drug administration Medicines and other chemicals, for both diagnostic and therapeutic reasons, and for purposes such as immunization or anaesthesia, can be administered in a wide variety of ways. The administration of drugs concerned the very earliest physicians. The ancient Babylonians (c.3000 bce) compounded laxatives — mixed vegetable and animal components with oils and honey for oral administration — and volatile oils were prepared using the newly-discovered technique of distillation. Ancient Egyptian papyri (c.1900–1100 bce) also mention many medicines prepared as potions, made up in water, milk or alcohol, or mixed into pills with dough or honey. There were ointments and vapours, and also suppositories and purgatives. These basic methods of administering drugs to patients have remained in use, improved by refinements of preparatory technique — especially with the advent of machinery to compound medicines — and the preparation of purer, unadulterated ingredients. To these have been added techniques for delivery by other routes — most notably that of injecting substances into the body.

The aim of therapeutic administration is for the active components of the medicine to reach the target site where it is intended to be effective. The technique and route used, such as an injection into a muscle, application of a cream to the skin, or ingestion of a pill, are influenced by both the formulation of the compound and the desired site and rapidity of action. An additional constraint is that medicines that could be degraded by natural digestive processes, or which would not be absorbed from the gut, cannot be given by mouth.

Injection and infusion

Injection is the act of introducing a substance into a body by means of some impulsive force, usually employing a syringe. The substance so injected is usually in a liquid form, and is employed to have a therapeutic effect either at the site of application (local actions including cooling, heating, antibiotic, and anti-inflammatory) or elsewhere in the body. Injected drugs usually act faster than those taken by mouth — and some substances, such as insulin, need to be injected, because they would be destroyed in the gut.

Injections can be made into practically any tissue, or cavity of the body, hence for example intradermal (into the skin), subcutaneous (just under the skin), intramuscular (deep into a muscle), or, less commonly, intra-peritoneal (into the peritoneal cavity), or intra-pleural. The site used depends on the purpose and the nature of the injection. Injection directly into the bloodstream (intravenous) has the most rapid effect — within minutes or even seconds — and so is suited to urgent treatment, such as reviving, by glucose injection, a diabetic person who has had an overdose of insulin. Substances given by intramuscular injection take longer to be absorbed into the circulation. The subcutaneous route has the slowest effect, and by comparison with the intramuscular route does not allow as large a volume to be injected without discomfort.

Infusion usually into a vein, but also sometimes into a body cavity, differs from injection in being a continuous, slow introduction of material, usually under pressure of gravity (as in a blood or saline infusion, or transfusion), and sometimes by a slow, mechanically-driven syringe (as in some methods of delivering post-operative analgesia). Materials to aid diagnosis, such as radioactive chemicals, or radioopaque dyes which show up on X-ray, are injected or infused, most commonly into veins or arteries.

One of the earliest attempts at intravenous injection was made in 1656 by the young Christopher Wren (1632–1723). Although best remembered for his architectural work, Wren was also a poet, a mathematician, and a keen experimentalist in the natural sciences, who was strongly influenced by William Harvey's views on the circulation of the blood. With colleagues in Oxford he experimented on introducing a slender quill into a dog's veins, and is recorded in the historical records of the Royal Society as ‘… the first Author of the Noble Anatomical Experiment of Injecting Liquid into the Veins of Animals’. This technique did not find immediate therapeutic application. Early attempts at inoculation did sometimes open a vein with a needle or scalpel, but the insertion of infective matter into a person's arm was usually accomplished by scratching an area of skin, a technique which continued for vaccination against smallpox until its eradication in the 1970s.

It was not until 1853 that the hypodermic syringe was invented by Charles Pravaz (1791–1853). Its first purpose was to inject iron perchloride into the veins to induce clotting, which he was using as an experimental treatment for aneurysms. In the same year, an Edinburgh doctor, Alexander Wood (1817–84), first thought of using a hollow needle to introduce medicinal agents through and under the skin. Originally thinking the technique could be used to remove birthmarks by injection directly into the blemish, he rapidly extended its application, by using a mixture of morphine dissolved in sherry to produce pain relief in a patient suffering from chronic neuralgia. Despite the fact that his patient fell into a deep sleep, Wood seemed to believe that the drug only acted locally, at the site of injection, rather than passing into the bloodstream and acting on the central nervous system. His views were of some importance, as many practitioners were not therefore alerted to the addictive nature of narcotic substances. Wood and others continued to develop injection techniques, principally for pain relief, despite practical problems such as the development of abscesses at the site of injection — this was before the recognition of bacterial infection and of the concomitant importance of antisepsis. A great variety of substances were injected into hapless patients: whisky and coffee to overcome opium poisoning, ammonia for snakebite, potassium permanganate for diphtheria.

It was the use of morphine injections that moved the technique of hypodermic drug administration from the realm of medical practice, into the underworld. The increasing availability of mass-produced syringes and uncontrolled access to narcotics, whose addictive properties were not known, not only led to many respectable people becoming inadvertent morphine addicts, but also facilitated illegal recreational use. Literature from the late nineteenth and early twentieth centuries frequently portrays morphine addicts, including the fictional detective Sherlock Holmes, created by the Edinburgh-trained doctor [ Sir] Arthur Conan Doyle. Modern concerns about infection, especially by AIDS sufferers, amongst intravenous drug-users has led to schemes of syringe and needle exchanges, offered by charities and local authorities, to encourage the hygienic use and disposal of equipment used by addicts.

Despite advances in hypodermic administration, at the turn of the twentieth century intravenous injection was still regarded in practice as a surgical procedure — the skin would be cut, a vein exposed, and a cannula tied into it. Increasing demand and practice, especially by anaesthetists; the production of improved needles and syringes; and the advent of sterilization of needles and aseptic procedures, all contributed to increasing confidence in the technique. Similarly, enhanced methods of drug preparation, especially to produce sterile material, and improved formulations, enabled further refinements. For example, enclosing the active medicinal agents in an inert vehicle, such as an oil, will delay its absorption and prolong its activity; these are called depot injections, and a range of preparations, including contraceptive drugs, can be administered in this form. Very powerful drugs, such as those used in chemotherapy, which could damage healthy tissues, are given by slow intravenous injection, so that they have an affect at their target site and are then rapidly diluted and removed by the circulation.

Oral medication

Drugs to be given by mouth are produced in a wide array of formulations, including tablets, pills, and liquids. Aspirin, and also alcohol, are absorbed in the stomach, but most oral medications are designed to be absorbed in the small intestine, where nutrients are normally absorbed, and they are coated with a protective material so that they pass through the stomach intact.

Fluid mixtures and elixirs have been used for centuries, and provided a convenient method by which a measured dose could be administered to a patient. Pills ‘balls cut from a solid mass and hand-rolled’ and lozenges ‘shaped pieces also cut from a solid mass’ have been known since ancient times. Various coatings were devised to disguise any bitter or unpleasant taste, gold and silver being particularly valued. There is some evidence that the Romans devised ridged stones on which the pill mass could be easily cut into equal portions. But it was not until the eighteenth century that ‘pill tiles’ were introduced into England from Delft. They had graduated grooves into which the pill mass, formed into a tube, was placed before being cut. These all depended on hand cutting and rolling of the pills, usually done by the druggist who dispensed the medicine. Later, mechanical mixing, rolling, and cutting instruments were devised, which greatly increased the production of pills, and heralded the advent of commercial manufacture.

During the 1830s a French pharmacist devised a mechanism for making soft-gelatin capsules which could then be filled — usually with unpalatable, oily, or semi-solid medicaments that could not easily be made into pills. In the following decade came a great breakthrough, the invention by William Brockedon in England of a hand-punch machine to make compressed medicines. Taken up by some English and American manufacturers, the products became known as ‘tablets’ because of the usage of that word by the pharmaceutical firm of Burroughs Wellcome and Co. In 1884 the company registered the word ‘Tabloid’ as their tradename for such medicines. The advantages of these compressed medicines were that they were convenient to carry, did not deteriorate in extremes of temperature, and were easier than other methods for the preparation of a standardized dose. One problem that remained, however, was that of ensuring that the tablet would disintegrate in the intestine. This was solved by the discovery that adding starch to the coating facilitated the absorption of water, and the consequent break up of the tablet.

Other routes

Some drugs are best absorbed through mucous membranes — such as the lining of the mouth, especially under the tongue — one of the best known being nitroglycerine for angina. Other sites for absorption can include the rectum, vagina, urethra, or nasal cavity, although these are more often used so that the drug can act locally, as in the case of anti-allergic nasal sprays, vaginal pessaries in the treatment of local infections, and spermicide preparations in contraception. Rectal suppositories are usually bullet shaped, and moulded from a substance that will slowly dissolve at body temperature, such as glycerine, and may be used to carry drugs for absorption as well as the commoner local lubricant function. Some drugs which would normally be given orally may have to be administered through the rectum, in cases where, for example, a patient is vomiting excessively, or is unconscious and unable to swallow. Approximately 50% of a drug can be absorbed through the rectal mucosa, although irritation often occurs. For a period in the nineteenth century the rectal route was also used to induce anaesthesia, being especially favoured by Russian military surgeons for the administration of ether.

Ointments are preparations of a fatty or oily consistency, for the application of medicines to the skin or mucous membranes, and are intended either to exert a local effect — such as warming, cooling, pain relief, anti-infection; or to provide a protective barrier — or to be absorbed and spread through the body to have more widespread effects.

Few drugs penetrate readily through the layers of the skin. Absorption is determined by both the surface area over which an ointment is spread, and the solubility of the ointment. Some chemicals, such as toxic substances in organic solvents, can be absorbed rapidly through the skin and cause poisoning. Absorption through skin patches can provide low-maintenance levels of drugs, such as oestrogen replacement therapy (a form of hormone replacement therapy) for post menopausal women, or a patch worn to release anti-motion sickness drugs whilst travelling. Absorption is enhanced through skin damaged by burns, wound, or abrasion, and particular care must be taken when applying medicaments to such injuries. Ointments are also prepared for application to the eyes, principally for their local effects, usually from absorption through the conjunctiva, often for infections or trauma. More recently, ocular inserts have been developed to provide continuous delivery of low levels of drugs, somewhat analogous to skin patches.

Some drugs can be delivered by inhalation, in the form of vapours or aerosols. They can be absorbed rapidly into the circulation through the pulmonary epithelium — the lining of the lungs. This route is used particularly for the treatment of respiratory diseases, such as asthma, and for the administration of volatile anaesthetics. Absorption is rapid because of the large surface area of the lungs. The main disadvantages to this route are the difficulties of regulating the dose, and the fact that many of the gases used in this way also act as irritants. During the twentieth century the main advances were to improve anaesthetic apparatus so as to control and monitor the dose received by the patient, and to minimize that accidentally received by the anaesthetist and other operating theatre staff. This can also be the route for inadvertent absorption of toxic chemicals in the environment, and substances used in chemical warfare, such as mustard gas.

E. M. Tansey