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The case that is about to be discussed here revolves around a patient diagnosed with pulmonary tuberculosis. The patient that was clerked, Mrs A, was

The patient was a female, age 89, with a BMI of 15.4 kg/m2 (underweight). Her presenting complaint was nausea and vomiting, bringing up coffee ground vomit, fatigue and loss of appetite since two days ago. Her past medical history included atrial fibrillation, paranoid psychosis and iron deficiency anaemia. She also had a cholestectomy done in year 2000. She was single and lived alone; she neither smoked nor drank. There was no relevant family history recorded for her case. On admission she was taking medication stated in Table 1 below. She was known to be allergic to ciprofloxacin.

Table 1 Repeat medication taken on admission

Drug

Dose

Digoxin

125 µg once daily

Lisinopril

2.5 mg once in the morning

Furosemide

40 mg once daily

Clopidrogel

75 mg once daily

Quetiapine fumarate

125 mg twice daily

Tramadol hydrochloride

100 mg twice daily

Codeine phosphate

60 mg one to be taken as required

Paracetamol

500 mg four times daily

Folic acid

5 mg once daily

Ferrous fumarate

322 mg twice daily (Last prescription dated three months ago)

Clinical data and diagnosis

On admission, her temperature was 36.4°C, pulse was 83 beats per minute, and her blood pressure was 124/46 mmHg. Her Abbreviated Mental Test (AMT) score was 7 out of 10, indicating mild confusion. A full blood count, renal function test, liver function test, and an electrocardiogram (ECG) were carried out. Her liver function test came back normal. The ECG showed some ST depression, but the patient denied any chest discomfort. Her haemoglobin levels were low at 9 g/dl (11.5-16.5 g/dl), while platelets were low at 108×109/l 150-400×109/l). her plasma urea was elevated at 38.2 mmol/l (2.5-7.5 mmol/l), and her creatinine was 273 µmol/l (50-80 µmol/l for female). Her creatinine clearance was calculated to be 8.1 ml/min, which indicated severe renal impairment. The diagnosis was acute renal failure, and gastritis or peptic ulcer disease.

Clinical progress

On day 1, patient was dehydrated and had some upper abdominal discomfort (Dyspepsia). The plan was to stop tramadol, clopidogrel, lisinopril and furosemide, due to the coffee ground vomit and acute renal failure. Two units of RCC (Red cell concentrate) and IV fluids were given. A urinary catheter was used to monitor urine output. Patient was continued on ferrous fumarate and given gaviscon 10mls. Quetiapine fumarate was not given as it was not available.

On day 3, patient was paranoid; as quetiapine fumarate was still not available, haloperidol 1 mg was given as an intramuscular injection according to the hospital guidelines. Her haemoglobin levels were back to normal (12 g/dl) and her creatinine clearance improved to 33.3 ml/min; measurements were taken again because the values were so different. The catheter was taken out, but she was to receive subcutaneous fluids hourly. Patient was passing black stools. She was given Peptac 10mls for abdominal discomfort and was scheduled for an endoscopy the next day. Quetiapine fumarate was given on day 4 and patient was taken off haloperidol.

On day 6, the patient’s confusion was thought to be influenced by digoxin; levels were checked and found to be 1.1 µg/l (0.5-2.0 µg/l); however dose of digoxin was decreased to 62.5 µg. a rectum examination was conducted to make sure patient was not bleeding from the lower gastrointestinal tract. The gastroscopy report came back stating patient had grade D oesophagitis (Reflux oesophagitis), that is an extenxive mucosal breaks engaging at least 75% of oesophageal circumference. She was also found to have a large chronic duodenal ulcer, non-bleeding with visible vessels. The plan was to start the patient on IV proton-pump inhibitor (PPI, pantoprazole 8 mg/hr) for 72 hours, oral omeprazole 20 mg daily, and eradicate H. pylori if infection was present (CLO test).

On day 9, the CLO test came back negative. Patient was taken off IV PPI and put onto oral PPI (Omeprazole 40 mg daily). A repeat endoscopy was scheduled for the week after.

Disease Overview

Prevalence

Oesophagitis is the inflammation of the lining of the oesophagus, usually caused by irritation due to stomach acid reflux.1,2 It is included under the boarder term of gastro-oesophageal reflux disease (GORD), which also includes endoscopy-negative reflux disease.3 In the UK, there is a 28.7% prevalence of GORD, and the risk is found to increase with age, especially for those over 40 years of age. There is an estimated of over 50% of GORD patients between 45 and 60 years of age.4 About 25 to 40% of people with GORD are found to have oesophagitis on endoscopy.5

Pathophysiology, risk and diagnosis

Acid reflux can occur because of incompetence of the lower oesophageal sphincter, a transient complete relaxation resulting from a failed swallow, that is, a swallow without the usual peristalsis wave (Found in 65% of patients). It can also be caused by a transient increase in intra-abdominal pressure (17% of patients), or a spontaneous free reflux due to the lower oesophageal sphincter having a low resting pressure (18% of patients).6

Possible risk factors for GORD are pregnancy, excess alcohol consumption, smoking and hiatus hernia. Obesity is thought to be a risk factor, as well as certain foods like onions, citrus fruits and coffee. Drugs that are thought to relax the lower oesophageal sphincter like calcium channel blockers are thought to play a role in promoting GORD. There is however very limited evidence to support these claims.4,5 It is now thought that more than 50% of GORD risk is genetic, as it is found that a first degree relative of a person with GORD is four times more at risk of getting the disease.4

Diagnosis of GORD is based mainly on the patients’ symptoms, predominantly acid regurgitation or heartburn.7 An endoscopy is usually the main diagnostic procedure done to confirm GORD.

Pharmacological treatments and mechanisms of action

The main drug used for this disease is a proton-pump inhibitor (PPI). PPIs are one of the most prescribed drugs for the treatment of acid-peptic diseases, including GORD and peptic ulcer disease.8,9 They are substituted 2-pyridyl methysulfinyl benzimidazoles, with pKa around 4, and have a very short plasma half life of one to two hours. They are weak bases that are lipophilic, which allows them to cross the membranes of the parietal cells easily. Once inside the parietal cells, where the pH value is less than 4, they protonate into the activated tetracyclic sulphenamide form of the drug and accumulate inside the cells. Here they form covalent bonds with the cysteine residues in the hydrogen/potassium adenosine triphosphatase (H+/K+ ATPase) enzymes, forming disulphide bonds, inhibiting the acid secretion activity of the pump irreversibly. Due to the covalent bonds, their duration of action exceeds their plasma half life. To resume acid production, the parietal cells must then generate, or activate, new proton pumps.8,9 Examples of PPIs are omeprazole, lansoprazole, pantoprazole, and rabeprazole, the last of which has a pKa of 5, and is activated at a broader range of pH compared to the other three, leading to a higher acid-suppression activity.

The common side-effects of PPIs are nausea, diarrhoea, abdominal pain and headache. Diarrhea seems to occur because of a change in the gut flora brought about by the PPI, and appears to be age-related.8 PPIs, especially omeprazole, are known to alter the activity of cytochrome P in the liver, an important consideration for patients taking drugs with narrow therapeutic windows like warfarin and phenytoin. They also cause a prominent gastric pH increase, and are able to inhibit or decrease the absorption of weak bases that require acid for absorption, like iron salts, griseofulvin, and vitamin B12.8

Other drugs that may be used in this case are H2 receptor antagonists, which inhibit the secretion of acid by stopping histamine from binding to the H2 receptors on the parietal cells; and prokinetic drugs, usual examples like cisapride, metoclopramide and domperidone, which work by increasing the pressure of the lower oesophageal sphincter, and accelerating gastric emptying.10

Evidence for treatment of the condition

The National Institute for Health and Clinical Excellence (NICE) guidelines state that, for the management of oesophagitis on endoscopy, patients are to be given full dose PPI for one to two months. If there is a response to the treatment, low dose PPI is given, probably on an as required basis. If there is no response, the dose of PPI is doubled for another month, before switching to low dose PPI. If there is no response to the doubled dose of PPI, treatment is then switched to a histamine H2 receptor antagonist or a prokinetic.11

Klinkenberg-Knol EC et al1 compared the effects of omeprazole and ranitidine in a randomised, double-blind, endoscopically-controlled trial done on patients with reflux oesophagitis. Omeprazole was given at a dose of 60 mg daily while ranitidine was given at 150 mg twice daily. The symptoms were evaluated before starting the trial, and at the second, fourth and eighth week. Endoscopy was done at the start of the trial, and repeated during week 4, with another after 8 weeks if there was an absence of healing at week 4. For patients taking omeprazole, 19 out of 25 patients improved from Grade 2 or 3 (erosions or ulcerations) to Grade 0 or 1 (erythema and friability)12 after 4 weeks; while for patients taking ranitidine 7 out of 26 showed similar improvement (P = 0.002). At week 8, corresponding improvement was shown in 22 out of 25 for the omeprazole group, and 10 out of 26 for the ranitidine group (P = 0.001). Omeprazole showed a significantly higher healing rate, which was reflected in a better improvement of reflux symptoms as well. Patients receiving omeprazole experienced a more profound and faster relief of heartburn, which was the most common symptom complained by the patients (P = 0.0001). After 2 weeks, 92% (23 out of 25 patients) of patients receiving omeprazole reported that their reflux symptoms were either gone or had improved, while only 65 % (17 out of 26) of the ranitidine group reported the same (P = 0.01). This study however, only showed the superiority of omeprazole over ranitidine in the short term treatment of reflux oesophagitis. Further studies were needed to evaluate the effects of omeprazole in long term management and at a lower dose.

Havelund T et al12 performed a double blind study on patients with Grade 1, 2 and 3 reflux oesophagitis. Patients were allocated randomly in this study to a treatment with omeprazole (40 mg once daily), and ranitidine (150 twice daily), for a period of 12 weeks. It was found that patients treated with omeprazole had a faster response to the treatment than those taking ranitidine (P < 0.0001). For the omeprazole group, healing rates were reported at 4, 8 and 12 weeks to be 90%, 100% and 100% respectively for those with Grade 1 reflux oesophagitis. For Grade 2 and 3, corresponding healing rates were 70%, 85% amd 91%. While for the ranitidine group, healing rates were 55%, 79% and 88% for Grade 1, and 26%, 44% and 54% for Grade 2 and 3. This pointed to a superiority of omeprazole at a lower dose (40 mg) over ranitidine. Sandmark S et al13 did a similar study, but with an omeprazole dose of 20 mg daily. Healing of oesophagitis was targeted in this study to be a complete healing of all ulcerative and erosive lesions in the oesophagus. At 4 weeks, healing rates were shown to be 67% in the patients taking omeprazole and 31% in those taking ranitidine (P < 0.0001). Corresponding healing rates were 85% (Omeprazole group) and 50% (Ranitidine group) after 8 weeks (P < 0.0001). This was also reflected in a more profound – and faster- improvement in reflux symptoms in the patients taking omeprazole (51% by the end of the first week compared to 27% for patients taking ranitidine).

Robinson M et al14 conducted a study to compare, in patients with erosive oesophagitis the efficacy and tolerability of omeprazole at a dose of 20 mg daily to ranitidine at a dose of 150 mg twice daily together with a prokinetic drug metoclopramide at a dose of 10 mg four times daily. It was found that healing rates for omeprazole were significantly greater than that for ranitidine in combination with metoclopramide. Omeprazole also provided a more profound relief for patients with reflux symptoms. More side effects and treatment-related withdrawals were found among the patients allocated the ranitidine-metoclopramide combination. Omeprazole was thus found to be more effective and better tolerated. Iskedjian M and Einarson TR conducted a meta-analysis15 of the three drugs cisapride, omeprazole and ranitidine for GORD treatment. At 12 weeks, 95% of patients were cured in the omeprazole group (40 mg daily), 81% in the ranitidine group (600 mg daily), and approximately 60% in the cisapride group (40 mg daily). In mild GORD, healing rate was 56% for cisapride versus 38% for ranitidine, while healing rates for cisapride and omeprazole showed no significant difference. In severe GORD, the healing rate for cisapride was only a half of that of omeprazole (43% versus 87%), while showing no significant difference when compared to that of ranitidine (50%). Thus it was concluded that omeprazole is favoured for treating severe GORD, while cisapride may be that of mild GORD.

Vigneri S et al16 compared 5 maintenance therapies after an initial treatment of omeprazole 40 mg daily for 1 to 2 months, and healing was confirmed by endoscopy. Patients were then randomly assigned 12 months of treatment in the 5 following groups: cisapride (10 mg three times daily), ranitidine (150 mg three times daily), omeprazole (20 mg daily), ranitidine and cisapride, or omeprazole and cisapride. At 12 months 54% of the cisapride group, 49% of the ranitidine group, 80% of the omeprazole group, 66% of the ranitidine-cisapride group, and 89% of the omeprazole-cisapride group were found to be in remission at 12 months of maintenance therapy. Omeprazole showed a significantly better efficacy than cisapride (P = 0.02), and ranitidine (P = 0.003). Ranitidine-cisapride combination therapy was found to show a more profound improvement than ranitidine alone (P = 0.05). Omeprazole-cisapride combination therapy showed better efficacy than cisapride (P = 0.003), ranitidine (P < 0.001), and also ranitidine and cisapride combination therapy (P = 0.03). Omeprazole as monotherapy or in combination with cisapride is found to be more effective for maintenance therapy of reflux oesophagitis, compared to ranitidine or cisapride alone. Omeprazole in combination with cisapride shows more efficacy than ranitidine and cisapride.

The effects of newer PPIs lansoprazole (30 mg daily), rabeprazole (20 mg daily) and pantoprazole (40 mg daily) were compared with that of omeprazole (20 mg daily), ranitidine (300mg daily) and placebo in randomised clinical trials brought together by Caro JJ et al.17 The healing rate ratios noted for the newer PPIs as well as omeprazole were as follow: lansoprazole 1.62; rabeprazole 1.36; pantoprazole 1.60; and omeprazole 1.58. There was a greater decrease in the heartburn symptoms in patients taking PPIs than those taking ranitidine (P < 0.002), as well as in the healing of ulcers (P < 0.05), and relapse (P < 0,01). Compared to placebo, the PPIs obtained a much more profound relief of reflux symptoms (P < 0.01), healing of ulcers (P < 0.001) and relapse (P < 0.006). From this study, it was found that there is not much difference between the newer PPIs and omeprazole when it comes to relief of reflux symptoms, ulcer healing and rate of relapse, while all PPIs are better than ranitidine and of course, placebo in terms of treatment for erosive oesophagitis.

Kahrilas PJ et al18 compared esomeprazole and omeprazole efficacies in reflux oesophagitis patients. It was found that more patients (P < 0.05) on esomeprazole 40 mg and esmoprazole 20 mg were healed after 8 weeks of treatment compared to omeprazole (94.1% and 89.9% compared to 86.9%). Adverse effects were common in both treatments. Esomeprazole was found to have a greater efficacy compared to omeprazole in reflux oesophagitis and both have a similar tolerability profile. Rohss K et al19 showed that esomeprazole at 40 mg daily had better acid control than omeprazole 40 mg daily. Since maintenance of intragastric pH > 4 is important for the effective management of GORD, the mean percentage of a 24 hour period with intragastric pH > 4 was taken as an indication of the efficacy of the treatments. Measurements were taken on day 1 and day 5, and on both days esomeprazole showed a greater mean percentage (P < 0.001) at 48.6% and 68.4% versus 40.6% and 62.0% for omeprazole.

Wahlqvist P et al20 compared,from the perspective of the National Health Service (NHS),the cost effectiveness of the actue treatment of esomeprazole (40 mg daily) with omeprazole (20 mg daily) in reflux oesophagitis patients.It was estimated that, taking into consideration of the healing probabilities over 8 weeks, treatment with esomeprazole saves up toa total of 1290 pounds compared to treatment with omeprazole. Esomeprazole was found to provide a greater effectiveness at a lower cost. This is reflected in another study conducted by Plumb JM and Edwards SJ,21 which found that esomeprazole is cost effective in comparison to all other PPIs for the treatment of reflux oesophagitis.

Conclusion

The treatment given to this patient was appropriate in terms of the algorithms stated in the NICE guidelines; she was started on a full dose PPI after eosophagitis was confirmed on the endoscopy. As stated above, PPIs are proven to have superior effects in comparison with histamine H2 receptor antagonists and prokinetic drugs, both providing relief of reflux symptoms but not healing the oesophagitis itself.10 Among all the PPIs currently available, esomeprazole, the S-isomer of omeprazole, has been found to show more improvement than all other PPIs. Current studies have shown that the treatment of reflux oesophagitis with esomeprazole is more cost effective than treatments using any other PPI, providing a greater healing rate at a lower cost. Thus it might be in the interest of the NHS to treat this patient with esomeprazole than omeprazole.

(2271 words)

 

a 61 year old woman. She was a Malay housewife. Her Body Mass Index value of 26.0 kg/m2 based on her height of 1.58 m and weight of 65 kg indicated that she fell into the overweight range.

The patient was admitted to the Accident & Emergency mode transferred in from another hospital via an ambulance. She presented symptoms such as shortness of breath(SOB) and her respiratory rate was 20 breaths per minute. She appeared pale and weak and her blood glucose levels were low (2.1 mmol/l) and her blood pressure values indicated she was hypertensive with a value of 152/93 mmHg. Upon physical examination, mild leg swelling was observed.

Based on her past medical history, patient was diagnosed with pulmonary tuberculosis for the past 3 months, hypertension for the past 5 years, diabetes for the past 5 years and advanced renal failure for the past 6 months.

Upon enquiry, she was seen to be a non-smoker and a non alcoholic. Patient lived with her daughter.

Several investigations were performed to evaluate the patient’s condition. A positive sputum smear test indicated that the patients tuberculosis was still active. Upon renal function assessment, creatinine clearance was calculated and a value of 5.5 ml/min indicated Stage 5 renal failure. Her potassium and urea levels were also above range based on Table 1. Upon haematology assessment, her low blood sugar levels indicated hypoglycaemia and patient’s haemoglobin count was also low signifying anemia. Chest X ray was conducted on this patient and minor lesions at the apical segments of the upper lobe were seen. This is a typical radiographic representation of patients with tuberculosis.

Table 1: Results of the investigations performed

Laboratory Test

Readings

Normal range

Sputum Smear Test

Positive

–

Renal Function

Creatinine, Cr

Urea

Potassium, K+

912 μmol/l

37.8 mmol/l

5.5 mmol/l

44-80 μmol/l

1.7 – 8.5 mmol/l

3.5 – 5.0 mmol/l

Haematology Assessment

Blood Sugar Level

Haemoglobin

2.1 mmol/l

9.8 g/dl

4.5 – 6.0 mmol/l

13.5 – 18 g/dl

Table 2 provides details about patient’s drug history giving information about patient’s drugs and their respective doses. Upon interview, patient informed that she had not been purchasing any over the counter medications. She also has no known drug allergy.

Table 2 : Drug History and their respective doses and their indication

Drug

Dose

Duration

Indication

Rifampicin

300 mg OD

2 months

Anti TB

Isoniazid

200 mg OD

2 months

Anti TB

Pyrazinamide

750 mg OD

2 months

Anti TB

Ethambutol

600 mg OD

2 months

Anti TB

Pyridoxine

20 mg OD

2 months

Treatment of neuropathy

Gliclazide

40 mg OD

5 years

Anti diabetic

Prazosin

2 mg TDS

5 years

Anti Hypertensive

Furosemide

80 mg OD

5 years

Anti Hypertensive

Nifedipine

20 mg TDS

5 years

Anti Hypertensive

Based on the investigations performed, the patient was diagnosed to be suffering from pulmonary tuberculosis and diabetes mellitus.

Patient’s daily condition was monitored and appropriate management was undertaken to control the patient’s condition. Patient’s overall progress is tabulated in the table 3 and the observation is recorded.

Table 3 : Patient’s clinical progress and management

Day

Clinical Progress

Management

1

Hypoglycemia = 2.1 mmol/L

AFB test positive

Chest X ray performed

SOB

Hyperkalaemia ( 5.5 mol/L)

Anemic ( 9.8 g/dL)

BP : 152/93 mmHg

Strict fluid intake

IV Dextrose 10%/24 hours

Refer to chest physician

Lesions at upper lobes

NPO2 to resolve SOB

Start on Calcium polystyrene

Start Ferrous (IV) sulphate

Start antihypertensives

Monitor input & output

2

AFB test +ve

Blood Sugar Level = 3.0 mmol/L

BP : 140/90 mmHg

Start TB regimen (EHRZ)

Continue IV Dextrose 10% & Monitor Blood Glucose

Continue antihypertensives

3

Blood Sugar level = 3.2 mmol/L

Severe renal impairment ( CrCl =5.6 ml/min )

Chest X ray done time to time

BP : 130/70 mmHg

Continue dextrose infusion

Send patient for dialysis

Lesions still present

Continue antihypertensives

4

No SOB

Hypoglycaemia resolved = 5.5 mmol/L

AFB +ve

BP : 130/75 mmHg

Remove nasal prongs

Stop Dextrose. Monitor blood glucose

Continue TB regimen

6

K+ level in normal range ( 4.5 mmol/L)

Blood Sugar level = 6.0 mmol/L

CrCl = 7.7 ml/min

BP : 130/65 mmHg

Stop Calcium polystyrene.

Monitor blood glucose

Send patient for dialysis

8

Hyperglycemia = 11.1 mmol/L

BP : 125/75 mmHg

Start on Insulin

DM counselling

13

AFB -ve

DXT = 10.2 mmol/L

BP : 120/70 mmHg

Transfer out of isolation

Continue insulin. Monitor blood glucose

Based on patient’s presentation and results from investigations performed on day 1, patient was started on dextrose and her blood glucose levels were regularly monitored. Based on patient’s previous history, a sputum smear test was ordered and two consecutive positive results resulted in the patient being referred to the chest physician. A chest X ray was performed and lesions in the apical segment were present. To resolve patient’s SOB, patient was started on Nasal Prongs at 3L/min. To control her hyperkalemia, patient was given calcium polystyrene sulphonate powder. Patient was also started on ferrous sulphate infusion to help her cope with her anaemia. A strict fluid intake was imposed on patient to resolve her leg swelling and this was monitored through an input output chart. Her blood pressure (BP) levels were also elevated and patient was given antihypertensives such as nifedipine, prazosin and furosemide to control her BP.

On day 2, her sputum smear remained positive and patient was commenced on the intial phase therapy for tuberculosis which consists of isoniazid, rifampicin, pyrazinamide and ethambutol. There was not much improvement in her blood glucose levels and patient was remained on the dextrose infusion. Moving on to day 3, not much improvement was observed and due to patient’s deteriorating renal function, patient was sent for peritoneal dialysis.

By day 4, patient could breath normally and no shortness of breath was seen. Nasal prongs were removed. When her blood glucose levels were monitored, the results indicated patient was within the normal range and dextrose was withheld. Blood glucose levels were still monitored to prevent sudden drops and increase in blood glucose. Her potassium levels were within range by day 6 and calcium polystyrene sulphonate was stopped and potassium levels were monitored as well.

Patient suffered from a hyperglycemia episode on day 8 and the patient was given biphasic insulin to treat this condition. By this day, her BP was also in the normal range but the antihypertensives were still continued. On day 13, patient was transferred out of the isolation ward as her sputum smear test produced negative results. Patient’s condition for tuberculosis was still being monitored. Her blood glucose levels were still in the high range and patient was to be continued on insulin.

To summarize this case, patient’s active tuberculosis state should be managed well to ensure patient does not suffer from further complications that might arise in the future. Patient’s history was well noted and this helped in treating the patient in early stages. Adequate investigations were performed to assist the healthcare professional team to diagnose the patient and also to manage the patient. Patient was admitted for a long period but the appropriate management that was undertaken resulted in improvement in patient’s condition. Further care for the patient would improve the patient’s quality of life in the future

Pathophysiology and Incidence

Tuberculosis (TB) is an infectious disease that has plagued many nations across the world. Based on the report by World Health Organization (WHO), almost 9.4 million cases of TB were reported 3. It is highly common of those with TB to contract the Human Immunodeficiency Virus (HIV) and a prevalence of almost 1.7 million deaths from TB among HIV-negative people was recorded around the globe 3. In the United Kingdom, an increasing trend in TB incidence has been reported and this is shown in Figure 1. In 2008, a rate of 14 per 100 000 population in the UK were reported to be suffering from TB 4. Malaysia on the other hand has a higher record of TB cases with 103 per 100 000 population being reported in 2007. Table 1 summarizes some of the data obtained from World Health Organization 3.

Figure 1: Number of TB cases reported in the UK from 2000 to 2008 4

Table 1: Statistics displaying number of TB cases in Malaysia in 2007 3

All

In HIV + people

Incidence

All forms of TB (per 100 000 population)

103

17

Mortality

All forms of TB (per 100 000 population)

121

8.3

Multi-drug Resistant TB (MDR-TB)

MDR-TB among new cases (%)

0.1

–

Notified relapse cases (per 100 000 pop/yr)

61

–

The bacteria that is responsible for this disease is the acid fast bacilli aerobic bacterium Mycobacterium tuberculosis 1. A key feature that enables this bacterium to survive would be its unique cell wall. Mycolic acids are linked covalently to arabinogalactan that provides a barrier to host defense mechanism. Antigens such as lipoarabinomannan present on the exterior of the cell wall facilitate the survival of the organism within macrophages 1. Tuberculosis is spread usually spread within droplets containing the microorganism that are produced when an infected person coughs, sneezes or even talks 1,2. Figure 1 gives a schematic impression of the progression of the disease. The inhaled droplets are initially trapped by dendritic cells that act to expel any foreign particles out. Most mycobacteria are able to surpass this defense mechanism and travels further to the alveoli where it gets ingested by macrophages 1. It then undergoes intracellular replication that might take duration of 4 to 6 weeks. Cytokines are further released during this period and this attracts T lymphocytes that are involved in mediating a cell immune response. The next natural defense system step would be the formation of granuloma that contains the activated T lymphocytes and macrophages. These nodular lesions disable further spread of the disease as the environment within restricts the growth of the bacilli and a latent period occurs 1. For less immunocompetent individuals, the granuloma will not be able to contain the bacilli and the active disease takes form 1.

Figure 1: Image depicting the progress of tuberculosis 2

The diagnostic tests available are summarized in Table 2. TB can be divided to latent and active and to diagnose each different test has been recommended. For latent TB, Mantoux test can be carried out and those with positive results can be considered for QuantiFERON TB test 5. To diagnose active pulmonary TB, a chest X-ray would be taken followed by multiple sputum samples that are sent for smear test 5.

Table 2: Diagnostic tests available for tuberculosis 1

Variable

Purpose

Time required for results

Sputum smear

Detect acid fast bacilli

< 24 hours

Sputum culture

Identify M tuberculosis

3-6 weeks with solid

media, 4-14 days with

high-pressure

liquid chromatography

Tuberculin skin test/ Mantoux

Detect exposure to mycobacteria

48 – 72 hours

QuantiFERON TB-test

Measure immune reactivity to M tuberculosis

12 – 24 hours

Chest radiography

Visualize lobar infiltrates with cavitation

Minutes

The drugs that are commonly used in tuberculosis are isoniazid, rifampicin, pyrazinamide and ethambutol. Rifampicin is a bactericidal agent that inhibits RNA synthesis by binding to the ß subunit of RNA polymerase. It can be given via oral administration and can even be distributed to the central nervous system due to its lipophilicity. Metabolism of this drug occurs in the liver and it is usually excreted in the urine. Isoniazid is a bactericidal pro-drug that inhibits ketoenoylreductase enzyme, InhA, that is responsible in synthesizing mycolic acids. Isoniazid can be administered orally, intramuscularly or intravenously and is acetylated in the liver and subsequently excreted in the urine. Pyridoxine 10 mg is given concurrently to minimize this risk. Pyrazinamide is another prodrug that is activated by nicotinamidase to pyrazinoic acid. This component at low pH carries proton into the cell and collapses the proton motive force present in the mycobacterium which results in cell death. It is only bactericidal against non growing bacilli forms.. Ethambutol works by binding to arabinosyl transferase enzyme and inhibits the polymerization of the cell wall arabinan component. Table 3 gives the details of the dose and side effects reported with the administration of the tuberculosis drugs.

Table 3: Tuberculosis drugs with their respective doses and side effects 6,7

Drug

Dose

Side effects

Isoniazid

5 -8 mg/kg (max 300 mg)

Peripheral neuropathy, hepatotoxicty

Rifampicin

10 – 15 mg/kg (max 600 mg)

Nausea, vomiting, thrombocytopenia, orange discolouration of urine

Pyrazinamide

20 – 40 mg/kg ( max 1.5 g <50kg, 2g >50 kg)

Nausea , vomitting, hyperuricemia

Ethambutol

15 – 25 mg/kg

Neuropathy, red green color blindness

Evidence based medication review

Treatment for Tuberculosis

In the past three decades, no new drugs have been discovered in fighting TB. The 4 drugs have been the gold standard in treating TB The chemotherapy regimen available for tuberculosis therapy can be divided to the initial phase and the continuation phase. In the initial phase, drugs such as rifampicin, isoniazid, pyrazinamide and ethambutol are used 6. These drugs act to decrease the amount of bacteria present and also prevent resistance from emerging from the strains. This regimen is usually for 2 months. The continuation phase would consist of drugs such as isoniazid and rifampicin.

Isoniazid was the first drug to be introduced into combating tuberculosis back in the 1950s. Rifampicin , an antibiotic, was later added to the market and was added to the isoniazid regimen in 1967. This resulted in shortening the duration of treatment from 12 months to a 6 to 9 month treatment 9. Addition of pyrazinamide to the regimen decreased the chemotherapy duration further. Clinical studies have indicated that a pyrazinamide containing short course regimen had a sputum negative conversion rate of 70-95% in the first two months compared to the treatment without pyrazinamide 11. The relapse rates recorded from these studies also were only 4%.

A clinical study conducted in East Africa compared the four 6-month daily regimens that comprised of Streptomycin, Isoniazid and Rifampicin (SHR), Streptomycin, Isoniazid and Pyrazinamide (SHZ); Streptomycin, Isoniazid and thiacetazone (SHZ) and Streptomycin and Isoniazid (SH) 10. The SHZ regimen that was the most effective amongst all the regimens and the SHR regimen had the lowest relapse rate of 2% 30 months post treatment 10. No significant difference results were obtained from the treatment regimen that was carried out for 18 months 10. This study gives an impression of the efficacy of the isoniazid, rifampicin and pyrazinamide regimen when used together

In a Poland study, the efficacy of the 4 different drug regimens containing rifampicin, isoniazid and ethambutol were assessed. During the initial phase, patients were given isoniazid 300 mg, rifampicin 600 mg and ethambutol 25 mg/kg 8. In the continuation phase the regimens given to patients comprised of rifampicin 600 mg, isoniazid 15mg/kg(Regimen A), isoniazid 15 mg/kg rifampicin 600 mg twice a week (Regimen B), Isoniazid 15kg/mg, rifampicin 600 mg ethambutol 50mg/kg once a week (Regimen C) and Isoniazid 15mg/kg, rifampicin 600 mg, ethambutol 50mg/kg twice a week (Regimen D) 8. The result of this study demonstrated that Regimen D had 47% of its patients displaying a significant change in their sputum result to a negative result compared to the other regimens. There were no significant differences in rates between all regimens by the end of the fifth month as all patients had their sputum converted to negative. This study had the limitation of not including pyrazinamide in its regimen but it can be seen that to achieve a quicker rate of sputum negative cultures a regimen containing ethambutol could be used in the continuation phase.

A trial conducted by Jindani et al. assessed the effectiveness of daily dosing of the intial phase drugs compared to the intermittent thrice weekly dosing. The drugs that were assessed were isoniazid, rifampicin, pyrazinamide and ethambutol. The doses that were given to the patients were based on WHO recommendations. The outcome measured after 2 months had 77% of the patients with negative sputum cultures after their 2 month stint (p=0.001) 13. A similar study was conducted in Hong Kong with the difference being a 12 month follow up period. By the end of the second month, 94% of patient receiving the daily regimen had improved. 90% of those under the intermittent regimen also had improved by the second month. Over the long term follow up, more relapse cases were recorded but the values were not significant 14.

Hypoglycemia Treatment

Patient was hypoglycemic upon arrival and dextrose infusion was provided to restore the patient’s normal blood glucose range. Two forms of treatment are usually available for hypoglycemic attacks namely glucagon and dextrose infusion. A study compared the efficacy between both the options and it was observed that both were capable of treating hypoglycemia effectively. The only disparity observed was the recovery. Patients on dextrose infusion are capable of regaining consciousness by 4 minutes compared to 6 minutes for patients that were on glucagon ( p<0.001)27. However, glucagon has the advantage of ease of administration and less vascular risk 27. A study by Moore et al. assessed the difference between the administration of 10% dextrose and 50% dextrose. Table 4 clearly displays that the dextrose 10% is the suitable alternative in hypoglycemic patients as the post treatment glucose levels are within the range and is not on the higher end as seen with dextrose 50%.

Table 4 : Results of 51 hypoglycemic patients treated with dextrose 10% and dextrose 50% 27

Dextrose 10%

Dextrose 50%

Median time needed to attain recovery (minutes)

8

8

Median total dose administered

10g ( p<0.001)

25g (p<0.001)

Median post treatment blood sugar levels

6.2 mmol/l (p=0.003)

9.4 mmol/l (p=0.003)

Diabetes Treatment

Oral antidiabetic agents such as gliclazide in the patient’s drug history would not be sufficient for her to have proper control over her glycemic levels. It was reported that tuberculosis affects the hormonal secretion by interfering with endocrinal organs such as pancreas 15. Rifampicin reduces the concentration of gliclazide by inducing liver microsomal enzymes CYP 2C9 that rapidly eliminates gliclazide from circulating in the system 15,16,17. In a study by Park et al., patients given with 80 mg gliclazide had the concentration of the drug present in the body reduced by 70% on day 7. The elimination half life of the drug also increased 3 fold 17. All these contribute to the inability of the sulfonyluea to reduce the glucose levels in this patient.

According to the stepwise approach in NICE guidelines, the next step to manage this patient would be to start the insulin regimen18. The type of insulin that was given was biphasic Mixtard insulin analogue that consists of a short acting analogue and also a long acting analogue. P.V. Rao reported that, due to the insulin resistance present in patients started on anti Tb therapy, the doses of insulin needed to manage these patients increase 15. It is well proven that insulin can achieve better HbA1c levels as a clinical trial by United Kingdom Prospective Diabetes Study (UKPDS) revealed that after 9 years monotherapy with insulin, 28% of patients achieved HbA1c levels below 7% and 42% patients achieved fasting plasma glucose levels below 7.8 mmol/l 19.

Hypertension Treatment

Patient was suffering from Stage 5 renal disease and the target for blood pressure in this patient would be 125/75 mm Hg 20. First line treatment for this patient would be loop diuretic, furosemide 20. They act by inhibiting the Na+/K+/2Cl- transporter on the ascending limb of loop of Henle which results in natriuresis and hence a fall in blood volume 21. This loop diuretic also performs its vasodilator actions via prostaglandin (PGE2 and prostacyclin) formation. This results in an increased blood flow in the medulla 21. In accordance to SIGN guidelines as well, long acting dihyrdopyridines such as nifedipine and α blockers can be added as supplementary therapy 20. Nifedipine, a calcium antagonist acts by causing vasodilatation due to reduction in peripheral resistance. α blockers such as prazosin block α1 receptors and this results in vasodilation.

A study by Vadasz displayed that Furosemide doses at 40 mg did not display any significant changes in systolic blood pressure. However, when the dose was increased to 60 mg, there was a significant reduction in blood pressure 21,22. A combined dose of 40 mg and 60 mg were effective in reducing the diastolic blood pressure. Based on this evidence, it is clear that furosemide on its own is not capable of decreasing blood pressure. When nifedipine was combined with diuretics it was observed that a statistically significant lower risk of cardiovascular events was observed compared to the non-statistically significant difference that was noted with nifedipine monotherapy 22. In another study by Psaty et al, nifedipine did not demonstrate an increase of risk in myocardial infarction compared to the other calcium channel blockers 25.

Prazosin’s efficacy in lowering blood pressure was studied and the lowest effective dose that is capable of reducing blood pressure was noted to be 10mg 26. Doses below 10 mg per day did not significantly reduce the blood pressure compared to the placebo arm.

Treatment of Anaemia

Patient had very low haemoglobin levels and this was indicative of anaemia. NICE guidelines have recommended that in order to manage anemia, patients are usually given eryhtropoetin stimulating agents and also iron supplements to help produce haemoglobin 23. There has been no evidence in the use of iron supplements in patients with chronic kidney disease prior to treatment with erythropoietin. But it is recommended that the erythropoietin therapy should not be commenced in conditions of complete iron absence 23. In some conditions, where patients were in Stage 5 renal failure also diagnosed with other co-morbidities, treatment with erythropoietin stimulating agents is decided based on clinical judgment by the professional team if the patient were to benefit from the treatment 23.

Treatment of Hyperkalaemia

Patient was suffering from mild hyperkalemia and it was necessary that this was be treated before it progresses to severe hyperkalemia that might lead to adverse events such as cardiac arrest. A study compared the effectiveness between sodium polystyrene sulfonate and calcium polysterene sulfonate and it is noted that treatement with sodium increases sodium concentration in the body and this escalates the risk of hypertension 24. Treatment with calcium polystyrene sulfonate resulted in 50% decrease in potassium content and an additional advantage of increase in calcium concentration was observed as well 24.

Conclusion

Based on all the evidence provided for the patient’s condition, it is clear that the guidelines were adhered in treating the patient’s individual disease with some minor differences. Tuberculosis treatment for the initial phase was extended for more than 2 months due to the positive result obtained from sputum smear. Patient eventually achieved negative sputum smear and the patient was to be monitored before the patient was commenced on the continuous phase drugs. Effective treatment was undertaken to treat patient’s hypoglycemia condition, and based on the evidence gathered, dextrose 10% is the suitable treatment option for the patient. The antihypertensive regimen that was chosen was due to the patient’s renal failure. Nifedipine, prazosin and furosemide collectively controlled the blood pressure of the patient. Ferrous sulphate was chosen as her treatment compared to erythropoietin and this was based on the doctor’s clinical judgement. Her hyperkalemia which was treated with calcium sulfonate did benefit the patient as her potassium levels were within the normal range at the end of the treatment.

PATIENT MEDICATION PROFILE

PATIENT DETAILS

Name

Mrs A

Consultant

–

General Practitioner

–

Address

Kuala Lumpur

Gender

Female

Weight

65

Height

158

Community Pharmacist

–

Date of Birth (Age)

61

Known Sensitivities

None

Social History

Non smoker & Non Alcoholic

PATIENT HOSPITAL STAY

Presenting complaint in primary care / reason for admission

Admission date

April

Low Sugar Level : 2.1 mmol/L

Discharge Date Discharged to

Not Known

Shortness of breath

RELEVANT MEDICAL HISTORY

RELEVANT DRUG HISTORY

Date

Problem Description

Date

Medication

Comments

Feb

Pulmonary Tuberculosis

Feb

Rifampicin

6 months

Advanced Renal Failure

Feb

Isoniazid

5 years

Hypertension

Feb

Pyrazinamide

5 years

Diabetes Mellitus

Feb

Ethambutol

Feb

Pyridoxine

6 months

Prazosin

6 months

Nifedipine

6 months

Furosemide

–

Gliclazide

RELEVANT NON DRUG TREATMENT

Peritoneal Dialysis

Prescribed Medication

Start

Stop

Clinical/Laboratory Tests

Date Result

1

Rifampicin

Day 1

–

Sputum Smear Test

Day 1

Positive

2

Isoniazid

Day 1

–

Creatinine

Day 1

912 µmol

3

Pyrazinamide

Day 1

–

Urea

Day 1

37.8 mmol/l

4

Ethambutol

Day 1

–

Potassium

Day 1

5.5 mmol/l

5

Pyridoxine

Day 1

–

Blood Glucose

Day 1

2.1 mmol/l

6

Prazosin

Day 1

–

Blood Pressure

Day 1

152/93

7

Nifedipine

Day 1

–

Haemoglobin

Day 1

9.8 g/dl