A Textbook of Clinical Pharmacology and Therapeutics

Transdermal absorption is sufficiently reliable to enable systemically
active drugs (e.g. estradiol, nicotine, scopolamine) to be
administered by this route in the form of patches. Transdermal
administration bypasses presystemic metabolism. Patches are
more expensive than alternative preparations.
LUNGS
Drugs, notably steroids, β 2-adrenoceptor agonists and muscarinic
receptor antagonists, are inhaled as aerosols or particles
for their local effects on bronchioles. Nebulized antibiotics are
also sometimes used in children with cystic fibrosis and recurrent
Pseudomonas infections. Physical properties that limit systemic
absorption are desirable. For example, ipratropium is a
quaternary ammonium ion analogue of atropine which is
highly polar, and is consequently poorly absorbed and has
reduced atropine-like side effects. A large fraction of an
‘inhaled’ dose of salbutamol is in fact swallowed. However,
the bioavailability of swallowed salbutamol is low due to inactivation
in the gut wall, so systemic effects such as tremor are
minimized in comparison to effects on the bronchioles.
The lungs are ideally suited for absorption from the gas
phase, since the total respiratory surface area is about 60 m 2 ,
through which only 60 mL blood are percolating in the capillaries.
This is exploited in the case of volatile anaesthetics, as
discussed in Chapter 24. A nasal/inhaled preparation of insulin
was introduced for type 2 diabetes (Chapter 37), but was not
commercially successful.
NOSE
Glucocorticoids and sympathomimetic amines may be administered
intranasally for their local effects on the nasal mucosa.
Systemic absorption may result in undesirable effects, such as
hypertension.
Nasal mucosal epithelium has remarkable absorptive
properties, notably the capacity to absorb intact complex peptides
that cannot be administered by mouth because they
would be digested. This has opened up an area of therapeutics
that was previously limited by the inconvenience of repeated
injections. Drugs administered by this route include desmopressin
(DDAVP, an analogue of antidiuretic hormone) for
diabetes insipidus and buserelin (an analogue of gonadotrophin
releasing hormone) for prostate cancer.
EYE, EAR AND VAGINA
Drugs are administered topically to these sites for their local
effects (e.g. gentamicin or ciprofloxacin eyedrops for bacterial
conjunctivitis, sodium bicarbonate eardrops for softening wax,
and nystatin pessaries for Candida infections). Occasionally,
they are absorbed in sufficient quantity to have undesirable systemic
effects, such as worsening of bronchospasm in asthmatics
caused by timolol eyedrops given for open-angle glaucoma.
However, such absorption is not sufficiently reliable to make
use of these routes for therapeutic ends.
INTRAMUSCULAR INJECTION
Many drugs are well absorbed when administered intramuscularly.
The rate of absorption is increased when the solution is
distributed throughout a large volume of muscle. Dispersion is
enhanced by massage of the injection site. Transport away from
the injection site is governed by muscle blood flow, and this
varies from site to site (deltoid � vastus lateralis � gluteus maximus).
Blood flow to muscle is increased by exercise and absorption
rates are increased in all sites after exercise. Conversely,
shock, heart failure or other conditions that decrease muscle
blood flow reduce absorption.
The drug must be sufficiently water soluble to remain in
solution at the injection site until absorption occurs. This is a
problem for some drugs, including phenytoin, diazepam and
digoxin, as crystallization and/or poor absorption occur when
these are given by intramuscular injection, which should therefore
be avoided. Slow absorption is useful in some circumstances
where appreciable concentrations of drug are required
for prolonged periods. Depot intramuscular injections are
used to improve compliance in psychiatric patients (e.g. the
decanoate ester of fluphenazine which is slowly hydrolysed to
release active free drug).
Intramuscular injection has a number of disadvantages:
1. pain – distension with large volumes is painful, and
injected volumes should usually be no greater than 5mL;
2. sciatic nerve palsy following injection into the buttock –
this is avoided by injecting into the upper outer gluteal
quadrant;
3. sterile abscesses at the injection site (e.g. paraldehyde);
4. elevated serum creatine phosphokinase due to enzyme
release from muscle can cause diagnostic confusion;
5. severe adverse reactions may be protracted because there
is no way of stopping absorption of the drug;
6. for some drugs, intramuscular injection is less effective
than the oral route;
7. haematoma formation.
SUBCUTANEOUS INJECTION
ROUTES OF ADMINISTRATION 21
This is influenced by the same factors that affect intramuscular
injections. Cutaneous blood flow is lower than in muscle so
absorption is slower. Absorption is retarded by immobilization,
reduction of blood flow by a tourniquet and local cooling.
Adrenaline incorporated into an injection (e.g. of local anaesthetic)
reduces the absorption rate by causing vasoconstriction.
Sustained effects from subcutaneous injections are extremely
important clinically, most notably in the treatment of insulindependent
diabetics, different rates of absorption being
achieved by different insulin preparations (see Chapter 37).