Pharmacology: Administration and Distribution of Drugs

Parenteral Administration

• Intravenous administration places the drug directly into the circulatory system, leading to rapid distribution throughout the body.
• Subcutaneous and intramuscular injections show slow distribution of the drug, as it must diffuse from the site of injection into systemic circulation.
• Parenteral routes produce a depot in the tissues from which the drug must reach the blood or lymph.

Blood-Brain Barrier (BBB)

• The BBB is composed of membranes of tightly joined epithelial cells lining the cerebral capillaries, protecting the brain from exposure to a large number of metabolites and chemicals.
• Parenterally administered drugs may not cross the BBB.
• It is possible to bypass the BBB by injecting the drug directly into specific organs or areas of the body, such as intraspinal or intracerebral routes.

Prodrug Design

• Prodrug design can alter the solubility characteristics of a drug, increasing the flexibility in formulating dosage forms.
• Examples of prodrug design include:
  • Methylprednisolone: slightly water-insoluble, used in tablets.
  • Methylprednisolone acetate: essentially water-insoluble, used in topical ointments and sterile aqueous suspensions for intramuscular injection.
  • Methylprednisolone sodium succinate: water-soluble, used in oral, intravenous, and intramuscular dosage forms.

Protein Binding

• Once a drug enters the systemic circulation, it can undergo protein binding, usually to albumin.
• Protein binding can have a profound effect on the drug's effective solubility, biodistribution, and biological half-life.
• Example: warfarin, with its high protein binding, increases the effective concentration at the receptor, leading to an increased prothrombin time and potential hemorrhage.

Tissue Depots

• The drug can be stored in tissue depots, such as neutral fat, which constitutes 20-50% of body weight.
• The more lipophilic the drug, the more likely it will concentrate in these pharmacologically inert depots.
• Example: thiopental, a lipophilic barbiturate, rapidly disappears into tissue protein, redistributes into body fat, and then slowly diffuses back out of the tissue depots.

Drug Metabolism

• All substances in the circulatory system, including drugs, metabolites, and nutrients, pass through the liver.
• The liver is the primary organ involved in the metabolism of xenobiotics.
• The mixed-function oxidase system, which includes the cytochrome P450 (CYP) enzymes, is responsible for the oxidative metabolism of foreign compounds.

Isomerism

• Geometric isomers (cis-trans isomerism or E-Z isomerism) of drugs can differ in their capabilities for interacting with biological receptors, distribution, metabolism, and excretion.
• Conformational isomers (anti, eclipsed, and gauche) exist due to rotation of atoms or groups of atoms around a single bond.
• Differences in reactivity of functional groups or interaction with biological receptors may be caused by differences in steric requirements of the receptors.

Cytochrome P450 (CYP)

• CYP is a superfamily of heme proteins responsible for transferring an oxygen atom to the substrate.
• The CYP enzymes are found in high concentrations in the liver, but are also present in other tissues, such as lung, kidney, intestine, skin, placenta, and adrenal cortex.
• The CYP system is able to metabolize an almost unlimited number of diverse substrates by various oxidative transformations.