Summary
Highlights
Pharmacokinetics begins with absorption, the process by which a drug enters circulation. Various routes of administration include oral (PO), rectal, intradermal, subcutaneous (Sub-Q), intramuscular (IM), intravenous (IV), topical, inhaled, buccal, and sublingual. Key routes to remember are oral and intravenous, with IV offering 100% bioavailability as it doesn't cross membranes.
Drugs must cross cell membranes to be absorbed. The mechanisms depend on drug characteristics: 1. Passive Diffusion: Small, hydrophobic (nonpolar) drugs move from high to low concentration. 2. Facilitated Diffusion: Larger, hydrophilic (polar) drugs use protein carriers to move from high to low concentration. 3. Active Transport: Large, hydrophilic drugs are pumped against their concentration gradient (low to high) using ATP. 4. Endocytosis: Very large molecules, like B12, bind to receptors and are engulfed by the cell, then exocytosed into the bloodstream.
Drug absorption is influenced by pH. Drugs exist as weak acids or weak bases. Weak acids are best absorbed in acidic environments (e.g., proximal duodenum) because they remain in their nonpolar, non-charged form. Weak bases are best absorbed in alkaline environments (e.g., distal ileum) for the same reason. This follows Le Chatelier's principle, where the reaction shifts to favor the nonpolar form in the appropriate pH.
Blood flow directly impacts absorption; decreased blood flow (e.g., during shock) reduces absorption, especially for oral, rectal, and transdermal routes. Surface area and contact time also play a role. Conditions like diarrhea decrease contact time and absorption, while constipation increases contact time and absorption. Diseases that reduce intestinal surface area (e.g., inflammatory bowel disease) will decrease absorption. P-glycoproteins can also decrease absorption by pumping drugs back into the GI tract, leading to multi-drug resistance.
Bioavailability (F) is the fraction of administered drug that reaches systemic circulation. IV drugs have 100% bioavailability. Oral drugs have lower bioavailability due to factors like absorption mechanisms, pH, blood flow, surface area, contact time, P-glycoproteins, solubility, and first-pass metabolism. The formula for bioavailability is AUC(oral) / AUC(IV), or the amount of drug absorbed orally divided by the amount absorbed (given) IV.
Bioavailability is affected by: 1. Solubility: Hydrophobic/lipophilic drugs are more bioavailable. Hydrophilic/large drugs are less bioavailable. 2. Instability: Drugs unstable in gastric acid (e.g., penicillin G) or prone to enzymatic breakdown (e.g., insulin) have decreased bioavailability when taken orally. 3. First-Pass Effect: After oral absorption, drugs enter the hepatic portal system and pass through the liver, which metabolizes a portion of the drug before it reaches systemic circulation. This significantly reduces bioavailability. Drugs like nitroglycerin are given sublingually or IV to bypass this effect.
To test understanding: 1. For a drug overdose, IV administration is best due to 100% bioavailability. 2. For a weakly basic drug with a pKa of 7.8, absorption is best in an alkaline environment closest to its pKa, such as the jejunum (pH 7.8).