The lipophilic characters of drugs are enhanced in non-ionizable hydrocarbon
chains and ring systems. Drug lipophilicity is required for:
Drug absorption from GIT and respiratory tract (through the lipid bilayers).
Drug penetration of the blood brain barrier.
Drug passage through the placental barrier.
Drug renal tubular reabsorption in the kidneys.
Enhanced depot effect of intramuscular injections.
Enhanced topical absorption through skin penetration.
Enhanced plasma protein binding.
Alternatively, the hydrophilic character of drugs is enhanced by the presence of
polar groups like nitrogen- and oxygen-containing functional groups. Drug
hydrophilicity is required for:
Drug dissolution in parenteral and ophthalmic preparations.
Drug dissolution in GIT.
Adequate urine concentration of the drug (for urinary tract infections for
example).
Most drugs are weak acids, weak bases or salts of either of them. Strong acids
and bases are nearly completely ionized in aqueous media, whilst the ionization and
hence dissolution weak acids and bases in aqueous media depends on the pH of the
medium. According to Le Chatelier's principle, weak acids like acetylsalicylic acid
are less ionized in acidic media. As the acidity of the medium increases (pH
decreases), the ratio of non-ionized portion of the acid increases and vice versa. For
this reason, weak acids are mostly non-ionized and hence more lipid soluble in acidic
media. The reverse is true for weak bases like morphine, where basic media enhance
their lipid solubility due to the predominance of the non-ionized portion and vice
versa.
This is particularly important for drug absorption and elimination kinetics. For
example, weakly acidic drugs are mostly unionized in the stomach (acidic medium)
and hence are lipid solube so can be absorbed from the stomach since absorption
requires hydrophobicity (lipophilicity) as absorption takes place through the lipid
bilayers of the GIT. Alternatively, basic drugs are ionized (hydrophilic) in the
stomach so absorption of such drugs is minimal in the stomach and is delayed until
the drug reaches the basic medium of the intestine.
Another example is renal elimination from the kidney. Excretion of weakly
acidic drugs can be enhanced from the kidney by the administration of urinary
alkalinizers like sodium bicarbonate. This will make the drug predominantly in the
polar (hydrophilic) form that dissolves in the urine and is not reabsorbed through the
renal tubules since this reabsorption requires lipophilicity (unionized forms).
Similarly, an intoxicated patient with a weakly basic drug can be administered a
urinary acidifier to enhance drug elimination. The reverse is true if reabsorption of
the drug is required to prolong its action.
2- Drug route of administration:
Different routes of drug administration differ in drug bioavailability (rate and
extent of drug absorption). This may dramatically modify drug effects, drug onset
and duration of action. These include routes for local action and routes for systemic
action (including enteral, inhalation and parenteral routes).
A) Transdermal and topical administration:
Transdermal (percutaneous) drug absorption is the placement of a drug
formulation (lotion, ointment, cream, paste or patch) on the skin surface for systemic
absorption. Small lipid-soluble drugs (e.g. nitroglycerin, nicotine, scopolamine,
clonidine, fentanyl, testosterone and 17-β-estradiol) are absorbed readily from the
skin. Alternatively, drugs may be applied topically for local effects (to avoid systemic
toxicity or to localize drug effect). Examples are antimicrobials (antibacterials and
antifungals) and local anaesthetics. Local anaesthetics may be applied together with a
vasoconstrictor like adrenaline to localize the anaesthetic (to increase action) and
prevent systemic absorption (to decrease drug toxicity).
Other topical routes of administration include:
Eye, ear and nose drops.
Urethral or vaginal solutions.
Mouthwashes and gargles.
B) Enteral administration:
This is represented by drug administration through the alimentary canal (from
mouth to anus), including:
1- Peroral (oral) administration:
Drug molecules are absorbed throughout the GIT but most absorption takes
place at the duodenal region due to the greater surface area (more villi and microvilli
that are responsible for absorption).
Although the oral route is the most convenient, most economic and safest route
of drug administration, many limitations of this route are present, including the
following:
Irritant drugs that cause excessive vomiting, e.g. tartaremetic.
Acid-labile drugs such as peptide hormones (insulin).
Drugs that are extensively inactivated in the liver through first-pass effect.
Insoluble and non-absorbable drugs, e.g. hexamethonium, except when
required for local effect in the GIT (e.g. streptomycin).
Complexation with some food components retards the absorption (e.g.
tetracycline and calcium).
Unconscious patients (unable to swallow).
Convulsions (loss of control on epiglottis may lead to respiratory tract
aspiration).
Emergency cases (due to slow action).
2- Buccal and sublingual administration:
A tablet or lozenge is placed in the mouth in contact with the buccal mucosa.
This allows for absorption of small, lipid-soluble molecules through the epithelial
lining of the mouth. Alternatively, a tablet can be placed under the tongue
(sublingual) and the drug is absorbed from the sublingual veins.
Buccal and sublingual drug administration allow for systemic absorption of the
drugs without passing into the liver (no first-pass effect).
3- Rectal administration:
Drugs are administered in the form of liquids (enemas) or suppositories.
Absorption takes place through the mucosal surface and rectal veins. The lower two-
thirds of the rectum allow for direct systemic absorption bypassing hepatic first-pass
effect.
C) Respiratory tract administration:
This includes:
1- Intra-nasal administration:
The drug is administered to the nasal mucosa in the form of drops or spray for
the purpose of local (e.g. decongestants) or systemic effects.
2- Pulmonary inhalation:
The drug is administered by various devices like metered dose inhalers (MDI),
spacers, nebulizers or dry powder aerosols. Drug absorption from the bronchial tree is
very rapid and avoids hepatic first-pass effect.
D) Parenteral administration:
This includes:
1- Intra-venous injection:
The drug is injected directly into venous blood, pooled to the heart during
diastole through superior and inferior vena cavae and then distributed to the whole
body by cardiac systole.
This route has many advantages:
Rapid action, so it is most suitable in emergency cases.
This type of administration also ensures 100% bioavailability.
Large volumes of drugs, nutrients electrolyte solutions can be given.
Irritant, hypertonic, acidic or alkaline solutions can be given by this route
slowly as the preparation is diluted in a large volume of blood.
However, this route has many disadvantages:
Allergic reactions are more common.
Rapid administration may cause toxic effects even at normal dose levels.
Overdoses can not be withdrawn nor absorption be retarded.
2- Intra-arterial injection:
The drug is injected into an artery to attain high drug concentration in a tissue
or an organ before being diluted in the general circulation.
3- Intra-muscular injection:
The drug is injected in the form of solution or suspension deep in skeletal
muscles. Drug absorption rate is dependent on lipid solubility of the drug, vehicle
composition and vascularity of the injected region.
4- Subcutaneous injection:
The drug is injected under the skin. The rate of drug absorption is slower than
intramuscular route as subcutaneous regions are less vascular than muscular tissue.
Some drugs in which slow absorption is necessary are given subcutaneously, e.g.
insulin and adrenaline.
5- Inta-articular injection:
This route is important when direct injection of a drug inside a joint is
required, e.g. corticosteroids in arthritis.
6- Intra-dermal (intra-cutaneous) injection:
The drug is injected in the dermis to minimize systemic absorption and
toxicity, e.g. allergic skin tests.
7- Intra-thecal injection:
The drug is injected into the spinal fluid. The specific gravity of the drug
determines the region of its effect.
3- Host's physiological, biochemical and nutritional status:
This is represented by:
1- Gastric emptying rate (GER): The average gastric emptying rate is about 55
minutes, but many factors cause delay or increase of this time. Factors that
increase gastric emptying increase drug absorption rate as most drugs are
absorbed from the intestine. Gastric emptying is affected by the nature of food
(bulky or hot meals tend to be retained in the stomach for a longer time),
emotional status and concurrent medication use (anti-cholinergics and pro-
kinetic agents).
2- Intestinal motility (peristalsis): A sufficient period of contact between the drug
and epithelial lining of the GIT (residence time) is required for drug
absorption. Increasing peristalsis (diarrhea, infections) may decrease drug
absorption in slowly-absorbed drugs.
3- Nature of diet: Protein, vitamin or essential fatty acid deficiency in diet retard
drug metabolism. Fasting induces liver microsomal enzymes.
4- Diseases: Diabetes potentiates liver microsomal enzymes increasing drug
metabolism. Liver disease impairs hepatic clearance of drugs causing
potentiation of drug effect. Renal disease impairs renal drug clearance.
Neoplastic diseases retard tissue metabolism.
5- Physical factors: Exposure to sublethal doses of radiation impairs hepatic drug
metabolism.
6- Species differences: Metabolizing enzymes may differ between different
species. The rabbit for example deaminates amphetamine to biologically
inactive ketone while the rat produces the biologically active vasopressor agent
4-hydroxyamphetamine.
7- Genetic differences: Some persons are rapid acetylators thus increasing the
hepatotoxic effects of isoniazid while others are slow acetylators thus
increasing the neurological toxicity of isoniazid. Some persons are deficient in
the intestinal intrinsic factor required for the absorption of vitamin B12.
8- Sex differences: Testosterone (male hormone) usually increases the rate of
drug metabolism.
.gif)
.gif)
No comments:
Post a Comment