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290 Antiviral Drugs

Drugs for the Treatment of AIDS

Replication of the human immunodeficiency virus (HIV), the causative agent of AIDS, is susceptible to targeted interventions because it entails several obligatory steps in virus-specific metabolism (A). First, the virus docks at the CD4 complex of T-helper lymphocytes by means of a glycoprotein in the viral coat (p.304). A fusion protein is then extruded from the viral coat, by which fusion of the latter and the cell membrane is initiated. Next, viral RNA is transcribed into DNA, a step catalyzed by viral “reverse transcriptase.” Double-stranded 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 not assembled individually but in the form of polyproteins. An N-terminal fatty acid (myristoyl) residue 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— Nucleoside Agents

Representatives of this group include zidovudine, stavudine, zalcitabine, didanosine, and lamivudine. They are nucleosides containing an abnormal sugar moiety and require bioactivation by phosphorylation (cf. zidovudine in A). As triphosphates, they inhibit reverse transcriptase and cause strand breakage following incorporation into viral DNA. The substances are administered orally. In part, they differ in their spectrum of adverse effects (e.g., leukopenia with zidovudine; peripheral neuropathy and pancreatitis with the others) and in the mechanisms

responsible for development of resistance. AIDS therapy mostly employs combinations of two members of this group plus either a nonnucleoside inhibitor (see below) or one to two protease inhibitors (see below).

Nonnucleoside Inhibitors

Nevirapine and efavirenz are active inhibitors of reverse transcriptase, that is, they do not require phosphorylation. Adverse reactions include rashes and interactions involving cytochrome P450 isozymes (CYP).

II. HIV protease Inhibitors

Inhibitors of viral protease prevent cleavage of inactive precursor proteins, and hence viral maturation. They are administered orally.

Saquinavir could be considered an abnormal peptide. Its bioavailability is low. Ritonavir, indinavir, nelfinavir, and amprenavir are other protease inhibitors that in part exhibit markedly higher bioavailability. Biotransformation of these drugs involves CYP enzymes and is therefore subject to interaction with various other drugs metabolized via this route. Prolonged administration may be associated with a peculiar redistribution of adipose tissue and metabolic disturbances (hyperlipidemia, insulin resistance, hyperglycemia).

III. Fusion Inhibitors

Enfuvirtide is a peptide that binds to the viral fusion protein in such a manner as to prevent the necessary change in conformation. It is a reserve drug.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Drugs for the Treatment of AIDS

291

A. AIDS drugs

 

 

 

 

 

 

Envelope

 

 

 

 

RNA

Fusion glycoprotein

 

 

 

 

 

 

 

 

 

 

Matrix protein

 

 

 

 

 

Reverse

 

 

 

 

 

transcriptase

 

 

 

 

 

Integrase

Fusion inhibitor Enfuvirtide,

 

 

 

 

a peptide, s.c. administration

Viral RNA

 

Inhibitors of

 

 

 

reverse

 

 

 

 

 

 

 

 

 

 

transcriptase

 

 

 

 

 

 

 

O

 

 

 

 

H N

CH 3

DNA

 

 

 

 

 

 

 

 

 

 

 

 

O

N

 

 

HOCH2

O

 

 

 

 

N

+

N

 

 

 

N

 

 

e.g., zidovudine

 

 

 

Inhibitors of

 

 

Viral RNA

Polyproteins

HIV protease

 

 

 

 

 

 

 

 

 

 

 

N

 

 

 

O

 

 

 

 

 

N

H

 

 

H2N

 

 

O

 

 

O

 

 

 

 

H

N

 

 

 

 

 

 

Protease

HO

 

 

 

 

 

 

 

Polyprotein

 

 

 

N

O

cleavage

 

 

 

 

 

 

 

 

 

 

 

 

 

 

N H

 

 

 

 

H3C

CH3

 

Mature virus

e.g., saquinavir

CH3

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

292 Antiparasitic Drugs

Drugs for Treating Endoparasitic and 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 and arachnicidalagents,respectively,canbeused. Endoparasites invade the intestines or even internal organs and are mostly members of the phyla of flatworms and roundworms. They are combated with anthelmintics.

Antihelmintics. 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. Whereasfleascanbeeffectively dealtwithbydisinfectionofclothesandliving quarters, lice and mites require the topical applicationofinsecticidestotheinfestedsubject.Thefollowingagentsactmainlybyinterfering with the activation or inactivation of neuralvoltage-gatedinsectsodiumchannels.

Chlorphenothane (DDT) kills insects after absorptionofaverylowamount,e.g.,viafoot contact with sprayed surfaces (contact insec-

ticide). 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 is degraded in the environment and the 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. Although it is more readily degraded than DDT, it should be used only as a secondline agent with appropriate precautions. In the United Kingdom its use for head lice has been banned; in the United States it is not recommended in young children and is contraindicated in premature infants.

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

Therapy of Worm Infestations

 

 

Worms (helminths)

Anthelminthic Drug of Choice

 

 

Flatworms (platyhelminths)

 

Tape worms (cestodes)

Praziquantela or niclosamide

Flukes (trematodes),

Praziquantel

e.g., Schistosoma species (bilharziasis)

 

 

 

Roundworms (nematodes)

 

Pinworm (Enterobius vermicularis)

Mebendazole or pyrantel pamoate

Whipworm (Trichuris trichiura)

Mebendazole

Ascaris lumbricoides

Mebendazole or pyrantel pamoate

Trichinella spiralisb

Mebendazole and thiabendazole

Strongyloides stercoralis

Thiabendazole

Hookworms (Necator americanus,

Mebendazole or pyrantel pamoate

Ancylostoma duodenale)

 

 

 

a Not for ocular or spinal cord cysticercosis.

 

b Thiabendazole in intestinal phase; mebendazole in tissue phase.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

 

Drugs against Endoand Ectoparasites

293

A. Endoparasites and ectoparasites: therapeutic agents

 

Tapeworms

Louse

 

e.g., beef

 

 

tapeworm

 

 

Spasm,

 

 

 

 

 

 

Cl

 

 

injury of

 

 

 

 

 

 

 

 

 

integument

 

 

 

 

 

 

 

 

 

O

C

 

 

 

 

Chlor-

 

Cl

 

 

N

 

 

 

 

HC

C

Cl

 

 

 

 

 

phenothane

 

N

 

 

 

 

(DDT)

 

Cl

 

 

 

O

 

 

death

 

 

 

 

 

 

Praziquantel

Cl

 

 

 

 

 

 

 

 

 

 

 

 

 

 

convulsions,

 

 

Round-

 

 

 

 

 

 

 

 

worms,

 

 

 

 

 

 

 

 

 

e.g.,

 

 

 

 

 

system:nervousto

 

 

 

ascaris

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pinworm

 

 

Flea

 

 

 

O

 

 

 

 

 

Damage

Cl

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Cl

 

 

Cl

C

 

 

 

 

 

 

 

 

 

NH

 

 

 

 

 

 

 

 

N

NH

COOC

3

Cl

 

 

Cl

 

 

 

 

Cl

 

 

 

 

 

 

H

 

 

 

 

 

 

 

 

 

 

Hexachlorocyclo-

Mebendazole

 

 

 

 

hexane (Lindane)

Trichinella

 

larvae

Scabies mite

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

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