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Pharmacokinetics

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The way in which a drug behaves in the body over time is known as its pharmacokinetic profile. This describes the way in which the drug is absorbed, distributed around the body, metabolised and excreted, once it has been administered.

While not immediately relevant to the nurse preparing to administer a medicine, these parameters frequently influence many practical aspects of how a drug may be given. For example, how well the drug is absorbed via the gastrointestinal tract will determine whether it can be formulated as an ‘oral’ medicine.

For people with insulin-dependent diabetes the fact that insulin cannot currently be formulated into an oral treatment means that, despite advances in the technology of insulin delivery such as disposable pen devices, managing the disease remains a cumbersome process for patients.

The recent launch of a formulation of inhaled insulin may go some way to relieving this burden, particularly for patients who find injections difficult, although early evidence suggests that the uptake for this development is likely to be low, particularly in light of a limited support issued by NICE (2006).

The rate at which the drug is metabolised and excreted will determine how often it needs to be administered, and if being given intravenously, whether or not it can be given by a direct injection or as an infusion.

In older patients, age-related changes in a variety of physiological functions - most notably hepatic and renal function - mean that the pharmacokinetic profile may be profoundly altered, and hence dose adjustments may be necessary to avoid toxicity from occurring.

In general terms older patients require smaller doses of all drugs compared with younger adults. It is therefore rational to start with the lowest possible dose and titrate upwards according to response (Royal College of Physicians, 1997).

A small number of drugs have narrow margins between optimal and sub-optimal dosing, the so-called narrow therapeutic index (for example, phenytoin and gentamicin). This means that detailed pharmacokinetic profiling is essential to their safe and effective use.

Another example is digoxin, which is used to treat atrial fibrillation. While its clinical effect is principally measured by monitoring the heart rate, analysis of its pharmacokinetics via therapeutic drug monitoring is often valuable in optimising its effect.

This is particularly important when factors are present which may influence the pharmacokinetic profile. Digoxin levels are affected by hepatic and renal function, and the presence of heart failure due to reduced elimination of the drug. Hypothyroidism increases the plasma concentration and increases cardiac sensitivity to the effects of the drug. Hypokalaemia, hypercalcaemia, and hypomagnesaemia all have a similar effect.

While the majority of modern drugs are administered orally, this route is arguably the least reliable in terms of delivering the drug to the intended site of action in an appropriate concentration. A number of factors may act singly or in combination to significantly reduce the amount of drug absorbed via the gastrointestinal tract into the systemic circulation. These include:

  • The effect of gastric motility
    • If the rate of gastric emptying is increased, drug absorption will be reduced
    • The small intestine is the major site of absorption for drugs administered orally and transit times through the small intestine ia a significant determining factor of drug absorption;
  • The existence of a malabsorption syndrome - for example Crohn’s or coeliac disease may decrease or in some instances increase drug absorption
  • The effect of gastric pH - some drugs are particularly sensitive to the acidic environment of the stomach and may be degraded before significant absorption can occur;
  • Food - many drugs undergo physicochemical reaction in the presence of food, which reduces their absorption.

Formulation of medicines

In many instances the formulation of a drug into a medicine offers a means of overcoming shortcomings in its pharmacokinetic. In the majority of such cases formulation is used to increase the amount of drug likely to reach the intended site of action.

For example, many drugs used in the treatment of asthma are suitable for administration by mouth, but would require very large doses to reach therapeutically active concentrations in the lung. This would increase the risk of side-effects and may make treatment difficult for patients to tolerate.

Formulated as aerosols the drugs can be administered directly into the lung thereby achieving high concentrations at the desired site of action, and reducing the risk of side-effects by avoiding the drugs’ entry into the systemic circulation.

In recent years, pharmaceutical manufacturers have increasingly used the transdermal route as a means of delivering drugs into the systemic circulation. Many patients now receive daily doses of analgesics, anti-anginals, hormone replacement therapy, and nicotine replacement therapy through a stick-on patch that delivers a constant amount of drug over a 12-hour, 24-hour or longer period.

Formulation may also be used to extend a drug’s duration of action by modifying the rate at which it is absorbed into the systemic circulation. Such modifications are usually used to reduce the number of doses required each day. For example, the development of modified-release formulations of morphine have made it possible to reduce the routine dose interval from every four hours or six times a day to once or twice a day. Such developments can have a significant influence on patients’ attitudes toward their drug therapy.

However, practitioners should be cautious about assuming all such modifications to a drugs’ formulation will be beneficial. The development of modified-release formulations is a strategy frequently used by the pharmaceutical industry to lengthen the life of products before the patent expires and the manufacturer loses its monopoly on the drug’s manufacture.

Many such developments lack sound evidence to support their use, and frequently attract criticism on the basis that they are often more expensive than equivalent non-modified-release formulations (Medicines Resource Centre, 1995).

Other examples of the use of formulation to alter pharmacokinetic profiling includes the use of enteric coating to avoid degradation by gastric acid and the use of ‘pro-drugs’, which use the body’s metabolic processes to convert agents into an active compound. The treatment of inflammatory bowel disease with aminosalicylates (sulfasalazine) illustrates the application of such formulation in clinical practice.

Mesalazine is used extensively in the management of ulcerative colitis. It is however unstable in an acid environment. Some preparations have been formulated with a pH-sensitive protective coating that protects the drug until it reaches a part of the bowel at the desired pH. A coat that dissolves at pH 7 releases mesalazine in the terminal ileum and colon, while one that dissolves at pH 6 and above releases in the jejunum and ileum. Other formulations, such as olsalazine and balsalazide, rely on bacterial breakdown of an inactive molecule to form mesalazine in the lower bowel.

The pharmaceutical industry has begun to make use of specific optical isomers of a drug to attempt to reduce side-effects and increase efficacy. This involves the development of drugs that are made up of slightly different molecular compounds but may have very different pharmacological properties.

Examples included esomeprazole (isomer of the proton pump inhibitor omprazole), desloratadine (isomer of the anti-histamine loratadine) and levobupivacaine (isomer of the local anaesthetic bupivacaine) (Dean, 2000).

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