Amlodipine versus Felodipine

A student wanted to know why some doctors prescribed Amlodipine while others prescribed Felodipine as the calcium channel blocker for treating hypertension. This is what I found in the published literature:

Amlodipine seems to be more effective than felodipine when these drugs are compared in the same dose, with regard to the effect on BP measured in the clinic 24 hours after dosing, and to ambulatory BP during the night. The longer elimination half-life of amlodipine as compared to felodipine is the probable reason for this finding. (1998) (reference). 

However another side to the story is this: Felodipine decreased BP sooner than amlodipine. Amlodipine and felodipine are similar antihypertensive agents and have comparable BP profiles during the day and night following 8 weeks of therapy in patients with mild to moderate hypertension.  (2001) (reference).

Current advice from NICE recommends calcium channel blockers as potential first line agents in older patients (over 55 years) or black patients of any age and as potential second line adjunctive agent in younger non-black patients. No specific calcium channel blocker is recommended.  The choice of calcium channel blocker may depend on local recommendations, with the least expensive one being preferred. For patients with both hypertension and angina, amlodipine or felodipine are suitable choices. (2012) (reference).

A patient with pernicious anemia

A young man with anemia had paresthesiae of his feet and difficulty in walking. Investigations revealed that he had a macrocytic anemia due to Vitamin B12 deficiency. 

Pernicious anemia is due to Vit B12 deficiency. This is a macrocytic anemia with a megaloblastic reaction in the bone marrow. Patients with pernicious anemia can also have pancytopenia because of defective cell formation in the bone marrow. Neurological disorders involving the spinal cord, peripheral nerves and sometimes the brain are what gives this anemia the adjective 'pernicious' which means dangerous. The neurological complications of Vit B12 deficiency can occur without the anemia and anemia can be present without the neurological complications.

Pernicious anemia is often associated with gastric atrophy and hypochlorhydria which leads to poor iron absorption and associated iron deficiency. Gastric atrophy increases the risk of gastric adenocarcinoma in patients with pernicious anemia.

Autoantibodies directed against the gastric parietal cells and the intrinsic factor produced by these parietal cells are the usual cause of pernicious anemia. These patients are therefore at increased risk of other autoimmune diseases involving the thyroid, pancreas and adrenal glands.

Serum LDH levels are useful in diagnosis because they are elevated in patients with haemolytic anemia. Once the diagnosis is made, treatment is started with either cyanocobalamin or hydroxocobalamin. These are given as injections subcutaneously or intramuscularly until the desired response is achieved. Maintenance doses of Vit B12 need only be given once a month because the body requires very low amounts of Vit B12 per day (1ug per day). It may also be possible for maintenance doses of Vit B12 to be given orally in high daily doses because, even without intrinsic factor, about 1 percent of Vit B12 is absorbed from the gut.

People at risk of pernicious anemia are those who do not consume either meat or milk because the natural source of Vit B12 is from these two dietary products.

Data published by the Institute of Medical Research in 1994 (article) gives us an idea of the prevalence of Vitamin B12 deficiency in Malaysia. In the year 1993 to 1994 it was around 8.2 percent (based on a sample of around 9000 patients who were suspected to have Vit B12 deficiency). 

Macrocytic anemia can also be due to folic acid deficiency. Folic acid deficiency can cause cognitive changes, depression, dementia and rarely the spinal cord and peripheral nerve damage of Vitamin B12 deficiency. Both folic acid and Vitamin B12 are therefore important vitamins for the blood and nervous system (article). 

A patient with rheumatoid arthritis on methotrexate

A patient with rheumatoid arthritis was prescribed Tab Methotrexate 5mg per week and Tab Folic acid 5mg per day. I know that methotrexate blocks the conversion of folic acid to folinic acid and hence can inhibit the action of certain important enzymes in the body.  

I asked myself two questions: 

1. Is folic acid really necessary when prescribing low dose long term methotrexate? 
2. Will folic acid reduce the efficacy of methotrexate? 

A Medscape article provided the answers. Low dose methotrexate refers to the use of less than 20mg of methotrexate per week. Studies have shown that folic acid supplementation has a beneficial effect in reducing the side effects of methotrexate like stomatitis, gastrointestinal upsets, liver dysfunction and bone marrow suppression. Folinic acid too has the same benefit but it is more expensive. It is not entirely clear whether folic acid supplementation will reduce the efficacy of methotrexate in rheumatoid arthritis but it probably will not. The beneficial effect of low dose methotrexate in rheumatoid arthritis appears not to be related to its inhibition of folic acid metabolism. 

A cardiovascular benefit in providing supplementation with folic acid is also present. Methotrexate tends to increase homocysteine levels (a cardiovascular risk factor) in the blood. This will be prevented by folic acid. 

A patient with pericardial effusion and an endocrine problem

An elderly man with diabetes and chronic renal failure was diagnosed with a pericardial effusion a few months ago. He underwent pericardial aspiration and analysis of the pericardial fluid at another hospital before coming to us. The cardiologist in that hospital felt that the pericardial effusion was due to his renal failure. This patient presented to us because of a feeling of extreme tiredness and a history of hypoglycemic episodes. We initially attributed his tiredness to his hypoglycemic episodes. He was on oral Glibeclamide for diabetes and we stopped that drug. When his blood reports showed a severe degree of hyponatremia and his physical examination showed pigmentation of the palms, palate and lips, we considered another diagnosis.

Discussion

The pigmentation over the skin and mucosa along with the hyponatremia and hypoglycemia are suggestive of adrenal insufficiency or Addison's disease. Since this patient has chronic renal failure and is on a long acting sulphonylurea - Glibenclamide - the hypoglycemic episodes can also be blamed on the inappropriate use of glibenclamide. The suspicion of Addison's disease can be tested by doing a random plasma cortisol level. If the random plasma cortisol value is more than 25mcg/dL in a patient whose serum albumin is normal, Addison's disease is unlikely. Confirmation of diagnosis of Addison's disease can be done by doing the ACTH stimulation tests to see if the adrenal cortex responds appropriately by producing glucocorticoids and mineralocorticoids to an injection of ACTH. Treatment of Adrenal insufficiency for this patient can be initiated with a higher than usual replacement doses of hydrocortisone (for example, 100mg three times a day for one day followed by 50mg three times a day for one day and tapering thereafter). Maintenance doses of hydrocortisone for Addison's disease is usually between 15 and 20mg per day: a larger portion of hydrocortisone (10 -15mg) is given in the morning and a smaller portion (5 -10mg) is given in the late afternoon. When hydrocortisone is given at night, it may cause insomnia and that is why it is preferable to give the evening dose in the late afternoon. One thing to remember is that the adrenal gland produces both glucocorticoids and mineralocorticoids and replacement for both is needed. However, since hydrocortisone has a slight degree of mineralocorticoid activity, it is not necessary to add a separate mineralocorticoid drug (fludrocortisone) if more than 100mg per day of hydrocortisone is being given. When maintenance doses of hydrocortisone are being used, fludrocortisone is needed.

The following facts are nice to know:

1. Cortisol is the name of the glucocorticoid produced by the adrenal gland. This is the same as hydrocortisone.

2. Cortisone is the inactive form of cortisol. When given as a tablet, it is converted to cortisol in the body.

3. Prednisolone is the active form of prednisone. This is a synthetic glucocorticoid. Prednisolone is preferred over prednisone in patients with liver disease.

4. All glucocorticoid hormones have anti-inflammatory activity. These are graded as:

5mg of prednisolone being equivalent to 20mg of hydrocortisone / 25mg cortisone / 0.75mg dexamethasone /4mg methylprednisolone.

14 lessons from HIV Update 2014

HIV update 2014 was held in Seremban on 22nd May 2014. 

1. As of 2011, there were approximately 34 million people living with HIV infection in the world.

2. In 2011, the incidence of new HIV cases in Malaysia was 12.2 per 100000 people. The state of Johor had reported the greatest number of new cases that year. 

3. Antiretroviral therapy should be started according to the CD4 cell count or when there is “double trouble” (HIV infection plus another condition). If we decide to start antiretroviral therapy based on the CD4 count, then for practical purposes, in Malaysia, we start when the CD4 count is below 350 cells per cubic mm. The ideal is probably to start when the count is below 500 cells per cubic mm. Conditions that constitute double trouble include: HIV plus active tuberculosis infection; HIV plus HBV infection; when an HIV patient has a sexual partner who is not positive; when a woman with HIV is pregnant or breastfeeding; when the patient with HIV is a child below 5 years of age.

4. A template for initiating antiretroviral therapy is: Efavirenz plus Tenofovir plus Lamivudine or Efavirenz plus Tenofovir plus Emtricitabine. Other combinations involving the cheaper drug zidovudine are also possible. An important update is that Efavirenz is no longer considered teratogenic now. Important points to remember are: Efavirenz causes CNS toxicity and skin rashes.

5. The HIV viral load (HIV RNA count) is more important for decision making than the CD4 count. This is because the CD4 count is subject to variations caused by factors other than HIV infection.

6. The gold standard for the diagnosis of HIV used to be the ELISA test (for detection of antibodies) and the Western Blot test (for detection of antigens).  Nowadays different methods (rapid assay tests) are used to detect antibodies and antigens.

7. One quarter of new deaths from HIV infection are due to tuberculosis in the world. The WHO recommendation is to give co-trimoxazole (Bactrim) for all patients who have both tuberculosis and advanced HIV infection because co-trimoxazole protects against infections that such people with advanced immunosuppression are also susceptible to. The drug should be given for at least six months.

8. Diagnosing tuberculosis can be difficult when resources to do so are not easily available. A useful aphorism to remember is: If patients do not have all these 4 symptoms of cough, fever, night sweats and loss of weight, they are unlikely to have tuberculosis. Conversely if they have one or more of these symptoms, the diagnosis of tuberculosis should be suspected and options to confirm or rule out the diagnosis should be explored.

9. It has been found that 57 percent of all people being treated for tuberculosis develop hepatitis. In this regard, pyrazinamide and isoniazid are more likely than rifampicin to be the cause of the hepatitis. Ethambutol and Streptomycin are very unlikely to cause hepatitis.

10. When Efavirenz is used along with Ethambutol, the serum levels of Efavirenz will decrease.

11. Efavirenz should be avoided in people prone to depression.

12. When a patient on antiretroviral therapy develops proteinuria or acute kidney injury, suspect Tenofovir induced damage to the proximal convoluted tubules of the kidney.

13. When a patient on antiretroviral therapy develops anemia, suspect zidovudine as a cause.

14. Failure of antiretroviral therapy can be defined thus: Virological failure is said to be present when the viral load is more than 1000 copies per millilitre on 2 occasions, more than 3 months apart. Immunological failure is said to be present when the CD4 count remains less than the baseline (before treatment) or remains less than 100 cells per millilitre persistently. Clinical failure is said to be present when a new illness due to immunosuppression occurs after 6 months of treatment. 

Using rubrics for decision making

Daniel Kahneman, the Nobel Prize winning Professor of Psychology from Princeton University, has written a book titled “Thinking, fast and slow”. In this book there is a chapter called “Intuitions versus Formulas”.  He explains that our evaluation of complex problems can sometimes be standardised by the use of algorithms or formulas with numerical values attached to them.  There are two examples that I wish to quote from that book because I feel it is relevant to how we can use rubrics (or formulas with scores) for standardising the evaluation of student portfolios.

1. How do you evaluate the stability of a marriage?

The formula (frequency of lovemaking – frequency of quarrels) will give a fair idea of marital stability. If the answer is not a negative number, the marriage is probably stable. 

2. How do you evaluate the chances of survival in a new born child?

Obstetricians have always known that infants who do not breathe well within a few minutes of birth are at high risk of brain damage or death. But until the anaesthetist Virginia Apgar wrote a simple algorithm incorporating five variables to observe in all new born infants, with a score assigned to each variable, doctors and midwives used their clinical judgement to determine whether babies were in distress. Some watched for breathing problems while others focused on how soon the baby cried. Without a standardised procedure, danger signs were often missed and many new born infants died. The Apgar scoring system gave everyone a consistent standard for determining risk and helped everyone evaluate this risk in the same way as experienced obstetricians. The Apgar test is credited with helping to reduce infant mortality.

A patient with hypernatremia

A 75 year old man with a history of chronic alcohol abuse presented with bleeding per rectum. He was diagnosed to have bleeding haemorrhoids and was admitted in the hospital and given intravenous fluids. A day later he became confused and agitated. He was suspected to have delirium tremens and was treated with parenteral Thiamine. His agitated behaviour subsided but he became drowsy and lethargic. At this point his serum sodium was noted to be 168mmol/L. His blood urea was elevated but his serum creatinine was within normal limits.

About hypernatremia

Hypernatremia should be considered a water-problem and not a salt-problem. People develop hypernatremia only when there is an impairment of the thirst mechanism or when there is limited access to water. This elderly man developed hypernatremia in the hospital in the setting of an alcohol-related change in behaviour and sensorium. We can assume that his hypernatremia reflects impaired release of vasopressin from the brain (diabetes insipidus) along with insufficient fluid intake. There is evidence that alcohol can damage the supraoptic and paraventricular nuclei in the brain. (Reference) 

The diagnosis of diabetes insipidus is suspected when a person has polyuria (more than 3 litres of urine in a day) with hypotonic urine (urine osmolality less than 300mOsm/kg). As a general rule, in all patients who have polyuria with hypotonic urine, we must suspect three possibilities: compulsive polydipsia, central diabetes insipidus and nephrogenic diabetes insipidus. The fluid deprivation test can help us confirm or rule out compulsive polydipsia. The desmopressin stimulation test will help us identify nephrogenic diabetes insipidus. 

Treating hypernatremia

Hypernatremia is dangerous because it dehydrates brain cells and damages them. Before treating hypernatremia, we should know the duration of hypernatremia. If the condition has been present for less than 24 hours, rapid correction is safe. In this patient we have to assume that the hypernatremia was present for more than 24 hours. Hence his hypernatremia should be corrected slowly. Rapid correction can lead to cerebral edema. Slow correction means reducing the sodium levels by not more than 10 to 12 mmol/L per day.

Correcting elevated serum sodium

In correcting hypernatremia we use 5 percent dextrose which does not contain any sodium at all. To know how much the serum sodium will fall by giving 1 litre of 5 percent dextrose, there is a formula:

(Amount of sodium in the infusate minus the serum sodium) divided by (total body water plus 1) is equal to the amount by which the serum sodium will fall. 

His total body water = 50 percent of body weight = 30 litres because his body weight was estimated to be 60kg.

The calculated fall in serum sodium by infusing one litre of 5 percent dextrose will be: (0 – 168) divided by (30+1) = 5.4mmol/L

A fall of 10mmol/L in serum sodium needs: 10 divided by 5.4 = 1.85 litres of 5 percent dextrose.

Now we must add in the insensible and obligatory losses of fluid from the body per day. This depends on factors like urine output, body temperature, ambient temperature and respiratory rate. As an approximation, if his urine output is 900 ml per day, and insensible losses are 600ml per day, we have to add (900+600) = 1.5 L to the daily fluid requirement.

Hence he should be given (1.85 + 1.5) = 3.15 L of 5 percent dextrose per day in order to reduce serum sodium by 10mmol/day. 

This means infusing the fluid at the rate of approximately 130ml per hour. This is a rough guide only. We must check the serum sodium every 1 to 2 hours and adjust our infusion rate accordingly. At all costs, we must avoid a rapid fall in serum sodium.

What predisposed this patient to develop a confusional state in hospital?

There are two possibilities. Delirium tremens and acute onset of beriberi.

Delirium tremens is a severe clinical manifestation of alcohol withdrawal and shows itself as a confusional state with features of sympathetic over-activity. It generally occurs 3 to 10 days after stopping alcohol intake. It is important to treat it urgently because cardiovascular collapse can occur. Benzodiazepines in adequate doses should always be used. Beta blockers can be added if necessary. Attention must be paid to fluid and electrolyte balance and management of other medical / surgical conditions in the patient.

Beriberi can present as a confusional state – Wernicke’s encephalopathy and Korsakoff psychosis. People who chronically abuse alcohol may have low levels of Vitamin B1 or thiamine in their bodies. When such people are given dextrose containing fluids, they can develop acute thiamine deficiency because whatever little thiamine is present in them is used up for the metabolism of glucose.

 How should diabetes insipidus be treated?

If this patient is confirmed to have central diabetes insipidus, he will need replacement doses of vasopressin. Vasopressin (trade name Pitressin) can be given intramuscularly or subcutaneously twice or thrice a day. There is also a form of vasopressin that can be given as a nasal spray or as a tablet.

References:

1. Diabetes insipidus. http://emedicine.medscape.com/article/117648-overview

2. Delirium tremens. http://emedicine.medscape.com/article/166032-overview

3. Beriberi. http://emedicine.medscape.com/article/116930-overview

Prescribing statins - current concepts

What is the dose of statin that should be prescribed to patients who have clinically evident coronary artery disease?

When a patient below the age of 75 years has evidence of coronary artery disease, statins in appropriately high doses should be prescribed irrespective of their serum cholesterol values. A high dose (or intensive dose) for Atorvastatin refers to 40 to 80mg per day; a similar dose for Simvastatin is 40mg per day.

Is the dose of statin prescribed to a patient determined by the LDL - cholesterol value?
The new 2013 cholesterol lowering guidelines tell us that the decision to start a statin can be determined, in part, by the LDL cholesterol level. But the dose (high intensity versus moderate intensity) is determined by parameters other than the LDL cholesterol value. 

When should serum creatine kinase (CK) be tested when patients are on statins?

CK needs to be tested only when patients on statins complain of muscle pain or muscle weakness.

How can muscle pain due to statins be differentiated from other causes of myalgia?

Myalgia due to statins will resolve within 2 weeks of stopping the drug. When muscle pain persists beyond 2 weeks after discontinuing statins, other causes of myalgia must be considered.

Should liver function tests be done routinely when patients are on statins?

No. It is not necessary.

Should all patients with diabetes be prescribed with a statin?

All diabetic patients between the ages of 40 and 75 years should generally receive a statin unless their LDL cholesterol level is unusually low (below 1.8mmol/L). Whether low dose (moderate intensity) or high dose (high intensity) statins are needed should be decided by their 10-year risk of developing atherosclerotic coronary artery disease.

Is there any role for the combination of a statin with a non-statin (fenofibrate / gemfibrosil / nicotinic acid)?

Yes. There is definite evidence for doing so in patients with familial hypercholesterolemia because the reduction in cardiovascular risk is proportional to the degree of lowering of LDL cholesterol. The diagnosis of familial hypercholesterolemia should be suspected in patients with LDL cholesterol levels more than 4.9mmol/L (190mg/dL). Whether there is a benefit in combining a statin with a non-statin for those with diabetes and coronary artery disease is still not clear. When a statin is combined with a fibrate, it is better to use fenofibrate (and not gemfibrosil) because it is safer.

Can statins be continued during pregnancy?
Statins and non-statin cholesterol lowering drugs are classified as pregnancy category X and should not be taken during pregnancy and while breast feeding. Those who are on statins should discontinue them 2 to 3 months before becoming pregnant. 

Is there an increased risk of new-onset diabetes due to statin therapy?
Yes, but the risk is modest. With low dose statin therapy, 1 out of 1000 will develop diabetes per year. With high dose statin therapy, 3 out of 1000 will develop diabetes per year according to available evidence. On the other hand, appropriately used statin therapy prevents 5 to 6 cases of atherosclerosis induced vascular disease per 1000 population per year. 

Is there any role for using statins for primary prevention in individuals who are younger than 40 years of age if they do not have diabetes or heart disease?
Yes, in selected individuals. Young people who have risk factors like: a strong family history of premature coronary artery disease, an LDL cholesterol more than 4.1mmol/L (160mg/dL), a high sensitivity CRP level more than 2mg/L, or a coronary calcium score more than 300units can be considered for statin therapy as primary prevention. Moderate intensity (lower dose) statins are recommended if their calculated lifetime risk of developing coronary artery disease is not high. High intensity statin therapy is recommended if the calculated lifetime risk is high.

How are the statins different from each other in their LDL- cholesterol lowering ability?
When statins are evaluated based on their ability to lower LDL cholesterol, we note that 5mg of Rosuvastatin is equal to 10mg of Atrovastatin is equal to 20mg of Simvastatin is equal to 40mg of Lovastatin. The relationship between dose of statin and degree of LDL-cholesterol lowering is not linear: doubling of a statin dose does not double the fall in LDL cholesterol, but only an extra 6 percent fall will be seen.

Based on the 2013 cholesterol lowering guidelines from the American Heart Association and the prevention guidelines clinical vignettes . 

Acute and chronic gout

The following is based on the Malaysian Clinical Practice Guidelines for Management of Gout (Published in October 2008)

1. The first line treatment for acute gouty arthritis is non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, diclofenac and indomethacin. Aspirin is not recommended because it increases uric acid levels in the blood unless given in very high doses.

Question: A patient with acute gouty arthritis has peptic ulcer disease and hence cannot be prescribed any of the traditional NSAIDs. What can be done for pain relief in this situation?

Answer: We can use either COX-2 (cyclooxygenase 2) inhibitors like Celecoxib or Etoricoxib. We can also use Colchicine. A third option for pain relief, particularly in elderly people and in those who have renal disease, is the use of glucocorticoids. Short courses of oral prednisolone are effective in providing pain relief. Intra-articular injections of corticosteroids are also helpful.

2. Long term therapy with Allopurinol to reduce serum uric acid levels should be initiated in those who have chronic gout – that is, those who have experienced 3 or more episodes of acute gouty arthritis in a year, those who have erosive gouty arthritis, those who have tophi, and those who have uric acid nephropathy or uric acid stones.

Question: How is Allopurinol prescribed?

Answer: Allopurinol should be started in a low dose of 100 to 150mg once a day. After 3 to 4 weeks, the dose can be increased to usual maximum dose of 300mg per day. In those who have renal impairment, the dose of Allopurinol should be appropriately reduced. For example, if a patient with gout has end stage renal failure, the dose of allopurinol should not exceed 100mg once in 2 to 3 days. If a patient with gout has Stage 3 CKD, the maximum dose should not exceed 200mg per day. The usual dose of 300mg per day should only be prescribed for those with normal renal function.

Question: Can Allopurinol be prescribed for those with asymptomatic hyperuricemia?

Answer: It is not necessary to prescribe Allopurinol for all asymptomatic people with elevated uric acid levels because most of them will never suffer from gout. However, if the uric acid level is very high (about twice the upper limit of normal), it is better to prescribe allopurinol to reduce the risk of developing nephropathy. Prophylactic use of allopurinol is also recommended when a rapid increase in serum uric acid  is anticipated – as in treatment of leukemias and lymphomas.

Question: Since allopurinol has the potential to cause severe allergic reactions and bone marrow depression, is there an alternative drug for reducing serum uric acid?

Answer: Probenecid is also a uric acid lowering drug. Unlike allopurinol, probenecid increases the excretion of uric acid in the urine. Hence probenecid is not recommended for those who have uric acid nephropathy or uric acid nephrolithiasis. Ideally, urinary excretion of uric acid should be measured and probenecid should be prescribed only for those who do not have elevated urinary uric acid levels. 

Question: Will allopurinol therapy increase the risk of acute gouty arthritis?

Answer: Yes, there is an increased risk of acute arthritis during the initial period after allopurinol is initiated. That is why one should not prescribe allopurinol during an acute episode. To minimise acute episodes while initiating allopurinol therapy, low doses of colchicine (0.5mg twice a day) can be given. Colchicine can be stopped when the patient has not suffered acute arthritis for 6 months or when serum uric acid levels are normal for one month.

Question: Should allopurinol be stopped when a person, who is already on allopurinol, develops acute gouty arthritis?

Answer: No. Allopurinol need not be stopped in this situation. 

Question: What is risk when Allopurinol is prescribed along with Ampicillin?

Answer: There is an increased risk of developing a skin rash due to allopurinol.

Question: What is the risk of prescribing allopurinol with warfarin?

Answer: There is the risk of bleeding because allopurinol reduces the metabolism of warfarin and increases its half-life.

3. Polyarticular gout mimics rheumatoid arthritis. Gouty arthritis can lead to osteoarthritis.

Question: How do the subcutaneous tophi in gout differ from the subcutaneous nodules of rheumatoid arthritis?

Answer: Tophi are painless while rheumatoid nodules are generally painful.

Question: Is it possible to differentiate gouty arthritis from osteoarthritis with an x-ray of a painful joint?

Answer: Yes. The joint space is preserved in acute gouty arthritis while the joint space is narrowed in osteoarthritis.

4. A normal serum uric acid in a person with acute arthritis does not exclude gout.

Question: Can a therapeutic response to colchicine be used to diagnose gout?

Answer: Yes. Acute gouty arthritis responds within 48 hours to colchicine.

5. Alcohol should be restricted or avoided in all patients with gout.

Question: Why is alcohol restriction necessary in gout?

Answer: Alcohol reduces the excretion of purines. Uric acid is the result of purine metabolism.

6. Drugs that increase uric acid levels can provoke acute gouty arthritis.

Question: A patient with diabetes, hypertension and ischemic heart disease experiences frequent gouty arthritis. Which of her medications may need to be changed?

Answer: Is she on thiazide diuretics for hypertension and low dose aspirin for heart disease? If yes, these should be changed.

7. Food that is high in purine content should be avoided by those who have gout.

Question: Should eggs be avoided by those who have gout?

Answer: No. Eggs have low purine content.

Question: Should mushrooms, beans and peas be avoided by those who have gout?

Answer: These foods have moderate purine content and should be eaten less frequently than usual.

Question: Can those with gout eat red meat, anchovies and sardines?

Answer: These are food items with high purine content and should be avoided.

Cyanosis without hypoxia

Clinically evident cyanosis is often due to increased levels of reduced hemoglobin in the blood caused by cardiac or pulmonary diseases. Recently a 23 year old woman presented with cyanosis of the tongue and finger tips. She was not anemic or icteric. She did not have any cardiac or pulmonary disease. Her capillary oxygen saturation was 93 percent. When a few drops of her blood (dark brown in colour) were spilled on a white filter paper, no change in colour was noted after adequate exposure to the atmosphere.

This provoked a discussion on the causes of cyanosis without hypoxia.

We discussed methaemoglobinemia as a possible cause. Methaemoglobinemia is a condition where the hemoglobin molecule has a ferric iron instead of the normal ferrous iron. This condition can occur following exposure to drugs like nitrites, sulphonamides and some chemical dyes. When iron is in the ferric state, hemoglobin does not easily release its oxygen to tissues. Methaemoglobinemia can also be due to inherited disorders: deficiency of the enzyme within red cells that normally converts iron from a ferric state to a ferrous state - an enzyme called methaemoglobin reductase - can result in methaemoglobinemia. Another reason is the presence of an abnormal hemoglobin called Hemoglobin M.

Our patient however did not have methaemoglobin reductase deficiency. Her hemoglobin electrophoresis showed the presence of the hemoglobin variant called Hemoglobin M. And that explained why she had cyanosis without hypoxia.

The Mantoux tuberculin skin test - interesting facts

The Mantoux test or the Tuberculin Skin Test (TST) is one of those tests that most doctors will do when faced with a patient who is suspected of having tuberculosis. The test involves the intradermal injection of 0.1ml of a protein called tuberculin purified protein derivative. The test is interpreted as positive or negative according to the size of induration on the skin (not erythema), measured perpendicular to the long axis of injection, between 48 and 72 hours after the injection.

The TST is not a very sensitive test. In those who are not suffering from any kind of disease that compromises their immunity, the test has a sensitivity of about 95 percent. This means that this test may miss one out of every twenty previously healthy people who develop tuberculosis. The sensitivity of the TST drops to 80 percent when an immunocompromised person develops tuberculosis. This means that for people with HIV, the TST is not reliable in excluding tuberculosis because it can be negative in 1 in 5 people with HIV infection who develop tuberculosis.

The size of induration required for a positive TST depends on who is being tested. An induration of 5mm is adequate if the person is immunocompromised in any way through disease or from medication. Otherwise an induration of 10mm is required for the test to be regarded as positive.

We would regard a person as being newly infected with tuberculosis when the tuberculin skin test was negative earlier but is positive now. If such a person has no signs of active tuberculosis (after being investigated), the person will be labelled as having latent tuberculosis.

There are situations where a positive TST is not due to latent tuberculosis or to active tuberculosis. BCG vaccination in childhood can result in a positive test for 3 to 5 years after the vaccination. The test can also remain positive for many years after a person has been successfully treated for tuberculosis in the past.

There is a peculiar phenomenon known as the booster phenomenon where a person may develop a positive test simply because of a tuberculin skin test done earlier within the past one year. This phenomenon is because the TST boosts cell mediated immunity that had previously waned. It occurs in people who had tuberculosis earlier. The danger in not being aware of this phenomenon is that we may label such patients as having latent tuberculosis because of the recent conversion in the TST.

To overcome the problem of misinterpreting the TST in people (like health care workers) who may undergo annual tuberculin skin testing, we can do the two-step tuberculin skin test. The details of how this test is done is given in the reference below.

References:
1. The two-step tuberculin skin test
2. Tuberculin skin testing

The 2013 Nobel Prize in Physiology or Medicine

 Some genetic diseases are caused by defects in the transport of proteins within cells.  An understanding of the mechanisms involving transport of proteins via vesicles was the research work that led to the 2013 Nobel Prize in Medicine / Physiology. (Read about it).  

Genetic diseases can be caused by single gene abnormalities, chromosomal abnormalities or by a combination of genetic and environmental factors. Abnormalities in genes cause diseases in various ways:

1. Excess production of proteins. An example is the fragile X syndrome which shows itself as learning disability or mental retardation and autistic behaviour. This is caused by excess production of a protein that is used in synapses of the brain.

2. Insufficient production of proteins. An example is the group of diseases called glycogen storage disorders which can present with hypoglycaemia, hepatomegaly and/or muscle weakness.

3. Production of an abnormal protein. An example is phenylketonuria which is due to production of an inactive form of the enzyme that hydrolyses the amino acid phenylalanine. This leads to delayed milestones in childhood, seizures, learning disabilities and mental retardation as well as reduced or absent pigmentation of skin, hair and eyes. 

4. Defective transport of proteins. Genetic diseases involving abnormalities in protein transport can manifest in patients as hypopigmentation of skin, defects in cell mediated immunity and/or neurological defects. Bardet-Biedl syndrome where the affected person has mental retardation, retinopathy and is of small stature with poorly developed external genitalia, Charcot Marie Tooth disease and Spinocerebellar ataxias where those affected have ataxic gait along with other neurological abnormalities, Hereditary Spastic paraplegia which causes a pure motor paraplegia, are examples of neurological conditions where the genetic defect affects protein transport within cells. Alzheimer’s disease and Type 2 diabetes mellitus may also have defects in the transport of proteins. The transport of amyloid precursor protein by vesicles has been noted to be defective in the early stages of Alzheimer’s disease.  

Reference: Insights into vesicular transport in inherited diseases

Managing patients with shock

A beautiful review about circulatory shock in the NewEngland Journal of Medicine gives us practical advice for dealing with patients in shock. I summarise here three important learning points from that article. 

1. Diagnosing circulatory shock

Do not define shock only by the presence of arterial hypotension even though a blood pressure lower than 90mm Hg systolic and a mean blood pressure less than 70mm Hg are often present. This is because in those with chronic hypertension, the fall in blood pressure may not reflect the degree of shock. Also, the blood pressure alone may be misleading as it can be low in people who have chronic hypotension or have just suffered a transient episode of vasovagal syncope. The diagnosis of shock needs signs of poor perfusion to tissues and organs. The article tells us to consider the diagnosis of shock when there is tachycardia and signs of poor tissue perfusion as seen through three windows in the body:

                a. The skin: Cold and clammy

                b. The brain: Confusion, disorientation or other signs of altered mental status

                c. The kidney: A urine output of less than 0.5ml per kg per hour.

2. The VIP rule for resuscitation

This is the Ventilate, Infuse and Pump rule.  Ventilate (when needed) to ensure adequate oxygen intake. In this context we must remember that pulse oximetry is unreliable as a measure of adequate oxygen in the blood when there is peripheral vasoconstriction. So blood gases must be measured for this purpose. 

Fluids must always be infused in patients with shock since even those with cardiogenic shock can benefit from fluid resuscitation. However infusion of fluids must be carefully monitored. A fluid challenge refers to the infusion of 300 to 500ml of fluids (usually crystalloids) over a period of 20 to 30 minutes in order to see whether there is any improvement in one or more of the parameters of circulatory shock. The results of such a fluid challenge can then guide decisions for further infusion of fluids. 

Inotropic agents need to be used when the hypotension is severe or when the response to fluid resuscitation is slow or insufficient.

3. Using inotropic agents in circulatory shock

The authors consider norepinephrine to be the agent of first choice in those with shock whose cardiac output is not decreased. This will be seen in conditions like the early stages of septic shock (distributive shock). In the dose range of 0.5 to 2ug per kg per minute, norepinephrine elevates mean blood pressure without increasing the heart rate. Dobutamine is considered the agent of first choice in those with shock who need an increase in cardiac output. Both dobutamine and norepinephrine can be used together when needed. The authors do not recommend either dopamine or epinephrine as agents of first choice. Dopamine increases the risk of arrhythmias and increases mortality in the acute stage when given to patients with cardiogenic shock. Epinephrine increases the risk of arrhythmias and reduces splanchnic blood flow. These agents can be used as second line agents if necessary. Low dose vasopressin is an agent that can be added to norepinephrine for those with septic shock who have an adequate cardiac output.

Prolonging life and the futility of medical care

We see and interpret the world according to our individual beliefs and values. This difference in interpretation can be seen in the way doctors and lay people make decisions regarding how patients, who are seriously ill and without a chance of cure, have to be managed. When doctors have exhausted all that they have in their therapeutic armamentarium, they speak of poor prognosis and of futility in prolonging life with the use of technology. It sometimes comes as an unpleasant surprise to the doctors when close family members hear them but insist on continuing whatever life-sustaining measures are in place for their loved ones. Doctors tend to feel that such people are in denial of the reality that should be readily apparent to everyone.  In this NEJM article, the author gives us a reason why the loved ones of critically ill patients may differ in their views from doctors. The author tells us that doctors base their reasoning on outcomes for deciding what is important: can the patient be cured or not, is the question for them. For family members, what they do for their loved ones (the process of providing care) is what matters most.  The process of providing care to a loved one can be therapeutic in itself, irrespective of the outcome.  Doctors have outcome-based ethical reasoning on prolonging life while the loved ones of a patient may have process-based ethical reasoning. Doctors need to understand that this is the reason for family members often insisting on continuing futile medical interventions for their loved ones. Instead of labeling such requests as unreasonable and such people as being in denial of reality, doctors should give them time to feel that they have done all that they need to do before letting go of their loved ones.  

Angiotensin receptor blockers: the story continues................

Angiotensin receptors are protein molecules that mediate the effect of the hormone angiotensin 2. These receptors are found in various parts of the body. The existence of angiotensin in the body was recognised by the work of people like Tigerstedt, Bergman and Goldblatt who, in different experiments in the late nineteenth and early twentieth centuries, showed the presence of a vasoconstrictor substance released by the kidneys¹. This substance was named renin and it was soon determined that renin led to the formation of angiotensin 1 and that angiotensin 1 had to be changed to angiotensin 2 in order to be effective. The conversion of angiotensin 1 to angiotensin 2 is facilitated by the enzyme called angiotensin – converting enzyme. Angiotensin 2 exerts its effects on blood vessels and other tissues through receptors called angiotensin receptors. These receptors are also of two types: angiotensin receptor 1 (AT1) and angiotensin receptor 2(AT2). The vasoconstrictor effect of angiotensin 2 is mediated through the AT1 receptor and the angiotensin receptor blockers used clinically are all AT1 receptor blockers.

Angiotensin receptor blockers (ARB) and angiotensin converting enzyme inhibitors (ACEI) are both used in medicine for patients with hypertension, cardiac failure, ischemic heart disease and proteinuric-renal disease. Angiotensin receptor blockers score over angiotensin converting enzyme inhibitors in a few ways: they provide a more comprehensive blockade of the renin angiotensin system and they do not affect the serum levels of bradykinin. Hence the effect of angiotensin receptor blockers is more consistent with dose, and bradykinin-related side effects – like cough and angioedema – are not seen².

Angiotensin Receptor Blockers have been shown to protect against myocardial infarctions and strokes in patients who are at high risk for these vascular events. A study reported in 2008 showed the benefit of these drugs in preventing cardiovascular events in patients undergoing long-term hemodialysis ³. A meta-analysis had also shown that ARB can prevent the development of atrial fibrillation in patients with heart failure⁴ and another meta-analysis had shown that these drugs could prevent new onset diabetes in patients who are predisposed to developing diabetes⁵. Hence angiotensin receptor blockers not only reduce blood pressure but also favourably influence cardiovascular risk factors.

There may however be differences in clinical benefit between various angiotensin receptor blockers. A study comparing Losartan, Irbesartan, Valsartan, Candesartan and Telmisartan in patients with heart failure found that Losartan showed poorer survival rates in elderly people with heart failure compared to the other drugs⁶.

Alzheimer’s disease is a common cause of dementia. A pathological finding in this disease is amyloid deposition in the brain.  There is very new evidence, based on autopsies, that those who take angiotensin receptor blockers for hypertension have less amyloid deposition in their brains than those who are on other kinds of antihypertensive drugs⁷ and this actually confirms some earlier anecdotal reports that treatment with angiotensin receptor blockers reduces the likelihood of developing Alzheimer’s disease.  It appears that angiotensin receptor blockers are able to reduce amyloid deposition in the brain by reducing inflammation within the brain.

In conclusion, we have learnt a great deal about the clinical benefits of blocking the renin-angiotensin-aldosterone system (RAAS) in the last decade. Since the ARB class of drugs are more expensive than the ACEI class of drugs, doctors are encouraged to use angiotensin-converting enzyme inhibitors wherever RAAS inhibition is needed and to use angiotensin receptor blockers only when patients are intolerant to ACEI. However, if the recent evidence of the possible benefit of angiotensin receptor blockers in preventing dementia can be verified through other studies, then the drugs in this class will have a distinct edge over their first cousins – the ACE inhibitors.

References:

1. Discovery and development of angiotensin receptor blockers, Wikipedia: http://en.wikipedia.org/wiki/Discovery_and_development_of_angiotensin_receptor_blockers

2. Amy Barreras, et al.Angiotensin 2 receptor blockers. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1200815/

3. Effect of angiotensin receptor blockers in patients undergoing hemodialysis http://www.ajkd.org/article/S0272-6386(08)00955-4/abstract

4. Prevention of atrial fibrillation with angiotensin converting enzyme inhibitors and angiotensin receptor blockers http://content.onlinejacc.org/article.aspx?articleid=1136655

5. Angiotensin converting enzyme inhibitors or angiotensin receptor blockers for prevention of Type 2 diabetes http://content.onlinejacc.org/article.aspx?articleid=1136856

6. Angiotensin 2 receptors for the treatment of heart failure http://www.ncbi.nlm.nih.gov/pubmed/17381379

7. Ihab Hajjar, et al. Impact of Angiotensin Receptor Blockers on Alzheimer Disease Neuropathology in a Large Brain Autopsy Series. Arch Neurol 2012; Published online Sept 2012. http://archneur.jamanetwork.com/article.aspx?articleid=1356776#METHODS

Flushing out excess glucose from the blood

There are many kinds of oral drugs used for reducing high blood sugar in diabetes. Drugs like metformin, the sulphonylureas, the glinides, the dipeptidyl peptidase 4 inhibitors and the thiazolidinediones promote entry of glucose into body cells by different mechanisms - by reducing insulin resistance (metformin, thiazolidinediones), by increasing secretion of endogenous insulin (sulphonylureas, glinides) and by increasing levels of glucagon-like peptide 1(DPP4 inhibitors). Now we have a new class of oral drugs that reduces blood sugar by flushing out the excess glucose in the urine. By reducing reabsorption of glucose from the proximal tubules of the kidney, these drugs (called the sodium glucose co-transporter 2 inhibitors) lower blood sugar by allowing more glucose to be excreted in the urine. In effect, it reduces the renal threshold for glucose excretion. An advantage of this method is that by flushing out the excess glucose, instead of storing it inside cells, patients will lose weight. The disadvantage is that osmotic diuresis (by the glucose in the urine) can cause intravascular volume depletion and postural hypotension. Excess glucose in the perineal region can also predispose to candida infection in women. Whether this class of drugs will improve the morbidity and mortality associated with diabetes and whether it will be safe for all diabetics will be seen in the next few years.

Ref.: Canagliflozin, a new drug for diabetes

Good in one situation but not in another

In September 2009, the New England Journal of Medicine informed its readers that the RE-LY study showed evidence of the thrombin inhibitor Dabigatran being as effective as, if not better than, Warfarin for the prevention of thromboembolic events in patients with atrial fibrillation. Those patients with atrial fibrillation who took Dabigatran in a dose of 110 mg twice daily had the same rates of stroke as those who took Warfarin but had significantly lower rates of major hemorrhage. Those patients who took Dabigatran in a higher dose of 150 mg twice daily had the same rates of major hemorrhage as Warfarin but with lower rates of stroke. So, either way, we see a benefit of Dabigatran over Warfarin.

Can we conclude that Dabigatran is at least as good as Warfarin in preventing undesired thrombosis and thromboembolic phenomena in the body?

The RE-ALIGN study published in the New England Journal of Medicine in September 2013 tells us that we cannot make that generalisation. It appears that a drug that is good in one situation is not necessarily good in all situations. In this RE-ALIGN study, the investigators report that Dabigatran was not as effective as Warfarin in preventing thromboembolic complications in patients who had mechanical heart valves. Furthermore, it was associated with an increased risk of bleeding. The message they send us is: use Warfarin, not Dabigatran, for preventing thromboembolism in patients with mechanical heart valves.

What is the reason for this paradox? The authors of the RE-ALIGN study tell us that this could be because the mechanisms involved in the clotting of blood are different in atrial fibrillation and in mechanical heart valves. Stasis of blood in the atria is the cause of thrombosis in atrial fibrillation while contact of blood with the mechanical valve and the release of tissue factor after surgery are the mechanisms of thrombosis in those with mechanical heart valves. These differences make Dabigatran good in one situation but not in the other. This reminds me of something else which is good in one situation but not not in another: the combination of aspirin and clopidogrel is good in acute coronary syndromes but not in chronic stable angina.

Chronic stable angina and the ST segment deviation vector in ECG

Coronary artery disease, as all physicians know, presents in different ways in different people. We have anecdotes of people who die suddenly without ever being aware that their coronary arteries were blocked. On the other end of this coronary artery disease spectrum we have the condition called chronic stable angina where patients experience chest pain only on exertion. And in between these two extremes lie the various categories of acute coronary syndrome. Intuitively we might believe that the milder manifestation of chronic stable angina represents the benign end of the spectrum where the coronary arteries are only minimally involved. This is not always true because we have learnt that even in patients with chronic stable angina there can be extensive coronary involvement.

What matters in coronary artery disease are the answers to three questions: Which artery is blocked? Is that artery blocked proximally or distally? What is the degree to which it is blocked? And of the two coronary arteries and their branches, high grade blocks in the left main coronary artery and in the proximal portion of the left anterior descending artery are the most dangerous. So when faced with patients who have chronic stable angina, one of the important things I want to know is whether they have involvement of the left main coronary artery or the proximal portion of the left anterior descending artery. Determining the ST segment deviation vector from the ECG is an attempt to answer this question without a coronary angiogram.

The ST segment deviation vector is determined in much the same way as the cardiac axis is determined from the QRS complexes. We use the limb leads and look at the ST segments in them. Wherever ST segments are depressed, the vector is moving away from those leads and wherever ST segments are elevated, the vector is moving towards those leads. And the vector is perpendicular to any lead whose ST segment is neither elevated nor depressed. With these basic electrophysiological principles, we can proceed to determine the ST segment deviation vector, if any, in patients with chest pain. A general rule is that when the ST segment deviation vector is in the quadrant between minus 90 degrees and minus 180 degrees (the "aVR quadrant"), there is a high probability of significant stenosis in either the left main or the proximal left anterior descending coronary arteries.

I use this information as a guide in deciding which patients with chronic stable angina should be referred for a coronary angiogram after an exercise stress test.

For an understanding of how ST segment deviations will look like in patient with significant blocks in the left main coronary and proximal left anterior descending coronary arteries, please see:
Proximal left anterior descending artery block
Left main coronary artery block

A patient with blepharospasm

The patient, a man in his early sixties, had been diagnosed as suffering from diabetes, hypertension and chronic renal failure. The notes in the patient's case record had however failed to record something that was very obvious. He had bilateral blepharospasm and used his hand to keep his eyes open when talking to me. He told me that he had seen a couple of doctors in various parts of the country for this disorder but nothing had helped. I listened sympathetically and, after the usual review of his various medical problems, prescribed him treatment for diabetes, hypertension and renal failure.

Later, I read an article on benign essential blepharospasm.

I realised that this condition, which was initially considered a psychiatric disorder, is now regarded as a form of focal dystonia affecting the orbicularis oculi and other muscles around the eyeball. No one knows where exactly the lesion is but it is generally regarded as a disorder of neural circuits that regulate blinking. The sensory component of this circuit is triggered by a variety of stimuli ranging from light, sensory stimuli from the trigeminal nerve, and strong emotions. The motor component is mediated by the facial nerve. Blepharospasm disappears when the patient is asleep and when deeply relaxed. Hence, there have been treatments designed to promote such relaxation using pharmacological and non-pharmacological methods. The results have been variable and no one method has been shown to be consistently better. Currently, the most effective treatment for benign essential blepharospasm is injection of Botox into the muscles around the eye. Botox is Botulinum A toxin. It inhibits the release of acetylcholine from presynaptic nerve terminals. The effect Botox injections can last from one to five months.

Ref: Medscape article

Nitrites in the urine of people without any urinary symptoms

Recently I tested the urine of  a male patient who had fever for 4 days with no localising symptoms and signs. The urine showed a trace of protein, some leukocytes and red blood cells (less than 10 cells per high power field). The urine nitrite test was positive. I wondered if this patient really had urinary infection because, if not for the positive urinary nitrite, I might have considered the urine protein and cellular abnormalities as being the result of the fever and not the cause of the fever. This led me to read an article in the American Family Physician which gave me some information as to why the urinary nitrite test may be falsely positive. I have quoted the relevant extract below:

Nitrites normally are not found in urine but result when bacteria reduce urinary nitrates to nitrites. Many gram-negative and some gram-positive organisms are capable of this conversion, and a positive dipstick nitrite test indicates that these organisms are present in significant numbers (i.e., more than 10,000 per mL). This test is specific but not highly sensitive. Thus, a positive result is helpful, but a negative result does not rule out UTI.⁶ The nitrite dipstick reagent is sensitive to air exposure, so containers should be closed immediately after removing a strip. After one week of exposure, one third of strips give false-positive results, and after two weeks, three fourths give false-positive results.³⁶