Methods and routes of administration the pharmaceutical phase

The form in which a medicine is administered is known as its dosage form. Dosage forms can be subdivided according to their physical nature into liquid, semisolid and solid formulations. Liquid formulations include solutions, suspensions, and emulsions. Creams, ointments and gels are normally regarded as semisolid formulations, whilst tablets, capsules and moulded products such as suppositories and pessaries are classified as solid formulations. These dosage forms normally consist of the active constituent and other ingredients (excipients). Excipients can have a number of functions, such as fillers (bulk providing agent), lubricants, binders, preservatives and antioxidants. A change in the nature of the excipients can significantly affect the release of the active ingredient from the dosage form. For example, the anticonvulsant phenytoin was found to be rapidly absorbed when lactose is used as a filler. This resulted in patients receiving toxic doses. In contrast, when calcium sulphate was used as a filler, the rate of absorption was so slow that the patient did not receive a therapeutic dose.

Changes in the preparation of the active principle, such as the use of a different solvent for purification, can affect the bioavailability of a drug (see section 11.5) and consequently its effectiveness. This indicates the importance of having all-inclusive quality control procedures for drugs, especially when they reach the manufacturing stage.

The design of dosage forms lies in the field of the pharmaceutical technologist but it should also be considered by the medicinal chemist when developing a drug from a lead compound. It is no use having a wonder drug if it cannot be packaged in a form that makes it biologically available as well as acceptable to the patient. Furthermore, the use of an incorrect dosage form can render the medicine ineffective and potentially dangerous.

Drugs are usually administered topically or systemically. The routes are classified as being either parenteral or enteral (Fig. 1.10). Parenteral routes are those which avoid the gastrointestinal tract (GI tract), the most usual method being intramuscular injection (IM). However, other parental routes are intravenous injection (IV), subcutaneous injection (SC) and transdermal delivery systems. Nasal sprays and inhalers are also parenteral routes. The enteral route is where drugs are absorbed from the alimentary canal (given orally, PO), rectal and sublingual routes. The route selected for the administration of a drug will depend on the chemical stability of the drug, both when it is across a membrane (absorption) and in transit to the site of action (distribution). It will also be influenced by the age and physical and mental abilities of the patients using that drug. For example, age-related metabolic changes often result in elderly patients requiring lower dosages of the drug to achieve the desired clinical result. Schizophrenics and patients with conditions that require constant medication are particularly at risk of either overdosing or underdosing. In these cases a slow-release intramuscular injection, which need only be given once in every two to four

Phenytoin

Phenytoin

ENTERAL PARENTERAL

route, route,

ENTERAL PARENTERAL

route, route,

Bodily Distribution Dilantin
Figure 1.10 The main routes of drug administration and distribution in the body. The distribution of a drug is also modified by metabolism, which can occur at any point in the system

weeks rather than a daily dose, may be the most effective use of the medicine. Consequently, at an appropriately early stage in its development, the design of a drug should also take into account the nature of its target groups. It is a waste of time and resources if it is found that a drug that is successful in the laboratory cannot be administered in a convenient manner to the patient.

Once the drug enters the blood stream it is distributed around the body and so a proportion of the drug is either lost by excretion, metabolism to other products or is bound to biological sites other than its target site. As a result, the dose administered is inevitably higher than that which would be needed if all the drug reached the appropriate site of biological action. The dose of a drug administered to a patient is the amount that is required to reach and maintain the concentration necessary to produce a favourable response at the site of biological action. Too high a dose usually causes unacceptable side effects, whilst too low a dose results in a failure of the therapy. The limits between which the drug is an effective therapeutic agent is known as its therapeutic window (Fig. 1.11). The amount of a drug the plasma can contain, coupled with elimination processes (see section 11.4) that irreversibly remove the drug from its site of action, results in the drug concentration reaching a so-called plateau value. Too high a dose will give a plateau above the therapeutic window and toxic side effects. Too low a dose will result in the plateau below the therapeutic window and ineffective treatment.

The dose of a drug and how it is administered is called the drug regimen. Drug regimens may vary from a single dose taken to relieve a headache, regular daily doses taken to counteract the effects of epilepsy and diabetes, to continuous intravenous infusions for

Drug concentration in the plasma

Drug concentration in the plasma

Therapeutic window

Therapeutic failure

Toxic overdose

Time

Figure 1.11 A simulation of a therapeutic window for a drug, given in fixed doses at fixed time intervals (")

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Therapeutic window

Therapeutic failure

Toxic overdose

Time

Figure 1.11 A simulation of a therapeutic window for a drug, given in fixed doses at fixed time intervals (")

seriously ill patients. Regimens are designed to maintain the concentration of the drug within the therapeutic window at the site of action for the period of time that is required for therapeutic success.

The design of an effective dosage regimen requires not just a knowledge of a drug's biological effects but also its pharmacokinetic properties, that is, its rate of absorption, distribution, metabolism and elimination from the body. It is possible for a drug to be ineffective because of the use of an incorrect dosage regimen. When quinacrine was introduced as a substitute for quinine in the 1940s it was found to be ineffective at low dose levels or too toxic at the high dose levels needed to combat malaria. Quinacrine was only used successfully after its pharmacokinetic properties were studied. It was found to have a slow elimination rate and so in order to maintain a safe therapeutic dose it was necessary to use large initial doses but only small subsequent maintenance doses to keep the concentration within its therapeutic window. This dosage regimen reduced the toxicity to an acceptable level.

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