Membrane Active Drugs

2.5.1. Effects on Membranes

In the following discussion the way in which various drugs may act on cellular membranes, and in turn be modified by this action, will be considered. One salient fact must be kept in

Figure 2-5. Nerve cell membrane.

Figure 2-5. Nerve cell membrane.

mind: Membranes pose an osmotic barrier between the internal contents of the cell and its external environment. Thus most studies are concerned with the mechanisms that help to explain the transport of drugs, ions, and biomolecules across membranes. Drug transport mechanisms essentially occur in two stages. The first stage involves the complexation of a drug with some membrane component, possibly an enzyme. The second stage follows with a movement of the complex to the inner surface of the membrane, where the drug may be released into the cell's aqueous interior. Once inside the compound will exert an effect on the cell's metabolism by mechanisms already considered or to be discussed.

Before considering medicinal agents relative to effects on membrane integrity, some basic aspects of membrane physiology will be noted. Figure 2-5 schematically illustrates that the interior of a nerve cell has a higher concentration of potassium ions (K+) than the extracellular fluid. The opposite is true of sodium ions (Na+). There is a normal tendency for K+ to flow out of the cell by diffusion, thus taking the positive charge to the membrane's exterior. The organic anions acting as counterions, to which the membrane is impermeable, cannot follow. Thus a charge separation occurs, resulting in a net negative charge on the membrane's interior. Equilibrium is attained when the positive charge on the outside of the membrane surface is sufficiently distributed to repel further diffusion of K+ from the cell's interior. External chloride ions (CI") will not enter the cell because of repulsion by the membrane's interior negative charge. The concentration gradient of external Na+ is usually sufficient to move some of them into the cell. These, then, are non-energy-requiring passive movements. The tendency of Na+ to be pushed into the cell by sheer weight of numbers is counteracted by the much lower permeability the membrane has for Na+ than it has for K+. In addition, there is an energy-requiring active transport system that extrudes three Na+ ions from the cell for every two K+s that enter.6

This polarized state is particularly characteristic of excitable cells such as nerve, muscle, and myocardial fibers. These cells have a unique feature in that stimulation will reverse the electrical potential across the membrane; that is, the membrane will go through a state of zero potential. During this transitional depolarized state the nature of the permeability is drastically altered with regard to Na+. They can now suddenly flux into the cell with ease.

When normalcy returns, however, the greatly increased Na+ concentration results in a positive charge on the inside of the membrane—the reverse of the initial resting state. During this action potential K+ permeability increases and Na+ begins to leave the cell. Finally, the sodium-potassium pump slowly brings about reversal by pushing Na+ out until the resting potential is restored. Thus both passive diffusion and active transport mechanisms are operative. These changes in electrical potential, although initiated locally, spread to other areas of the cell. This results in impulse transmission in fibrous cells such as myocardial and nerve cells.

6 This is the so-called sodium-potassium pump, catalyzed by adenosine triphosphatase ATP-ase; ATP hydrolysis supplies the energy.

It can now be understood how certain drugs exert their pharmacologic effect—at least in part—by affecting membrane transport processes. Local anesthetics are believed to act on the movement of cations. The anticancer drug methotrexate is known to enter leucocytes by facilitated diffusion. Acetylcholine generally increases membrane potential of myocardial cell membranes by increasing both the time they are polarized and the time they are depolarized, thus helping to restore cardiac arrhythmias to normalcy. Cardiotonic digitalis glycosides inhibit the sodium-potassium pump, thus affecting K+ influx and Na+ outflow. The so-called calcium channel blockers are now believed to exert their beneficial cardiac effects by inhibiting calcium ion (Ca2+) influx through "slow channels" into both conductile and contractile myocardial and smooth muscle cells. It is the electromechanical coupling caused by a transmembrane influx of Ca2+, and the activation of Ca2+-dependent ATP-ase, resulting from elevated Ca2+ levels in myofibrillar cells, that causes activation of the contractile system in these cells. Inhibiting Ca2+ influx through these membranes will decrease hypercontractility such as arrhythmias and affect hemodynamics of blood vessels, thus reducing blood pressure.

It is not surprising that the membranes of prokaryotic cells such as bacteria and fungi have characteristics differing considerably from eukaryotic cells. Compounds that will disrupt the functions of these membranes, but not similarly affect mammalian cells, may be useful as selectively toxic antimicrobials. In fact, there now exist a number of important antifungal and antibacterial drugs that do just that—they disrupt the membranes of these pathogens.

2.5.2. Membrane Disrupters—Antimicrobials

There are antibiotics that disorganize cytoplasmic membranes, resulting in leakage of intracellular constituents, particularly small molecules. The result is a rapid killing action. One such group can be classified as macrocyclic polypeptides. These bacterial products are not, strictly speaking, proteins, because some of the amino acids have the d configuration and several that are never encountered in proteins, for example, a, ydiaminobutyric acid (DAB).

Tyrothricin, first investigated in 1944, was obtained from Bacillus brevis. It is actually a mixture of polypeptides, two of which, tyrocidin and gramicidin, have been crystallized and sequenced. They are two of a large group of cyclic peptide antibiotics called tyro-cidins. Their effectiveness is primarily against gram-positive bacteria. Because of toxicity, such as lysis of erythrocytes if given systemically, use is limited to topical application and throat lozenges.

Another group of cyclic peptide antibiotics elaborated by several strains of Bacillus polymixa are the polymixins. They contain a seven-amino-acid ring portion with a high DAB content, plus a side chain terminating in a methylalkanoic acid chain varying in length from 8 to 10 carbon atoms. Polymixin B, consisting of B| and B2 (Aerosporin), and Colistin, consisting of Polymixin E! and E2, are of clinical interest (Fig. 2-6) since their toxicities are somewhat less than most others in this group. The polymyxins are more effective against gram-negative organisms, even the virulent Pseudomonas aeruginosa, which is so resistant to most other antibiotics.

The mechanism of action first involves binding to the plasma membrane. Since it is protected by an elaborate structure in gram-negative bacteria, including an outer membrane, it can be assumed that the drug must disrupt, or somehow penetrate, this barrier first. The result is a disruption of the membrane's integrity, which causes a leakage of phosphates,

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    What does it mean for drugs to be membrane actve?
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