Lipophilicity and passage across membranes into the brain
A lipophilic (fat-soluble) drug dissolves in the fatty double layer of a cell membrane, so it crosses easily and reaches the central nervous system.
Remember
Lipid solubility sets where a drug can go, and blood flow sets how fast it arrives: a lipophilic drug slips through membranes into the brain, whereas a charged (ionised) or water-soluble one tends to cross poorly.
Every cell membrane is built around a lipid bilayer, a double layer of fatty molecules. A drug that dissolves easily in fat is lipophilic, literally 'fat-loving', so it can slip through that layer. A hydrophilic ('water-loving') drug tends to stay in the extracellular fluid, the fluid outside cells, and needs junctions (joins between cells) or transporters to leave the bloodstream.
Most drugs are weak acids or weak bases, so each one is part ionised (carrying an electrical charge) and part non-ionised (uncharged). The uncharged form is usually the lipid-soluble one and crosses membranes readily, while the charged form dissolves in water and crosses poorly. The proportion that is uncharged depends on the surrounding pH and on the drug's pKa (the pH at which half of the drug is ionised).
In the small intestine, passive diffusion (movement down a concentration gradient) needs no energy or carrier, and it is quickest for a lipid-soluble, non-ionised drug. Small molecules tend to cross more quickly than large ones.
Tightly joined cells line the brain's capillaries and form the blood-brain barrier, which slows water-soluble drugs, whereas lipid-soluble drugs such as thiopental (an intravenous anaesthetic) enter readily.
Blood flow then sets the speed. Well-perfused tissues (those with a rich blood supply), such as the brain, heart, liver and kidneys, reach equilibrium with the blood quickly, meaning the drug entering and leaving the tissue balances. Poorly perfused tissues such as fat and bone take much longer. Given intravenously, a highly lipophilic drug therefore reaches the brain within seconds and builds up in body fat over time.
Plasma protein binding (the reversible attachment of a drug to blood proteins such as albumin) modifies how a drug spreads, because only the unbound fraction can leave the bloodstream. It does not stop a lipophilic drug distributing (spreading) into tissues.
Key facts
- Lipophilic drugs
- cross cell membranes easily and reach the central nervous system and adipose tissue (body fat).
- Hydrophilic drugs
- tend to stay in the extracellular fluid and need junctions or transporters to leave the bloodstream.
- Absorption
- passive diffusion is quickest for a drug that is lipid soluble and in its non-ionised (uncharged) form.
- Blood-brain barrier
- tightly joined cells lining the brain's capillaries slow water-soluble drugs, while lipid-soluble drugs such as thiopental enter readily.
- Speed of entry
- well-perfused brain, heart, liver and kidneys equilibrate with the blood quickly, whereas poorly perfused fat and bone take much longer.
- Protein binding
- only the unbound fraction can leave the bloodstream, but reversible binding does not stop a lipophilic drug distributing.
Exam traps
- High plasma protein binding does not help a drug cross membranes: it reduces the free drug, and only the unbound drug is available to diffuse into tissues.
- A lipid-soluble drug still crosses membranes poorly if it is predominantly ionised (charged) at the local pH, because the charged form has low lipid solubility.
- High binding to plasma albumin does not confine a lipophilic drug to the extracellular fluid, because the binding is reversible and the unbound fraction can still diffuse into tissues.
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