Parenteral administration
a. Intravenous bolus injection: The drug is injected directly into the bloodstream, distributes throughout the body, and acts rapidly. Any side effects, including an intense pharmacologic response, anaphylaxis, or overt toxicity, also occur rapidly.
b. Intra-arterial injection: The drug is injected into a specific artery to achieve a high drug concentration in a specific tissue before drug distribution occurs throughout the body. Intra-arterial injection is used for diagnostic agents and occasionally for chemotherapy.
c. Intravenous infusion: The drug is given intravenously at a constant input rate. Constant-rate intravenous infusion maintains a relatively constant plasma drug concentration once the infusion rate is approximately equal to the drug’s elimination rate from the body (i.e., once steady state is reached).
d. Intramuscular injection: The drug is injected deep into a skeletal muscle. The rate of absorption depends on the vascularity of the muscle site, the lipid solubility of the drug, and the formulation matrix.
e. Subcutaneous injection: The drug is injected beneath the skin. Because the subcutaneous region is less vascular than muscle tissues, drug absorption is less rapid. The factors that affect absorption from intramuscular depots also affect subcutaneous absorption.
f. Miscellaneous parenteral routes
- Intra-articular injection: The drug is injected into a joint.
- Intradermal (intra-cutaneous) injection: The drug is injected into the dermis (i.e., the vascular region of the skin below the epidermis).
- Intrathecal injection: The drug is injected into the spinal fluid.
Enteral administration
a. Buccal and sublingual administration: A tablet or lozenge is placed under the tongue (sublingual) or in contact with the mucosal (buccal) surface of the cheek. This type of administration allows a nonpolar, lipid-soluble drug to be absorbed across the epithelial lining of the mouth. After buccal or sublingual administration, the drug is absorbed directly into the systemic circulation, bypassing the liver and any first-pass effects.
b. Peroral (oral) drug administration: The drug is administered orally, is swallowed, and undergoes absorption from the gastrointestinal tract through the mesenteric circulation to the hepatic portal vein into the liver and then to the systemic circulation. The peroral route is the most common route of administration.
(1) The peroral route is the most convenient and the safest route.
(2) Disadvantages of this route include the following:
(a) The drug may not be absorbed from the gastrointestinal tract consistently or completely.
(b) The drug may be digested by gastrointestinal enzymes or decomposed by the acid pH of the stomach.
(c) The drug may irritate mucosal epithelial cells or complex with the contents of the gastrointestinal tract.
(d) Some drugs may be incompletely absorbed because of first-pass effects or pre-systemic elimination (e.g., the drug is metabolized by the liver before systemic absorption occurs).
(e) The absorption rate may be erratic because of delayed gastric emptying or changes in intestinal motility.
(3) Most drugs are xenobiotics or exogenous molecules and, consequently, are absorbed from the gastrointestinal tract by passive diffusion and partitioning. Carrier-mediated transport, paracellular transport, and vesicular transport play smaller but critical roles, particularly for endogenous molecules.
(4) Drug molecules are absorbed throughout the gastrointestinal tract; but the duodenal region, which has a large surface area because of the villi and microvilli, is the primary absorption site. The large blood supply provided by the mesenteric vessels allows the drug to be absorbed more efficiently.
(5) Altered gastric emptying affects arrival of the drug in the duodenum for systemic absorption. Gastric emptying time is affected by food content, food composition (fats, acids delay gastric emptying), emotional state, circadian effects (gastric emptying tends to be more rapid in the morning than in the evening), and drugs that alter gastrointestinal tract motility (e.g., anticholinergics, narcotic analgesics, prokinetic agents). In general, the Tmax (time of peak systemic drug concentration) occurs earlier, when gastric emptying is faster than normal, and later, when gastric emptying is slower than normal.
The effect of gastric emptying on Cmax (peak systemic drug concentration) varies, depending on the absorption mechanism, pH dependence of dissolution, extent of pre-systemic elimination, etc.
(6) Normal intestinal motility from peristalsis brings the drug in contact with the intestinal epithelial cells. A sufficient period of contact (residence time) is needed to permit drug absorption across the cell membranes from the mucosal to the serosal surface.
(7) Some drugs, such as cimetidine and acetaminophen, when given in an immediate release peroral dosage form to fasted subjects produce a systemic drug concentration time with two peaks. This double-peak phenomenon is attributed to variability in stomach emptying, variable intestinal motility, and enterohepatic cycling.
c. Rectal administration: The drug in solution (enema) or suppository form is placed in the rectum. Drug diffusion from the solution or release from the suppository leads to absorption across the mucosal surface of the rectum. Drug absorbed in the lower two-thirds of the rectum enters the systemic circulation directly, bypassing the liver and any first-pass effects.
Respiratory tract administration
a. Intranasal administration: The drug contained in a solution or suspension is administered to the nasal mucosa, either as a spray or as drops. The medication may be used for local (e.g., nasal decongestants, intranasal steroids) or systemic effects.
b. Pulmonary inhalation: The drug, as liquid or solid particles, is inhaled perorally (with a nebulizer or a metered-dose aerosol) into the pulmonary tree. In general, particles >60 µm are primarily deposited in the trachea. Particles >20 µm do not reach the bronchioles, and particles <0.6 µm are not deposited and are exhaled. Particles between 2 and 6 µm can reach the alveolar ducts, although only particles of 1 to 2 µm are retained in the alveoli.
Transdermal and topical administration
a. Transdermal (percutaneous) drug absorption is the placement of the drug (in a lotion, ointment, cream, paste, or patch) on the skin surface for systemic absorption. An occlusive dressing or film improves systemic drug absorption from the skin. Small lipid-soluble molecules, such as nitroglycerin, nicotine, scopolamine, clonidine, fentanyl, and steroids are readily absorbed from the skin.
b. Drugs (e.g., antibacterial, local anesthetic agents) are applied topically to the skin for a local effect.
Miscellaneous
Miscellaneous routes of drug administration include ophthalmic, otic, urethral, and vaginal administration. These routes of administration are generally used for local therapeutic activity. However, some systemic drug absorption may occur.
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