книги студ / Color Atlas of Pharmacology

Isoniazid

CNS damage and peripheral neuropathy

(Vit. B6-administration) Liver damage

Ethambutol

Optic nerve damage

Rifampin

Liver damage

and enzyme induction

Dapsone

Mycobacterium

tuberculosis

Isonicotinic acid

Nicotinic acid

1

2

p-Aminobenzoic acid

Folate synthesis

Pyrazinamide

Liver damage

Streptomycin

an aminoglycoside antibiotic

Vestibular and cochlear ototoxicity

Clofazimine

Drugs Used in the Treatment of

Fungal Infections

Infections due to fungi are usually confined to the skin or mucous membranes: local or superficial mycosis. However, in immune deficiency states, internal organs may also be affected: systemic or deep mycosis.

Mycoses are most commonly due to dermatophytes, which affect the skin, hair, and nails following external infection. Candida albicans, a yeast organism normally found on body surfaces, may cause infections of mucous membranes, less frequently of the skin or internal organs when natural defenses are impaired (immunosuppression, or damage of microflora by broad-spectrum antibiotics).

Imidazole derivatives inhibit ergosterol synthesis. This steroid forms an integral constituent of cytoplasmic membranes of fungal cells, analogous to cholesterol in animal plasma membranes. Fungi exposed to imidazole derivatives stop growing (fungistatic effect) or die (fungicidal effect). The spectrum of affected fungi is very broad. Because they are poorly absorbed and poorly tolerated systemically, most imidazoles are suitable only for topical use (clotrimazole, econazole oxiconazole, isoconazole, bifonazole, etc.). Rarely, this use may result in contact dermatitis. Mi- conazole is given locally, or systemically by short-term infusion (despite its poor tolerability). Because it is well absorbed, ketoconazole is available for oral administration. Adverse effects are rare; however, the possibility of fatal liver damage should be noted. Remarkably, ketoconazole may inhibit steroidogenesis (gonadal and adrenocortical hormones).

Fluconazole and itraconazole are newer, orally effective triazole derivatives. The topically active allylamine naftidine and the morpholine amorolfine also inhibit ergosterol synthesis, albeit at another step.

The polyene antibiotics, ampho- tericin B and nystatin, are of bacterial origin. They insert themselves into fun-

gal cell membranes (probably next to ergosterol molecules) and cause formation of hydrophilic channels. The resultant increase in membrane permeability, e.g., to K+ ions, accounts for the fungicidal effect. Amphotericin B is active against most organisms responsible for systemic mycoses. Because of its poor absorbability, it must be given by infusion, which is, however, poorly tolerated (chills, fever, CNS disturbances, impaired renal function, phlebitis at the infusion site). Applied topically to skin or mucous membranes, amphotericin B is useful in the treatment of candidal mycosis. Because of the low rate of enteral absorption, oral administration in intestinal candidiasis can be considered a topical treatment. Nystatin is used only for topical therapy.

Flucytosine is converted in candida fungi to 5-fluorouracil by the action of a specific cytosine deaminase. As an antimetabolite, this compound disrupts DNA and RNA synthesis (p. 298), resulting in a fungicidal effect. Given orally, flucytosine is rapidly absorbed. It is well tolerated and often combined with amphotericin B to allow dose reduction of the latter.

Griseofulvin originates from molds and has activity only against dermatophytes. Presumably, it acts as a spindle poison to inhibit fungal mitosis. Although targeted against local mycoses, griseofulvin must be used systemically. It is incorporated into newly formed keratin. “Impregnated” in this manner, keratin becomes unsuitable as a fungal nutrient. The time required for the eradication of dermatophytes corresponds to the renewal period of skin, hair, or nails. Griseofulvin may cause uncharacteristic adverse effects. The need for prolonged administration (several months), the incidence of side effects, and the availability of effective and safe alternatives have rendered griseofulvin therapeutically obsolete.

Chemotherapy of Viral Infections

Viruses essentially consist of genetic material (nucleic acids, green strands in

(A) and a capsular envelope made up of proteins (blue hexagons), often with a coat (gray ring) of a phospholipid (PL) bilayer with embedded proteins (small blue bars). They lack a metabolic system but depend on the infected cell for their growth and replication. Targeted therapeutic suppression of viral replication requires selective inhibition of those metabolic processes that specifically serve viral replication in infected cells. To date, this can be achieved only to a limited extent.

Viral replication as exemplified by Herpes simplex viruses (A): (1) The viral particle attaches to the host cell membrane (adsorption) by linking its capsular glycoproteins to specific structures of the cell membrane. (2) The viral coat fuses with the plasmalemma of the host cell and the nucleocapsid (nucleic acid plus capsule) enters the cell interior (penetration). (3) The capsule opens (“uncoating”) near the nuclear pores and viral DNA moves into the cell nucleus. The genetic material of the virus can now direct the cell’s metabolic system. (4a) Nucleic acid synthesis: The genetic material (DNA in this instance) is replicated and RNA is produced for the purpose of protein synthesis. (4b) The proteins are used as “viral enzymes” catalyzing viral multiplication (e.g., DNA polymerase and thymidine kinase), as capsomers, or as coat components, or are incorporated into the host cell membrane. (5) Individual components are assembled into new virus particles (maturation). (6) Release of daughter viruses results in spread of virus inside and outside the organism. With herpes viruses, replication entails host cell destruction and development of disease symptoms.

Antiviral mechanisms (A). The organism can disrupt viral replication with the aid of cytotoxic T-lymphocytes that recognize and destroy virus-pro- ducing cells (viral surface proteins) or

by means of antibodies that bind to and inactivate extracellular virus particles. Vaccinations are designed to activate specific immune defenses.

Interferons (IFN) are glycoproteins that, among other products, are released from virus-infected cells. In neighboring cells, interferon stimulates the production of “antiviral proteins.” These inhibit the synthesis of viral proteins by (preferential) destruction of viral DNA or by suppressing its translation. Interferons are not directed against a specific virus, but have a broad spectrum of antiviral action that is, however, species-specific. Thus, interferon for use in humans must be obtained from cells of human origin, such as leukocytes (IFN-α), fibroblasts (IFN-β), or lymphocytes (IFN-γ). Interferons are also used to treat certain malignancies and autoimmune disorders (e.g., IFN-α for chronic hepatitis C and hairy cell leukemia; IFN-β for severe herpes virus infections and multiple sclerosis).

Virustatic antimetabolites are “false” DNA building blocks (B) or nucleosides. A nucleoside (e.g., thymidine) consists of a nucleobase (e.g., thymine) and the sugar deoxyribose. In antimetabolites, one of the components is defective. In the body, the abnormal nucleosides undergo bioactivation by attachment of three phosphate residues (p. 287).

Idoxuridine and congeners are incorporated into DNA with deleterious results. This also applies to the synthesis of human DNA. Therefore, idoxuridine and analogues are suitable only for topical use (e.g., in herpes simplex keratitis).

Vidarabine inhibits virally induced DNA polymerase more strongly than it does the endogenous enzyme. Its use is now limited to topical treatment of severe herpes simplex infection. Before the introduction of the better tolerated acyclovir, vidarabine played a major part in the treatment of herpes simplex encephalitis.

Among virustatic antimetabolites, acyclovir (A) has both specificity of the highest degree and optimal tolerability,

because it undergoes bioactivation only in infected cells, where it preferentially inhibits viral DNA synthesis. (1) A virally coded thymidine kinase (specific to H. simplex and varicella-zoster virus) performs the initial phosphorylation step; the remaining two phosphate residues are attached by cellular kinases. (2) The polar phosphate residues render acyclovir triphosphate membrane impermeable and cause it to accumulate in infected cells. (3) Acyclovir triphosphate is a preferred substrate of viral DNA polymerase; it inhibits enzyme activity and, following its incorporation into viral DNA, induces strand breakage because it lacks the 3’-OH group of deoxyribose that is required for the attachment of additional nucleotides. The high therapeutic value of acyclovir is evident in severe infections with H. simplex viruses (e.g., encephalitis, generalized infection) and varicella-zoster viruses (e.g., severe herpes zoster). In these cases, it can be given by i.v. infusion. Acyclovir may also be given orally despite its incomplete (15%–30%) enteral absorption. In addition, it has topical uses. Because host DNA synthesis remains unaffected, adverse effects do not include bone marrow depression. Acyclovir is eliminated unchanged in urine

(t1/2 ~ 2.5 h).

Valacyclovir, the L-valyl ester of acyclovir, is a prodrug that can be administered orally in herpes zoster infections. Its absorption rate is approx. twice that of acyclovir. During passage through the intestinal wall and liver, the valine residue is cleaved by esterases, generating acyclovir.

Famcyclovir is an antiherpetic prodrug with good bioavailability when given orally. It is used in genital herpes and herpes zoster. Cleavage of two acetate groups from the “false sugar” and oxidation of the purine ring to guanine yields penciclovir, the active form. The latter differs from acyclovir with respect to its “false sugar” moiety, but mimics it pharmacologically. Bioactivation of penciclovir, like that of acyclovir, involves formation of the triphosphory-

lated antimetabolite via virally induced thymidine kinase.

Ganciclovir (structure on p. 285) is given by infusion in the treatment of severe infections with cytomegaloviruses (also belonging to the herpes group); these do not induce thymidine kinase, phosphorylation being initiated by a different viral enzyme. Ganciclovir is less well tolerated and, not infrequently, produces leukopenia and thrombopenia.

Foscarnet represents a diphosphate analogue.

As shown in (A), incorporation of nucleotide into a DNA strand entails cleavage of a diphosphate residue. Fos- carnet (B) inhibits DNA polymerase by interacting with its binding site for the diphosphate group. Indications: system- ic therapy of severe cytomegaly infection in AIDS patients; local therapy of herpes simplex infections.

Amantadine (C) specifically affects the replication of influenza A (RNA) viruses, the causative agent of true influenza. These viruses are endocytosed into the cell. Release of viral DNA requires protons from the acidic content of endosomes to penetrate the virus. Presumably, amantadine blocks a channel protein in the viral coat that permits influx of protons; thus, “uncoating” is prevented. Moreover, amantadine inhibits viral maturation. The drug is also used prophylactically and, if possible, must be taken before the outbreak of symptoms. It also is an antiparkinsonian (p. 188).

Drugs for the Treatment of AIDS

Replication of the human immunodeficiency virus (HIV), the causative agent of AIDS, is susceptible to targeted interventions, because several virusspecific metabolic steps occur in infected cells (A). Viral RNA must first be transcribed into DNA, a step catalyzed by viral “reverse transcriptase.” Doublestranded DNA is incorporated into the host genome with the help of viral integrase. Under control by viral DNA, viral replication can then be initiated, with synthesis of viral RNA and proteins (including enzymes such as reverse transcriptase and integrase, and structural proteins such as the matrix protein lining the inside of the viral envelope). These proteins are assembled not individually but in the form of polyproteins. These precursor proteins carry an N-ter- minal fatty acid (myristoyl) residue that promotes their attachment to the interior face of the plasmalemma. As the virus particle buds off the host cell, it carries with it the affected membrane area as its envelope. During this process, a protease contained within the polyprotein cleaves the latter into individual, functionally active proteins.

I. Inhibitors of Reverse Transcriptase

IA. Nucleoside agents

These substances are analogues of thymine (azidothymidine, stavudine), adenine (didanosine), cytosine (lamivudine, zalcitabine), and guanine (car- bovir, a metabolite of abacavir). They have in common an abnormal sugar moiety. Like the natural nucleosides, they undergo triphosphorylation, giving rise to nucleotides that both inhibit reverse transcriptase and cause strand breakage following incorporation into viral DNA.

The nucleoside inhibitors differ in terms of l) their ability to decrease circulating HIV load; 2) their pharmacokinetic properties (half life ! dosing interval ! compliance; organ distribution !passage through blood-brainbar-

rier); 3) the type of resistance-inducing mutations of the viral genome and the rate at which resistance develops; and 4) their adverse effects (bone marrow depression, neuropathy, pancreatitis).

IB. Non-nucleoside inhibitors

The non-nucleoside inhibitors of reverse transcriptase (nevirapine, delavirdine, efavirenz) are not phosphorylated. They bind to the enzyme with high selectivity and thus prevent it from adopting the active conformation. Inhibition is noncompetitive.

II. HIV protease inhibitors

Viral protease cleaves precursor proteins into proteins required for viral replication. The inhibitors of this protease (saquinavir, ritonavir, indinavir, and nelfinavir) represent abnormal proteins that possess high antiviral efficacy and are generally well tolerated in the short term. However, prolonged administration is associated with occasionally severe disturbances of lipid and carbohydrate metabolism. Biotransformation of these drugs involves cytochrome P450 (CYP 3A4) and is therefore subject to interaction with various other drugs inactivated via this route.

For the dual purpose of increasing the effectiveness of antiviral therapy and preventing the development of a therapy-limiting viral resistance, inhibitors of reverse transcriptase are combined with each other and/or with protease inhibitors.

Combination regimens are designed in accordance with substancespecific development of resistance and pharmacokinetic parameters (CNS penetrability, “neuroprotection,” dosing frequency).

Disinfectants and Antiseptics

Disinfection denotes the inactivation or killing of pathogens (protozoa, bacteria, fungi, viruses) in the human environment. This can be achieved by chemical or physical means; the latter will not be discussed here. Sterilization refers to the killing of all germs, whether pathogenic, dormant, or nonpathogenic. Anti- sepsis refers to the reduction by chemical agents of germ numbers on skin and mucosal surfaces.

Agents for chemical disinfection ideally should cause rapid, complete, and persistent inactivation of all germs, but at the same time exhibit low toxicity (systemic toxicity, tissue irritancy, antigenicity) and be non-deleterious to inanimate materials. These requirements call for chemical properties that may exclude each other; therefore, compromises guided by the intended use have to be made.

Disinfectants come from various chemical classes, including oxidants, halogens or halogen-releasing agents, alcohols, aldehydes, organic acids, phenols, cationic surfactants (detergents) and formerly also heavy metals. The ba- sic mechanisms of action involve denaturation of proteins, inhibition of enzymes, or a dehydration. Effects are dependent on concentration and contact time.

Activity spectrum. Disinfectants inactivate bacteria (gram-positive > gram-negative > mycobacteria), less effectively their sporal forms, and a few (e.g., formaldehyde) are virucidal.

Applications

Skin “disinfection.” Reduction of germ counts prior to punctures or surgical procedures is desirable if the risk of wound infection is to be minimized. Useful agents include: alcohols (1- and 2-propanol; ethanol 60–90%; iodine-re- leasing agents like polyvinylpyrrolidone [povidone, PVP]-iodine as a depot form of the active principle iodine, instead of iodine tincture), cationic surfactants,

and mixtures of these. Minimal contact times should be at least 15 s on skin areas with few sebaceous glands and at least 10 min on sebaceous gland-rich ones.

Mucosal disinfection: Germ counts can be reduced by PVP iodine or chlorhexidine (contact time 2 min), although not as effectively as on skin.

Wound disinfection can be achieved with hydrogen peroxide (0.3%–1% solution; short, foaming action on contact with blood and thus wound cleansing) or with potassium permanganate (0.0015% solution, slightly astringent), as well as PVP iodine, chlorhexidine, and biguanidines.

Hygienic and surgical hand disinfection: The former is required after a suspected contamination, the latter before surgical procedures. Alcohols, mixtures of alcohols and phenols, cationic surfactants, or acids are available for this purpose. Admixture of other agents prolongs duration of action and reduces flammability.

Disinfection of instruments: Instru- ments that cannot be heator steamsterilized can be precleaned and then disinfected with aldehydes and detergents.

Surface (floor) disinfection employs aldehydes combined with cationic surfactants and oxidants or, more rarely, acidic or alkalizing agents.

Room disinfection: room air and surfaces can be disinfected by spraying or vaporizing of aldehydes, provided that germs are freely accessible.