Distribution - PK4 Flashcards
What is drug distribution?
The reversible transfer of a drug between blood and tissues.
What determines the extent and speed of drug distribution?
Drug properties, tissue characteristics, and blood flow.
How does distribution differ from absorption?
Absorption = drug enters bloodstream; Distribution = drug moves from blood to tissues.
What are the key compartments a drug can distribute into?
Plasma, interstitial fluid, intracellular fluid, transcellular fluid.
What percentage of body weight is total body water (TBW)?
~60% of body weight.
How is total body water (TBW) divided?
Intracellular fluid (28L) + Extracellular fluid (14L).
What are the components of extracellular fluid?
Plasma (3L) + Interstitial fluid (9L) + Lymph (1.2L).
How does drug distribution relate to body water compartments?
Drugs distribute differently based on their molecular weight, lipid solubility, and protein binding.
What is Volume of Distribution (Vd)?
A pharmacokinetic concept that quantifies drug distribution between plasma and tissues.
How is Vd calculated?
Vd = Dose (mg) / Plasma concentration (mg/L).
What does a high Vd indicate?
Drug is widely distributed in tissues.
What does a low Vd indicate?
Drug is mainly confined to plasma and extracellular fluids
What does a Vd of ~4L suggest?
Drug is confined to plasma (e.g., Heparin, Insulin).
What does a Vd of 4-14L suggest?
Drug distributes in extracellular fluid but not intracellularly (e.g., Aminoglycosides).
What does a Vd of 42L suggest?
Drug distributes throughout total body water (e.g., Ethanol).
What does a Vd > 42L suggest?
Drug accumulates in tissues (e.g., Digoxin, Morphine, Chloroquine).
What factors influence drug distribution?
- Blood flow & capillary permeability 2. Physiochemical properties (MW, pKa, lipid solubility) 3. Plasma protein binding 4. Tissue binding.
How does blood flow affect distribution?
Highly perfused organs (brain, liver, kidney) receive drugs faster than poorly perfused ones (fat, muscle, bone).
How does capillary permeability affect distribution?
Capillary structure varies—tight junctions in the BBB limit distribution, while fenestrated capillaries in liver/kidney allow easy drug movement
What is plasma protein binding?
Drugs bind to proteins like albumin (for acidic drugs) and α1-acid glycoprotein (for basic drugs).
What happens when a drug is highly protein-bound?
Less free drug is available for distribution and action.
How does protein binding affect Vd?
High protein binding → Low Vd (drug stays in plasma).
Give an example of a highly protein-bound drug.
Warfarin (99% protein-bound, Vd = 10L).
What is the “free drug hypothesis”?
Only the unbound fraction of a drug is pharmacologically active and able to distribute
What happens when a drug binds to tissues?
Lower plasma concentration → Increased Vd → Potential for prolonged drug action.
What is a major advantage of tissue binding?
It can act as a reservoir, prolonging drug effect (e.g., bisphosphonates in bone for osteoporosis).
What is a major disadvantage of tissue binding?
Can cause toxicity (e.g., aminoglycoside-induced nephrotoxicity).
How does fat act as a drug reservoir?
Lipophilic drugs accumulate in fat and slowly release back into circulation (e.g., Thiopental, THC)
What is the blood-brain barrier (BBB)?
A protective barrier that restricts drug entry into the brain.
How do drugs cross the BBB?
Only lipid-soluble drugs or actively transported drugs can cross.
What happens to BBB permeability in meningitis?
It increases, allowing hydrophilic drugs to enter the brain.
What is the placental barrier?
A membrane that limits drug transfer from mother to fetus.
What types of drugs cross the placenta more easily?
Lipid-soluble drugs with MW <600 Da
Why is Vd important in dosing?
Helps determine the loading dose needed to achieve a target plasma concentration.
How does Vd affect drug clearance by dialysis?
Small Vd → Dialysis is effective (drug stays in plasma). High Vd → Dialysis is ineffective (drug in tissues).
How does Vd affect drug overdose treatment?
For high Vd drugs, dialysis is not useful because most of the drug is stored in tissues.
What is the formula for loading dose?
D = Vd × Cp (target plasma concentration).
A 70 kg patient needs Lidocaine therapy (Vd = 1 L/kg, Cp = 2 mg/L). What is the loading dose?
70 L × 2 mg/L = 140 mg.
What does a low Vd suggest about drug location?
Drug is mostly in plasma and extracellular fluid.
What does a high Vd suggest about drug location?
Drug accumulates in tissues.
Why do lipophilic drugs have a high Vd?
They cross membranes easily and distribute into tissues.
What happens when a patient has low serum protein levels?
Higher free drug fraction → Increased Vd → Potential for toxicity.
