Pharm Ch 36
Malarial Plasmodia
 Malaria caused by one of 5 species of plasmodial parasites: Plasmodium falciparum, P. vivax, P. ovale, P.
malariae, and P.knowlesi
o Most serious type caused by P. falciparum
 Life cycle – Anopheles species mosquito ingests sexual forms of malarial parasites (gametocytes) when taking
blood meal from infected human
o After fusion of male and female gametocytes and maturation of zygote in mosquito, sporozoites
released from oocysts
o Sporozoites migrate to mosquito’s salivary glands and can be inoculated into blood of another human
host during subsequent blood meal
o In human, sporozoites leave blood and multiply in liver, forming tissue schizonts (exoerythrocytic
hepatic stage; asymptomatic)
o 1-12 weeks after infective bite, liver cells release parasites into bloodstream as merozoites; single
sporozoite can produce 30,000+ merozoites
o Merozoites invade RBCs, multiply asexually, and form blood schizonts; erythrocytic stage
o Infected RBCs rupture, releasing another generation of merozoites that continue erythrocytic cycle
o Rare merozoites mature into gametocytes, and ingestion of circulating gametocytes by mosquito
completes life cycle
 Clinical symptoms caused by intravascular lysis of RBCs and subsequent release of merozoites into blood
 P. falciparum-infected RBCs express knobs on their surface; composed of both host and parasite proteins
o Parasite proteins include PfEMP-1 (mediates attachment of infected RBCs to cellular receptors, including
CD36, ICAM-1, ELAM-1, and chondroitin sulfate on endothelial surfaces in human host)
o Intravascular binding during malarial episode only occurs during P. falciparum infection; contributes to
intravascular sludging of RBCs
o Attachment lessens amount of time where infected RBCs circulate systemically, decreasing likelihood
that infected RBCs will be cleared via splenic sequestration
o Sludging damages organs by tissue hypoxia, focal necrosis, and hemorrhage
 Untreated, cerebral malaria almost uniformly fatal; even w/optimal treatment, case fatality exceeds 20%
 Due to increasing ineffectiveness of older drugs, recommended that those in sub-Saharan Africa w/malaria be
treated w/artemisinin derivative in combo w/second agent as first line
 Because P. falciparum and P. malariae infections involve only one cycle of hepatic cell invasion, drugs that
eliminate species from RBCs usually sufficient to clear infection
o P. vivax and P. ovale have dormant hepatic forms (hypnozoites) that release merozoites over several
months to 2 years; treat these pts w/agents effective against both blood-stage and liver-stage parasites
 Plasmodia have limited capacity for de novo amino acid synthesis; rely on amino acids released from ingested
host hemoglobin
o In RBCs, plasmodia degrade hgb in digestive vacuole
o Hgb sequentially degraded to constituent amino acids by plasmodial aspartic proteases (plasmepsins),
cysteine protease (falcipain), and metalloprotease (falcilysin)
o Degradation of hgb releases protonated basic amino acids and toxic heme metabolite
(ferriprotoporphyrin IX), which is detoxified by polymerization to crystalline hemozoin
o If ferriprotoporphyrin IX doesn’t polymerize, it causes lysosomal membrane damage and toxicity to
malarial parasite
o Quinolone antimalarials act by inhibiting heme polymerization, creating toxic environment to
intraerythrocytic plasmodia
 Plasmodia possess mitochondria w/genome that encodes 3 cytochromes that, together w/mitochondrialtargeted proteins derived from plasmodial nuclear genome, make up rudimentary electron transport chain
o Energy liberated by electron transport used to drive proton pumping across mitochondrial membrane,
and energy stored in proton gradient drives ATP synthesis; oxygen is final electron acceptor (reducing it
to water)
o Plasmodia derive most ATP directly from glycolysis; electron transport chain isn’t significant source of
energy, they do rely on electron transport for oxidation of key enzymes involved in nucleotide synthesis
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Dihydroorotate dehydrogenase (DHOD) – mediates early step in pyrimidine synthesis; catalyzes
oxidation of dihydroorotate to orotate; DHOD reduced in this reaction and must be reoxidized
before it can continue another cycle of catalysis
 Ubiquinone – integral membrane protein located near beginning of electron transport chain;
accepts electrons from reduced DHOD, regenerating oxidized form of DHOD
 Because plasmodia depend on de novo pyrimidine synthesis for DNA replication, interrupting
ability of ubiquinone to oxidize DHOD can disrupt plasmodial DNA replication
 Folic acid – involved in transfer of one-carbon units in variety of biosynthetic pathways, including those of DNA
and RNA precursors and certain amino acids
o Essential vitamin in humans
o In parasites, folate synthesized de novo
o Antifolate drugs act against parasite-specific isoforms of dihydropteroate synthetase and dihydrofolate
reductase
Treatment of Malaria
 Can use roots of Dichroa febrifuga, leaves of hydrangea, or bark of cinchona tree to treat malaria because they
all have quinoline compound in them
 Chloroquine – weak base that in neutral form freely diffuses across membrane of parasite’s food vacuole; once
inside, it is rapidly protonated, making it unable to diffuse out again
o Protonated chloroquine accumulates to high concentrations inside food vacuole, where it binds to
ferriprotoporphyrin IX and inhibits polymerization
o Accumulation of ferriprotoporphyrin IX leads to oxidative membrane damage and is toxic to parasite
o Concentration of chloroquine required to alkalinize mammalian lysosomes much higher than that
needed to raise pH in malarial food vacuoles
o Taken in supratherapeutic doses, it can cause vomiting, retinopathy, hypotension, confusion, and death
o Chloroquine-resistant plasmodia accumulate less chloroquine inside food vacuoles; in food vacuole,
protonated amino acids generated by parasite as it degrades Hgb; protonated amino acids exit lysosome
by transmembrane protein PfCRT (mutations in PfCRT associated w/chloroquine resistance)
 Mutated PfCRT pumps chloroquine out of food vacuole
 Mutations in PfCRT often carry second mutation in gene pfmdr1 encoding Pgh2 (food vacuole
membrane protein involved in pH regulation); provides corrective action that allows chloroquine
resistance, but continued growth despite PfCRT often pumping out amino acids as well
o Strains of P. falciparum in Africa, Asia, and South America resistant to chloroquine
o Strains of P. vivax with decreased susceptibility to chloroquine in Papua New Guinea, Indonesia, and
focal areas of Oceania and Latin America
 Quinine – alkaloid that consists of quinoline ring linked by secondary carbinol to quinuclidine ring
o Optical isomer quinidine has identical pharmacologic actions
o Intercalates into DNA through H bonding, thus inhibiting DNA strand separation, transcription, and
translation; overall effect is decrease in growth and replication of erythrocytic form of plasmodia
o Used to treat individuals w/acute blood-stage malaria but not used prophylactically
o Can cause cinchonism (syndrome that includes tinnitus, deafness, headaches, vomiting, nausea, and
visual disturbances)
o Can prolong QT interval
 Mefloquine – quinoline compound; exact mechanism of action unknown; disrupts polymerization of hemozoin
in intraerythrocytic malarial parasites
o Can cause nausea, cardiac conduction abnormalities (bradycardia, prolonged QT interval, and
arrhythmia), and neuropsychiatric effects (vivid dreams/nightmares, insomnia, anxiety, depression,
hallucinations, seizures, and rarely psychosis)
o Used therapeutically and prophylactically
o Strains of P. falciparum resistant to both chloroquine and mefloquine in SE Asia
 Artemisinin – from wormwood plant Artemisia annua; both sesquiterpene lactone and cyclic endoperoxide
o When activated by free or heme-bound iron, it forms carbon-centered free-radical compound, which
alkylates many proteins as well as heme
o Specific for plasmodia-infected erythrocytes, but not known why
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Drug action related to free radical production in food vacuole and subsequent inhibition of PfATP6 (Ca2+
ATPase that is ortholog of mammalian SERCA Ca2+ pump)
o Administration of artemisinin and derivatives associated w/rapid decrease in level of malaria parasites in
blood and rapid resolution of symptoms in patients in blood-stage
o Affect blood-stage gametocytes, so decreases transmission
o Not effective as prophylactic agent against malaria
o Advised against as monotherapy because short half-life and subsequent risk of recrudescence of malaria
 Artemisinin combination therapy (ACT) – using artemisinin w/longer half-life drug
 ACT – first line treatment for chloroquine-resistant P. falciparum malaria
o Oral, parenteral, and rectal suppository formulations available
o Resistance to artemisinin associated w/mutations in PfATP6; some strains in Asia
Primaquine – attacks hepatic forms of malaria caused by P. vivax and P. ovale, so used to prevent recrudescence
of infections; only standard drug available for this use
o Severely disrupts metabolic processes of plasmodial mitochondria
o Antimalarial activity due to quinone (primaquine metabolite that interferes w/function of ubiquinone as
electron carrier in respiratory chain); could also be because certain primaquine metabolites cause
nonspecific oxidative damage to plasmodial mitochondria
o Predominantly used to clear hepatic hypnozoites
o May be used as prophylactic agent
o Individuals w/G6PD deficiency have limited ability to protect RBCs against oxidative damage (G6PD
needed to reduce NADP+ to NADPH, which converts oxidized glutathione to reduced glutathione)
 Reduced glutathione protects RBCs by catalyzing breakdown of toxic oxidant compounds
 Primaquine causes significant oxidative stress because of formation of numerous oxidized
compounds; can induce massive, potentially fatal hemolysis in individuals w/G6PD deficiency
o Never administer to pregnant women because it crosses placenta and can induce fatal hemolysis in fetal
RBCs independent of maternal G6PD status
Atovaquone – structural analogue of ubiquinone; under physiologic conditions, transfer of 2 electrons from
reduced ubiquinone to cytochrome bc1 complex oxidizes ubiquinone; atovaquone inhibits interaction between
reduced ubiquinone and cytochrome bc1 complex, disrupting electron transport
o Because plasmodia depend on electron transport chain to regenerate oxidized dihydroorotate
reductase, treatment w/atovaquone disrupts pyrimidine synthesis and prevents plasmodia from
replicating DNA
o Selectivity of atovaquone for plasmodia relies on differences in sequences of amino acids between
human and plasmodial ubiquinone cytochrome bc1 binding regions
 Selectivity easily disrupted (single point mutation in cytochrome bc1 complex can render
plasmodia resistant to atovaquone), so usually used w/doxycycline (protein synthesis inhibitor)
or proguanil (dihydrofolate reductase inhibitor)
 Proguanil and atovaquone synergistic in antimalarial activity; proguanil acts as uncoupling agent
in mitochondrial membranes, enhancing atovaquone-mediated mitochondrial depolarization
o Associated w/low incidence of adverse GI effects and occasional rash
o Can be used therapeutically or prophylactically in combo w/second antimalarial drug
Doxycycline – structural isomer of tetracycline; produced semisynthetically from oxytetracycline or methacycline
o Inhibits parasite protein synthesis by binding to 30S ribosomal subunit, blocking binding of aminoacyl
tRNA to mRNA
o Because of high lipophilicity, penetrates well into body tissues, has large volume of distribution, and is
reabsorbed in renal tubules and GI tract, resulting in long half-life
o Useful for treatment of chloroquine-resistant P. falciparum in combination w/artesunate or quinine);
not for use as single antimalarial agent
o Advwerse effects include cutaneous photosensitivity, tooth discoloration in children, and vaginal
candidiasis; GI effects (nausea, diarrhea, and dyspepsia) typically mild; esophageal ulceration rare
Tetracycline and doxycycline have similar pharmacologic profiles, but tetracycline must be taken 4x/day
o May be used in combo w/quinine for treatment of chloroquine-resistant malaria, but not prophylactic
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Clindamycin inhibits protein synthesis by binding to 50S ribosomal subunit; may be used in combo w/artesunate
or quinine for treatment of malaria when tetracycline or doxycycline contraindicated (pregnant woman or child
under age 8)
o Major adverse effect is increased risk of antibiotic-associated diarrhea and colitis caused by C. difficile
o Not used as malaria chemoprophylactic
 Sulfadoxine – PABA analogue that competitively inhibits parasite dihydropteroate synthetase (essential enzyme
in folic acid synthesis pathway)
o Pyrimethamine – folate analogue that competitively inhibits parasite dihydrofolate reductase (enzyme
that converts dihydrofolate to tetrahydrofolate)
o In combo, sulfadoxine and pyrimethamine act synergistically to inhibit growth of malarial parasite
o Convenient single dose; used for treatment or prophylaxis
o Most serious drug reactions involve hypersensitivity to sulfonamide component
o Severe skin reactions such as Stevens-Johnson syndrome or erythema multiforme reported; incidence
rare after single-dose therapy for malaria
o Adverse hematologic effects include megaloblastic anemia, leukopenia, and thrombocytopenia
 Sulfonamide-pyrmethamine combinations highly effective against blood schizonts stages of P. falciparum
malaria, but not against gametocytes; less effective against other species
o Both drugs highly protein-bound, resulting in long elimination half-lives; long half-life of combo provides
selective pressure for development of drug resistance in areas w/high-level malaria transmission
o Increasing resistance to combo makes it ineffective in many parts of world
o Not used as chemoprophylactic agent against malaria
 Proguanil – derivative of pyrimidine; inhibitor of dihydrofolate reductase
o Acts against hepatic, pre-erythrocytic forms of P. falciparum and P. vivax
o May be used in synergistic combo w/atovaquone for both treatment and prevention of malaria
o Usually well tolerated; associated w/oral ulcerations, pancytopenia, thrombocytopenia, and
granulocytopenia
Antimalarial Drug Resistance
 Chloroquine resistance reported everywhere except Hispaniola and focal parts of Central America, South
America, and Asia
 Factors that contribute to development of drug resistance by malaria parasites – inappropriate and/or
unsupervised drug use, inconsistent drug availability, poor adherence to treatment regimens, inconsistent
quality of drug manufacturing, presence of counterfeit drugs, and prohibitive drug costs
 Strongly recommended that no single treatment be used against malaria
Physiology of Entamoeba histolytica
 Entamoeba dispar and E. histolytica morphologically identical but told apart w/monoclonal antibodies
o E. dispar doesn’t cause invasive disease
o E. histolytica can cause asymptomatic carrier state, invasive colitis, or metastatic infections (usually
hepatic abscesses)
o 50 million cases of dysentery per year caused by E. histolytica
 Colonic infection occurs as result of ingestion of cysts through fecal-oral route; parasite feeds on enteric bacteria
 Disease results when active trophozoites invade intestinal epithelium
o Secondary spread to liver can occur via portal circulation
 Lyses and destroys human tissue; trophozoites typically multiply superficial to muscularis mucosae of intestines
and spread laterally; may also penetrate more deeply, occasionally perforating intestinal wall and spreading
locally
o Seeding of liver common
 Exists in 2 forms: inactive but infective cyst and active trophozoite
o Cysts ingested in contaminated food or water
o Excystation occurs in small intestine, where trophozoites mature
o Trophozoite form capable of invading host tissue; trophozoites move using pseudopods and ingest
bacteria, other protozoa, and host RBCs
 Trophozoite can convert to binucleated cyst form, which matures into tetranucleated cyst that
travels through colon but isn’t capable of mucosal invasion
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Symptoms of amebiasis vary from diarrhea and abdominal cramps to fulminant dysentery and hepatic abscess
formation
o Onset of symptoms can range from a few days to a year after exposure
 Utilizes novel enzymes to provide source for electron transfers that drive metabolism
o Lacks fermentation enzymes (lactate dehydrogenase and pyruvate decarboxylase)
o Lack enzymes of oxidative phosphorylation, Krebs cycle, and pyruvate dehydrogenase
 Obligate fermenters of glucose to ethanol; most enzymes contain set of iron-sulfur centers (ferredoxins) that
transfer electrons under strongly reducing (anaerobic) conditions
o Pyruvate-ferredoxin oxidoreductase (PFOR) – catalyzes decarboxylation of pyruvate to acetyl-CoA with
production of CO2
 Activity produces reduced ferredoxin, which reduces H+ to form H2 or reduces NADP+ to NADPH
o Acetyl-CoA reduced to EtOH via alcohol dehydrogenase E (ADHE) w/recovery of 2 NAD+ cofactors
o Anaerobic bacteria (Helicobacter and Clostridia) express PFORs, ferredoxins, and ADHEs similar to those
of luminal protozoa
Pharmacology of Antiprotozoal Agents
 Metronidazole – inactive until reduced in host or microbial cells that possess large negative redox potential
o Redox potentials present in many anaerobic or microaerophilic luminal parasites; activation can occur
by interaction w/reduced ferredoxin or with specific nitroreductases
o Activated metronidazole forms reduced cytotoxic compounds that bind to proteins, membranes, and
DNA in target cells, causing severe damage
o Sensitivity directly related to presence of PFOR activity (selectively toxic for ameba and anaerobics)
o H. pylori resistant to metronidazole due to null mutation in rdxA gene (encodes oxygen insensitiveNADPH nitroreductase)
o Low-level resistance seen in trichomonads (caused by decreased expression of ferredoxin), Giardia
(caused by decreased PFOR activity and decreased drug permeability), and ameba (caused by increased
expression of superoxide dismutase)
o Reasons for slow development of resistance in luminal parasites
 Luminal parasites generally diploid, so single mutation won’t confer resistance
 Luminal parasites have few metabolic alternatives for PFOR activity
 Metronidazole is hydrophilic, so overexpression or modification of P-glycoprotein, which confers
resistance to hydrophobic drugs, doesn’t increase metronidazole efflux
o Causes nausea and flushing when taken concomitantly w/alcohol (disulfiram-like effect caused by
inhibition of ethanol metabolism)
o Active against E. histolytica trophozoites in tissues, but has much less activity against intraluminal ameba
(because of drug’s extensive absorption in upper GI tract, leading to low drug concentration in lumen)
o Patients w/invasive amebiasis typically treated first w/metronidazole to eradicate trophozoites actively
invading human tissue and then w/second agent that has more intraluminal activity
 Tinidazole – nitroimidazole (related to metronidazole); effective against number of protozoa; used to treat
giardiasis, amebiasis, and vaginal trichomoniasis
o Mechanism related to generation of cytotoxic free radicals
o Duration of therapeutic course shorter than metronidazole
o Better tolerated; ineffective as luminicidal agent for treatment of ameba infections
o Adverse effects rare and mild
o Not recommended for use during first trimester of pregnancy, breastfeeding, or in children less than 3 yr
 Nitazoxanide – nitrothiazolyl-salicylamide derivative structurally related to metronidazole
o Broad spectrum of action (against protozoa, anaerobic bacteria, and helminths)
o Approved for treatment of children w/giardiasis and adults and children w/cryptosporidiosis
o Structural analogue of thiamine pyrophosphate, so inhibits PFOR; mechanism against helminths unclear
o After oral administration, rapidly hydrolyzed to active metabolite tizoxanide; active metabolite excreted
in urine, bile, and feces
 Pentamidine – used to treat early-stage African trypanosomiasis (caused by Trypanosoma brucei gambiense and
certain strains of T. b. rhodesiense); doesn’t yet involve CNS
o Inhibits DNA, RNA, protein, and phospholipid synthesis
o
High affinity for DNA in kinetoplasts (DNA-containing organelle in certain protozoa); suppresses
kinetoplast replication and function
o May also inhibit dihydrofolate reductase
o Some strains of Trypanosoma have high-affinity uptake system for drug, contributing to selectivity
o Used most commonly as second-line treatment for individuals w/Pneumocystis jiroveci pneumonia (PCP)
common in AIDS patients
 Suramin – used to treat early-stage African trypanosomiasis; interacts w/many macromolecules and inhibits
numerous enzymes, including those involved in energy metabolism (e.g., glycerol phosphate dehydrogenase)
o Inhibits RNA polymerase and thus interferes w/parasite replication
o Can cause pruritis, paresthesias, vomiting, and nausea
 Melarsoprol – used as first-line drug in treatment of late-stage African trypanosomiasis (disease involves CNS)
o Developed by conjugating heavy-metal chelator dimercaptopropanol to trivalent arsenic of melarsen
oxide
o Insoluble in water; dissolved in propylene glycol
o Blood trypanosomes lack functional TCA cycle and are entirely dependent on glycolysis for ATP
production; melarsoprol inhibits pyruvate kinase, inhibiting glycolysis and decreasing ATP production
 Affected trypanosomes quickly lose motility and lyse
o Inhibits uptake of adenine and adenosine by trypanosomal transporters
o Mammalian cells less permeable to drug than trypanosomes, but still quite toxic (4-6% death rate)
o Administered IV and can cause severe phlebitis; corrosive to plastics
o 5-10% of patients develop intense inflammation of brain after administration (reactive encephalopathy)
o Concomitant administration of corticosteroids lessens likelihood of reactive encephalopathy
o Polyneuropathy after administration common and can be lessened by combo w/thiamine
 Eflornithine (α-difluoromethylornithine) – much less toxic alternative to melarsoprol in treatment of African
trypanosomiasis caused by T. b. gambiense (West Africa sleeping sickness)
o Highly effective against both early and late-stage disease; not effective against East Africa sickness
o Selective and irreversible inhibitor of ornithine decarboxylase (and thus polyamine synthesis)
 Ornithine decarboxylase converts ornithine to putrescine (rate-limiting step of synthesis of
putrescine and polyamines spermine and spermidine)
 Polyamines involved in nucleic acid synthesis and regulation of protein synthesis
 T. b. gambiense susceptible to eflornithine because of slow turnover of ornithine decarboxylase
 T. b. rhodesiense organisms have higher rate of turnover (as do human cells)
 Nifurtimox – used in treatment of New World trypanosomiasis (Chagas’ disease) caused by Trypanosoma cruzi
o Drug undergoes reduction and generates toxic intracellular oxygen radicals in parasite; first forms
reduced intermediates (nitro anion radicals); radicals can be reoxidized and in process generate
superoxide anions, which react w/water to produce cytotoxic H2O2
o Mammalian cells protected because of complement of antioxidant enzymes such as catalase,
glutathione peroxidase, and superoxide dismutase
o Can cause anorexia, vomiting, memory loss, sleep disorders, and convulsions
 Sodium stibogluconate and meglumine antimonates used to treat leishmaniasis
o Contain pentavalent antimony and act by unknown mechanism
o Can have many nonspecific effects, such as modification of sulfhydryl groups
o Can cause bone marrow suppression, prolonged QT interval, pancreatitis, and rash
o Resistance of Leishmania to antimonial agents developing in S Asia (use amphotericin or miltefosine)
 Miltefosine – synthetic ether phospholipid analogue chemically similar to natural phospholipids present in PM
o Has antineoplastic, immunomodulatory, and antiprotozoal activity
o Cytostatic and cytotoxic effects caused by inhibition of enzyme systems associated w/PMs (such as PKC)
and inhibition of phosphatidylcholine biosynthesis
o May inhibit platelet activating factor-induced responses and inositol phosphate formation
o Immunomodulatory effects include T-cell activation, IFN-γ production in peripheral mononuclear cells,
and increased IL-2 receptor and HLA-DR expression
o Can be administered orally and used in treatment of visceral leishmaniasis
Physiology of Helminths
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Divided into nematodes (roundworms), trematodes (flukes), and cestodes (tapeworms)
Physiology of Onchocerca volvulus (causes onchocerciasis (river blindness)), gives target for antihelminthic drugs
Humans become infected when they ingest food or water contaminated w/eggs or larvae; larvae in soil can
penetrate human skin, and insects transmit larvae through bites
o Eggs or larvae develop into adult worms if humans definitive host
o During sexual stage, adult worms release additional eggs or larvae, which pass through GI or urinary
tracts and can be transmitted fecal-oral or ingested by insects during blood meal
 Onchocerciasis – adult worms large and can live 10-15 years; nodules (onchocercomata) have characteristic
appearance; from nodules, gravid females release millions of microfilariae, which migrate freely through skin
and cornea, and if ingested by Simulium fly, additional maturation can occur and cycle continues
o Diagnosis based on microscopic detection of microfilariae in skin snips
 As microfilariae degenerate and die, they cause local inflammatory reactions, provoking itching,
dermatitis, and eventually scarring
 When microfilariae die in cornea, they induce punctate keratitis that over years leads to scarring
and blindness
 Subcuticular layer of longitudinal muscle in nematodes inhibited by GABAergic transmitters and excited by
cholinergic transmitters
o Motor neurons unmyelinated, making them more vulnerable to neurotoxins than myelinated somatic
motor neurons of humans
Pharmacology of Antihelminthic Agents
 Ivermectin – semisynthetic macrocyclic lactone that acts against broad range of helminths and arthropods and
has been used most extensively to treat and control onchocerciasis
o Exact mechanism unclear; involves potentiation or direct activation of glutamate-gated Cl- channels in
nematode PM, resulting in hyperpolarization of neuromuscular cells and pharyngeal paralysis
o Affects GABA inhibitory transmission by potentiating release of GABA from presynaptic terminals,
directly activating GABA receptors, and/or potentiating binding of GABA to receptor
 All of above increases GABA-mediated transmission of signals in peripheral nerves, resulting in
hyperpolarization
 Ultimate result is blockade of neuromuscular transmission and paralysis of worm
o Pharyngeal paralysis of O. volvulus inhibits nutrient uptake and kills developing larvae (microfilariae)
o Doesn’t kill adult filarial worms, but destroys microfilariae in utero, preventing production and release of
new microfilariae from adult female worms for at least 6 months
o Used to prevent microfilaria-mediated ocular damage and decrease human-to-vector transmission
(microfilariae infectious to Simulium flies), but can’t cure human hosts of infection
o Interacts w/GABA receptors in vertebrates, but affinity for invertebrate GABA receptors 100x greater
o GABA receptors in humans present mainly in CNS, but ivermectin doesn’t cross BBB (except when
hyperpermeable as in patients w/meningitis); can then cause headaches, ataxia, and coma
o Adverse effects usually attributable to inflammatory or allergic responses to dying microfilariae
(Mazzotti-type reaction) and include headaches, dizziness, weakness, rash, pruritus, edema, abdominal
pain, hypotension, and fever
o In livestock, ivermectin-resistant nematode infections recognized
 P-glycoprotein involved; hypersensitivity results from disruption of mdr1a gene that encodes Pglycoprotein membrane transporter; P-glycoprotein mRNA expression higher in ivermectinselected strains of H. contortus and verapamil (reverses multidrug resistance by blocking Pglycoprotein channels) increases efficacy of ivermectin
o Used to treat strongyloidiasis, onchocerciasis, and cutaneous larva migrans (all nematodal) and scabies
(ectoparasitic infestation)
 Piperazine and pyrantel pamoate – antihelminthic agents
 Albendazole, mebendazole, and thiabendazole inhibit tubulin polymerization by binding to β-tubulin
o Selective for nematodal isoform of β-tubulin, decreasing host toxicity
o Inhibition of tubulin polymerization disrupts nematodal motility and DNA replication, leading to
degenerative changes in integumental and intestinal cells of helminths, and eventually causing
immobilization and death of worms
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Also affect immotile tissue forms of cestodal larval parasites (e.g., cysticercosis and echinococcosis);
drugs disrupt integumental integrity of protoscolex (larval structure that eventually becomes head of
adult cestode)
o Thiabendazole causes significant nausea, vomiting, and anorexia at therapeutic doses (rarely used)
o Mebendazole and albendazole better tolerated
o Albendazole has highest oral bioavailability
Praziquantel – drug of choice for treating adult cestode (tapeworm) and trematode (fluke) infections
o Drug of choice for treating individuals w/schistosomiasis (trematodal infection that causes considerable
mortality and morbidity worldwide)
o Increases parasite’s membrane permeability to Ca2+, resulting in contraction and paralysis of womrms
Diethylcarbamazine (DEC) – piperazine derivative; drug of choice for treating certain filarial infections (lymphatic
filariasis); kills adult filarial worms and is thus curative agent (for filarial onchocerciasis)
o Reasonably well tolerated at low doses
o Administration can precipitate Mazzotti reactions in individuals w/heavy microfilarial burdens (reactions
can be fatal if severe enough)
 Administration of gradually increasing doses reduces possibility
o Excreted by kidneys, so dosing may need to be adjusted in individuals w/decreased kidney function
O. volvuluscontains obligate symbiont (Wolbachia endobacteria) important in helminths fertility; use of
doxycycline to treat individuals w/onchocerciasis leads to decreased fertility, embryogenesis, and viability