Abstract
Many drugs need to pass through one or more cell membranes to reach their site of action. A common feature of all cell membranes is a phospholipid bilayer, about 10 nm thick, arranged with the hydrophilic heads on the outside and the lipophilic chains facing inwards. This gives a sandwich effect, with two hydrophilic layers surrounding the central hydrophobic one. Spanning this bilayer or attached to the outer or inner leaflets are glycoproteins, which may act as ion channels, receptors, intermediate messengers (G-proteins) or enzymes. The cell membrane has been described as a ‘fluid mosaic’ as the positions of individual phosphoglycerides and glycoproteins are by no means fixed (Figure 1.1).
Many drugs need to pass through one or more cell membranes to reach their site of action. A common feature of all cell membranes is a phospholipid bilayer, about 10 nm thick, arranged with the hydrophilic heads on the outside and the lipophilic chains facing inwards. This gives a sandwich effect, with two hydrophilic layers surrounding the central hydrophobic one. Spanning this bilayer or attached to the outer or inner leaflets are glycoproteins, which may act as ion channels, receptors, intermediate messengers (G-proteins) or enzymes. The cell membrane has been described as a ‘fluid mosaic’ as the positions of individual phosphoglycerides and glycoproteins are by no means fixed (Figure 1.1). An exception to this is a specialised membrane area such as the neuromuscular junction, where the array of postsynaptic receptors is found opposite a motor nerve ending.
The general cell membrane structure is modified in certain tissues to allow more specialised functions. Capillary endothelial cells have fenestrae, which are regions of the endothelial cell where the outer and inner membranes are fused together, with no intervening cytosol. These make the endothelium of the capillary relatively permeable; fluid in particular can pass rapidly through the cell by this route. In the case of the renal glomerular endothelium, gaps or clefts exist between cells to allow the passage of larger molecules as part of filtration. Tight junctions exist between endothelial cells of brain blood vessels, forming the blood–brain barrier, intestinal mucosa and renal tubules. These limit the passage of polar molecules and also prevent the lateral movement of glycoproteins within the cell membrane, which may help to keep specialised glycoproteins at their site of action (e.g. transport glycoproteins on the luminal surface of intestinal mucosa) (Figure 1.2).
Figure 1.2 Modifications of the general cell membrane structure.
Methods of Crossing the Cell Membrane
Passive Diffusion
This is the commonest method for crossing the cell membrane. Drug molecules move down a concentration gradient, from an area of high concentration to one of low concentration, and the process requires no energy to proceed. Many drugs are weak acids or weak bases and can exist in either the unionised or ionised form, depending on the pH. The unionised form of a drug is lipid-soluble and diffuses easily by dissolution in the lipid bilayer. Thus the rate at which transfer occurs depends on the pKa of the drug in question. Factors influencing the rate of diffusion are discussed below.
In addition, there are specialised ion channels in the membrane that allow intermittent passive movement of selected ions down a concentration gradient. When opened, ion channels allow rapid ion flux for a short time (a few milliseconds) down relatively large concentration and electrical gradients, which makes them suitable to propagate either ligand- or voltage-gated action potentials in nerve and muscle membranes.
The acetylcholine (ACh) receptor has five subunits (pentameric) arranged to form a central ion channel that spans the membrane (Figure 1.3). Of the five subunits, two (the α subunits) are identical. The receptor requires the binding of two ACh molecules to open the ion channel, allowing ions to pass at about 107 s−1. If a threshold flux is achieved, depolarisation occurs, which is responsible for impulse transmission. The ACh receptor demonstrates selectivity for small cations, but it is by no means specific for Na+. The GABAA receptor is also a pentameric, ligand-gated channel, but selective for anions, especially the chloride anion. The NMDA (N-methyl D-aspartate) receptor belongs to a different family of ion channels and is a dimer; it favours calcium as the cation mediating membrane depolarisation.
Figure 1.3 The acetylcholine (ACh) receptor has five subunits and spans the cell membrane. ACh binds to the α subunits, causing a conformational change and allowing the passage of small cations through its central ion channel. The ε subunit replaces the fetal-type γ subunit after birth once the neuromuscular junction reaches maturity.
Ion channels may have their permeability altered by endogenous compounds or by drugs. Local anaesthetics bind to the internal surface of the fast Na+ ion channel and prevent the conformational change required for activation, while non-depolarising muscle relaxants prevent receptor activation by competitively inhibiting the binding of ACh to its receptor site.
Facilitated Diffusion
Facilitated diffusion refers to the process where molecules combine with membrane-bound carrier proteins to cross the membrane. The rate of diffusion of the molecule–protein complex is still down a concentration gradient but is faster than would be expected by diffusion alone. An example of this process is the absorption of glucose, a highly polar molecule, which would be relatively slow if it occurred by diffusion alone. There are several transport proteins responsible for facilitated glucose diffusion; they belong to the solute carrier (SLC) family 2. The SLC proteins belonging to family 6 are responsible for transport of neurotransmitters across the synaptic membrane. These are specific for different neurotransmitters: SLC6A3 for dopamine, SLC6A4 for serotonin and SLC6A5 for noradrenaline. They are the targets for certain antidepressants; serotonin-selective re-uptake inhibitors (SSRIs) inhibit SLC6A4.
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