Routes of drug administration
To obtain a general effect, the drug is usually given by oral or parenteral route. The choice depends on the drug i.e. the existence of preparations appropriate for these uses and on the state of the patient. Emergency or the impossibility of intake by mouth makes the parenteral route necessary.
To obtain a local effect, special preparations like the ophthalmic solutions, but it should be remembered that a systemic diffusion is always possible after local administration.
A drug to be injected by parenteral route, must be sterile and little irritant. The injection requires a syringe and a needle or a device of administration already set up.
- Intradermal route, especially used for intradermal reactions.
- Subcutaneous route
The volume of fluid injected is limited and the rate of resorption variable, depending on local factors: sclerosis, circulatory state (vasodilation, vasoconstriction). Heparin and insulin are among the drugs generally administered drugs by subcutaneous route.
- Intramuscular route
The rate of resorption is fast and it is possible to inject aqueous or oily solutions.
There are delayed preparations gradually releasing over one or many weeks the active product from the anatomic site of injection into the circulation, sexual hormones or neuroleptic agents for example. The intramuscular injection should not be made in a vessel, nor in contact with a nerve. It is contra-indicated if the patient is undergoing anticoagulant therapy.
- Intravenous route
There are two possibilities: direct injection with the syringe or administration by perfusion.
The bioavailability is by definition 100%; it is necessary however to pay attention to the speed of administration because it should not be:
- too rapid, which can be the case with direct administration by a syringe, with risk of severe reactions.
- too slow, as observed during certain perfusions, because if the rate of elimination is rapid, the effective therapeutic concentration can not be reached.
Oily solutions should not be given by intravenous route.
There are implantable devices for intravenous administration, set up surgically and used for long courses, in particular for chemotherapy. It gives intravenous access with an administration of subcutaneous type.
It is little used, some examples of intraarterial administration: a vasodilator for arteritis, a thrombolytic to dissolve a clot, an antineoplastic for localized treatment of a cancer.
Routes of particular local injections
They are used to introduce a drug for diagnosis or treatment purposes in particular anatomical sites, for examples by intraspinal, intra-articular, intrapleural, intraperitoneal injections
The digestive tract goes from the mouth to the rectum. The membranes which the drug must cross are the digestive epithelium and the vascular endothelium.
The oral route can be used for a local or general treatment:
- Local treatment: gastrointestinal protectants of the digestive tract itself, treatment of an intestinal infection or a parasitosis. In this case, one wishes, in general, that the drug will not be absorbed or only poorly absorbed.
- General treatment: it is the usual route of administration of drugs and digestive absorption is followed of their diffusion in the body.
The oral route is not usable if the drug intended for a general treatment is degraded in the digestive tract (pH, microbial flora, enzymes of the digestive tract) or is not absorbed or if the patient refuses to take it or vomits.
Digestive absorption can take place at any level of the digestive tract.
- Mouth: the absorption of the drug by the oral mucous membrane allows a fast absorption and avoids the hepatic transfer. It is generally called sublingual route. Nitroglycerin, in the form of sugar-coated tablets to be crunched, intended for the treatment of attacks of angina pectoris, is absorbed at this level.
- Stomach: the area of the stomach is approximately 1m2. The pH of the gastric fluid is acid. The flow rate of blood drainage of the stomach is low, approximately 0.2 L/min.
Intestine: the area of the intestine is large: from 200 to 300m2. The pH is alkaline: 6 to 8. The blood irrigation is important, 1 L/minute. The majority of drugs are absorbed at this level.
Rectum: although absorption can occur at this level, the use of suppositories to obtain a general effect is disadvised because the bioavailability is variable.
- Neutral molecules and acids not ionized in an acid pH are absorbed from the stomach.
- Many molecules are secreted into the gastric fluid from the blood , in particular bases which are ionized by protonation in the acid gastric fluid.
At the level of the digestive tract are absorbed:
- by passive diffusion through the lipid bilayer , neutral, liposoluble molecules but not those completely insoluble in water.
- by secondary active transport, amino acids and sugars, certain peptides.
- by complex mechanisms, elements in the form of ions, cations and anions, such as sodium, potassium, calcium, chloride.
The ionized molecules containing, for example, a quaternary ammonium are not or poorly absorbed, in a not very reproducible and variable way according to patients.
A characteristic of digestive absorption is first-pass metabolism: the drug, absorbed from the digestive tract, passes through the liver, reaches the right heart and after pulmonary transfer is distributed by the left heart to the whole body. Both in the intestinal mucous membrane and in the liver, the drug meets enzymes able to transform it into one or more metabolites, sometimes active but generally inactive. This first-pass metabolism explains the low efficacy of certain drugs, especially when they are given in low doses, because they are mainly metabolized before arriving into the blood.
Fate of a drug administered orally and parentally, RH = Right Heart, LH = Left Heart
Factors modifying digestive absorption and bioavailability
Form or presentation of the drug
The digestive absorption of the same molecule, taken at the same dose, by the same patient, but under a different presentation, drops or tablets for example, will not have necessarily the same kinetics of absorption, nor the same bioavailability. Drugs supplied in the form of drops are immediately available for absorption whereas tablets must be first disintegrated so as to release the powder which is emulsified.
In general, drops give a more rapid and higher Cmax than tablets, the bioavailability being identical or not. This difference between drops and tablets explains the greater severity of poisonings due to the intake of drops than the intake of tablets which can stagnate a long time in the digestive tract before being absorbed.
There are preparations known as sustained-release which gradually release the active molecule into the digestive tract, which delays and extends its absorption. This artifice makes it possible to reduce the frequency of administration compared to that which one could calculate according to the real elimination half-life. The persistence of digestive absorption avoids the fast decrease of the plasma concentration.
When should a drug be taken: under fasting conditions, before, during, after meals? There is no simple response to this question. It is necessary to consider pharmacokinetic and pharmacodynamic parameters.
The bioavailability of certain drugs when they are taken during meals can be reduced, unchanged or increased:
- reduced: it is the case of tetracyclines, isoniazid, penicillamine, captopril.
- unchanged or little modified: it is the case of amoxicillin.
- increased: it is the case of propranolol; the increase in its bioavailability comes from a decrease of first-pass intestinal and hepatic metabolism . It is the case of griseofulvine when it is taken with lipids, but the responsible mechanism is not well understood.
The desired effect or the tolerance of a drug can depend on the moment of its administration compared to meals:
- An hypoglycemic drug is generally given before meals to compensate for the hyperglycemia caused by food.
- A gastric protectant is taken apart from meals and in the evening at bedtime for a better adhesion to the gastric mucous membrane.
- Nonsteroidal antiinflammatory drugs are taken during meals to reduce the gastric irritation which they elicit.
The responses to these questions are generally found in the user information sheet accompanying each drug and in the “summary of product characteristics” of each drug.
Any modification of the transit of the bolus, either of pathological origin (vomiting, diarrhea, etc), or drug-induced (acceleration or slowing of transit), is likely to modify the kinetics of absorption and the bioavailability. Atropine slows down the transit and the absorption; metoclopramide and cisapride accelerate it.
Drug interaction in the digestive tract
In addition to the modifications of transit elicited by certain drugs, there are also direct chemical interactions between drugs:
- Cholestyramine is an anion exchanging resin, able to bind drugs, such as diuretics, and reduce their absorption.
- Metals such as iron and aluminum can reduce the bioavailability of certain antibiotics, like tetracyclines, with which they form organometallic complexes.
- Activated charcoal has been known for a long time for its capacity to adsorb a great number of molecules, in particular drugs. It is used, by oral or gastric administration, to reduce or prevent the absorption of toxic products or drugs taken in excess by oral route. Preparations of activated charcoal have a large area of adsorption which 2000 m2 by gram. The activated charcoal must be given as soon as possible after ingestion of the supposed poison.
Preparations available for oral route
Knowledge of the various available preparations of the drugs is necessary to physicians. Indeed, if their prescription contains an error, for example “capsule” instead of “tablet”, the pharmacist who dispenses the drug and the patient who takes it can wonder about the error, if it concerns the presentation or the drug itself.
The principal available preparations containing powder (active substance+ excipient) are as follows:
- Packages and sachets: containing generally about 10 to 20g of product
- Capsules: made of two often coloured encasable cylindrical parts of a mixture of gelatin and carboxymethyl cellulose, containing the active product. They can be made resistant to gastric acidity.
- Tablets: obtained by compression of the powder. There have various forms, and can be effervescent.
- Sugar-coated tablets: covered by a layer of sugar often aromatized and coloured.
These “dry” forms (, capsules, tablets…) must be taken with a glass of water in a sitting or upright position, but not lying, to facilitate their esophageal transit and to prevent their binding to the esophageal wall which they could damage with possible severe ulcerations.
The available preparations containing fluid are as follows:
- Drinkable vials in coloured glass to distinguish them from the injectable vials in transparent glass except if the active product must be protected from light.
- Aqueous or alcoholic solutions, in bottle with a graduated dropper or mesurette.
- Syrups: concentrated aqueous solution of sucrose containing the active products. The syrups are administered by spoonfuls and preferably by a spoon/dose provided with each bottle.
- Suspensions: the granules contained in a bottle are dispersed in a given quantity of water before use.
- Hydrosols are pseudo-solutions containing water-soluble and liposoluble molecules.
Preparations for rectal route
They are suppositories. One of disadvantages of suppositories is the variability of the resorption of the active product.
It is a route of fast absorption avoiding the liver: drugs absorbed by the lungs, reach the left atrium and the left ventricle, and then the general circulation. The pulmonary route is used:
- for local treatment: bronchial indications but with possibility of partial absorption and general effects. The forms used are aerosols conveying drugs such as antibiotics, mucolytic, beta-adrenergic mimetic, muscarinic receptor antagonists. A lot of devices like pressurized atomizers, aerosol-batchers or sprays, inhalers of dry powder are used to introduce drugs into bronchial airways.
- for general treatment: medical gases and general anesthetics by inhalation. Oxygen, nitric oxide and nitrous oxide which are in gas form are administered naturally by pulmonary route. The anesthetics such as fluothane, liquids easily volatile, are administered by inhalation
The interest of the pulmonary route is to avoid intestinal and hepatic first-pass metabolism. Its efficacy makes it a route used for cannabis, cocaine and, of course, of nicotine (tobacco). It could be used for drugs such as heparin and insulin.
It is used:
- for local treatment with vasoconstrictive and antiallergic drugs but with possibility of absorption and general effects.
- for general treatment: the nasal route can be used for the administration of polypeptide hormones such as desmopressin.
The nasal route also avoids the first-pass metabolism.
Cutaneous or transdermal route
The permeability of the skin to drugs depends on the drug itself, in particular its liposolubility and on the vehicle in which the drug is introduced. Resorption varies with several parameters:
- localisation: it is low at the level of the plant of the feet, of the palm of the hands, important at the level of armpits, of the angle of the jaw and the scrotum.
- temperature and cutaneous circulation: if the temperature is high, there is a vasodilation which facilitates absorption.
- state of the skin: the existence of lesions (burns, for example) increases the absorption.
- age: it decreases with the age, i.e. it is more important in the new-born baby. In addition the body area compared to the weight is more important in the new-born baby and the infant that in adults.
The cutaneous route is used for local treatments by disinfectants, antimycotics, antibiotics or glucocorticoids which can sometimes be absorbed, diffuse in the whole body and be at the origin of general effects. The severe poisonings which occurred in France in 1972 in infants following applications of talc contaminated by hexachlorophene, neurotoxic product, shows that the skin, especially in new-born babies and infants, can absorb various molecules.
The cutaneous route called transdermal route is used for introducing drugs into the body, in particular for avoiding hepatic catabolism. There are various devices for cutaneous administration, from simple application to the use of complex transdermal devices. It is used for various drugs: hormones like androstanolone, estradiol and progesterone, others such as nitroglycerin, scopolamine, fentanyl.
The cutaneous route like the pulmonary and the nasal routes avoid first-pass metabolism.
Other routes: ocular, ear and vaginal
These routes are used for local treatment but a diffusion in the body is possible, with adverse effects, for example, after prescription of ophthalmic solutions, containing beta-blockers. The drugs administered by these routes are called ophthalmic solutions for the eyes, drops for the ears, and ovules for the vagina.
Liposomes are microscopic vesicles, generally made up of phospholipids, in which an active drug is introduced to protect it and allow its absorption or its specific tissue distribution. There are uni-lamellate and plurilamellate preparations. They have several advantages:
- a progressive release of the active product,
- the absorption of a drug which, if not, would be degraded or would not cross the membranes,
- a specific distribution in a particular organ or a type of cells. In this last case, the lipid membranes could carry antibodies able to bind specifically to such or such tissue.
Preparations containing microparticles or nanoparticles in which the drug is inserted are under development.
The use of viruses as means of introduction of a drug in the body and of its penetration into cells is a relatively recent technique, developed for gene therapy. The drug used can be DNA itself which, to be active, must penetrate in the nucleus of the cell and use the cellular machinery for the synthesis of a desired protein. The virus vectors are retroviruses or adenoviruses. The virus vector, like the other drugs, can be given by various routes, parenteral, oral, etc.