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Pharmacology Quiz

Lipids in Pharmacology and Drug Absorption

Lipids matter in pharmacology for two connected reasons: the barriers a drug must cross are themselves made of lipid, and lipids are used deliberately as carriers and formulation aids to move drugs where water alone cannot. Because every cell membrane is a lipid bilayer, a drug's lipid solubility largely decides whether it is absorbed, how it is distributed, whether it reaches the brain, and how it is finally eliminated. These notes explain the lipid bilayer, the pH partition principle, lipophilicity and the partition coefficient, the role of lipids in absorption across the gut and other routes, lipid-based drug delivery systems such as liposomes, and why very lipid-soluble drugs behave as they do. A 20-question practice set follows.

Why Lipids Govern Drug Movement

A drug in the body is constantly meeting membranes: the wall of the gut, the lining of blood vessels, the barrier around the brain, the membrane of the target cell. Every one of these is a phospholipid bilayer, a double sheet of fat molecules with water-loving heads facing outward and water-hating tails facing inward. The interior of this sheet is oily.

The direct consequence is that a small, uncharged, lipid-soluble molecule slips through a membrane easily by simple diffusion, dissolving into the oily middle and out the other side, while a large, charged, water-soluble molecule cannot and must use a channel, a transporter, or be left behind. Lipid solubility is therefore one of the master variables of pharmacokinetics.

  • The cell membrane is a phospholipid bilayer described by the fluid mosaic model, with proteins floating in a sea of lipid and cholesterol stiffening it.
  • Passive diffusion across this bilayer is the commonest way drugs cross membranes, and it favours lipid-soluble, un-ionised, small molecules.
  • The rate of passive diffusion is described by Fick's law: it rises with the concentration gradient, the surface area, and the lipid solubility (the partition coefficient), and falls with membrane thickness.
  • Water-soluble drugs cross poorly by diffusion and instead use aqueous pores, carrier proteins (facilitated diffusion or active transport), or the gaps between cells.
  • The same lipophilicity that speeds absorption also promotes storage in fat and entry into the brain, so it shapes distribution and duration of action, not just uptake.

Lipophilicity, Ionisation and the pH Partition Principle

Most drugs are weak acids or weak bases, which means they exist as a mixture of a charged (ionised) form and an uncharged (un-ionised) form. Only the un-ionised, lipid-soluble form crosses a membrane freely. Which form dominates depends on the drug's pKa and the pH of the fluid it sits in. This is the pH partition principle, and it explains a large part of drug absorption.

  • The partition coefficient, often written as log P, measures how a drug distributes between an oily phase (octanol) and water. A high log P means high lipid solubility.
  • The un-ionised form is lipid-soluble and crosses membranes; the ionised form is water-soluble and is trapped on one side.
  • A weak acid is un-ionised, and so best absorbed, in an acidic environment. Aspirin, a weak acid, is partly absorbed from the acidic stomach.
  • A weak base is un-ionised, and so best absorbed, in an alkaline environment, which favours absorption from the small intestine.
  • In practice the small intestine absorbs most drugs, acids and bases alike, because its enormous surface area outweighs the pH effect.
  • Ion trapping: a drug accumulates on the side of a membrane where the pH pushes it into the ionised form, for example a weak base concentrating in acidic gastric juice or in acidic urine.
  • Manipulating urine pH uses this principle in overdose: alkalinising the urine keeps a weak acid such as aspirin ionised in the tubule so it cannot be reabsorbed and is excreted faster.

Lipids and Drug Absorption by Route

Absorption is the movement of a drug from its site of administration into the bloodstream, and lipid solubility affects every route differently.

  • Oral route: after passing the stomach, most absorption occurs in the small intestine, whose villi give a vast lipid surface. Highly lipophilic drugs cross the enterocyte membrane readily.
  • Fatty meals can increase the absorption of very lipophilic drugs by stimulating bile, which emulsifies fat and dissolves the drug; the antifungal griseofulvin and some formulations of the antiretroviral and antiparasitic agents are absorbed better with fatty food.
  • Lymphatic absorption: some highly lipophilic drugs are taken up with dietary fat into the intestinal lymphatics and bypass the liver's first-pass metabolism, which can raise the amount reaching the circulation.
  • Skin (transdermal): the outer layer, the stratum corneum, is rich in lipid, so only lipophilic drugs of low dose cross it. This is why nicotine, fentanyl and hormone patches work while water-soluble drugs do not.
  • The blood-brain barrier is a tight lipid barrier; only lipid-soluble drugs enter the brain easily, which is why lipophilic anaesthetics and many psychoactive drugs act centrally while polar drugs do not.
  • Very high lipid solubility can also reduce the fraction absorbed if the drug is so insoluble in water that it never dissolves in the gut fluid in the first place, so an optimum, not a maximum, lipophilicity is wanted.

Lipids as Drug Carriers and Formulation Aids

Beyond being the barrier, lipids are used on purpose to carry drugs, to dissolve drugs that water cannot, and to target delivery. This is a large and growing part of modern pharmaceutics.

  • Liposomes are tiny spheres made of a phospholipid bilayer enclosing an aqueous centre; they can carry a water-soluble drug inside or a fat-soluble drug in the membrane, and they reduce toxicity. Liposomal amphotericin B is far less toxic to the kidney than the plain drug.
  • Lipid nanoparticles are the delivery system behind the messenger RNA vaccines: the fragile RNA is wrapped in a lipid coat that protects it and helps it enter cells.
  • Emulsions and lipid emulsions, such as those used for intravenous nutrition and for the anaesthetic propofol, dissolve fat-soluble drugs for injection.
  • Oily depot injections dissolve a lipophilic drug in oil so it is released slowly over weeks, as with some long-acting antipsychotics and hormones.
  • Self-emulsifying and lipid-based oral formulations improve the absorption of poorly water-soluble drugs by presenting them already dissolved in lipid.
  • Cholesterol itself is the raw material of the steroid hormones, so lipids are also the chemical starting point of an important drug class.
  • A practical caution: highly lipophilic drugs distribute into body fat, which acts as a reservoir. This lengthens their action and can cause accumulation in obese or elderly patients, an effect seen with fat-soluble anaesthetics and some sedatives.

Key Terms

Partition coefficient (log P)
A measure of a drug's lipid solubility, defined as how it distributes between an oily phase and water at equilibrium. A high value means the drug is lipophilic and crosses membranes readily.
pH partition principle
The rule that a weak acid or base crosses a membrane only in its un-ionised, lipid-soluble form, so the pH of the fluid, relative to the drug's pKa, controls how much is absorbed.
Ion trapping
The accumulation of a drug on the side of a membrane where the local pH converts it to the ionised, membrane-impermeable form, for example a weak base concentrating in acidic gastric juice.
Liposome
A microscopic vesicle made of one or more phospholipid bilayers around an aqueous core, used to carry drugs, lower their toxicity and target their delivery, as in liposomal amphotericin B.

Practice Quiz — 20 Questions

correct out of 20

  1. The main structural reason lipid solubility governs drug absorption is that cell membranes are made of:

    • A.A protein sheet
    • B.A phospholipid bilayer
    • C.Cellulose
    • D.A carbohydrate coat
    B. A phospholipid bilayer — Every cell membrane is a phospholipid bilayer with an oily interior, so lipid-soluble drugs cross it easily.

  2. The commonest mechanism by which drugs cross cell membranes is:

    • A.Active transport
    • B.Passive diffusion
    • C.Endocytosis
    • D.Filtration through pores
    B. Passive diffusion — Most drugs cross by passive diffusion down a concentration gradient, which favours lipid-soluble molecules.

  3. According to Fick's law, the rate of passive diffusion increases with all of the following EXCEPT:

    • A.The concentration gradient
    • B.The surface area
    • C.The lipid solubility
    • D.The membrane thickness
    D. The membrane thickness — Diffusion falls as membrane thickness rises; the other three increase it.

  4. Which form of a weak-acid or weak-base drug crosses a lipid membrane most easily?

    • A.The ionised form
    • B.The un-ionised form
    • C.The salt form
    • D.The hydrated form
    B. The un-ionised form — Only the un-ionised, lipid-soluble form diffuses through the membrane; the ionised form is water-soluble and trapped.

  5. A high log P value indicates that a drug is:

    • A.Highly water-soluble
    • B.Highly lipid-soluble
    • C.Strongly ionised
    • D.Poorly absorbed everywhere
    B. Highly lipid-soluble — The partition coefficient log P measures lipid solubility; a high value means the drug is lipophilic.

  6. A weak acid such as aspirin is best absorbed, in terms of ionisation, from:

    • A.An acidic environment like the stomach
    • B.An alkaline environment like bile
    • C.Only the colon
    • D.Only after injection
    A. An acidic environment like the stomach — In acid, a weak acid stays un-ionised and lipid-soluble, so some aspirin is absorbed from the stomach.

  7. The pH partition principle states that absorption depends on the drug's pKa and the:

    • A.Temperature of the gut
    • B.pH of the surrounding fluid
    • C.Colour of the tablet
    • D.Blood pressure
    B. pH of the surrounding fluid — The proportion of un-ionised drug depends on the pH of the fluid relative to the drug's pKa.

  8. Despite pH effects, most oral drugs are actually absorbed mainly in the small intestine because of its:

    • A.Acidic pH
    • B.Very large surface area
    • C.Lack of enzymes
    • D.Thick mucus
    B. Very large surface area — The huge villous surface area of the small intestine outweighs the pH effect for both acids and bases.

  9. Ion trapping refers to a drug accumulating where the local pH makes it:

    • A.Un-ionised and lipid-soluble
    • B.Ionised and unable to cross the membrane
    • C.Chemically inactive
    • D.Bound to plasma protein
    B. Ionised and unable to cross the membrane — The drug is converted to the charged form on one side of the membrane and cannot diffuse back, so it is trapped.

  10. Alkalinising the urine speeds the excretion of aspirin, a weak acid, because it:

    • A.Keeps the drug un-ionised for reabsorption
    • B.Keeps the drug ionised so it cannot be reabsorbed
    • C.Destroys the drug chemically
    • D.Increases blood flow to the kidney
    B. Keeps the drug ionised so it cannot be reabsorbed — In alkaline urine a weak acid is ionised and cannot be reabsorbed, so more is excreted.

  11. A fatty meal can increase the absorption of a very lipophilic drug such as griseofulvin mainly by:

    • A.Lowering stomach pH
    • B.Stimulating bile that emulsifies and dissolves the drug
    • C.Speeding gastric emptying
    • D.Blocking metabolism
    B. Stimulating bile that emulsifies and dissolves the drug — Fat stimulates bile secretion, which emulsifies fat and helps dissolve the lipophilic drug for absorption.

  12. Some highly lipophilic drugs avoid first-pass liver metabolism by being absorbed into the:

    • A.Portal vein
    • B.Intestinal lymphatics
    • C.Gastric mucosa
    • D.Renal tubule
    B. Intestinal lymphatics — Uptake with dietary fat into the intestinal lymphatics bypasses the portal circulation and the liver.

  13. The skin barrier that limits transdermal drug delivery to lipophilic drugs is the:

    • A.Dermis
    • B.Stratum corneum
    • C.Hypodermis
    • D.Sweat gland
    B. Stratum corneum — The lipid-rich stratum corneum admits only lipophilic, low-dose drugs, which is why fentanyl and nicotine patches work.

  14. Only lipid-soluble drugs readily enter the brain because of the:

    • A.Blood-brain barrier
    • B.Large size of neurons
    • C.High blood flow to the brain
    • D.Absence of capillaries
    A. Blood-brain barrier — The blood-brain barrier is a tight lipid barrier that admits lipophilic drugs and excludes polar ones.

  15. Liposomal amphotericin B is preferred over the plain drug mainly because it is:

    • A.Cheaper
    • B.Less toxic to the kidney
    • C.More acidic
    • D.Given orally
    B. Less toxic to the kidney — Enclosing the drug in liposomes markedly reduces its nephrotoxicity.

  16. The delivery system that protects messenger RNA and helps it enter cells in mRNA vaccines is the:

    • A.Aqueous buffer
    • B.Lipid nanoparticle
    • C.Sugar coating
    • D.Protein cage
    B. Lipid nanoparticle — Lipid nanoparticles wrap and protect the fragile mRNA and mediate its uptake into cells.

  17. Propofol, a fat-soluble anaesthetic, is formulated for injection as:

    • A.A dry powder
    • B.A lipid emulsion
    • C.An aqueous solution
    • D.A gas
    B. A lipid emulsion — Propofol is presented as an oil-in-water lipid emulsion because it is not water-soluble.

  18. Dissolving a lipophilic drug in oil for injection produces a long-acting effect because the drug is:

    • A.Destroyed slowly
    • B.Released slowly from the oily depot
    • C.Excreted faster
    • D.More ionised
    B. Released slowly from the oily depot — An oily depot releases the drug gradually over weeks, as with long-acting antipsychotic and hormone injections.

  19. A drug that is extremely lipophilic may still be poorly absorbed because it:

    • A.Cannot dissolve in the aqueous gut fluid to reach the membrane
    • B.Is too small
    • C.Cannot enter fat
    • D.Is always destroyed by acid
    A. Cannot dissolve in the aqueous gut fluid to reach the membrane — If a drug will not dissolve in water at all it never reaches the membrane, so an optimum rather than maximum lipophilicity is best.

  20. Storage of a very lipophilic drug in body fat tends to:

    • A.Shorten its duration of action
    • B.Prolong its action and cause accumulation
    • C.Prevent it entering the brain
    • D.Make it water-soluble
    B. Prolong its action and cause accumulation — Fat acts as a reservoir that releases the drug slowly, prolonging action and risking accumulation, especially in the obese or elderly.

References