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Encyclopedia of Physical Science and Technology EN011J-559 July 25, 2001 18:57

810 Pharmacokinetics

intermediates, or result in metabolites with no biological Subcutaneous injections deliver the drug just below the
activity. dermis and therefore bypass the barrier of the skin. The
The large intestine or colon is not designed as a primary drug will quickly diffuse to lymphatic or blood capillar-
site of absorption. It does not have the infoldings or mi- ies and be taken up and distributed systemically. Because
crovilli which the small intestine has. However, the last lymphatics take up large molecules, this is an excellent
part of the large intestine, the rectum, is an excellent site site for injections of high-molecular weight agents such
of absorption for several reasons. Drugs can be directly as vaccines.
introduced via the anal opening into the rectum without Intramuscular (i.m.) injections are an alternative when
passage through the proximal portions of the intestines. i.v. access is not available. For example, lidocaine has been
Once absorbed into the circulation of the rectum, sub- shown to be rapidly absorbed after i.m. injection, with
stances do not undergo a first-pass effect since the blood the deltoid muscle being a superior site to either the but-
does not flow through the portal vein but circulates directly tocks or lateral thigh. Many drugs show great variability
to the general circulation. in absorption after intramuscular or subcutaneous injec-
tion. Because of the uncertainty in the bioavailability of
the drug from these routes, in an emergency the i.v. route
B. Transdermal, Subcutaneous, Intramuscular
is clearly superior for rapid administration of a defined
Routes of Absorption
dose.
The outer layer of the skin, termed the epidermis, presents
a major barrier to the passage of water or solute. The out-
C. Intraperitoneal Administration
ermost, horny layer is made up of dead cell product and
keratin and prevents loss of water from the body. Because The intraperitoneal (i.p.) route of administration is par-
of the dense cell packing, passive diffusion is slow, but ticularly advantageous if access to the cavity already ex-
substances are capable of transporting through the skin ists (i.e., a peritoneal dialysis catheter) and if the infec-
over a prolonged time. Heavy metals such as mercury or tion or disease process is confined to the cavity. Medica-
lead or organic solvents or toxic insecticides are absorbed tion levels in the i.p. solution can be maintained one to
in this fashion. In recent years, transdermal delivery de- two orders of magnitude above toxic levels in the plasma.
vices have been developed which provide continuous slow Transfer to the systemic circulation is relatively slow, and
transfer of drug from a flat patch reservoir placed directly peak concentrations in the plasma will be a fraction of
on the skin. The controlled delivery rate depends on an in- what they would be if the same dose were administered
tact epidermis and dermis and a stable local blood supply. i.v. This provides for maximal pharmacologic activity lo-
Various studies have demonstrated that drugs are often not cally while sparing the remainder of the body from the
totally taken up in the dermis but penetrate to underlying toxic side effects. The pharmacokinetic advantage of re-
tissue and result in very high local tissue concentrations. gional administration into the peritoneal cavity (or any
These devices are commonly used in the 24-hr delivery body cavity) over that of intravenous administration can be
of nitrates to patients with heart disease or in the con- calculated by
tinuous administration of antihypertensive medication to
(C PC /C B ) IP
individuals with high blood pressure. Because of the slow pharmacokinetic advantage =
(C PC /C B ) IV
infusion properties of these devices, drugs with relatively
short half-lives can be administered continuously for up to Clr total body
= 1 + , (8)
1 week. Nitropaste (a paste form of nitroglycerin), for ex- PA
ample, can be applied in the form of topical ointment, and where C PC is the concentration in the peritoneal cavity,
the rate of delivery can be adjusted by changing the area C B is the concentration in blood, and PA is the mass
of application until intravenous access can be obtained. transfer area coefficient governing transport between the
Some drugs such as nitrates can permeate the skin rapidly; peritoneal cavity and the blood: the mass transfer rate is
the amount prescribed is typically written in terms of sur- PA peritoneum (C PC − C B ).
face area covered. The available surface area may become
important in the cardiac patient who has unstable angina
D. Inhalation
and does not have intravenous access. Advantages of the
transdermal route include avoidance of hepatic first-pass Thelungsaretheoptimumportalofentryofgasesandvery
metabolism, ability to discontinue treatment by removal small particulate aerosols (<2µm in size). The area of the
2
of the system, ability to continue delivery of the drug for a alveoli is approximately 100–200 m , with a very thin (1–
longer period of time than the usual oral form of the drug, 2 µm) series of membranes separating the air and blood
and a potentially large area of application. spaces. Drugs reaching the alveoli are therefore absorbed