A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

20 DRUG ABSORPTION AND ROUTES OF ADMINISTRATION
4. drug metabolism by intestinal flora – this may affect drug
absorption. Alteration of bowel flora (e.g. by concomitant
use of antibiotics) can interrupt enterohepatic recycling and
cause loss of efficacy of oral contraceptives (Chapter 13);
5. drug metabolism by enzymes (e.g. cytochrome P450 family
3A (CYP3A)) in the gastro-intestinal epithelium
(Chapter 5);
6. drug efflux back into the gut lumen by drug transport
proteins (e.g. P-glycoprotein (P-gp), ABCB1).
Prolonged action and sustained-release preparations
Some drugs with short elimination half-lives need to be administered
frequently, at inconveniently short intervals, making adherence
to the prescribed regimen difficult for the patient. A drug
with similar actions, but a longer half-life, may need to be substituted.
Alternatively, there are various pharmaceutical means of
slowing absorption of a rapidly eliminated drug. The aim of such
sustained-release preparations is to release a steady ‘infusion’ of
drug into the gut lumen for absorption during transit through
the small intestine. Reduced dosing frequency may improve
compliance and, in the case of some drugs (e.g. carbamazepine),
reduce adverse effects linked to high peak plasma concentrations.
Absorption of such preparations is often incomplete, so it is
especially important that bioavailability is established and substitution
of one preparation for another may lead to clinical problems.
Other limitations of slow-release preparations are:
1. Transit time through the small intestine is about six hours,
so once daily dosing may lead to unacceptably low trough
concentrations.
2. If the gut lumen is narrowed or intestinal transit is slow,
as in the elderly, or due to other drugs (tricyclic
antidepressants, opiates), there is a danger of high local
drug concentrations causing mucosal damage.
Osmosin, an osmotically released formulation of
indometacin, had to be withdrawn because it caused
bleeding and ulceration of the small intestine.
3. Overdose with sustained-release preparations is difficult
to treat because of delayed drug absorption.
4. Sustained-release tablets should not be divided.
5. Expense.
BUCCAL AND SUBLINGUAL ROUTE
Drugs are administered to be retained in the mouth for local
disorders of the pharynx or buccal mucosa, such as aphthous
ulcers (hydrocortisone lozenges or carbenoxolone granules).
Sublingual administration has distinct advantages over oral
administration (i.e. the drug to be swallowed) for drugs with
pronounced presystemic metabolism, providing direct and
rapid access to the systemic circulation, bypassing the intestine
and liver. Glyceryl trinitrate, buprenorphine and fentanyl are
given sublingually for this reason. Glyceryl trinitrate is taken
either as a sublingual tablet or as a spray. Sublingual administration
provides short-term effects which can be terminated by
swallowing the tablet. Tablets for buccal absorption provide
more sustained plasma concentrations, and are held in one
spot between the lip and the gum until they have dissolved.
RECTAL ROUTE
Drugs may be given rectally for local effects (e.g. to treat proctitis).
The following advantages have been claimed for the rectal
route of administration of systemically active drugs:
1. Exposure to the acidity of the gastric juice and to digestive
enzymes is avoided.
2. The portal circulation is partly bypassed, reducing
presystemic (first pass) metabolism.
3. For patients who are unable to swallow or who are
vomiting.
Rectal diazepam is useful for controlling status epilepticus in
children. Metronidazole is well absorbed when administered
rectally, and is less expensive than intravenous preparations.
However, there are usually more reliable alternatives, and
drugs that are given rectally can cause severe local irritation.
SKIN
Drugs are applied topically to treat skin disease (Chapter 51).
Systemic absorption via the skin can cause undesirable effects,
for example in the case of potent glucocorticoids, but the
application of drugs to skin can also be used to achieve a systemic
therapeutic effect (e.g. fentanyl patches for analgesia).
The skin has evolved as an impermeable integument, so the
problems of getting drugs through it are completely different
from transport through an absorptive surface such as the gut.
Factors affecting percutaneous drug absorption include:
1. skin condition – injury and disease;
2. age – infant skin is more permeable than adult skin;
3. region –plantar forearm scalp scrotum posterior
auricular skin;
4. hydration of the stratum corneum – this is very important.
Increased hydration increases permeability. Plastic-film
occlusion (sometimes employed by dermatologists)
increases hydration. Penetration of glucocorticosteroids is
increased up to 100-fold, and systemic side effects are
more common;
5. vehicle – little is known about the importance of the
various substances which over the years have been
empirically included in skin creams and ointments. The
physical chemistry of these mixtures may be very complex
and change during an application;
6. physical properties of the drug – penetration increases with
increasing lipid solubility. Reduction of particle size
enhances absorption, and solutions penetrate best of all;
7. surface area to which the drug is applied – this is especially
important when treating infants who have a relatively
large surface area to volume ratio.