Adverse reactions

Any drug capable of doing good is also capable of doing harm, and unwanted reactions may be unexpected. Some of these adverse reactions are dose-related, but others are idiosyncratic. Problems may relate to the drug’s main pharmacological action in the body, or to some secondary action (‘side effect’). The recognition of adverse reactions is of vital importance, but their proper documentation and reporting is frequently neglected. The Commission on Human Medicines operates a simple ‘Yellow Card’ reporting system in the United Kingdom for the Medicines and Healthcare Regulatory Agency (MHRA) that is designed to make it easier for staff to initiate such notifications. Copies of the prepaid lettercard can be found in the back of the British National Formulary. The MHRA website (www.mhra.gov.uk) offers advice on what to report and how to complete a ‘Yellow Card’. Reporting of adverse reactions can be made via the related website (www.yellowcard.mhra.gov.uk) or by telephone (0808 100 3352).

All prescribers have a professional duty to report all serious suspected reactions even if they are already well recognised, especially if they are fatal, life-threatening, disabling or incapacitating. This is necessary so that reports can be prepared comparing the risk/benefit ratio seen with other drugs of a similar class. Prescribers should also report any adverse or unexpected event, however minor, where this could conceivably be a response to a drug that has only been on the market for a relatively short time. Pharmacists also have a responsibility to report all important adverse reactions coming to their attention. Nurses and midwives are often the first to suspect an adverse reaction: they have a duty to see that any such reaction is brought to the attention of the appropriate doctor or pharmacist, and to initiate a report themselves if necessary. Deaths have, by law, to be reported to the coroner (Procurator Fiscal in Scotland).

The Commission on Human Medicines are interested in hearing about adverse reactions caused by any therapeutic agent (including any drug, blood product, vaccine, dental or surgical material, X-ray contrast medium, intra-uterine device, etc.). Reactions observed as a result of self medication should be reported in the same way as those seen with prescribed drugs. Drug interactions of a serious nature should also be reported. Drugs can sometimes have a delayed effect, causing problems such as later anaemia, jaundice, retroperitoneal fibrosis or even cancer. Any suspicion of such an association should always be reported. Whenever a baby is miscarried, is aborted or is born with a congenital abnormality, healthcare professionals should always consider whether this might have been an adverse drug reaction and report all the drugs (including any self-medication) taken during the pregnancy.

Adverse reactions are particularly common when drugs are given at the extremes of life. This is, in part, because the liver and the kidneys handle drugs less efficiently, both in the first weeks of life, and in old age. Nevertheless, although the MHRA receives many reports relating to drug medication in the elderly, relatively few reports are received in relation to adverse events in the neonatal period. This is not because such events are uncommon, as many of the individual drug monographs in this compendium bear testimony, but because a proper tradition of reporting never seems to have become established. Yet, without such reporting, the identification of many important side effects is avoidably delayed. Because, in particular, some of the most important side effects seen in the neonatal period differ from those normally seen later in life, failure to report can also delay the recognition, and quantification, of a very real drug hazard.

Defective medicines constitute a related but different problem. Problems can occur either during manufacture, or during distribution, rendering the product either dangerous or ineffective. Whenever such a problem is suspected it should be reported at once to the hospital pharmacy who will, in turn, notify the MHRA’s Defective Medicines Report Centre in London if the suspicions are confirmed. Contact may be made by telephone (020 3080 6574 or out of office hours 07795 641532) or using the on-line form on the MHRA website (www.mhra.gov.uk under the header ‘Safety Information’).

Overtreatment

Identifying the right dose of medicine to give a newborn baby is never easy, and the problem is made even more difficult if kidney or liver immaturity is compounded by illness or organ failure. Progressive drug accumulation is a very real possibility in these situations. A major error can easily arise during the drawing up of the small dose needed in a small preterm baby, particularly if prior dilution is involved. Few of these events ever get widely reported. Indeed, where the baby is already ill, the cause of death may go unrecognised. Tenfold administration errors are not unheard of.

Luckily even after serious overtreatment, most babies recover with supportive or symptomatic care (although this is not always true where drugs such as atropine, chloramphenicol, digoxin, lidocaine and potassium chloride are concerned). If the drug has been given by mouth, it may be worth giving a stomach washout. A 1 g/kg oral dose of activated charcoal (repeatable every 4 hours until charcoal appears in the stool) may also be of some help, especially if it is started within 4 hours. Do not try to make the baby sick. Other forms of forced elimination such as exchange transfusion, haemoperfusion, dialysis and forced diuresis are only of limited value for a small number of drugs taken in severe excess. Whole bowel irrigation with a polyethylene glycol-electrolyte solution (such as Klean-Prep®) may occasionally be appropriate. Always seek the immediate help and advice of the nearest Poisons Centre (see below) if there are severe symptoms. For a limited number of drugs, specific antidotes, antagonists or chelating agents are available; these are mentioned briefly, where appropriate, under the name of the drug for which they are of use, in the various monographs in the main section of this compendium. Specific antagonists include naloxone for opioid drugs, DigiFab® for digoxin, and flumazenil for benzodiazepines. Acetylcysteine is of value after paracetamol over-dosage, methylthioninium chloride (methylene blue) is used to control methaemoglobinaemia and the chelating agent desferrioxamine mesylate is used in iron poisoning. Following are the main components of supportive care.

Respiration: Airway obstruction is a real hazard in patients who become unconscious. Vomiting is not uncommon and inhalation a real risk. Most poisons that impair consciousness also depress breathing, so artificial respiratory support may well be required. While specific opioid and benzodiazepine antagonists can be helpful, respiratory stimulants should not be used. Correct any serious metabolic acidosis (pH < 7.2) with sodium bicarbonate or trometamol.

Fluid and glucose intake: Reduce fluid intake to a minimum and monitor urine output while retaining normoglycaemia until it is clear that kidney function is unaffected. Stop all oral feeds if there is acidosis, hypotension and/or suspected ileus.

Blood pressure: Do not use vasopressor drugs without first getting expert advice. Cautious plasma volume expansion may help if there is serious hypotension.

Arrhythmia: Do not give drugs, especially if output is tolerably well maintained, before defining the nature of the arrhythmia and seeking advice as outlined in the monograph on adenosine. A beta-blocker (such as propranolol) may help to moderate the tachyarrhythmia sometimes seen with excess theophylline, chloral hydrate, quinine, amfetamine or some of the antihistamines, and may improve cardiac output. These drugs do not seem to cause an arrhythmia in children as often as they do in adults.

Convulsions: While short-lived seizures do not require treatment, prolonged seizures should be controlled, especially if they seem to be impeding respiration. A slowly infused intravenous dose of diazepam (preferably the emulsified formulation) is the anticonvulsant most often used in older patients, but phenobarbital is more usually used in the neonatal period. Either drug can, in itself, cause further respiratory depression.

Temperature control: Poisoning can cause both hypo- and hyperthermia. The rectal temperature should be measured to monitor deep body temperature, using a low reading thermometer if necessary so as not to miss hypothermia, and appropriate environmental measures taken.