Pharma Tips

Routes of Drug Entry and Exit : A Review

By: Pharma Tips | Views: 1474 | Date: 26-Apr-2013

In order for a drug to have an effect, it is necessary for it to reach some specific tissue of the body. The classification of drugs and the description of drug effects is usually based upon the interaction of the drug with this receptor tissue. In the parlance of traditional pharmacology, this interaction at the cellular level is the drug action, whereas the more complicated consequences of this action are termed the drug effect. These terms, action and effect, are frequently used interchangeably, but it i

Routes of Drug Entry and Exit : A Review

In order for a drug to have an effect, it is necessary for it to reach some specific tissue of the body. The classification of drugs and the description of drug effects is usually based upon the interaction of the drug with this receptor tissue. In the parlance of traditional pharmacology, this interaction at the cellular level is the drug action, whereas the more complicated consequences of this action are termed the drug effect. These terms, action and effect, are frequently used interchangeably, but it is important to recognize that different issues must be considered in each instance.

The basic question that is being addressed here is, "How does the drug get from the shelf to the receptive tissue?" We know from casual experience with pharmaceuticals that drug effects are neither immediate (the headache does not go away at the instant the pill is taken), nor permanent (repeated dosages must be taken). The full consideration of these issues requires a knowledge of membrane biophysics, acid-base kinetics, and other aspects of cell physiology; all of which are of critical importance in the design of pharmaceutical products and in understanding certain aspects of drug actions. Fortunately, we need only consider some of the more global aspects of these topics at this point.

One of the most important determinants of a drug effect is the concentration of drug molecules in the bloodstream or plasma compartment of the body. The drug concentration is determined by the rate of entry into the blood stream and the rate of exit from the bloodstream. In each case, the compound must cross a membrane barrier. 
The various membrane surfaces of the body are very similar in terms of their properties that allow specific types of molecules to pass through them. The membrane can be considered as a double layer of lipid molecules sandwiched between an inner and outer layer of protein molecules.


























Small membrane pores (about 4-8 Angstroms in diameter) penetrate these layers at intervals along the surface. This physical structure determines the way in which a particular molecule will pass through the membrane:

a. Molecules that are smaller than the diameter of the pores cross the membrane by passive diffusion
b. Molecules that are lipid soluble dissolve in the membrane and diffuse through it according to the concentration gradients.
c. Molecules that are too large and not lipid soluble do not pass through the membrane, except when special metabolic systems called active transport systems carry the molecules through the membrane. Such transport mechanisms are fairly common for endogenous compounds, but do not appear very frequently in the case of pharmaceutical compounds.

There are many different ways in which a drug can be administered, or in terms of the above discussion, different ways to make the drug accessible to the membranes that allow passage into the circulatory system. One way to modify the accessibility of the drug is to change the vehicle, or carrier, of the drug. For example, the drug may be mixed with distilled water, saline, oil, or even solutions of other drugs to systematically change the characteristics of entry into the bloodstream. The rate at which a drug enters the circulatory system varies tremendously, depending upon the route of administration: 

Major Routes of Drug Administration
Oral, Rectal, Mucous membranes, Inhalation, Subcutaneous injection, Transdermal infusion, Intramuscular injection, Intravenous injection, Intraarterial injection, Intraperitoneal injection, Intrathecal injection, Intracranial injection.

Oral administration:
This is certainly the most common method of drug administration, and unless otherwise specified, we assume that taking medication means oral ingestion. This route of administration has the advantage of quickly and easily placing the drug in contact with the relatively large surface membrane of the stomach, which has a rich supply of capillaries for entry into the plasma compartment. The stomach wall is relatively resistant to the irritating properties of most drugs, and the churning action of the stomach will improve the physical distribution of the compound. Finally, the presence or absence of food in the stomach can be manipulated to increase or decrease the rate of absorption, to minimize irritating effects, or to change the chemical environment of the stomach.

There are, however, some special characteristics of the gastric environment that may cause difficulties for the administration of certain drugs. The high acidity of the stomach may alter the structure of the drug, causing it to precipitate and be less easily absorbed. Depending on the acid-base characteristics of the drug, the gastric environment may either increase or decrease the tendency of the drug to split into ionized (or charged) forms. This is a very important consideration for large molecules, because only the non-ionized forms of otherwise lipid soluble compounds will pass through the lipid barrier of the membranes. Because of the differences in pH of the stomach and the intestines, some drugs which are not readily absorbed through the stomach walls because of ionization change their state when they pass from the stomach to the intestine and become lipid soluble. This effectively delays the entry of the drug into the bloodstream. By contrast, other drugs may become ionized and ineffective upon leaving the stomach, so that the amount of the original dosage that actually becomes useful is determined by the length of time it was in the stomach. Modern manufacturing methods now produce several different "time release" formulations that encapsulate the drug into a vehicle that dissolves at some specified rate to release the drug dosage gradually over time.

Rectal administration
The absorption of drugs administered rectally is essentially the same as that of drugs that reach the intestine via oral administration. This method is most frequently used under direct medical supervision when it is difficult or impossible for the drug to be administered orally. One of the disadvantages of the method is that the drug may be eliminated before complete absorption has occurred.

Mucous membranes
There are many drugs that readily pass through the mucous membranes of the mouth and nasal passages. The best known examples of these routes of administration are probably the "nitro" capsules that cardiac patients place under the tongue for almost immediate relief of symptoms, and the snorting of cocaine into the nostrils by users of recreational drugs. In both cases, the drugs are quickly absorbed and significant levels of the drugs enter the bloodstream within seconds.

Inhalation
Drugs that are volatile can enter the bloodstream very rapidly when inhaled. This is, in fact, just an extension of the mucous membrane route discussed above, but the very large surface area and rich blood supply of the lungs make this an exceptionally rapid route of administration. The major disadvantage is the difficulty of controlling dosage levels, and possible harmful effects upon the membranes. Because of these practical difficulties, this route of administration is usually limited to drugs that are used specifically for their local effects (e.g, anti-asthmatic compounds), and medically supervised anesthesia. It should also be kept it mind that this extremely efficient route of administration renders us vulnerable to the accidental administration of toxic levels of volatile compounds that may be airborne in our environment. Each year, physicians see a number of serious if not fatal cases of poisoning due to exposure to solvents, cleaning fluids, and even the burning of poison ivy along with autumn leaves. On the street drug scene, one of the most dangerous forms of cocaine use is the inhalation of the drug known as "crack". Less acute, but perhaps no less dangerous on a global scale, are the effects of voluntary (and involuntary) inhalation of the contents of tobacco smoke.

Subcutaneous injection.
The skin provides a relatively impermeable barrier to most substances (we will see exceptions later), which led to the development of the hypodermic(literally meaning under the skin) syringe for the administration of drugs through this barrier. When administered in this manner, the drug is sequestered in a localized area, being forced into the interstitial fluid that surrounds the local cells and capillaries. The drug will enter the bloodstream via these local capillaries. Because of the limited physical dispersion of the drug dosage, the absorption of drugs administered subcutaneously tends to be slow and uniform. A further advantage is that the rate of absorption can be controlled by varying the conditions under which the drug is administered. For example, the application of heat or mixing the drug with vasodilators will increase the rate of absorption. More commonly, the physician is interested in slowing down the rate of absorption and may administer the drug in combination with a local vasoconstrictor, mix the drug in an oil vehicle, apply ice over the area of injection, or in emergency situations, even apply a tourniquet between the site of injection and the systemic circulation. Although less commonly used, it is also possible to surgically implant a capsule under the skin, where the drug is slowly released, sometimes over a period of weeks or months.
 
Intramuscular injection
Some drugs have irritant or caustic effects upon local tissues that will cause the skin to sluff off if administered subcutaneously. If the injection route is still preferable, these problems can be minimized by administering drugs deeply into the muscle mass. Certain forms of penicillin are commonly injected via the intramuscular route.

Intravenous injection
This is the most direct route for the systemic administration of a drug, because it is placed directly into the circulatory system without having to cross any membranes. The rapidity of effects can actually be a disadvantage with this route of administration, since acute overdosage is possible. The most common usage of the intravenous route is the administration of anesthetics, since the level of anesthesia can be carefully titrated by monitoring vital signs. Additionally, drugs that would otherwise be severe irritants to local tissue can sometimes be administered via this route, owing to the resistant nature of the walls of the bloodstream and the rapid dilution of the drug in the moving fluid environment. The self administration of narcotic drugs by this route (sometimes referred to as mainlining) is exceptionally hazardous because of the likelihood of acute overdosage and infections.

Intraarterial injection
This method also places the drug directly into the bloodstream, but is usually reserved for experimental purposes to inject a drug directly into the blood supply of a specific organ (e.g., the liver or the brain) to assay the effects of the drug upon that organ. One particularly interesting application of this method is to inject a fast acting anesthetic into one of the carotid arteries. This results in the brief anesthetization of one side of the brain, which can be useful in diagnosing the location of brain functions (e.g., language areas) or disorders such as tumors.

Intraarterial injection
This method also places the drug directly into the bloodstream, but is usually reserved for experimental purposes to inject a drug directly into the blood supply of a specific organ (e.g., the liver or the brain) to assay the effects of the drug upon that organ. One particularly interesting application of this method is to inject a fast acting anesthetic into one of the carotid arteries. This results in the brief anesthetization of one side of the brain, which can be useful in diagnosing the location of brain functions (e.g., language areas) or disorders such as tumors.

Intraperitoneal injection
The intraperitoneal route of administration involves the injection of the substance through the wall of the abdomen into the peritoneal cavity. Absorption of the compound occurs largely through the rich vascular bed of the intestines, though from the outside rather than the inside. It is by far the most common method for administering drugs to small experimental animals, owing to the relative difficulty of the intravascular route and the inconsistency of oral administration in laboratory animals. This technique is rarely used in humans because of the potential (though slight) for damaging internal organs and the greater risk of infection.

Transpleural injection
This is an interesting procedure that occasionally has been used for experimental purposes, especially in small animals. Procedurally, it is somewhat comparable to the intraperitoneal injection, except that the needle is inserted through the rib cage above the diaphragm so that the drug is injected into the pleural cavity. For some drugs, the effect is almost as rapid as an intravenous injection because of the extremely fast absorption through the rich vascular supply of the lungs (hence, the term transpleural, which means across the lungs).

Intracranial injection
In some cases, it is advantageous to administer a behaviorally active drug more locally into the brain, rather than indirectly through the systemic circulation. There are actually two subdivisions of this route, which overlap to a considerable extent in both theory and practice. The intracisternal route involves the injection of the drug directly into the cerebrospinal fluid (usually abbreviated, csf) of the brain ventricles. In some cases, this is done via a cannula (tube) that has been permanently positioned, but in other cases it is done (with skilled hands!) by direct injection through the foramen magnum at the back of the skull of experimental rats or mice. The intracerebral route involves the application of a drug directly onto brain tissue. A common experimental procedure for intracerebral injections involves the permanent placement of a cannula into a specific region of the brain. Minute quantities of drugs can then be administered in either liquid or crystal form to determine the response (both neurophysiological and behavioral) of the specific brain region to a specific drug. These techniques have been very useful as experimental procedures for studying drug effects in experimental settings, but have had limited use in human applications.

Intrathecal injection
The major application for this route of administration has been the use of the so-called "spinal" anesthetics. In this procedure, a needle is inserted between the vertebrae and through the sheath of the spinal cord. Small quantities of drugs can act on the local cell population and produce anesthesia (usually of the lower body and limbs) while having few if any systemic effects.

Transdermal infusion
The skin surface normally serves as an effective barrier against the entry of foreign substances into the body. There are, however, some substances that will penetrate the skin and enter the bloodstream. There even have been cases of infant intoxication or death resulting from being wrapped in alcohol soaked bandages as an attempt to reduce fever. (This effect is compounded by inhalation due to rapid breathing of the evaporating alcohol. Recently, researchers have been studying the transdermal route of administration for drugs that need to be administered in continuous low dosage over long periods of time (e.g., certain hormones). The drug could be applied on a skin patch, which could be changed every few days or weeks as needed, thereby avoiding the necessity (or inconsistency) of frequent oral or hypodermic administration. There are a number of technical problems in developing this procedure, the most important of which are the facts that most drugs do not penetrate the skin readily, and compounds that facilitate their entry also may indiscriminately carry other substances (e.g., household chemicals, insecticides, etc.) through the protective barrier of the skin.
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