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concept_pharmacokinetics_and_toxicokinetics [2025/04/17 09:46] – [3. Distribution] jkohtsconcept_pharmacokinetics_and_toxicokinetics [2025/04/18 01:58] (current) – jkohts
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 ===== - Distribution ===== ===== - Distribution =====
  
-Once a substance reaches the systemic circulation it is distributed around the body. The pattern of distribution depends on factors such as blood flow to various organs, and specific drug properties including protein binding and ability to cross cell membranes. These factors vary enormously between drugs. For example, enoxaparin has a very small volume of distribution (5 L), remains largely within the vascular compartment, and does not readily enter cells. In contrast, drugs such as chloroquine, which are highly effective against intracellular pathogens, have a massive volume of distribution (200-800 L/kg) and can achieve intracellular concentrations up to 200 times higher than those of plasma.+Once a substance reaches the systemic circulation it is distributed around the body. The pattern of distribution depends on factors such as blood flow to various organs and specific drug properties including protein binding and ability to cross cell membranes. These factors vary enormously between drugs. For example, enoxaparin has a very small volume of distribution (5 L), remains largely within the vascular compartment, and does not readily enter cells. In contrast, drugs such as chloroquine, which are highly effective against intracellular pathogens, have a massive volume of distribution (200-800 L/kg) and can achieve intracellular concentrations up to 200 times higher than those of plasma.
  
 **Volume of distribution (Vd)**  is a theoretical volume that represents the extent to which a drug distributes in body tissues in order to produce the measured plasma concentration, assuming no elimination has occurred. **Volume of distribution (Vd)**  is a theoretical volume that represents the extent to which a drug distributes in body tissues in order to produce the measured plasma concentration, assuming no elimination has occurred.
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 Vd is not an actual physiological volume, but a constant used to estimate or calculate the expected concentration (C) of a drug following administration of a known dose (D). Vd is not an actual physiological volume, but a constant used to estimate or calculate the expected concentration (C) of a drug following administration of a known dose (D).
  
-C = D / Vd +$$ 
 +Expected\ plasma\ concentration\ (C) = \frac {Amount\ of\ drug\ (D)}{Volume\ of\ distribution\ (V_d)} 
 +$$
  
 Vd is drug-specific and relatively consistent across individuals of similar demographics (e.g. age, sex, weight, physiological status). For IV administration, this allows reasonably accurate prediction of initial plasma concentration. For non-IV routes, bioavailability must also be considered. Vd is drug-specific and relatively consistent across individuals of similar demographics (e.g. age, sex, weight, physiological status). For IV administration, this allows reasonably accurate prediction of initial plasma concentration. For non-IV routes, bioavailability must also be considered.
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-**Protein Binding** +**Protein binding** describes the reversible interaction between drug and plasma protein or tissue protein. Drugs exist in equilibrium between protein-bound and unbound (free) states, and only the unbound fraction is pharmacologically active and diffusible. Whilst changes in protein binding are generally not very important in clinical medicine, significant clinical effects from altered protein binding may manifest in toxicology or when protein binding >90%. Drug–drug interactions affecting protein binding are rarely clinically meaningful due to compensatory increases in metabolism and clearance. 
-Drugs exist in equilibrium between protein-bound and unbound (free) states, and only the unbound fraction is pharmacologically active and diffusible. Whilst changes in protein binding are generally not very important in clinical medicine, significant clinical effects from altered protein binding may manifest in toxicology or when protein binding >90%. Drug–drug interactions affecting protein binding are rarely clinically meaningful due to compensatory increases in metabolism and clearance. +
  
 Most assays measure total (bound + unbound) drug concentration. Most assays measure total (bound + unbound) drug concentration.
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-===== - Clearance =====+==== - Clearance ==== 
 + 
 +**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).  
 + 
 +It can be estimated by the formula: 
 +$$Clearance\ (mL/min) = \frac{Rate\ of\ elimination\ (mg/min)}{Plasma\ concentration\ (mg/mL)}$$ 
 + 
 + 
 +Drugs can be cleared via: 
 +  * Kidneys (renal excretion) 
 +  * Liver (metabolism, biliary excretion) 
 +  * Lungs 
 +  * Organ-independent metabolism (plasma esterases, Hofmann elimination)
  
-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 = Rate of elimination / Concentration+**Total body clearance** is the sum of all individual organ clearances: 
 +$$Total\ body\ clearance = Cl_{renal} + Cl_{hepatic} + Cl_{lung} + ...$$
  
-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.+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. 
 +$$Cl_{renal} = Renal\ blood\ flow\ × Renal\ extraction\ ratio$$
  
-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). 
  
-  * 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. 
  
-Since the rate of elimination of most drugs is proportional to the concentration, clearance is generally a constant value for most individuals. 
  
-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.+==== - Drug Elimination Kinetics ====
  
-**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 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. 
  
-**First order and Saturated 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. 
 +$$t½ = \frac{0.693\ × V_d}{Cl}$$
  
-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**.+**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.
  
-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**). 
  
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