книги студ / Color Atlas of Pharmacology

Drugs for Treating Endoand

Ectoparasitic Infestations

Adverse hygienic conditions favor human infestation with multicellular organisms (referred to here as parasites). Skin and hair are colonization sites for arthropod ectoparasites, such as insects (lice, fleas) and arachnids (mites). Against these, insecticidal or arachnicidal agents, respectively, can be used. Endoparasites invade the intestines or even internal organs, and are mostly members of the phyla of flatworms and roundworms. They are combated with anthelmintics.

Anthelmintics. As shown in the table, the newer agents praziquantel and mebendazole are adequate for the treatment of diverse worm diseases. They are generally well tolerated, as are the other agents listed.

Insecticides. Whereas fleas can be effectively dealt with by disinfection of clothes and living quarters, lice and mites require the topical application of insecticides to the infested subject.

Chlorphenothane (DDT) kills insects after absorption of a very small amount, e.g., via foot contact with

sprayed surfaces (contact insecticide). The cause of death is nervous system damage and seizures. In humans DDT causes acute neurotoxicity only after absorption of very large amounts. DDT is chemically stable and degraded in the environment and body at extremely slow rates. As a highly lipophilic substance, it accumulates in fat tissues. Widespread use of DDT in pest control has led to its accumulation in food chains to alarming levels. For this reason its use has now been banned in many countries.

Lindane is the active γ-isomer of hexachlorocyclohexane. It also exerts a neurotoxic action on insects (as well as humans). Irritation of skin or mucous membranes may occur after topical use. Lindane is active also against intradermal mites (Sarcoptes scabiei, causative agent of scabies), besides lice and fleas. It is more readily degraded than DDT.

Permethrin, a synthetic pyrethroid, exhibits similar anti-ectoparasitic activity and may be the drug of choice due to its slower cutaneous absorption, fast hydrolytic inactivation, and rapid renal elimination.

Antimalarials

The causative agents of malaria are plasmodia, unicellular organisms belonging to the order hemosporidia (class protozoa). The infective form, the sporozoite, is inoculated into skin capillaries when infected female Anopheles mosquitoes

(A) suck blood from humans. The sporozoites invade liver parenchymal cells where they develop into primary tissue schizonts. After multiple fission, these schizonts produce numerous merozoites that enter the blood. The preerythrocytic stage is symptom free. In blood, the parasite enters erythrocytes (erythrocytic stage) where it again multiplies by schizogony, resulting in the formation of more merozoites. Rupture of the infected erythrocytes releases the merozoites and pyrogens. A fever attack ensues and more erythrocytes are infected. The generation period for the next crop of merozoites determines the interval between fever attacks. With

Plasmodium vivax and P. ovale, there can be a parallel multiplication in the liver (paraerythrocytic stage). Moreover, some sporozoites may become dormant in the liver as “hypnozoites” before entering schizogony. When the sexual forms (gametocytes) are ingested by a feeding mosquito, they can initiate the sexual reproductive stage of the cycle that results in a new generation of transmittable sporozoites.

Different antimalarials selectively kill the parasite’s different developmental forms. The mechanism of action is known for some of them: pyrimetha- mine and dapsone inhibit dihydrofolate reductase (p. 273), as does chlorguanide (proguanil) via its active metabolite. The sulfonamide sulfadoxine inhibits synthesis of dihydrofolic acid (p. 272). Chlo- roquine and quinine accumulate within the acidic vacuoles of blood schizonts and inhibit polymerization of heme, the latter substance being toxic for the schizonts.

Antimalarial drug choice takes into account tolerability and plasmodial resistance.

Tolerability. The first available antimalarial, quinine, has the smallest therapeutic margin. All newer agents are rather well tolerated.

Plasmodium (P.) falciparum, re- sponsible for the most dangerous form of malaria, is particularly prone to develop drug resistance. The incidence of resistant strains rises with increasing frequency of drug use. Resistance has been reported for chloroquine and also for the combination pyrimethamine/ sulfadoxine.

Drug choice for antimalarial chemoprophylaxis. In areas with a risk of malaria, continuous intake of antimalarials affords the best protection against the disease, although not against infection. The drug of choice is chloroquine. Because of its slow excretion (plasma t1/2 = 3d and longer), a single weekly dose is sufficient. In areas with resistant P. falciparum, alternative regimens are chloroquine plus pyrimethamine/sulfadoxine (or proguanil, or doxycycline), the chloroquine analogue amodiaquine, as well as quinine or the better tolerated derivative mefloquine (blood-schizonticidal). Agents active against blood schizonts do not prevent the (symptom-free) hepatic infection, only the disease-causing infection of erythrocytes (“suppression therapy”). On return from an endemic malaria region, a 2 wk course of primaquine is adequate for eradication of the late hepatic stages (P. vivax and P. ovale).

Protection from mosquito bites (net, skin-covering clothes, etc.) is a very important prophylactic measure.

Antimalarial therapy employs the same agents and is based on the same principles. The blood-schizonticidal halofantrine is reserved for therapy only. The pyrimethamine-sulfadoxine combination may be used for initial selftreatment.

Drug resistance is accelerating in many endemic areas; malaria vaccines may hold the greatest hope for control of infection.

Chemotherapy of Malignant Tumors

A tumor (neoplasm) consists of cells that proliferate independently of the body’s inherent “building plan.” A malignant tumor (cancer) is present when the tumor tissue destructively invades healthy surrounding tissue or when dislodged tumor cells form secondary tumors (metastases) in other organs. A cure requires the elimination of all malignant cells (curative therapy). When this is not possible, attempts can be made to slow tumor growth and thereby prolong the patient’s life or improve quality of life (palliative therapy). Chemotherapy is faced with the problem that the malignant cells are endogenous and are not endowed with special metabolic properties.

Cytostatics (A) are cytotoxic substances that particularly affect proliferating or dividing cells. Rapidly dividing malignant cells are preferentially injured. Damage to mitotic processes not only retards tumor growth but may also initiate apoptosis (programmed cell death). Tissues with a low mitotic rate are largely unaffected; likewise, most healthy tissues. This, however, also applies to malignant tumors consisting of slowly dividing differentiated cells. Tissues that have a physiologically high mitotic rate are bound to be affected by cytostatic therapy. Thus, typical adverse effects occur:

Loss of hair results from injury to hair follicles; gastrointestinal disturbances, such as diarrhea, from inadequate replacement of enterocytes whose life span is limited to a few days; nausea and vomiting from stimulation of area postrema chemoreceptors (p. 330); and lowered resistance to infection from weakening of the immune system (p. 300). In addition, cytostatics cause bone marrow depression. Resupply of blood cells depends on the mitotic activity of bone marrow stem and daughter cells. When myeloid proliferation is arrested, the short-lived granulocytes are the first to be affected (neutropenia), then blood platelets (thrombopenia) and, finally,

the more long-lived erythrocytes (anemia). Infertility is caused by suppression of spermatogenesis or follicle maturation. Most cytostatics disrupt DNA metabolism. This entails the risk of a potential genomic alteration in healthy cells (mutagenic effect). Conceivably, the latter accounts for the occurrence of leukemias several years after cytostatic therapy (carcinogenic effect). Furthermore, congenital malformations are to be expected when cytostatics must be used during pregnancy (teratogenic ef- fect).

Cytostatics possess different mech- anisms of action.

Damage to the mitotic spindle (B).

The contractile proteins of the spindle apparatus must draw apart the replicated chromosomes before the cell can divide. This process is prevented by the so-called spindle poisons (see also colchicine, p. 316) that arrest mitosis at metaphase by disrupting the assembly of microtubules into spindle threads. The vinca alkaloids, vincristine and vin- blastine (from the periwinkle plant, Vin- ca rosea) exert such a cell-cycle-specific effect. Damage to the nervous system is a predicted adverse effect arising from injury to microtubule-operated axonal transport mechanisms.

Paclitaxel, from the bark of the pacific yew (Taxus brevifolia), inhibits disassembly of microtubules and induces atypical ones. Docetaxel is a semisynthetic derivative.

Inhibition of DNA and RNA synthesis (A). Mitosis is preceded by replication of chromosomes (DNA synthesis) and increased protein synthesis (RNA synthesis). Existing DNA (gray) serves as a template for the synthesis of new (blue) DNA or RNA. De novo synthesis may be inhibited by:

Damage to the template (1). Alkylating cytostatics are reactive compounds that transfer alkyl residues into a covalent bond with DNA. For instance, mechlorethamine (nitrogen mustard) is able to cross-link double-stranded DNA on giving off its chlorine atoms. Correct reading of genetic information is thereby rendered impossible. Other alkylating agents are chlorambucil, melphalan, thio-TEPA, cyclophosphamide (p. 300, 320), ifosfamide, lomustine, and busul- fan. Specific adverse reactions include irreversible pulmonary fibrosis due to busulfan and hemorrhagic cystitis caused by the cyclophosphamide metabolite acrolein (preventable by the uroprotectant mesna). Cisplatin binds to (but does not alkylate) DNA strands.

Cystostatic antibiotics insert themselves into the DNA double strand; this may lead to strand breakage (e.g., with bleomycin). The anthracycline antibiotics daunorubicin and adriamycin (doxorubicin) may induce cardiomyopathy. Bleomycin can also cause pulmonary fibrosis.

The epipodophyllotoxins, etopo- side and teniposide, interact with topoisomerase II, which functions to split, transpose, and reseal DNA strands (p. 274); these agents cause strand breakage by inhibiting resealing.

Inhibition of nucleobase synthesis (2). Tetrahydrofolic acid (THF) is required for the synthesis of both purine bases and thymidine. Formation of THF from folic acid involves dihydrofolate reductase (p. 272). The folate analogues aminopterin and methotrexate (amethopterin) inhibit enzyme activity as false substrates. As cellular stores of THF are depleted, synthesis of DNA and RNA building blocks ceases. The effect of these antimetabolites can be reversed

by administration of folinic acid (5-for- myl-THF, leucovorin, citrovorum factor).

Incorporation of false building blocks (3). Unnatural nucleobases (6- mercaptopurine; 5-fluorouracil) or nucleosides with incorrect sugars (cytarabine) act as antimetabolites. They inhibit DNA/RNA synthesis or lead to synthesis of missense nucleic acids.

6-Mercaptopurine results from biotransformation of the inactive precursor azathioprine (p. 37). The uricostatic allo- purinol inhibits the degradation of 6- mercaptopurine such that co-adminis- tration of the two drugs permits dose reduction of the latter.

Frequently, the combination of cytostatics permits an improved therapeutic effect with fewer adverse reactions. Initial success can be followed by loss of effect because of the emergence of resistant tumor cells. Mechanisms of resistance are multifactorial:

Diminished cellular uptake may result from reduced synthesis of a transport protein that may be needed for membrane penetration (e.g., methotrexate).

Augmented drug extrusion: in- creased synthesis of the P-glycoprotein that extrudes drugs from the cell (e.g., anthracyclines, vinca alkaloids, epipodophyllotoxins, and paclitaxel) is reponsible for multi-drug resistance (mdr-1 gene amplification).

Diminished bioactivation of a prodrug, e.g., cytarabine, which requires intracellular phosphorylation to become cytotoxic.

Change in site of action: e.g., increased synthesis of dihydrofolate reductase may occur as a compensatory response to methotrexate.

Damage repair: DNA repair enzymes may become more efficient in repairing defects caused by cisplatin.

Inhibition of Immune Responses

Both the prevention of transplant rejection and the treatment of autoimmune disorders call for a suppression of immune responses. However, immune suppression also entails weakened defenses against infectious pathogens and a long-term increase in the risk of neoplasms.

A specific immune response be- gins with the binding of antigen by lymphocytes carrying specific receptors with the appropriate antigen-binding site. B-lymphocytes “recognize” antigen surface structures by means of membrane receptors that resemble the antibodies formed subsequently. T-lympho- cytes (and naive B-cells) require the antigen to be presented on the surface of macrophages or other cells in conjunction with the major histocompatibility complex (MHC); the latter permits recognition of antigenic structures by means of the T-cell receptor. T-help- er cells carry adjacent CD-3 and CD-4 complexes, cytotoxic T-cells a CD-8 complex. The CD proteins assist in docking to the MHC. In addition to recognition of antigen, activation of lymphocytes requires stimulation by cytokines. Interleukin-1 is formed by macrophages, and various interleukins (IL), including IL-2, are made by T-helper cells. As antigen-specific lymphocytes proliferate, immune defenses are set into motion.

I. Interference with antigen recognition. Muromonab CD3 is a monoclonal antibody directed against mouse CD-3 that blocks antigen recognition by T-lymphocytes (use in graft rejection).

II. Inhibition of cytokine production or action. Glucocorticoids mod- ulate the expression of numerous genes; thus, the production of IL-1 and IL-2 is inhibited, which explains the suppression of T-cell-dependent immune responses. Glucocorticoids are used in organ transplantations, autoimmune diseases, and allergic disorders. Systemic use carries the risk of iatrogenic Cushing’s syndrome (p. 248).

Cyclosporin A is an antibiotic polypeptide from fungi and consists of 11, in part atypical, amino acids. Given orally, it is absorbed, albeit incompletely. In lymphocytes, it is bound by cyclophilin, a cytosolic receptor that inhibits the phosphatase calcineurin. The latter plays a key role in T-cell signal transduction. It contributes to the induction of cytokine production, including that of IL-2. The breakthroughs of modern transplantation medicine are largely attributable to the introduction of cyclosporin A. Prominent among its adverse effects are renal damage, hypertension, and hyperkalemia.

Tacrolimus, a macrolide, derives from a streptomyces species; pharmacologically it resembles cyclosporin A, but is more potent and efficacious.

The monoclonal antibodies daclizumab and basiliximab bind to the α- chain of the II-2 receptor of T-lympho- cytes and thus prevent their activation, e.g., during transplant rejection.

III. Disruption of cell metabolism with inhibition of proliferation. At dosages below those needed to treat malignancies, some cytostatics are also employed for immunosuppression, e.g., azathioprine, methotrexate, and cyclophosphamide (p. 298). The antiproliferative effect is not specific for lymphocytes and involves both T- and B- cells.

Mycophenolate mofetil has a more specific effect on lymphocytes than on other cells. It inhibits inosine monophosphate dehydrogenase, which catalyzes purine synthesis in lymphocytes. It is used in acute tissue rejection responses.

IV. Anti-T-cell immune serum is obtained from animals immunized with human T-lymphocytes. The antibodies bind to and damage T-cells and can thus be used to attenuate tissue rejection.