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