Gases
The physics of gases and the partial pressure at
which they can achieve anesthesia is beyond the
scope of this chapter. For one thing, this huge
subject begs the question of how the state of
anesthesia can be measured, and this is one of the
more difficult clinical trial end points. One wit, a
famousBritish cardiothoracic anesthesiologist, has
commented,‘If you can tell mewhat consciousness
is, then I will tell you what anesthesia is’!
Gases are usually administered either ‘pure’ (i.e.
with limits on impurities) or in combination with
excipients, for exampleoxygen, air or helium in the
gas stream which is vaporizing a liquid haloge-
nated hydrocarbon (validated vaporizers, usually
designated for use with a single active compound,
are required). When the route of administration
includes mechanical ventilator (including a hand-
squeezed bag), then drug economy, occupational
exposure of the staff, carbon dioxide scrubbing and
other pharmacokinetic problems emerge that are
rarely encountered elsewhere. Gas flow can be
measured with various devices, and exhaled gas
concentrations (including carbon dioxide) can now
be measured instantaneously. A rare adverse event,
malignant hyperthermia, is associated with the
inhalation of halogenated hydrocarbons (as well
as some depolarizing neuromuscular junction
blocking drugs), and this can be treated with intra-
venous dantrolene (Strazis and Fox, 1993).
There are some uses for gaseous drugs outside of
surgery. Nitrous oxide and oxygen mixtures are
sometimes used as analgesics during labor or
when transferring patients in pain by road or heli-
copter. In very cold weather, nitrous oxide can
liquefy, reducing the delivered dose; shaking the
container helps.
Helium/oxygen mixtures are used to improve
oxygenation in patients with subtotal airways
obstruction, exploiting the superior flow (pro-gli-
dant) properties of the lighter gas. The use of this
mixture as prophylaxis against nitrogen narcosis at
high inspired pressures (deep sea divers) or to
minimized fire hazard is also well described. Fire
hazard due to oxygen (arguably a gaseous drug
under some circumstances) is important. Patients
are often burned when on oxygen therapy for lung
disease which they are encouraging with an illicit
cigarette. The disastrous fire inside the command
capsule of Apollo 3, during a launch rehearsal on
Pad 39B at Cape Kennedy, started in a pure oxygen,
normal pressure, atmosphere. Reduction in total
atmospheric pressure and excipient nitrogen has
since been employed in all pressurized American
space vehicles, but they still contain supra-atmo-
spheric partial pressures of oxygen, and a fire was
recently reported in the Russian–American Space
Station.Metered dose inhalers and nebulized
drugsIn general, and with a few rare exceptions (see
below), the inhaled route of administration is the
most difficult that is commonly encountered.
Metered dose inhalers and nebulizers are consid-
ered together here because theyare both aerosols of
drug solution.
In textbooks for a general audience, it is custom-
ary to insert, at this point, a graph that relates
aerosol particle size to the penetration by drugs
of various levels of the airway. Particles> 10 mm
are stated to commonly impact in the pharynx,
those< 5 mm are assumed to be ideal for alveolar
delivery and those<0.05mm are said not to deposit
in the lung at all, being liable to be exhaled. This is
an oversimplification.
Particle deposition is actually dependent on a
large number of factors, attested to by a vast litera-
ture in the fields of respiratory medicine, pulmon-
ary physiology and industrial hygiene. These
factors include (with example studies)coughing (Camneret al., 1979);mucociliary action (Lippmannet al., 1980);exercise and minute ventilation (Bennettet al.,
1985);mucous production and ability to expectorate
(Agnewet al., 1985);apnoeic pause at the end of inhalation (Legath
et al., 1988);56 CH5 PHARMACEUTICS