Q3 LONG ANSWER 10M ★ High-yield

Describe the distribution of drugs. Explain the volume of distribution, plasma protein binding and the barriers to distribution.

Pharmacology · 2nd Professional — Para-Clinical

Definition

Distribution is the reversible movement of a drug from the systemic circulation into the tissues and body compartments.

Volume of Distribution

The apparent volume OF distribution (Vd) is the hypothetical volume of body fluid into which a drug appears to be distributed at the concentration measured in plasma. Vd = total amount of drug in the body ÷ plasma concentration.

Vd	Interpretation	Examples
About 3–5 L	Confined to plasma — large or highly protein-bound molecules	Heparin, warfarin
About 12–15 L	Extracellular fluid	Gentamicin, mannitol
About 40–42 L	Total body water	Ethanol, phenytoin
Far exceeding body volume	Extensively bound or sequestered IN tissues	Digoxin about 440 L; chloroquine about 13,000 L; amiodarone; imipramine

It is called "apparent" because it is a mathematical construct, not a real anatomical space — a value of 13,000 L for chloroquine simply means very little of it remains in plasma
Clinical uses — it determines the loading dose (loading dose = Vd × target plasma concentration), and it predicts whether a drug can be removed by dialysis

CLINICAL PEARL

A high volume of distribution means dialysis will not help. If a drug is sequestered in tissue — digoxin, chloroquine, tricyclic antidepressants — only a trivial fraction is in the plasma at any moment, so cleaning the plasma removes almost nothing. Dialysis is useful only for drugs with a small Vd, low protein binding and low molecular weight — lithium, methanol, salicylate, ethylene glycol.

Factors Affecting Distribution

Factor	Effect
Lipid solubility	Highly lipid-soluble drugs enter the brain and adipose tissue and have a large Vd
Plasma protein binding	Bound drug cannot leave the circulation; restricts distribution
Tissue binding	Sequestration greatly increases Vd — digoxin in cardiac and skeletal muscle, tetracycline in bone and teeth, chloroquine in liver and retina, iodine in thyroid
Regional blood flow	Well-perfused organs (brain, heart, liver, kidney) receive drug first; this underlies redistribution
Barriers	The blood–brain and placental barriers
Physiological state	Age, obesity, pregnancy, oedema, dehydration
Disease	Meningitis increases blood-brain barrier permeability

Redistribution

A highly lipid-soluble drug given intravenously first enters the well-perfused brain, producing rapid action
It then redistributes to less well-perfused muscle and fat, and the brain concentration falls
Action is terminated by redistribution, not by metabolism
The classical example is thiopentone — anaesthesia lasts only about 10 minutes after a single dose, although the drug is eliminated over many hours. Repeated doses saturate the fat and produce prolonged action, which is why it is unsuitable for maintenance

Plasma Protein Binding

Protein	Binds	Examples
Albumin	Chiefly acidic drugs	Warfarin, phenytoin, sulphonamides, aspirin, NSAIDs, furosemide
Alpha-1 acid glycoprotein	Chiefly basic drugs	Lignocaine, propranolol, quinidine, imipramine
Beta-globulins and specific proteins	Steroids, thyroxine, vitamins	Corticosteroid-binding globulin, transferrin

Only the free (unbound) drug is pharmacologically active, and only the free drug can be metabolised, excreted or cross membranes
Binding is reversible and acts as a reservoir — as free drug is eliminated, bound drug is released, prolonging the duration of action
Highly bound drugs — over 90%: warfarin (99%), phenytoin, diazepam, furosemide, sulphonylureas, NSAIDs
Displacement interactions — one drug displaces another from albumin, transiently raising the free concentration; clinically important only for highly bound drugs with a small Vd and a narrow therapeutic index, such as warfarin displaced by aspirin, phenylbutazone or sulphonamides
Hypoalbuminaemia in nephrotic syndrome, cirrhosis, malnutrition and burns raises the free fraction; a "normal" total phenytoin level may then represent a toxic free level

Barriers to Distribution

Barrier	Structure	Consequences
Blood–brain barrier	Capillary endothelium with tight junctions and no fenestrations, surrounded by astrocyte foot processes; efflux by P-glycoprotein	Only lipid-soluble, unionised drugs enter. Levodopa crosses (by an amino acid carrier) but dopamine does not; penicillin penetrates poorly unless the meninges are inflamed, which increases permitivity — hence high-dose penicillin works in meningitis
Placental barrier	A thin lipid membrane; a poor barrier in practice	Most drugs cross by passive diffusion. Teratogens — thalidomide, warfarin, phenytoin, valproate, retinoids, ACE inhibitors, tetracycline, aminoglycosides, live vaccines
Blood–testis barrier	Sertoli cell tight junctions	Limits penetration of many drugs
Milk	Milk is slightly acidic relative to plasma	Weak bases are ion-trapped and concentrated in milk — relevant for the breastfed infant

Drug Reservoirs and Sequestration

Reservoir	Consequence	Examples
Plasma proteins	Restricts distribution; prolongs action by slow release	Warfarin, phenytoin
Fat	A large, poorly perfused depot; drug accumulates on repeated dosing and is released slowly, greatly prolonging the effective half-life	Thiopentone, diazepam, amiodarone, organochlorine insecticides (DDT)
Bone and teeth	Chelation with calcium; deposition is essentially permanent	Tetracyclines (staining and enamel hypoplasia in children under 8 and in pregnancy), lead, radium, bisphosphonates
Transcellular compartments	Accumulation in cerebrospinal fluid, aqueous humour, joint fluid	Various
Specific organ binding	High local concentration and organ-specific toxicity	Iodine in the thyroid; chloroquine in the retina (retinopathy); digoxin in cardiac and skeletal muscle; griseofulvin in keratin

A reservoir prolongs action but also prolongs toxicity — which is why chloroquine retinopathy appears after cumulative use and why amiodarone toxicity persists for months after the drug is stopped

Applied Aspects

Calculate the loading dose from Vd when a rapid effect is needed — digoxin, amiodarone, phenytoin — because reaching steady state otherwise takes four to five half-lives
Measure free phenytoin in hypoalbuminaemia, uraemia and pregnancy, or correct the total level, since the total is misleading
Dialysis is futile for drugs with a large Vd; for digoxin poisoning, digoxin-specific antibody fragments are used instead
In obesity, dose lipid-soluble drugs on total body weight and water-soluble drugs (aminoglycosides, digoxin) on ideal or adjusted body weight
Neonates have less albumin and a higher free fraction, and sulphonamides displace bilirubin from albumin, risking kernicterus — which is why they are avoided in the newborn
Assume any drug given to a pregnant woman reaches the fetus, and prescribe only where the benefit clearly outweighs the risk

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