Drug therapy is divided into two major categories depending on the therapeutic intent:
Given these distinctions, it is apparent that the action of chemotherapeutic agents should be highly specific for the foreign cell with minimal effect on the host. In contrast, a pharmacotherapeutic agent must have activity on the host.
For both chemotherapy and pharmacotherapy the desire is to achieve SPECIFICITY (SELECTIVITY) in the drug's action, that is to produce the desired action with no adverse effects on the host. Because all drugs produce adverse effects at some dose, the ratio of doses required to produce the various effects is an important indicator or specificity. The concept of specificity may be illustrated by noting that the dose response curve for a highly specific drug is far to the left (i.e., a much lower dose is required) of the curve for the most significant adverse reaction.
The very idea of chemotherapeutic agents is a PARADOX. How can one kill or inhibit the growth of an organism living inside another without, at the same time, also causing severe toxicity to that host? Modern emphasis in drug design and development is on EXPLOITING DIFFERENCES between parasites and hosts IN ESSENTIAL PROCESSES so that specificity, i.e., selective inhibition can be achieved.. As conceived by Wang (in Katzung, 2nd ed.), there are three major types of differences between host and invaders that can be exploited.
These are:
Drugs that inhibit enzymes unique to the pathogen are particularly attractive because may have little, if any, action in the host because the host does not have that enzyme or pathway.
Evolution and the ecological niche occupied by many pathogens results in a need for some metabolic pathways that are different from those of their hosts. As a result, some pathways shared by host and pathogen may be essential only in the pathogen. The host may have other pathways that produce the same end product. In this case, the host has redundancy and can function, although perhaps less effectively, even if a particular path is depressed.
Pathogens and their hosts have many biochemical pathways and receptor systems in common that are important in both. However, a drug may have a much greater affinity for a pathogen's enzyme or protein than for the host's. The importance of a neurologic path may be quite different in a simple metazoan and a vertebrate. Pathogens and hosts may inactivate or activate drugs at widely different rates. Important receptors may be relatively protected by barriers that are absent in the pathogen. An example is the blood brain barrier, in vertebrates.
Enzymes that are found only in pathogens are attractive targets for the development of chemotherapeutic agents because of the possibility that such agents will have a wide margin of safety. Cell wall synthesis in bacteria and the folic acid system in a variety of organisms are examples of the value of drugs acting on unique enzymes. Animals have no cell walls. Therefore, drugs such as the beta-lactam antibiotics, i.e., penicillins and cephalosporins, that inhibit cell wall synthesis have the possibility of powerful actions on bacteria with minimal effects on animals.
The folic acid system is less clearcut because it, or a closely related counterpart, is nearly ubiquitous. This system is crucial for inosine synthesis, hence DNA and RNA synthesis are severely curtailed when it is inhibited. Vertebrates must have folic acid in their diet whereas many bacteria must synthesize their own. Drugs, such as the sulfonamides, that inhibit formation of dihydrofolic acid (DHF) will have profound effects on folic acid concentration and function in bacteria. Parenthetically, one should note that methotrexate (an anticancer drug) and trimethoprim (an antibacterial related to many antiprotozoals) act at later steps in the folic acid system and selectivity is achieved pharmacokinetically rather than through the uniqueness of their targets.
Hosts and pathogens may have a similar enzyme, but if it is crucial only in the pathogen it constitutes a good target for the development of chemotherapeutic agents. In contrast to the other two major target categories, this one has no widely known clinically useful examples. The best example stems from nucleic acid synthesis wherein many parasitic organisms depend on salvage enzymes for their growth and survival. Whereas host cells can synthesize nucleic acids from salvaged precursors or from precursors they have synthesized de novo, many protozoans and schistosomes must have preformed purine nucleotides (inosine, adenine, and guanine). If one were to inhibit an enzyme that is crucial for the incorporation of salvaged precursors into nucleic acid, one could dramatically affect the parasite. Hypoxanthine-Guanine phosphoribosyltransferase (HGPT) is a key salvage enzyme and inhibiting it would deprive the parasite of adenine, dramatically affecting all processes that depend on ATP. However, no drugs that affect this enzyme have widespread clinical use. One should expect this to change in the future as more is known about the molecular biology of parasites and their hosts.
Many biological mechanisms are HIGHLY CONSERVED in evolution, but the exact characteristics may differ sufficiently to be exploited therapeutically. Differences may be in pharmacodynamic or pharmacokinetic properties. The majority of drugs used clinically achieve whatever specificity they exhibit by a mechanism in this category.
Conceiving of new drugs that achieve specificity by a pharmacodynamic or pharmacokinetic difference between host and parasite is extremely difficult and tends to be done on an empirical basis through drug screening. This is because key differences between organisms cannot be always be predicted with current levels of knowledge. However, once a drug is found that makes a difference known, we can exploit the knowledge with rational attempts to design a more effective drug that exploits that difference.
Examples will be provided here of drugs that achieve specificity by a) inhibiting a transport system, b) more cells in a susceptible state so drug effect will be reater, c) having a different binding affinity for a cellular component, and d) having differential access to key receptor sites.
Amprolium [CORID], is a well known anticoccidial drug with a rather narrow spectrum of activity that includes Eimeria spp. in poultry. Thiamine is an important coenzyme in carbohydrate metabolism, the main energy source of coccidia. Amprolium, a thiamine analog, inhibits the transport of thiamine into the protozoan, competitively, resulting in its death.
Microtubules are important components of the cytoskeleton and mitotic spindle. The mitotic spindle has obvious importance during cell division so the binding of vincristine [ONCOVIN], an anticancer drug, to spindle proteins causing their disaggregation will have obvious effects. Specificity is achieved by the fact that cell division occurs in a higher proportion of cancer cells than of normal cells.
Cytoskeleton proteins (e.g., tubulin) are important in movement of secretory granules and other cellular organelles. Inhibition of their aggregation into functional units could lead to starvation (glucose deprivation, etc.) of affected parasites and this is how many benzimidazoles, e.g., mebendazole and fenbendazole, affect ascarids. Tubulin has both alpha and beta subunits. The beta subunits are highly conserved and are similar in all species. In contrast, the alpha subunits vary dramatically across species lines. For example, mebendazole and fenbendazole compete with colchicine (a classical antimitotic agent) for binding sites. Mebendazole and febendazole compete 250-400 times more effectively for Ascaris lumbricoides tubulin than for bovine brain tubulin. These drugs cause the microtubular system of affected ascarids to disappear with no apparent effect on those of the host. Because of this difference, it has been possible to develop dosage regimens with large safety margins.
Barriers to drug movement may cause widely different drug concentrations throughout the body. Inhibitory GABA receptors are present on neuromuscular junction receptors of arthropods and nematodes, but only on interneurons in vertebrates. Drugs acting to increase GABA release and action on receptors, like the ivermectins, that do not readily cross the blood-brain barrier will have minimal effects on vertebrates. In contrast, they cause flaccid paralysis in arthropods and nematodes. Ivermectin has a surprisingly broad spectrum of antiparasitic action whereas it is relatively non-toxic to vertebrates in therapeutically effective doses because of this pharmacokinetic difference.