INTRODUCTION

Patients rely on nursing staff and pharmacists to ensure that medicines are administered appropriately. It is essential that nurses have a sound understanding of what happens to a drug following administration. Pharmacokinetics is the term used to describe how the body handles a drug over a period of time, including how the body absorbs, distributes, metabolises and excretes the drug (Fig. 8.1). These processes influence the effectiveness of the drug because, in order for a drug to be effective, it must be available at the site of action in the correct concentration. In the simplest terms, pharmacokinetics can be described as what the body does to the drug, as opposed to pharmacodynamics, which is what drugs do to the body.

Fig. 8.1 Absorption, distribution, metabolism and excretion of an oral drug.

PHARMACOKINETICS

ABSORPTION

Except for the intravenous route, a drug must be absorbed across cell membranes before it enters the systemic circulation. The oral route is the one most commonly used for drug administration. Most drugs are absorbed by diffusion through the wall of the intestine into the bloodstream, which is aided by the very large surface of the gut wall. The rate of absorption also depends on the lipid-solubility of the drug. Drugs are normally formulated to make them as lipid-soluble as possible to enable them to cross the cell membranes of the intestinal wall. However, sometimes a drug’s low lipid-solubility is used to good effect, because it reaches the colon largely unabsorbed, for example aminosalicylates for use in ulcerative colitis and the antibiotics vancomycin and neomycin. In these examples, the aim is to get the drug into the lumen of the colon for therapeutic purposes while avoiding systemic absorption. A few drugs are absorbed by active transport processes. Iron, levodopa and fluorouracil are examples of drugs actively transported across the intestinal mucosa.

The presence or absence of food in the stomach can affect the rate and amount of drug absorbed. Penicillins, erythromycin and rifampicin are examples of drugs that are better absorbed on an empty stomach and should be given half an hour before meals. Absorption of drugs from the gastrointestinal tract may be complete or incomplete. This can be influenced by the lipid-solubility of the drug and, as a result, the rate it crosses cell membranes, the rate at which the stomach empties and the presence or absence of food in the stomach.

Following absorption from the gastrointestinal tract, drugs are transported via the portal vein to the liver before reaching the general circulation. Many drugs are broken down (metabolised) as they pass through the liver, so that only a proportion of the amount absorbed reaches the general circulation to be carried to the site of action. This is called the first-pass effect. Some drugs show a very significant first-pass effect. Examples include glyceryl trinitrate, which is often given sublingually, resulting in absorption through the mucosa, and lignocaine (lidocaine), which is given by injection, in both instances bypassing the portal circulation. The manufacturers will, of course, be aware of the first-pass effect and, when drugs are affected by this, they will have tailored the dose accordingly in order to ensure a therapeutic effect.

DISTRIBUTION

When a drug enters the bloodstream, it is rapidly diluted and transported throughout the body. Movement from the blood to tissues is influenced by a number of factors that can greatly affect the resultant drug action. Plasma proteins, particularly albumin, can bind many drugs. Only the unbound fraction of the drug is free to move from the bloodstream into tissues to exert a pharmacological effect. The bound drug is pharmacologically inactive, because the drug–protein complex is unable to cross cell membranes. It provides a reserve of drug, because the complex can dissociate and quickly replenish the unbound drug as it is removed from the plasma. The degree of protein binding will thus affect the intensity and duration of a drug’s action.

In addition, if a patient suffers from a disease in which plasma proteins are deficient (e.g. liver disease, malnutrition), more of the drug is free to enter the tissues. A normal dose of a drug could then be dangerous, because so little is bound by available protein, thus increasing the availability of unbound drug.

In practice, changes in the protein-bound drug, resulting in increased levels of unbound drug, are important only for highly bound drugs with a narrow therapeutic index, such as warfarin or phenytoin. The term narrow therapeutic index is used to describe drugs for which the toxic level is only slightly above the therapeutic range, and a slight increase in unbound drug may therefore result in toxic symptoms. It is important therefore that the nurse has an awareness of these drugs and knowledge of the symptoms that the patient may show should toxic levels be reached.

Drugs diffuse out of the plasma into tissue spaces, and some enter cells and spread through the total water of the body. The total body water represents about 0.55 L/kg. Therefore the more widely a drug diffuses, the lower will be the concentration produced by a given dose. Factors that affect the rate and extent of distribution are cardiac output and regional blood flow. If the patient is nursed in a warm environment, this will help to maintain a better blood circulation and improve drug distribution, an important factor in patients receiving antibiotics. Similarly, inflamed tissues have increased vascularity and permeability, which lead to an increased rate of passage of drugs, especially antibiotics.

TRANSFER BARRIERS

The central nervous system is surrounded by a specialised membrane consisting of the blood–brain and blood–cerebrospinal fluid barriers (Fig. 8.2). This membrane is highly selective for lipid-soluble drugs; for example, the penicillins diffuse well into body tissues and fluids but penetration into the cerebrospinal fluid is poor, except when the meninges are inflamed. Chloramphenicol, because of its lipid-solubility, is one of the few antibiotics that reach the cerebrospinal fluid in appreciable concentrations. Dopamine in the treatment of Parkinson’s disease cannot be given in this form, because it does not cross the blood–brain barrier. It is administered orally as the precursor, levodopa, which is absorbed, crosses the blood–brain barrier and is broken down to dopamine by the enzyme dopa decarboxylase.

Fig. 8.2 The blood–brain barrier.

During pregnancy, the placenta provides a barrier between mother and fetus. Some drugs (e.g. chlor-promazine and morphine) cross it relatively easily, while others (e.g. suxamethonium chloride) are not transferred. Because fetal liver and kidney are unable to metabolise or excrete drugs, and the fetus is likely to be more sensitive to them, drugs must be used with caution in pregnancy and, in general, few are used.

METABOLISM AND EXCRETION

The most common route for drug excretion is through the kidneys into the urine. Drugs and their metabolites are filtered out from the plasma through the capillaries within the glomeruli of the kidneys. Drugs and metabolites can also be eliminated by the body in other ways (e.g. salivary glands, sweat glands).

Several factors, including certain characteristics of the drug, affect the kidneys’ ability to excrete drugs. To be extensively excreted in urine, a drug or metabolite must be water-soluble and must not be bound too tightly to proteins in the bloodstream. The acidity of urine, which is affected by diet, drugs and kidney disorders, can affect the rate at which the kidneys excrete some drugs. Some drugs, such as atenolol, digoxin and captopril, are water-soluble and are readily eliminated by the kidney without prior metabolism. However, many drugs require to be changed into a form that can be readily eliminated by the body, and this process is called metabolism.

Most drugs are very lipid-soluble, and this enables them to cross cell membranes or the blood–brain barrier in order to reach their site of action. If a lipid-soluble drug is filtered by the kidney, it is largely reabsorbed from the distal tubule (Fig. 8.3) and retained in the body. Metabolism increases the water-solubility of the molecule and aids its elimination. Most metabolism takes place in the liver, but it can also be carried out in other organs, including the gut wall, lungs and kidney, and in the plasma.

Fig. 8.3 Filtration of drugs through the kidney.

In the process of metabolism, drugs may be broken down or combined with a chemical. This is brought about by substances called enzymes. The nurse should be aware that the rate at which this occurs in the liver can vary. If the liver cells are damaged or the circulation to the liver is reduced, as in cardiac failure, the inactivation process may be slowed and a lower dose of drug would be indicated.

DOSE–EFFECT RELATIONSHIP

Safe and effective therapy can be achieved only with doses that produce optimal concentrations of a drug in the plasma and target tissues. Smaller doses will be ineffective, while larger doses will not increase the benefits and may have toxic effects. Between the minimal dose that gives the required therapeutic response and the dose at which toxic symptoms appear is a dose range called the therapeutic dose range. Some drugs have a narrow range, whereas others have a wide therapeutic range.

After administration of a drug, its plasma level rises; the more rapidly the drug is absorbed, the faster its plasma level rises (Fig. 8.4).

Fig. 8.4 Effects of absorption, distribution, metabolism and excretion on the plasma concentration of an administered drug.

As drug absorption decreases, and distribution, metabolism and excretion rates increase, the curve reaches its peak. It then descends, as elimination occurs more rapidly than absorption. As previously noted, the route of administration influences the time taken for the drug to reach maximal concentration. This is fastest with an intravenous injection and slower with intramuscular and subcutaneous injections and with oral doses.

As the dose of a drug is increased, its therapeutic effect increases as more receptors are occupied. Eventually, the dose is reached that produces a maximal effect when all the receptors of the target organs are occupied by drug molecules. Increasing the dose further will therefore not increase the therapeutic effect.

HALF-LIFE OF DRUGS

The rate at which drugs are eliminated from plasma is commonly expressed in terms of the drug’s half-life (t½). This is the time required for the concentration of the drug in the plasma to decrease to one-half of its initial value.

The plasma concentration of a drug at one half-life is 50% of its initial value; at two half-lives, 25%; at three half-lives, 12.5%; at four half-lives, 6.25%; and at five half-lives, just over 3%. Thus, most of a drug (almost 97%) is eliminated in five half-lives, regardless of the dose or route of administration. This rule of thumb can be applied in calculating the time required to elapse when discontinuing one drug and starting another that may interact if given in conjunction with the first. It is also useful in estimating how long it will take a toxic plasma concentration (after overdosing) to clear the body.

Half-lives of different drugs vary widely; for example, the half-life of theophylline is 3 h, that of aspirin, 6 h; of metronidazole, 9 h; of digoxin, about 36 h; and of phenobarbital, about 5 days. A short half-life may result from extensive tissue uptake, rapid metabolism or rapid excretion, and a long half-life may be the consequence of extensive plasma protein binding, slow metabolism or poor excretion. The knowledge of half-lives of drugs is essential in determining the intervals between drug doses.

Certain conditions can be treated with a single dose of medication (e.g. analgesics for a headache). Many conditions, however, require continuous drug action (e.g. diabetes mellitus, infections, arthritis). This can be achieved through the administration of repeated doses at regular intervals. In such therapy, the second, third and subsequent doses will add to whatever remains of the previous dose, causing gradual accumulation until stable concentrations are maintained (Fig. 8.5).

Fig. 8.5 Concentration of drug after repeated dosage.

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