Toxic side effects of drugs

Medical Matters: "Man has an inborn craving for medicine . . . the desire to take medicine is one feature which distinguishes man, the animal, from his fellow creatures." - William Osler

Every drug we take has at least one side effect. Many of these side effects are relatively minor, involving discomfort rather than danger. But some side effects can be life threatening, as separate inquests this month have shown.

Two elderly women, one from Limerick and the other from Dublin, died as a result of brain haemorrhage caused by the anti-clotting drug warfarin. Their deaths are a reminder that certain drugs have a narrow therapeutic index or "window", outside of which they become either ineffective or toxic.

Warfarin works by thinning out the blood and making it difficult to clot. It is used to treat deep vein thrombosis ( a clot in the leg) pulmonary embolus ( a clot in the lung) and in-patients with a rhythm disturbance of the heart called atrial fibrillation. People with artificial heart valves must also take anticoagulants because of the risk of a clot forming in the valve.

Unlike most other medications, the maintenance dose of which remain constant, the dose of warfarin regularly changes depending on the results of a blood test called the prothrombin time. This test, which measures the rate of clotting, is an essential part of warfarin treatment.

It must be constantly monitored so that the level of the drug in the body produces the correct amount of blood thinning. If the level rises above a certain threshold, there is a high risk of internal bleeding, including brain haemorrhage.

Should the level drop below a certain point, the therapeutic effect of the drug is lost. The level of active warfarin in the system is sensitive to changes, such as the development of an acute illness.

A deterioration in liver or kidney function or the development of heart failure will also significantly alter the activity of warfarin in the body.

Moreover warfarin interacts with a large number of other medications, including certain painkillers and antibiotics in ways that can either increase or reduce warfarin's activity in the body.

Patients taking warfarin should seek medical help if they develop bleeding in the nose or gums, discoloured urine or prolonged bleeding from cuts and bruises.

The appearance of red or black bowel motions is another warning sign.

Another drug with a narrow therapeutic window is digoxin (digitalis). One of the oldest drugs known to man and originally extracted from the foxglove, digitalis has been used to treat heart failure for over 200 years.

Treatment with digoxin must be started carefully as there is a relatively narrow gap between the amount of the drug in the blood that is therapeutic and concentrations that are toxic. Normal therapeutic levels are about one-third of those that are fatal, while serious toxic rhythm disturbances begin at two-thirds of fatal levels.

Digoxin is most frequently used in older patients in whom particular care is required. Age brings with it reduced kidney function, meaning less of the drug is excreted by the body and so higher concentrations circulate in the blood.

Older people tend to lose body mass, another reason why digoxin levels can be higher in the elderly. Nowadays, doctors aim to keep blood digoxin levels between 0.5-1.0 ng/ml.

Blood levels must be closely checked until the patient is established on a regular dose of the drug.

Signs of digitalis toxicity include nausea, vomiting and diarrhoea. The patient may experience palpitations and typical rhythm disturbances in the heart. Among the neurological effects are the appearance of green or yellow haloes around lights, drowsiness and fatigue.

Lithium, used in the treatment of bipolar disorder (manic depression), is another example of a drug that needs careful monitoring to ensure its level in the blood is kept within a narrow range.

Lithium levels are monitored closely, with blood samples taken weekly early in treatment. For those people stabilised on the drug, levels are monitored every three months. The dose is adjusted until blood levels in the range of 0.4 to 1.0 mmol/l are achieved.

If lithium concentrations rise above 1.5 mmol/l then signs of toxicity occur. Symptoms include drowsiness, hand tremor, muscle weakness and abdominal pain.

As the levels rise further, the brain is affected giving rise to confusion and difficulty with movement. Seizures and coma lead to death in about one in 10 patients who develop chronic lithium toxicity.

While lithium, digoxin and warfarin are extreme examples of the need to treat medication with respect, they may well have been the trigger for the following advice given by William Osler : "One of the first duties of a physician is to educate the masses not to take medicine."

Dr Muiris Houston is pleased to hear from readers but regrets he cannot answer individual queries.