A patient is given an intravenous drug what is the bioavailability of the drug in this patient

A graphic showing the bioavailability as the concentration over time (in hours) for medicines given orally.

Figure 2: The concentration of medicine (in % of dose administered)  in the blood for a tablet taken orally, and observed over the period of 15 hours. The area under the curve (AUC) is shaded. Tmax is the time when the highest concentration of the medicine is found in the blood, Cmax the maximum concentration.

The lower bioavailability of the oral route compared to injection is explained in the following example from Figure 3. After a tablet or capsule is swallowed, it reaches the stomach within a minute or two. In the stomach, it is then dissolved and some of the active substance is absorbed into the bloodstream.

An image which compares the absorption of medicine from an intravenous injection with that of a medicine from a capsule taken orally.

Figure 3: Schematic illustration of absorption from a capsule taken orally (by mouth) versus injection directly into the bloodstream (IV). After reaching the stomach, the capsule is further transported to the small intestine, where further absorption occurs.

After some time in the stomach, the components are transported to the small intestine. Here they will be fully absorbed. Absorption from the gastrointestinal tract can vary greatly. A poor absorption or a lack of absorption from the stomach and the intestines can lower the bioavailability. When the API is absorbed, it first reaches the hepatic portal vein, and is then transported to the liver. This is the first time the active substance is metabolised in the liver, which is called the ‘first pass metabolism’. Some APIs are metabolised more than others during this first pass metabolism. The non-metabolised part of the active substance, normally less than 100%, will reach systematic circulation via the hepatic vein. The amount that actually reaches systemic circulation is referred to as the ‘absolute bioavailability’.

The administration of a medicine is a common but important clinical procedure.

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The administration of a medicine is a common but important clinical procedure. It is the manner in which a medicine is administered that will determine to some extent whether or not the patient gains any clinical benefit, and whether they suffer any adverse effect from their medicines.

For example, intravenous (IV) furosemide administered too quickly can cause deafness; oral penicillin V given with food will not be well absorbed; over-application of topical steroids will cause thinning of the skin and may lead to systemic side-effects.

Two main factors determine whether or not a drug will reach its intended site of action in the body:

• The bioavailability of the drug;
• How the drug is given (route of administration).

Bioavailability is the proportion of an administered drug that reaches the systemic circulation and is therefore available for distribution to the intended site of action.

Drugs that are given by direct IV injection are said to have 100% bioavailability. Some drugs that are particularly well absorbed by the gastrointestinal mucosa may have bioavailability comparable to that of an IV dose – for example the antibiotic ciprofloxacin. Most drugs do not have this availability by the oral route so the dose given orally is usually higher than that given parenterally. For example, the beta-blocker propranolol when given orally is administered in doses of 40mg and above. The equivalent IV dose is 1mg.The route of administration and its formulation (tablet, capsule, liquid) can clearly influence the bioavailability of a drug.

Routes of administration

There are various routes of administration available, each of which has associated advantages and disadvantages. All the routes of drug administration need to be understood in terms of their implications for the effectiveness of the drug therapy and the patient’s experience of drug treatment.

Routes of administration:

• Oral
• Sublingual
• Rectal
• Topical
• Parenteral – Intravenous, intramuscular, subcutaneous

Oral administration

This is the most frequently used route of drug administration and is the most convenient and economic. Solid dose forms such as tablets and capsules have a high degree of drug stability and provide accurate dosage. The oral route is nevertheless problematic because of the unpredictable nature of gastro-intestinal drug absorption. For example the presence of food in the gastrointestinal tract may alter the gut pH, gastric motility and emptying time, as well as the rate and extent of drug absorption.

The extent to which patients can tolerate solid dose forms also varies, particularly in very young and older patients. In such cases the use of liquids or soluble formulations may be helpful. Many drugs, however, are not stable in solution for liquid formulation and in such cases careful consideration should be given to the option of switching to alternative drug treatment.

Difficulties frequently arise with patients who are prescribed modified-release preparations as these must not be crushed or broken at the point of administration. Modified-release formulations can delay, prolong or target drug delivery. The aim is to maintain plasma drug concentrations for extended periods above the minimum effective concentration.

For patients, their main advantage is that doses usually only need to be taken once or twice daily. Damage to the release controlling mechanism, for example by chewing or crushing, can result in the full dose of drug being released at once rather than over a number of hours. This may then be absorbed leading to toxicity or may not be absorbed at all leading to sub optimal treatment.

Nurses should seek advice from a pharmacist or the prescribing doctor if they are uncertain about a formulation of solid dose forms and whether or not they are suitable for crushing.

The sublingual mucosa offers a rich supply of blood vessels through which drugs can be absorbed. This is not a common route of administration but it offers rapid absorption into the systemic circulation. The most common example of sublingual administration is glyceryl trinitrate in the treatment of acute angina.

The pharmaceutical industry has formulated and marketed ‘wafer’-based versions of tablets that dissolve rapidly under the tongue. These are aimed at particular markets where taking tablets may be problematic, such as the treatment of migraine (rizatriptan) where symptoms of nausea may deter patients from taking oral treatments. The formulation is also used to treat conditions where compliance with prescribed drug regimens may be problematic, for example, olanzapine used to treat schizophrenia can be administered by the sublingual route.

Rectal administration

The rectal route has considerable disadvantages in terms of patient acceptability (in the UK at least) and unpredictable drug absorption but it does offer a number of benefits. It offers a valuable means of localised drug delivery into the large bowel, for example the use of rectal steroids in the form of enemas or suppositories in the treatment of inflammatory bowel disease. Antiemetics can be administered rectally for nausea and vomiting and paracetamol can be give to treat patients with a pyrexia who are unable to swallow.

Topical administration

The topical application of medicines has obvious advantages in the management of localised disease. The drug can be made available almost directly at the intended site of action, and because the systemic circulation is not reached in great concentration, the risk of systemic side-effects is reduced. For example:

• The use of eye drops containing beta blockers in the treatment of glaucoma;
• The application of topical steroids in the management of dermatitis;
• The use of inhaled bronchodilators in the treatment of asthma;
• The insertion of pessaries containing clotrimazole in the treatment of vaginal candidiasis.

Topical administration has also become a popular way of introducing drugs into the systemic circulation through the skin. The development of transdermal patches that contain drugs began with the introduction of a hyoscine-based product for the treatment of nausea in the early 1980s.

The market for such products has since grown to include a wide range of disease management areas including the prophylaxis of angina (glyceryl trinitrate), the treatment of chronic pain (fentanyl) and hormone replacement (oestrogens). While the use of transdermal drug administration is not without its problems - for example, some preparations can cause local skin reactions - many patients find it a welcome alternative to taking tablets.

Parenteral administration

Parenteral drug administration can be taken literally to mean any non-oral means of drug administration, but it is generally interpreted as relating to injection directly into the body, by-passing the skin and mucous membranes. The common routes of parenteral administration are intramuscular (IM), subcutaneous and IV.

Advantages of parenteral administration:

• Drugs that are poorly absorbed, inactive or ineffective if given orally can be given by this route
• The intravenous route provides immediate onset of action
• The intramuscular and subcutaneous routes can be used to achieve slow or delayed onset of action
• Patient compliance problems are largely avoided .

Disadvantages of parenteral administration:

• Requires trained staff to administer
• Can be costly
• Can be painful
• Aseptic technique is required
• May require supporting equipment for example, programmable infusion devices

NB: The correct administration of parenteral doses requires the use of appropriate injection technique. If performed incorrectly, for example using the wrong sized needle it can cause damage to nerves, muscle and vasculature and may adversely affect drug absorption.

In general the injection of drugs into the muscle or the adipose tissue beneath the skin allows a deposit or ‘depot’ of drug to become established that will be released gradually into the systemic circulation over a period of time. By altering the formulation of the drug, the period over which it is released can be influenced. For example, the formulation of antipsychotic agents such as flupentixol in oil allows them to be administered once a month or every three months.

Intravenous injection

In many respects the administration of medicines via the IV route is an admission that the use of other routes will not allow for an intended therapeutic outcome or goal of the treatment to be met. Not only is the IV route inconvenient for the patient and practitioner, but it carries the greatest risk of any route of drug administration. By administering directly into the systemic circulation either by direct injection or infusion, the drug is instantaneously distributed to its sites of action.

Such administration is frequently complex and confusing. It may require dose calculations, dilutions, information to be gathered on administration rates and compatibilities with other IV solutions, and the use of programmable infusion devices.

Moreover the preparation of IV medicines requires the use of an aseptic technique, often in a ward environment that is unsuited for such work. It is imperative that to minimise the risk of errors occurring in the administration of IV medicines that practitioners can demonstrate their competence to practice safely in this area, and have access to appropriate sources of expert information and advice.

Considerations when preparing an intravenous injection or infusion:

• Is the drug suitable for preparation at ward level or should it be prepared in pharmacy?
• Does the drug require initial dilution?
• If so what diluent is required and in what volume?
• Does the drug require further dilution?
• If so to what volume and with what diluent?
• Is the drug suitable for direct injection or must it be infused over time?
• What length of time can it be administered over?
• Is an infusion device required?
• Is the drug compatible with other drugs or fluids to be administered at the same time?
• Does the drug cause any local reaction when given?
• Is any monitoring required during or after administration?

Administration of drugs via enteral feeding tubes

Drugs should only be administered via fine-bore enteral feeding tubes as a last resort and other routes of administration should be considered first. Most drugs are not licensed for administration via enteral feeding tubes.

Interaction can occur between drugs and the enteral feed. Clinically significant interactions include, phenytoin, digoxin, ciprofloxacin and rifampicin. A pharmacist should therefore be involved in any decision to administer drugs via this route.

The British Association for Parenteral and Enteral Nutrition has produced a step-by-step guide for administration of drugs via enteral feeding tubes as well as information leaflets for GPs and patients.

Patient self-administration

For many years the standard method of medicines administration in the healthcare settings such as hospitals and nursing homes has been based on nurses interpreting a prescription and giving the relevant medicine in the required dose via the required route. The patient’s role in the process has been passive.

Self-administration as an alternative means of administering medicines is based on the patient being encouraged to play a central and active part in their drug treatment, just as they would be expected to do if at home.

The safety and success of a self-administration scheme is based on an ongoing nursing assessment that measures individual patients’ ability to interpret and participate in their prescribed treatment regimen.

This assessment must initially evaluate whether or not patients administer any prescribed treatment at home, whether or not they are able to read medicine labels, can understand dose instructions and open medicine containers or packaging (Box 1). The assessment must also reflect events that take place during the hospital stay.

For example a patient judged to be capable of self-administration before surgery is unlikely to be able to do so in the immediate postoperative period. Such changes in patient capability must be reflected in the patient’s care plan, and any indications that the ability to self-administer is compromised should trigger a return to nurse-administered treatment.

The system requires that safe and secure arrangements are in place for patients’ medicines and that local policies and procedures are in place to guide practice (NMC, 2006).

A number of factors have stimulated hospital practitioners to look at the benefits of self-administration for patients and carers. There is now widespread acknowledgement that traditional methods of medicines administration in hospitals do little to encourage patient compliance and often leave patients being discharged with a bewildering bag of medicines that they may never have seen before and may not be sure how to take.

Encouraging those patients who are able to administer their own medicines, as they would do at home, raises the possibility of identifying their education needs and improving concordance. For those assessed as unable to self-administer, consideration needs to be given prior to discharge to the problems this may present.

Criteria for patient assessment for self-administration:

• Is the patient receiving medicines and willing to participate?
• Does the patient appear confused or forgetful?
• Does the patient have a history of drug / alcohol abuse / self harm?
• Does the patient self-administer at home?
• Can the patient read medicines labels?
• Can the patient open medicines containers?
• Can the patient open his or her medicines locker?
• Do the patient know what his or her medicines are for (and dosage, instructions, side-effects)?

The successful operation of an extensive self-administration scheme throughout an acute hospital offers insights into the complexities and contradictions of modern medicines management which may have been hidden by the drug trolley approach.

It requires an acknowledgement that the traditional manner of working does not meet the needs of most patients, and for ward-based practitioners to be committed to adopting this approach in their practice. It also requires a truly integrated multi-professional approach that focuses on ensuring patients gain the maximum benefit from their medicines.

Other resources: British National Formulary

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Nursing and Midwifery Council (2006) Medicines management. A-Z advice sheet. London: NMC