Pharmacology: Drug Distribution and Binding

Drug Absorption

• Absorption is the process of drug movement from administration site to bloodstream.
• The rate and efficiency of absorption vary by route and dosage form; oral route often has lower bioavailability due to first-pass metabolism.
• The duodenum is the primary site for drug absorption, impacting onset and magnitude of drug action.

Factors Influencing Drug Absorption

• Bioavailability: Amount of drug reaching systemic circulation unchanged; e.g., 100 mg administered with 70 mg absorbed results in 70% bioavailability.
• First Pass Metabolism: Drugs absorbed via the GI tract may be partially metabolized by the liver, decreasing the amount reaching systemic circulation.
• Solubility: Drugs must be hydrophobic yet also soluble in aqueous solutions for effective absorption; extreme hydrophilicity or hydrophobicity hinders absorption.
• Chemical Instability: Some drugs are sensitive to gastric pH, affecting their stability and absorption (e.g., Penicillin G).
• Drug Formulation: Factors like particle size, salt form, and excipients impact dissolution and thus absorption rate and bioavailability.

Drug Passage Across Membranes

• Drugs must traverse various barriers to reach receptor sites, including the blood-brain barrier and epithelial barriers.
• Passive Diffusion: Drug movement according to concentration gradient; influenced by lipid solubility and molecular size.
• Filtration: Allows low molecular weight substances to cross membranes; demonstrated in kidney filtration.
• Facilitated Diffusion: Less common; involves specific carriers to assist drug passage, such as glucose and vitamin B12 transport.
• Active Transport: Involves specialized transport proteins; drugs can be actively absorbed against concentration gradients (e.g., iodine in the thyroid).
• Pinocytosis: Minor absorption method for larger molecules and proteins; important in the gut for larger particles.

Route of Drug Administration

• IV administration bypasses absorption process by placing drug directly into circulation.
• Oral Administration: Although it is the safest method, it has lower bioavailability due to first-pass metabolism; influenced by factors like food presence and digestive differences across species.

Binding to Plasma Proteins

• Only unbound drugs can cross cell membranes; binding is reversible and affects drug distribution and elimination.
• Acidic drugs primarily bind to albumin while basic drugs bind to alpha-1-acid glycoprotein; this binding slows pharmacologic effect onset.
• Drug-protein binding impacts elimination, particularly via glomerular filtration, as bound drugs cannot be filtered.

Drug Interactions

• Competition for binding sites on plasma proteins can increase the amount of free drug, enhancing therapeutic or toxic responses.

Interspecies Differences

• Variations in gastrointestinal tract mass among species affect interspecies drug distribution, particularly in veterinary pharmacology.

Drug Redistribution

• Redistribution refers to drug sequestration in low blood flow tissues, terminating its action; often seen in highly lipid-soluble drugs like thiopental.

CNS Distribution

• CNS drug distribution is limited by the blood-brain barrier, which consists of tight junctions in capillaries; drugs need high lipid solubility to cross.
• Active transport systems in the choroid plexus regulate organic acid and base transport, maintaining low CNS concentrations of certain drugs.
• Cerebrospinal fluid circulation continuously dilutes drug concentration in the CNS.

Transplacental Distribution

• Drugs cross the placenta primarily through simple diffusion; CNS-affecting drugs generally possess properties enabling easy placental transfer.

Barriers in Other Tissues

• Specific tissues such as the prostate, testicles, and eye have barriers that limit drug penetration, influencing drug concentration in those areas.