Pharmacokinetics: Distribution
Topic: Drug Distribution
- Subtitle: Apparent Volume of Distribution (Vd), Redistribution, Brain Penetration, Placental Passage, Plasma Protein Binding, and Influencing Factors.
Introduction to Drug Distribution
Definition:
Drug distribution refers to the movement of a drug from the bloodstream to
tissues and organs after absorption.
Key
Points:
- Distribution depends on blood
flow, tissue permeability, and binding to plasma proteins.
- Determines drug action and
duration.
Example:
- Thiopental: Rapid distribution to the
brain → quick anesthetic effect, then redistributes to fat → wears off
quickly.
Apparent Volume of Distribution (Vd)
Definition:
Theoretical volume of fluid needed to dissolve a drug to achieve the same
concentration as in plasma.
Significance:
- Low Vd → Drug stays in plasma
(high plasma protein binding).
- High Vd → Drug distributes
extensively into tissues (lipophilic drugs).
Examples:
- Low Vd: Warfarin (3–5 L), confined
to plasma.
- High Vd: Chloroquine (>100 L), accumulates in tissues like liver.
Significance of High and Low Vd
- High Vd:
- Extensive tissue binding →
Longer duration of action.
- Example: Digoxin (Vd
= ~500 L), binds to cardiac and skeletal muscles.
- Low Vd:
- Drug confined to plasma →
Shorter duration, easier to clear.
- Example: Heparin,
stays in blood vessels due to large size.
Clinical
Significance:
- Drugs with high Vd require
larger loading doses to achieve therapeutic levels.
Story:
- During World War II,
chloroquine's high Vd allowed it to treat malaria with long-acting
effects.
Conditions Altering Vd
- Body Composition:
- Obesity: Lipophilic drugs
have increased Vd (e.g., diazepam).
- Cachexia: Reduced tissue
stores → lower Vd.
- Plasma Protein Levels:
- Hypoalbuminemia reduces
protein-bound drugs (e.g., phenytoin).
- Disease States:
- Liver failure → Increased
free drug levels due to reduced protein.
- Kidney disease → Fluid
retention alters distribution.
Example:
- Phenytoin toxicity in
hypoalbuminemic patients due to low protein binding.
Redistribution
Definition:
Movement of a drug from its site of action (e.g., brain) to other tissues,
reducing its effect.
Significance:
- Explains rapid recovery
after short-acting anesthesia.
Example:
- Thiopental: Rapidly penetrates the brain → produces anesthesia → redistributes to fat → anesthesia wears off quickly.
Penetration into Brain and CSF
Mechanism:
- Blood-Brain Barrier (BBB): Tight junctions prevent
polar or large molecules from entering.
- Lipophilic, un-ionized, and
small molecules cross easily.
Examples:
- L-Dopa: Crosses the BBB and
converts to dopamine (treatment for Parkinson’s).
- Penicillin: Poor brain penetration but
can cross if BBB is inflamed (e.g., meningitis).
Historical
Fact:
- In 1960s, L-Dopa revolutionized Parkinson’s treatment by bypassing dopamine's inability to cross the BBB.
Passage Across the Placenta
Mechanism:
- Passive diffusion allows
drugs to cross the placental barrier.
Factors
Influencing Passage:
- Molecular size: Smaller drugs cross easily
(e.g., ethanol).
- Lipid solubility: Lipophilic drugs cross
readily.
- Ionization: Non-ionized drugs
penetrate faster.
Examples:
- Thalidomide: Crossed placenta, causing
birth defects in 1960s.
- Alcohol: Crosses easily and can
cause fetal alcohol syndrome.
Story:
- The thalidomide tragedy
in the 1960s highlighted the need for testing drug effects on the fetus.
Plasma Protein Binding
Definition:
Reversible binding of drugs to plasma proteins (e.g., albumin).
Significance:
- Bound drug: Pharmacologically
inactive.
- Free drug: Active and available for
distribution.
Clinical
Importance:
- Highly protein-bound drugs
are displaced by other drugs → Toxicity.
Examples:
- Warfarin: 99% bound → Small
displacement causes significant toxicity.
- Sulfonamides displace bilirubin in neonates → Kernicterus.
Factors Affecting Drug Distribution
- Physicochemical Properties:
- Lipid solubility, molecular
size, and ionization.
- Blood Flow:
- Highly perfused organs
(brain, liver, kidney) receive drugs quickly.
- Plasma Protein Binding:
- Higher binding → Less free
drug available for distribution.
- Disease States:
- Liver disease →
Hypoalbuminemia reduces protein binding.
- Tissue Binding:
- Fat acts as a reservoir for
lipophilic drugs.
Examples:
- Obesity: Lipophilic drugs like
diazepam accumulate in fat.
- Hypoalbuminemia: Increases free warfarin
concentration → toxicity.
Summary
- Distribution determines the drug's
journey from plasma to tissues.
- Vd reflects how extensively a
drug distributes.
- Factors like redistribution,
plasma protein binding, and placental passage influence drug
effects.
- Conditions like obesity, hypoalbuminemia, and blood flow alter drug distribution.
References
- Goodman & Gilman's
Pharmacology.
- Katzung's Basic and Clinical
Pharmacology.
- Thalidomide Case Study
(WHO).
END OF THE CHAPTER
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