kg
Height: 168cm
Community pharmacist: –
Age: 41
Known sensitivities: NKDA
Social history: Non-smoker, No alcohol abuse.
Patient hospital stay
Reason for admission
Admission date: –
Chest pain.
Discharge date: –
Relevant medical history
Relevant drug history
Date
Problem description
Medication
Comments
1994
Pacemaker fixed
Warfarin 5mg OD
Atrial fibrillation
2007
Pacemaker not functioning, did not go for replacement due to financial constraint
T digoxin 125mcg OD
Atrial fibrillation
2007
Angiogram, 2 blocked vessels
T frusemide 40mg BD
Hypertension
Hypertension
Perindropil (coversylƒ’) 8mg OD
Hypertension
T amlodipine 10mg OD
Hypertension
Hydrochlorthiazide 25mg OD
Hypertension
T simvastatin 40mg ON
Prevention of cardiovascular event
Prescribed medication
Route of administration
Start
Stop
Nifedipine (adalat) 10mg
PO
Day 1
Aspirin 300mg
PO
Day 1
Day 1
Clopidogrel (plavixƒ’) 300mg
PO
Day 1
Day 1
Clopidogrel (plavixƒ’) 75mg OD
PO
Day 2
Enoxaparin (Clexaneƒ’) 60mg stat, BD
subcutaneous
Day 1
GTN 1 tablet PRN
sublingual
Day 1
Simvastatin 40mg ON
PO
Day 1
Amlodipine 10mg OD
PO
Day 1
Hydrochlorothiazide 25mg OD
PO
Day 1
Warfarin 5mg OD
PO
Day 1
Furosemide (Lasix) 40mg stat, BD
IV
Day 1
Day 3
Furosemide 40mg BD
PO
Day 3
Perindopril (Coversylƒ’) 8mg OD
PO
Day 1
Ranitidine (zantac) 50mg tds
IV
Day 1
Digoxin 125mcg OD
PO
Day 1
Clinical/ Laboratory Tests
Date
Results
Potasium (3.5-5.0 mmol/L)
Day 2
3.3
BP
Day 2
150/118
Day 3
134/100
Day 4
122/86
Pharmaceutical Care Plan
Care Issue
Action
Actual output/ Desired output
Long term treatment with aspirin.
Patient should be given 75mg of aspirin for the secondary prevention of UA.
Patient has gastritis.
He should be started on long term treatment of aspirin once his gastritis has resolved and ranitidine should be prescribed as prophylaxis against NSAIDs induced GI complications.
Long term treatment with beta blockers.
Beta blocker should be given to the patient as the secondary prevention treatment.
Patient should be started on labetalol 100mg twice daily and titrate up to 200mg twice daily.
Inappropriate use of nifedipine for the management of hypertensive urgency.
Nifedipine should be substituted with labetalol 200-300mg every 3-4 hours when required.
Not taken.
Interaction between digoxin and diuretics when hypokalaemia occur.
Potasium level should be monitored.
Inform the patient on signs and symptoms of digoxin toxicity.
Patient’s potassium level was lower than the normal range on day 2. He should be given potassium sparing diuretics or potassium supplement if the potassium level keeps going down.
Monitoring should be continued.
High risk of bleeding due to warfarin, aspirin, clopidogrel and enoxaparin.
Bleeding tendency should be monitored.
Patient should be told to inform the GP if there is any unusual bleeding like blood in the stool.
Patient’s INR and prothrombin time were within the normal range. Monitoring was continued.
Changing of IV ranitidine to oral ranitidine.
Patient should be switched to oral ranitidine150mg twice daily after being discharged.
Not taken.
GTN for relief of angina symptoms.
Patient should be prescribed GTN spray or sublingual tablet for the relief of chest pain shoul the patient has another angina attack.
GTN sublingual tablet was prescribed as discharge medication.
Poor patient compliance
Patient should be informed on the reason behind taking his medication, the importance of compliance.
Compliance aid should be given.
Patient was counselled on the importance of compliance.
Side effects of simvastatin
-muscular side effects
-liver disease
Patient should be advised to report immediately any unexplained muscle pain, weakness nor tenderness.
Regular LFT monitoring should be done.
No monitoring of cholesterol level.
Cholesterol level should be monitored suring the hospital stay so that the dosage of simvastatin can be adjusted accordingly.
Cholesterol level should be maintained below 5.2mmol/L.
Patient education on healthy lifestyle.
Patient should be told on the importance of low salt diet for his HT and encouraged to exercise more.
Patient was counselled on the importance of healthy lifestyle before being discharged.
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