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--- concept_pharmacokinetics_and_toxicokinetics [2025/04/17 18:32] – [3. Distribution] jkohts
+++ concept_pharmacokinetics_and_toxicokinetics [2025/04/18 01:58] (current) – jkohts
@@ Line 101: / Line 101: @@
-===== - Clearance =====
+==== - Clearance ====
-Clearance is the volume of blood or plasma from which a drug would have to be completely removed to account for the fall in concentration.
+**Clearance (Cl)** is the volume of plasma (or blood) from which a drug is completely removed per unit time. It is expressed as volume/time (e.g. mL/min or mL/hr).
-  * Clearance = Rate of elimination / Concentration
+It can be estimated by the formula:
+$$Clearance\ (mL/min) = \frac{Rate\ of\ elimination\ (mg/min)}{Plasma\ concentration\ (mg/mL)}$$
-Thus, the clearance of a drug is used to describe the rate of removal by either excretion or metabolism. This is the total body clearance.
-Clearance may also be divided according to organs of elimination (e.g. renal clearance of hepatic clearance; in which case it is the amount of blood or plasma from which drug has been removed by that organ).
+Drugs can be cleared via:
+  * Kidneys (renal excretion)
+  * Liver (metabolism, biliary excretion)
+  * Lungs
+  * Organ-independent metabolism (plasma esterases, Hofmann elimination)
-  * Total clearance = Cl (renal) + Cl (liver) + Cl (lung)… etc
-Clearance can be a tricky concept to grasp. It is closely related to Volume of Distribution (Vd) and is expressed as a volume / time (e.g. ml/min or L/hr). It is also not directly measured but calculated from the concentration and the rate with which the concentration falls.
+**Total body clearance** is the sum of all individual organ clearances:
+$$Total\ body\ clearance = Cl_{renal} + Cl_{hepatic} + Cl_{lung} + ...$$
-Since the rate of elimination of most drugs is proportional to the concentration, clearance is generally a constant value for most individuals.
+For a specific organ, the clearance is a function of blood flow through that organ, and the proportion of drug that is removed during each pass of the organ (extraction ratio). Thus, ↓ renal blood flow (e.g. shock) will ↓ renal clearance.
+$$Cl_{renal} = Renal\ blood\ flow\ × Renal\ extraction\ ratio$$
-The clearance of a particular organ is a function of the blood flow through that organ and the proportion of the drug that is removed (the extraction ratio).
-  * Cl (renal) = Renal blood flow x Extraction Ratio
-Therefore, as an example, the renal clearance of most drugs will be reduced if renal blood flow is reduced such as in a hemodynamically shocked patient.
-**Half-life (t1/2)**  generally refers to the elimination half-life of a substance and is the time taken for the concentration of a drug to fall to half its original value.
-**First order and Saturated Kinetics **
-For most drugs used in therapeutic doses the body does not have to utilise all its capacity to metabolism or eliminate the drug. Instead, a **fixed proportion of whatever concentration**  is present in the metabolic process is removed. In this situation the concentration declines exponentially with time. This is termed **1st order kinetics**.
-For a small number of agents, this is not the case. Two examples are phenytoin and alcohol. For these agents all enzyme capacity is being used (saturated) and a **fixed amount of drug**  is removed regardless of concentration and the concentration falls in a linear fashion (**zero order kinetics**).
+==== - Drug Elimination Kinetics ====
+**First-order kinetics** describe a constant __fraction__ of a drug eliminated per unit time. Here, the plasma concentration of a drug declines exponentially. Clearance remains constant because the rate of elimination is proportional to the drug plasma concentration. For most drugs at therapeutic doses, the body's capacity to metabolize or eliminate the drug is not saturated, so elimination follows first-order kinetics.
+**Half-life (t½)** generally refers to the __elimination__ half-life of a substance, and is the time required for a drug concentration to fall to half its original value. It is related to volume of distribution and clearance by the following formula.
+$$t½ = \frac{0.693\ × V_d}{Cl}$$
+**Zero-order kinetics** describe a constant __mass__ of a drug eliminated per unit time, regardless of its plasma concentration. This occurs because the enzymes responsible for metabolism become saturated and only a fixed amount of drug is eliminated per unit time. The plasma concentration of the drug declines linearly. Classic examples include ethanol and phenytoin.
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