Drug Administration part VII

From Application to Distribution
in the Body
As a rule, drugs reach their target organs
via the blood. Therefore, they must first
enter the blood, usually the venous limb
of the circulation. There are several possible
sites of entry.
The drug may be injected or infused
intravenously, in which case the drug is
introduced directly into the bloodstream.
In subcutaneous or intramuscular
injection, the drug has to diffuse
from its site of application into the
blood. Because these procedures entail
injury to the outer skin, strict requirements
must be met concerning technique.
For that reason, the oral route
(i.e., simple application by mouth) involving
subsequent uptake of drug
across the gastrointestinal mucosa into
the blood is chosen much more frequently.
The disadvantage of this route
is that the drug must pass through the
liver on its way into the general circulation.
This fact assumes practical significance
with any drug that may be rapidly
transformed or possibly inactivated in
the liver (first-pass hepatic elimination;).
Even with rectal administration,
at least a fraction of the drug enters the
general circulation via the portal vein,
because only veins draining the short
terminal segment of the rectum communicate
directly with the inferior vena
cava. Hepatic passage is circumvented
when absorption occurs buccally or
sublingually, because venous blood
from the oral cavity drains directly into
the superior vena cava. The same would
apply to administration by inhalation
. However, with this route, a local
effect is usually intended; a systemic action
is intended only in exceptional cases.
Under certain conditions, drug can
also be applied percutaneously in the
form of a transdermal delivery system
. In this case, drug is slowly released
from the reservoir, and then penetrates
the epidermis and subepidermal
connective tissue where it enters blood
capillaries. Only a very few drugs can be
applied transdermally. The feasibility of
this route is determined by both the
physicochemical properties of the drug
and the therapeutic requirements
(acute vs. long-term effect).
Speed of absorption is determined
by the route and method of application.
It is fastest with intravenous injection,
less fast which intramuscular injection,
and slowest with subcutaneous injection.
When the drug is applied to the
oral mucosa (buccal, sublingual route),
plasma levels rise faster than with conventional
oral administration because
the drug preparation is deposited at its
actual site of absorption and very high
concentrations in saliva occur upon the
dissolution of a single dose. Thus, uptake
across the oral epithelium is accelerated.
The same does not hold true for
poorly water-soluble or poorly absorbable
drugs. Such agents should be given
orally, because both the volume of fluid
for dissolution and the absorbing surface
are much larger in the small intestine
than in the oral cavity.
Bioavailability is defined as the
fraction of a given drug dose that reaches
the circulation in unchanged form
and becomes available for systemic distribution.
The larger the presystemic
elimination, the smaller is the bioavailability
of an orally administered drug.

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Drug Administration part VI

Dermatologic Agents

Pharmaceutical preparations applied to
the outer skin are intended either to
provide skin care and protection from
noxious influences, or to serve as a
vehicle for drugs that are to be absorbed
into the skin or, if appropriate, into the
general circulation .

Skin Protection
Protective agents are of several kinds to
meet different requirements according
to skin condition (dry, low in oil,
chapped vs moist, oily, elastic), and the
type of noxious stimuli (prolonged exposure
to water, regular use of alcoholcontaining
disinfectants , intense solar irradiation).
Distinctions among protective
agents are based upon consistency, physicochemical
properties (lipophilic, hydrophilic),
and the presence of additives.

Dusting Powders are sprinkled onto
the intact skin and consist of talc,
magnesium stearate, silicon dioxide
(silica), or starch. They adhere to the
skin, forming a low-friction film that attenuates
mechanical irritation. Powders
exert a drying (evaporative) effect.

Lipophilic ointment (oil ointment)
consists of a lipophilic base (paraffin oil,
petroleum jelly, wool fat [lanolin]) and
may contain up to 10 % powder materials,
such as zinc oxide, titanium oxide,
starch, or a mixture of these. Emulsifying
ointments are made of paraffins and
an emulsifying wax, and are miscible
with water.

Paste (oil paste) is an ointment
containing more than 10 % pulverized
constituents.

Lipophilic (oily) cream is an emulsion
of water in oil, easier to spread than
oil paste or oil ointments.

Hydrogel and water-soluble ointment
achieve their consistency by
means of different gel-forming agents
(gelatin, methylcellulose, polyethylene
glycol). Lotions are aqueous suspensions
of water-insoluble and solid constituents.

Hydrophilic (aqueous) cream is an
emulsion of an oil in water formed with
the aid of an emulsifier; it may also be
considered an oil-in-water emulsion of
an emulsifying ointment.
All dermatologic agents having a
lipophilic base adhere to the skin as a
water-repellent coating. They do not
wash off and they also prevent (occlude)
outward passage of water from
the skin. The skin is protected from drying,
and its hydration and elasticity increase.
Diminished evaporation of water
results in warming of the occluded skin
area. Hydrophilic agents wash off easily
and do not impede transcutaneous output
of water. Evaporation of water is felt
as a cooling effect.
Dermatologic Agents as Vehicles
In order to reach its site of action, a drug
must leave its pharmaceutical preparation
and enter the skin, if a local effect
is desired (e.g., glucocorticoid ointment),
or be able to penetrate it, if a
systemic action is intended (transdermal
delivery system, e.g., nitroglycerin
patch, ). The tendency for the drug
to leave the drug vehicle is higher
the more the drug and vehicle differ in
lipophilicity (high tendency: hydrophilic
D and lipophilic V, and vice versa). Because
the skin represents a closed lipophilic
barrier, only lipophilic
drugs are absorbed. Hydrophilic drugs
fail even to penetrate the outer skin
when applied in a lipophilic vehicle.
This formulation can be meaningful
when high drug concentrations are required
at the skin surface (e.g., neomycin
ointment for bacterial skin infections).

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Drug Administration part V

Drug Administration by Inhalation
Inhalation in the form of an aerosol
, a gas, or a mist permits drugs to
be applied to the bronchial mucosa and,
to a lesser extent, to the alveolar membranes.
This route is chosen for drugs intended
to affect bronchial smooth muscle
or the consistency of bronchial mucus.
Furthermore, gaseous or volatile
agents can be administered by inhalation
with the goal of alveolar absorption
and systemic effects (e.g., inhalational
anesthetics, ). Aerosols are
formed when a drug solution or micronized
powder is converted into a mist or
dust, respectively.
In conventional sprays (e.g., nebulizer),
the air blast required for aerosol
formation is generated by the stroke of a
pump. Alternatively, the drug is delivered
from a solution or powder packaged
in a pressurized canister equipped
with a valve through which a metered
dose is discharged. During use, the inhaler
(spray dispenser) is held directly
in front of the mouth and actuated at
the start of inspiration. The effectiveness
of delivery depends on the position
of the device in front of the mouth, the
size of aerosol particles, and the coordination
between opening of the spray
valve and inspiration. The size of aerosol
particles determines the speed at which
they are swept along by inhaled air,
hence the depth of penetration into
the respiratory tract. Particles >
100 μm in diameter are trapped in the
oropharyngeal cavity; those having diameters
between 10 and 60μm will be
deposited on the epithelium of the
bronchial tract. Particles < 2 μm in diameter
can reach the alveoli, but they
will be largely exhaled because of their
low tendency to impact on the alveolar
epithelium.
Drug deposited on the mucous lining
of the bronchial epithelium is partly
absorbed and partly transported with
bronchial mucus towards the larynx.
Bronchial mucus travels upwards due to
the orally directed undulatory beat of
the epithelial cilia. Physiologically, this
mucociliary transport functions to remove
inspired dust particles. Thus, only
a portion of the drug aerosol (~ 10 %)
gains access to the respiratory tract and
just a fraction of this amount penetrates
the mucosa, whereas the remainder of
the aerosol undergoes mucociliary
transport to the laryngopharynx and is
swallowed. The advantage of inhalation
(i.e., localized application) is fully exploited
by using drugs that are poorly
absorbed from the intestine (isoproterenol,
ipratropium, cromolyn) or are subject
to first-pass elimination (beclomethasone
dipropionate, budesonide,
flunisolide, fluticasone dipropionate).
Even when the swallowed portion
of an inhaled drug is absorbed in unchanged
form, administration by this
route has the advantage that drug concentrations
at the bronchi will be higher
than in other organs.
The efficiency of mucociliary transport
depends on the force of kinociliary
motion and the viscosity of bronchial
mucus. Both factors can be altered
pathologically (e.g., in smoker’s cough,
bronchitis) or can be adversely affected
by drugs (atropine, antihistamines).

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Drug Administration part IV

Dosage Forms for Parenteral ,
Pulmonary , Rectal or Vaginal ,
and Cutaneous Application
Drugs need not always be administered
orally (i.e., by swallowing), but may also
be given parenterally. This route usually
refers to an injection, although enteral
absorption is also bypassed when
drugs are inhaled or applied to the skin.
For intravenous, intramuscular, or
subcutaneous injections, drugs are often
given as solutions and, less frequently,
in crystalline suspension for
intramuscular, subcutaneous, or intraarticular
injection. An injectable solution
must be free of infectious agents,
pyrogens, or suspended matter. It
should have the same osmotic pressure
and pH as body fluids in order to avoid
tissue damage at the site of injection.
Solutions for injection are preserved in
airtight glass or plastic sealed containers.
From ampules for multiple or single
use, the solution is aspirated via a
needle into a syringe. The cartridge ampule
is fitted into a special injector that
enables its contents to be emptied via a
needle. An infusion refers to a solution
being administered over an extended
period of time. Solutions for infusion
must meet the same standards as solutions
for injection.
Drugs can be sprayed in aerosol
form onto mucosal surfaces of body cavities
accessible from the outside (e.g.,
the respiratory tract). An aerosol
is a dispersion of liquid or solid particles
in a gas, such as air. An aerosol results
when a drug solution or micronized
powder is reduced to a spray on being
driven through the nozzle of a pressurized
container.
Mucosal application of drug via the
rectal or vaginal route is achieved by
means of suppositories and vaginal
tablets, respectively. On rectal application,
absorption into the systemic circulation
may be intended. With vaginal
tablets, the effect is generally confined
to the site of application. Usually the
drug is incorporated into a fat that solidifies
at room temperature, but melts in
the rectum or vagina. The resulting oily
film spreads over the mucosa and enables
the drug to pass into the mucosa.

Powders, ointments, and pastes
are applied to the skin surface. In
many cases, these do not contain drugs
but are used for skin protection or care.
However, drugs may be added if a topical
action on the outer skin or, more
rarely, a systemic effect is intended.

Transdermal drug delivery
systems are pasted to the epidermis.
They contain a reservoir from which
drugs may diffuse and be absorbed
through the skin. They offer the advantage
that a drug depot is attached noninvasively
to the body, enabling the
drug to be administered in a manner
similar to an infusion. Drugs amenable
to this type of delivery must: (1) be capable
of penetrating the cutaneous barrier;
(2) be effective in very small doses
(restricted capacity of reservoir); and
(3) possess a wide therapeutic margin
(dosage not adjustable).

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Drug Administration part III

matrix-type tablet,
the drug is embedded in an inert
meshwork from which it is released by
diffusion upon being moistened. In contrast
to solutions, which permit direct
absorption of drug , the use
of solid dosage forms initially requires
tablets to break up and capsules to open
(disintegration) before the drug can be
dissolved (dissolution) and pass
through the gastrointestinal mucosal
lining (absorption). Because disintegration
of the tablet and dissolution of the
drug take time, absorption will occur
mainly in the intestine . In
the case of a solution, absorption starts
in the stomach .
For acid-labile drugs, a coating of
wax or of a cellulose acetate polymer is
used to prevent disintegration of solid
dosage forms in the stomach. Accordingly,
disintegration and dissolution
will take place in the duodenum at normal
speed and drug liberation
per se is not retarded.
The liberation of drug, hence the
site and time-course of absorption, are
subject to modification by appropriate
production methods for matrix-type
tablets, coated tablets, and capsules. In
the case of the matrix tablet, the drug is
incorporated into a lattice from which it
can be slowly leached out by gastrointestinal
fluids. As the matrix tablet
undergoes enteral transit, drug liberation
and absorption proceed en route

coated tablets,
coat thickness can be designed such that
release and absorption of drug occur either
in the proximal or distal
bowel. Thus, by matching
dissolution time with small-bowel
transit time, drug release can be timed to occur
in the colon.

Drug liberation and, hence, absorption
can also be spread out when the
drug is presented in the form of a granulate
consisting of pellets coated with a
waxy film of graded thickness. Depending
on film thickness, gradual dissolution
occurs during enteral transit, releasing
drug at variable rates for absorption.
The principle illustrated for a capsule
can also be applied to tablets. In this
case, either drug pellets coated with
films of various thicknesses are compressed
into a tablet or the drug is incorporated
into a matrix-type tablet. Contrary
to timed-release capsules
, slow-release tablets have the advantage
of being dividable ad libitum;
thus, fractions of the dose contained
within the entire tablet may be administered.

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Drug Administration part II

Solid dosage forms include tablets,
coated tablets, and capsules (B).

Tablets have a disk-like shape, produced
by mechanical compression of
active substance, filler (e.g., lactose, calcium
sulfate), binder, and auxiliary material
(excipients). The filler provides
bulk enough to make the tablet easy to
handle and swallow. It is important to
consider that the individual dose of
many drugs lies in the range of a few
milligrams or less. In order to convey
the idea of a 10-mg weight, two squares
are marked below, the paper mass of
each weighing 10 mg. Disintegration of
the tablet can be hastened by the use of
dried starch, which swells on contact
with water, or of NaHCO3, which releases
CO2 gas on contact with gastric acid.
Auxiliary materials are important with
regard to tablet production, shelf life,
palatability, and identifiability (color).

Effervescent tablets (compressed
effervescent powders) do not represent
a solid dosage form, because they are
dissolved in water immediately prior to
ingestion and are, thus, actually, liquid
preparations.


The coated tablet contains a drug within
a core that is covered by a shell, e.g., a
wax coating, that serves to: (1) protect
perishable drugs from decomposing; (2)
mask a disagreeable taste or odor; (3)
facilitate passage on swallowing; or (4)
permit color coding.

Capsules usually consist of an oblong
casing — generally made of gelatin
— that contains the drug in powder or
granulated form

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Drug Administration part I

Dosage Forms for Oral, Ocular, and
Nasal Applications
A medicinal agent becomes a medication
only after formulation suitable for
therapeutic use (i.e., in an appropriate
dosage form). The dosage form takes
into account the intended mode of use
and also ensures ease of handling (e.g.,
stability, precision of dosing) by patients
and physicians. Pharmaceutical
technology is concerned with the design
of suitable product formulations and
quality control.
Liquid preparations (A) may take
the form of solutions, suspensions (a
sol or mixture consisting of small water-
insoluble solid drug particles dispersed
in water), or emulsions (dispersion
of minute droplets of a liquid agent
or a drug solution in another fluid, e.g.,
oil in water). Since storage will cause
sedimentation of suspensions and separation
of emulsions, solutions are generally
preferred. In the case of poorly
watersoluble substances, solution is often
accomplished by adding ethanol (or
other solvents); thus, there are both
aqueous and alcoholic solutions. These
solutions are made available to patients
in specially designed drop bottles, enabling
single doses to be measured exactly
in terms of a defined number of
drops, the size of which depends on the
area of the drip opening at the bottle
mouth and on the viscosity and surface
tension of the solution. The advantage
of a drop solution is that the dose, that
is, the number of drops, can be precisely
adjusted to the patient‘s need. Its disadvantage
lies in the difficulty that
some patients, disabled by disease or
age, will experience in measuring a prescribed
number of drops.
When the drugs are dissolved in a
larger volume — as in the case of syrups
or mixtures — the single dose is measured
with a measuring spoon. Dosing
may also be done with the aid of a
tablespoon or teaspoon (approx. 15 and
5 ml, respectively). However, due to the
wide variation in the size of commercially
available spoons, dosing will not
be very precise. (Standardized medicinal
teaspoons and tablespoons are
available.)
Eye drops and nose drops (A) are
designed for application to the mucosal
surfaces of the eye (conjunctival sac)
and nasal cavity, respectively. In order
to prolong contact time, nasal drops are
formulated as solutions of increased
viscosity.

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