Lecture 4 - Drug Distribution 2 - 12 Sep 2006
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DRUG DISTRIBUTION
Patterns of drug distribution reflect certain physiological factors and physiochemical properties of drugs.
Phases of distribution: • An initial phase of distribution may be distinguished that reflects cardiac output and regional blood flow.
Heart, liver, kidney, brain and other well-perfused organs receive most of the drug during the first few minutes after absorption.
(2) Delivery of drug to muscle, most viscera, skin and fat is slower, and these tissues may require several minutes to several hours before steady state is attained.
(3) A third phase of distribution is also possible for some drugs where the drug slowly accumulates in some tissues like fat tissue and other tissues.
These tissues can become reservoirs for the maintenance of the plasma concentration.
Factors influencing drug distribution 1. Membrane permeability of various tissues 2. Blood flow 3. Plasma protein binding 4. Regional differences in pH 5. Capillary permeability
Drug Reservoirs The body compartments in which a drug accumulates are potential reservoirs for the drug.
If stored drug is in equilibrium with that in plasma and is released as the plasma concentration declines, a concentration of the drug in plasma and at its locus of action is sustained, and pharmacological effects of the drug are prolonged.
Fat as a reservoir: Many lipid-soluble drugs are stored fat. In obese persons, the fat content of the body may be as high as 50% and fat can serve as an important reservoir for lipid-soluble drugs.
For example, as much as 70% of the highly lipid-soluble barbiturate thiopental may be present in body fat 3 hours after administration.
Bone: Tetracycline antibiotics and heavy metals may accumulate in bone and bone can become a reservoir for the slow release of toxic agents such as lead or radium into the blood; their effects can thus persist long after exposure has ceased.
In a suspected overdose, the most appropriate site for sampling to identify the drug depends on the drug’s chemical characteristics:
Acidic drugs will concentrate in the plasma and blood is an appropriate sample site for identifying the drug.
The stomach is a reasonable site for sampling basic drugs.
The actions of amphetamine can be prolonged by ingesting bicarbonate to alkalinize the urine.
As a result of alkalinization, an increasing fraction of urinary amphetamine is in the un-ionized form and as such is readily reabsorbed.
urine
out
circulation
Volume of distribution (Vd) The actual volume in which drug molecules are distributed within a patient’s body cannot be measured.
However, an apparent volume of distribution (Vd) can be obtained and may be of some clinical usefulness.
Vd is defined as the factor relating the concentration of drug in blood to the total amount of drug in the body:
Volume of Distribution (Vd) = Amount of drug in the body Plasma drug concentration
The volume of distribution can serve as a guide in determining whether a drug is distributed primarily into plasma or into extracellular space.
In some clinical situations it is important to achieve the target concentration instantaneously.
A loading dose is often used and Vd is the determinant of the size of the loading dose: Loading dose (mg) = (Vd, L)x (Desired plasma concentration, mg/L)
Many acids including salicylates, sulfonamides and penicillins are either too highly bound to plasma proteins or too water soluble to enter cells and adipose tissue in large amounts. Therefore, their Vd is low (approximately 8-20 L).
In contrast, bases are taken up by many tissues. Concentrations in plasma are low, and Vd exceeds the volume of total body fluids. For example, Vd for antihypertensive drug propranolol is about 200L.
Patterns of drug distribution reflect certain physiological factors and physiochemical properties of drugs.
Phases of distribution: • An initial phase of distribution may be distinguished that reflects cardiac output and regional blood flow.
Heart, liver, kidney, brain and other well-perfused organs receive most of the drug during the first few minutes after absorption.
(2) Delivery of drug to muscle, most viscera, skin and fat is slower, and these tissues may require several minutes to several hours before steady state is attained.
(3) A third phase of distribution is also possible for some drugs where the drug slowly accumulates in some tissues like fat tissue and other tissues.
These tissues can become reservoirs for the maintenance of the plasma concentration.
Factors influencing drug distribution 1. Membrane permeability of various tissues 2. Blood flow 3. Plasma protein binding 4. Regional differences in pH 5. Capillary permeability
Drug Reservoirs The body compartments in which a drug accumulates are potential reservoirs for the drug.
If stored drug is in equilibrium with that in plasma and is released as the plasma concentration declines, a concentration of the drug in plasma and at its locus of action is sustained, and pharmacological effects of the drug are prolonged.
Fat as a reservoir: Many lipid-soluble drugs are stored fat. In obese persons, the fat content of the body may be as high as 50% and fat can serve as an important reservoir for lipid-soluble drugs.
For example, as much as 70% of the highly lipid-soluble barbiturate thiopental may be present in body fat 3 hours after administration.
Bone: Tetracycline antibiotics and heavy metals may accumulate in bone and bone can become a reservoir for the slow release of toxic agents such as lead or radium into the blood; their effects can thus persist long after exposure has ceased.
In a suspected overdose, the most appropriate site for sampling to identify the drug depends on the drug’s chemical characteristics:
Acidic drugs will concentrate in the plasma and blood is an appropriate sample site for identifying the drug.
The stomach is a reasonable site for sampling basic drugs.
The actions of amphetamine can be prolonged by ingesting bicarbonate to alkalinize the urine.
As a result of alkalinization, an increasing fraction of urinary amphetamine is in the un-ionized form and as such is readily reabsorbed.
urine
out
circulation
Volume of distribution (Vd) The actual volume in which drug molecules are distributed within a patient’s body cannot be measured.
However, an apparent volume of distribution (Vd) can be obtained and may be of some clinical usefulness.
Vd is defined as the factor relating the concentration of drug in blood to the total amount of drug in the body:
Volume of Distribution (Vd) = Amount of drug in the body Plasma drug concentration
The volume of distribution can serve as a guide in determining whether a drug is distributed primarily into plasma or into extracellular space.
In some clinical situations it is important to achieve the target concentration instantaneously.
A loading dose is often used and Vd is the determinant of the size of the loading dose: Loading dose (mg) = (Vd, L)x (Desired plasma concentration, mg/L)
Many acids including salicylates, sulfonamides and penicillins are either too highly bound to plasma proteins or too water soluble to enter cells and adipose tissue in large amounts. Therefore, their Vd is low (approximately 8-20 L).
In contrast, bases are taken up by many tissues. Concentrations in plasma are low, and Vd exceeds the volume of total body fluids. For example, Vd for antihypertensive drug propranolol is about 200L.
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