Women at higher risk of death due to heart attack

Posted by: Ramesh Venkatraman

Results of a new study reveal that women (particularly younger women) are more likely than men to present without chest pain following a heart attack. Hospitalized women also show higher mortality (death) rates than men within the same age group. Excerpts (Table) from a new observational study from the National Registry of Myocardial Infarction, 1994-2006, of 1,143,513 registry patients (481,581 women and 661,932 men):

 Ref: Canto JG, et al. JAMA. 2012;307(8):813-822.

MI = Myocardial Infarction (Heart Attack)

The dark side of Paracetamol/Acetaminophen: Liver Toxicity and Death

Posted by: Ramesh Venkatraman

Paracetamol known as Acetaminophen in the US, is arguably the commonest drug used for treating pain and fever. It is today an over-the-counter (OTC) medication across the world. Sold under popular brand names such as Crocin, Calpol, Dolopar, and Tylenol, paracetamol is probably the first drug that the common man pops the moment he/she experiences a headache or feels even slightly warm.

Now stop for just a moment and consider the facts below:

1. In England and Wales, alone it is estimated that  150 to 200 deaths and 15 to 20 liver transplants occur each year due to paracetamol overdose [http://en.wikipedia.org/wiki/Paracetamol_toxicity]
2. In the US paracetamol/acetaminophen toxicity is the one of the leading causes of serious liver damage accounting for more than 56,000 emergency visits, 2,600 hospitalizations, and an estimated 450 deaths annually [Highleyman L, Franciscus A. HCSP Fact Sheet, ver 2.2;2009.].

These statistics fly in the face of the commonly held belief that paracetamol/acetaminophen is completely safe and can be used by anyone to get quick relief from pain/fever.

Is it unsafe at any dose?
The quick answer is NO. However it is quite easy for the uninformed to risk popping in more than the recommended daily dose of paracetamol. This is because the "window" between a therapeutic dose and a toxic/lethal dose in the case of paracetamol is very narrow. Paracetamol tablets in India are available as 500mg and sometimes even as 650mg tablets. The maximum recommended dose of paracetamol is 4 grams a day, which means that a person taking 3 or 4 tablets during a day could easily be consuming 50 to 60% of a potentially lethal dose of paracetamol!

A bigger danger comes from a little snippet of information featured in the US FDA fact-sheet on acetaminophen which points out that some people may be more susceptible to acetaminophen/paracetamol toxicity than others - these people may suffer from liver toxicity with paracetamol doses of as low as 2.5 grams/day - approximately 4 tablets! Studies have shown that about 20% of people with acetaminophen-related liver toxicity had actually consumed less than even the recommended daily dose of acetaminophen.

Alcohol and paracetamol make a lethal cocktail - Paracetamol/acetaminophen is more likely to cause liver toxicity at normal and near-normal doses in people who consume alcohol regularly. The current packing of Tylenol (the US brand of acetaminophen) contains a warning which states that people who consume 3 or more alcoholic drinks everyday must consult their doctor before taking acetaminophen/paracetamol. In fact Tylenol has been carrying a more generic version of this warning since the mid-1990s. Interestingly Crocin the most popular brand of paracetamol/acetaminophen in India does not contain this warning with regard to alcohol consumption and paracetamol use.

How acetaminophen/paracetamol harms the liver:
When you swallow a pill of acetaminophen/paracetamol it is absorbed into your blood stream and then reaches the liver where it is metabolized. If a large dose of the drug enters the liver system then the normal pathway can become overwhelmed and the liver pushes the drug into a new/different metabolic pathway called the Cytochrome P450 enzyme system. When this meatabolic pathway kicks in, a toxic metabolic byproduct is produced called NAPQI (N-acetyl-p-benzoquinone imine) which has the potential to kill the liver cells. Alcohol and many other drugs also use this same Cytochrome P450 processing system and the risk of a "bottleneck traffic" jam is significantly greater if the liver is asked to process acetaminophen along with other substances such as alcohol at the same time.

Acetaminophen/Paracetamol poisoning usually happens in 3 stages:

1. Stage-1 (12-24 hours) - the person usually complains of nausea/vomiting
2. Stage-2 (24-48 hours) - the person may feel better
3. Stage-3 (48-72 hours) - Blood tests however may reveal elevated levels of liver enzymes (ALT and AST) a clear marker of liver injury. In severe poisoning, the patient may slip into coma and only a liver transplant can prevent death.

The key is to go to a doctor as soon as you feel nauseous and any gastrointestinal discomfort following a dose of paracetamol/acetaminophen. Antidotes such as glutathione and/or N-acetylcysteine (NAC) work best when taken within 16 hours of poisoning - However most people do not recognize the signs and symptoms of paracetamol/acetaminophen poisoning early enough to initiate treatment. 

Does this mean that we shun paracetamol altogether? No. However, caution and understanding the risks involved is extremely important - More so because paracetamol/acetaminophen is not only available as plain paracetamol/acetaminophen tablets/syrups but also comes as a combination with over 200 other medications - small doses of acetaminophen/paracetamol in combination remedies can add up and cause serious trouble.