Lecture 2
Non-oral
II - Rectal administration
 Certain drugs are given rectally in the form of enemas or
suppositories for local therapy or systemic effect.
 The rectal administration of drugs intended for systemic
effect is limited to situations in which oral administration is
difficult or contraindicated.
 Suppositories are used more frequently in children than in
adult.
 Drugs that are given by this route include: aspirin,
acetaminophen, indomethacin, theophylline, chlorpromazine,
prochlorperazine, promethazine and certain barbiturates and
anticonvulsive drugs.
 Drug absorption from the rectum is often slow. (why?)
- Although the rectum has a good blood supply, it is devoid
of villi and has relatively small surface area.
 General principle with respect to drug absorption following
rectal administration to man:
1) Absorption from the rectum is more rapid and more
efficient where drugs are given in solution form
(microenemas) than in suppository form.
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2) The presence of fecal matter in the rectum retards
absorption (absorption is more rapid and efficient if a
cleansing enema precedes drug administration).
3) Some suppository bases such as PEG (poly ethylene
glycol) are irritating to the human rectum and tend to
promote defecation and loss of the drug.
4) Bioavailability from suppositories may be poor
because the drug is not released or is slowly released.
5) PH of the rectal solution also may influence
absorption. Example: an improvement in the rectal
absorption of morphine was occurred in going from
PH 4.5 to PH 7.4 of rectal solution.
- The rectal solutions of theophylline are a reasonable
alternative when the oral dosing is not possible.
- The absorption of tetracycline hydrochloride & sodium
pencillin G after rectal administration of penicillin G
aqueous solution is only about to 10 % that observed after
oral administration of drug solutions to fasting subjects.
- The rectal absorption of lincomycin in children after
administration of an aqueous solution as only 50% that
observed after oral administration of a syrup form of the
drug.
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- The absorption of lincomycin after rectal administration of
an aqueous solution to adults, who were given an enema to
cleanse the lower colon & rectum the night before, was
comparable to that observed after oral administration of
the capsule of the drug.
- The absorption of the drug from PEG suppositories was
poor and erratic.
- The bioavailability of lincomycin form suppository was
only about third that found with capsule given orally.
- Rectal administration for systemic action may be preferred
for drugs destroyed or inactivated by stomach & intestine.
- The administration of drug by the rectal route may be
indicated when the oral route is precluded because of
vomiting or when the patent is unconscious or incapable of
swallowing drugs safely.
- Approximately 50% of a dose of drug absorbed from rectal
administration is likely to bypass the liver, an important
factor when considering orally administration drug that
are rapidly destroyed in the liver by first - pass effect.
- On the negative side, compared with oral administration,
rectal administration of drugs is inconvenient and the
absorption of drugs from the rectum is frequently irregular
and difficult to predict.
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Lecture 3
Non-oral medications
III - Application to the skin:
- Dermatologic preparations are usually intended to act locally
in the treatment of the skin disorders.
- Application of the drugs to the skin minimizes systemic
exposure. For example the safe and effective topical use of 5fluorouracil to treat premalignant and malignant skin lesions.
The systemic administration of 5-fluorouracil often results in
serious adverse effects.
- Systemic administration of glucocorticoids gives excellent
results for inflammatory skin lesions, but their adverse effects
are considerable. Many of these diseases can be controlled by
topical application with dramatic decrease in side effects.
 Human skin consists of three layers.
- The epidermis, the dermis and the subcutaneous layers (fatty).
 The epidermis is nonvascular, multilayered, outer region of
the skin. The most superficial layer of epidermis is stratum
corneum.
- Stratum corneum composed of several layers of dead
keratinized cells and is the skin barrier to loss of water and to
entry of foreign substances.
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 Dermis or true skin is a highly vascular region and the
drugs penetrating to this region are reached the systemic
circulation.
 The site of application and state of the skin play an
important role in percutaneous absorption of drugs.
 Absorption is rapid in regions with large or numerous hair
follicles.
 Absorption is decreased in some region of skin having
thickened stratum corneum (foot).
 Skin permeability varied substantially depending both on
the properties of drug and on the site of application.
 It was found that, whatever the compound applied, the
forehead was about twice as permeable as the arm or
abdomen and application behind the ear produced
intermediate results.
- Cuts, diaper rash, inflammation, mild burns or any other
condition in which the stratum corneum is damaged or
destroyed promotes the absorption of drugs through the skin.
 Hydration of the skin (by soaking in water or by occluding
the skin surface with an impermeable material as plastic
film) alters the barrier characteristics of stratum corneum
and promotes drug absorption.
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 Also, certain lipophilic ointment bases may retard water loss
from skin and promote hydration and drug absorption.
 Aging and environmental factors that lead to dehydration of
skin can retard drug absorption, example: environmental
temperature can affect the hydration of stratum corneum and
the local blood flow.
 Chemical forms of drug and vehicle in which drug is
incorporated can have an important influence on
percutaneous absorption.
 For example: the efficacy of fluocinolone acetonide in
inflammatory dermatoses (eczema and psoriasis) strongly
depends on vehicle.
 It was found that the preparation containing drug dissolved
in propylene glycol was more effective in the treatment than
the drug dispersed in soft paraffin ointment.
 The incorporation of dimethyl sulfoxide (DMSO) (as
penetration enhancers) into topical formulations enhances
penetration (percutaneous absorption) of many drugs.
- This by producing structural changes in the skin such as
swelling of the stratum corneum or by replacement of water as
the continuous membrane phase of the skin barrier.
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 The other penetration enhancers such as: propylene glycol,
oleic acid, dimethylformamide.
 Long-term application of some drugs may alter the
percutaneous barrier and resulting in enhanced penetration.
As with salicylic acid because of the keratolytic effects.
 Systemic toxicity of topically applied drugs is of particular
concern in infants because they absorb drugs through the
skin as efficiently as adult do and the ratio of surface area to
the body weight in new born is 3 times that in adults which
result in much higher blood levels.
 There is now considerable interest in the topical application
of drugs intended for systemic effects. This may be useful
for drugs with low bioavailability after oral administration
due to the first -pass metabolism.
 Also this route of administration may be useful for shortacting drugs. Since percutaneous absorption tend to be slow
and produce prolonged effects.
Example: topical preparation of nitroglycerin, a compound
with a low oral bioavailability and short duration of action.
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IV- Inhalations
- The lungs are remarkably efficient organs for the
transport of gases for the following reasons:
1- The lung has a large surface area of the alveoli.
2- The high permeability of the alveolar epithelium.
3- The rich blood supply perfusing the lungs facilitates rapid
exchange between blood and inspired air. These
characteristics are important for drug absorption and ensure
the rapid uptake of drugs given by inhalation.
4- The drug is not subjected to first –pass hepatic metabolism
and is absorbed directly into blood stream.
- Gaseous or volatile anesthetics are the most important
example of drugs given by this route.
Similarities between gastrointestinal and pulmonary
absorption are:
1- Most compounds absorbed by passive diffusion across a
lipid-pore membrane.
2- Large polar molecules (heparin) are slowly absorbed.
3- Absorption of weak electrolytes (p-amino salicylic acid,
procainamide, sulfisoxazole) is a function of PH.
4- The absorption of lipid soluble molecules is rapid.
- Although in principle, any drug introduced for systemic effect
may be given by way of the lung, practice aerosol
administration has been limited to those drugs affect pulmonary
function.
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- Examples for Aerosolized drugs used in treatment of
ashthma and other reversible airflow obstructions include:
- Adrenocorticoid steroids (e.g. Beclomethasone),
bronchodilators (e.g. Metaproterenol), and antiallergics (e.g.
Cromolyn).
- Reasons for the limited use of aerosols for inhalation:
1- The relatively poor efficiency of dosage form with respect to
delivery of drugs to respiratory tract.
2- A large fraction of an aerosolized dose impacts in the mouth
and throat and is swallowed rather than inhaled.
3- Considerable variability may be observed in the amount of
drug actually reaching the lung. Therefore, despite the rapid
absorption take place from the lungs, aerosol administration
cannot be an alternative to I.V. Injection. (Give the reason).
4- In the presence of increasing airway obstruction, where
aerosol penetration is limited, the I.V route is preferred.
- Inhales bronchodilators are delivered directly to the target
organ and minimize the systemic side effects. (Advantage).
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- Aerosolized Pentamidine may be able to effective in the
prophylaxis and therapy of pneumonia in the patients with
(AIDS) without the systemic (serious) side effects if it
administered parentally (advantage).
- The particle size of the aerosolized droplets is a critical
factor in the efficacy of the dosage form.
- Because large particles (20 micrometer) impact in the mouth,
throat and upper respiratory tract .Small particles (0.6
micrometer) penetrate more efficiently into the lung from which
absorption is rapid but the large fraction of the dose is exhaled.
- The condition of the patient may limit the penetration of
aerosolized drug in to respiratory tract.
- The lack of effect of bronchodilator aerosols in severe
asthma appear to be related to inability of patients to inhale
adequate amount rather than to an intrinsic resistance to drug.
- The cromolyn aerosol dosage form is indicated for
prophylactic treatment of bronchial asthma and the drug
poorly absorbed from GIT.
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Lecture 4
V- Intranasal applications
- Drugs are usually administered intranasally for the alleviation
of local symptoms.
- These products contain decongestants, antihistamines, and
corticosteroids.
- There is interest in the intranasal route for systemic
administration of drugs because:
1. The nasal mucosa appears to be more permeable to drug
than GIT mucosa.
2. No local metabolism is known.
3. Drugs absorbed through the nasal mucosa go directly to
blood stream and are not subjected to first-pass hepatic
metabolism.
Examples:
- The advantages of intranasal administration were
demonstrated with propranolol which subjected to
presystemic metabolism after oral administration.
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- The time course of propranolol in serum and total area
under the serum level time curve after intranasal
administration of the drug were identical to I.V.
administration (rapid and complete absorption of
therapeutic doses after intranasal application).
- In contrast the total area under the curve after oral
administration was only 25% of that found after I.V.
The drug characteristics for good nasal absorption seem
to be similar to those for good absorption from GIT but:
 Membrane of nasal mucosa appears to be more
permeable than those of gut.
 Peptides are not well absorbed after intranasal
application but with certain additives (surface active agent),
the absorption can be promoted.
 The addition of 0.5% sodium deoxycholate to the
nasal preparations resulted in increase in the nasal
permeability.
 The same result observed by the addition of bile salts
(enhance the nasal permeability by removing the epithelial
cells, which constitute the major permeability barrier). And
this explains the extreme caution in using bile salts as
adjuvants for intranasal administration of therapeutic agents.
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- There are two mechanisms for drug transport
from nasal cavity:
a) Fast rate mechanism:
That is dependent on lipophilcity.
b) Slower rate mechanism:
That is dependent on molecular weight.
- A high degree of absorption was found for low molecular
weight and polar compound.
- The examples for intranasal administration for
systemic effect are:
 Oxytocin (stimulate lactation).
 Demsopressin (antidiuretic hormone).
 Intranasal buserclin is an effective, simple and safe way in
the treatment for advanced prostatic cancer.
 The nasal absorption of some hormones such as insulin
and calcitonin was studied and a great interest to develop a
dosage form of insulin that not required injection.
- The intranasal administration resulted in measurable blood
level and a hypoglycemic response, but the absorption is
limited and not reproducible.
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 The nasal absorption of insulin with a promoter such as
bile salts improves bioavailability.
 The rectal insulin was more effective in lowering plasma
glucose than nasal, buccal or sublingual.
 The bioavailability of rectal insulin is 20% compare with
less than 1% for intranasal insulin.
 The addition of 5% sodium glycocholate increased the
nasal absorption of insulin and both the nasal and rectal
insulin have the same bioavailability and were about half
as effective as I.M. insulin in reducing glucose level.
 It was found that an insulin nasal spray administered
before meal (lunch) not only prevented the increase but
also induced a decrease in the blood glucose level without
side effect (only slight nasal irritation for 1 to 2 minutes).
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