• Most anesthetic drugs are lipophilic, resulting in a Vd that exceeds total body water (∼ 40 L). For example the Vd of fentanyl is about 350 L in adults, and the Vd for propofol may exceed 5000 L.
Biotransformation: The chemical alteration of the drug molecule. Also referred to as metabolism.
• The liver is the primary organ of metabolism. The end products are usually—but not necessarily—inactive and water soluble. The latter property allows excretion by the kidney.
• Can be divided into phase I and phase II reactions.
° Phase I reactions convert drug into more polar metabolites through oxidation, reduction, or hydrolysis.
° Phase II reactions couple (conjugate) a parent drug or a phase I metabolite with an endogenous substrate (e.g., glucuronic acid) to form water-soluble metabolites that are eliminated in the urine or stool.
• Phase I metabolites may be excreted without undergoing phase II biotransformation, and a phase II reaction can precede or occur without a phase I reaction.
Hepatic clearance: Volume of plasma or blood cleared of drug per unit of time
• The hepatic clearance is liver blood flow times the hepatic extraction ratio (which is the fraction of drug entering the liver that is metabolized.)
• Example: If the extraction ratio is 50%, then hepatic clearance is half of liver blood flow.
Excretion
• The kidneys are the principal organ of excretion. The nonionized fraction of drug is reabsorbed in the renal tubules, and the ionized portion is excreted in urine.
• Renal clearance is the rate of elimination of a drug from kidney excretion and can be calculated by renal blood flow times the renal extraction ratio.
• Enterohepatic recirculation: drug excreted into the bile and then reabsorbed in the intestine.
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