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.
Oct 29, 2013
Oct 12, 2013
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
Oct 4, 2013
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
Ref.: Canagliflozin, a new drug for diabetes
Oct 1, 2013
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.
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.
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