• cause- roundworm (Nematodes) (Ascaris lumbricoides)
• pathogenesis
  1. ova hatch in small intestin after ingestion
  2. larvae released, penetrate intestinal wall, and migrates to the lungs by way of venous circulation (pulmonary ascariasis)
  3. enter alveoli and migrate to bronchi and trachea
  4. they are swalloed and returned to intestines, where they mature into adult worms

• cause- several species of Schistosoma aka flukes (Trematodes)
• pathogenesis
  1. penetrate skin and travel through circ. system
  2. immature parasites migrate to lungs to develop, migrate to liver to feed on RBC's, migrate to mesentetric and rectal veins to reproduce
  3. eggs dposited throughout body eliciting an immune response
  4. eggs released in urine or stool repeat life cycle
  5. repeated infections damage liver, intestines, lungs, bladders
• epi- South America, Africa, Asia, areas of freshwater that harbor snails (int. hosts)

• during life cycle in primary host (us), they will involve the GI tract at some point in their lives (released in feces and ingested by pig and cattle)
• secondary host can also involve invertabrates (ex: snails in schistosoma)
• infections come about by eating contaminated meat or penetrate skin

• non grwoth mechanisms
  • metabolic energy production
  • motor activity
• usually effective in larvae (immature forms)
• effectiveness against eggs or adult worms willd epend on number of factors
  • genus of worm
  • GI transit time
  • intensity of infection
  • single vs. multiple does

NONE on growth phase

• biochemistry
  • unique essential enzyme found only in parasite
  • similar enzyme in host and parasite, but indispensible in parasite
  • parasite and host enzyme same but exhibit different pharmacology (higher affinity for parasite enzyme)
• tx w/nonabsorbable drugs (killing action localized in lumen of gut)
  • menbendazole
  • pyratol pyrate

• albendazole
• mebendazole

Differ by R1 and R2 constituents

• nematodes- GI lumen and systemic
  • ascariasis
  • intestinal capillariasis- Capillaria phillipensis
  • trichuriasis
  • hookworm infection- Necator americanus
  • lymphatic filiarisis- infec. via W. bancrofti B. malayi
    • combo albendazole with ivermectin OR diethylcarbamazine

• single dose regimen or 3 day regimen
• kills eggs and larvae, some evidence of killing adult worms

• inhibit MT polymerization
  1. binds to beta tubulin w/colchicine (higher affinity for parasite than mammalian beta tubulin)
  2. inh. assembly
  3. faster depolymerization that polymerization
  4. MT disappear
• leads to
  • decrease or abscence of MT's
  • cessation of secretion
  • inh cellular organelle mov't
  • immobilization and death of parasite
• also causes
  • inh. glucose uptake
  • inhibit mit. fumarate reductase
  • uncoupling of oxidative phosphorylation

• two mechanisms
  • change in beta tublin isotype usage (isotype 2 is resistant)
  • pt mutation: Phe to Tyr at position 200
    • mutant now resemble human beta tubulin, so drug wont bind

• poorly absorbed
• rapid first pass metabolism to inactive metabolite
• excreted in urine
• little systemic activity
• this is the pharmacologically active species

Great for GI infection

• erractic absorption, so enhance with fatty food meal and bile salts
• rapid first pass met. to active metabolite albendazole sulfate
  • readily penetrates into tissues and hydatid cysts (sac containing tapeworm larvae- EXCEPTION that it can be used in tapeworm)
    • explains why its good for systemic infections

• alopecia (loss of hair)
• mild epigastric distress
• diarrhea
• headach
• dizziness
• nausea
• tiredness

• pregnant women- shown to be teratogenic and embryotoxic
• young children (under 2)
  • but well tolerated in older kids

• due to low systemic bioavailability
• rare HS rxn
  • rash
  • neutropenia
  • fever
  • acute pain
  • musculoskel pain
• transient liver enzyme abnormalities
• cases of drug induced agranulocytosis
• occipital seizures associated with use

• rash, pruritis
• transient liver abnormalities (aminotransferase elevations)
• rare bone marrow depression

• generally more toxic with greater GI affects (abdominal cramping)
• more CNS toxicity
  • giddiness
  • drowsiness
  • may impair ability to function
• aspargus like odor in urine
• rare HS rxn
  • fever
  • chills
  • skin rashes, pruritis
  • angioedema
  • anaphylaxis

• induces own metabolism to inactive metabolite
• caution when giving high doses of albendazole with general inhibitors of CYP's (ex:cimetidine), leading to increase albendazole sulfoxide concentrations

• onchocerciasis (aka river blindness)- controls microfilaria in the eye; decrease ocular inflammatory affects with corticosteroids
• intestinal strongyloidiasis due to threadworms
• w/albendazole, for lymphatic filariasis due to W. bancrofti or B. malayi

• isolated from soil actinomycete bacteria (streptomyces avermitilis)
• chemical structure
  • semi synthetic derivative of avermectin
  • 16 membered lactone

• in onchocerciasis
  • kills microfilariae
  • single dose not affective aginst worms
  • in repeated doses, some low level killing of adult worms
• lymphatic filariasis and loiasis
  • microfilaricidal
  • not affective against adult worms

1. induces tonic paralysis of muscles in parasite
2. leads to inhibition of feeding behavior
3. activate glutamate sensitive chloride channel
   • found only in invertabrates
   • leads to hyperpolarization, muscle paralysis
   • expressed in nerve cells and pharyngeal muscles

• also binds GABA gated chloride channel (role unclear), BUT affinity for parasite one 100x that of the GABA channels in humans

• ATP dep. P glycoprotein transporter mediated drug efflux from parasite
• mutation in channel such that drug is ineffective

• absorbed
• peak plasma levels in 4-5 hrs
• half life: 57 hrs
• met- CYP3A4
• only low levels in brain (P glycoprotein transporter at BBB)

toxicity of ivermectin

• well tolerated
• most toxicity due to inflammatory reactions from dying microfilariae
  • Mazzotti like rxn
    • mild itch, swollen tender lymph nodes tx with aspirin, antihistamines
    • headache, dizziness, somnolence, fever, tachycardia, hypotension, myalgia, arthralgia, facial and peripheral edema
  • may require steroids
• Loa loa patients- marked disability and encephalopathy

• impaired BBB (BBB has P glycoprotein transporter)

• drug of choice for all schistosomiasis
  • effective against microfilariae and the adult worms
• other flukes (trematodes)
• Taenia solium (cestode) when intestinal and cystercosis

1. increase calcium influx across tegument
2. leads to disruption of tegument and Ag exposure
3. causes increased muscle contraction, followed by spastic paralysis
4. this causes the worm to detach from the bv walls

• generally not a problem
• only form reported in Senegal and Egypt
  • mutate voltage gated calcium channel beta subunit

• readily absorbed
  • max plasma levels in 1-2 hrs after dose
• dose related PK's with half life less than three hours
• increase plasma conc. by
  • taking high carb meal
  • cimetidiine
• decrease conc. by
  • antiepileptics (phenytoin)
  • corticosteroids

• prolong half life with hepatic disease
• abdominal discomfort- pain, nausea
• headache, dizziness, droowsiness
• side effects possibly due to parasite burden
  • myalgia
  • pruritis
  • urticaria
  • rashes
  • arthralgia
  • fever
• CYP inducers decrease bioavailability

• pregnacy
• ocular cystercosis (caused by pork tapeorm in eye)
  • parasite destruction in eye can cause irreversible damage due to inflammatory response to dying worm
  • tx- surgical excision of larval cyst (outcome is often poor)
• liver damage, MUST reduce dosage

• indication
  • Loa Loa- kill microfilariae and adults
  • lymphatic filariasis (w/albendazole)- kill microfilaria
• contraindications
  • onchocerciasis (river blindness)
    • cause sever inflammatory reaction to dying worms and worsen ocular lesions
    • tx- ivermectin with corticosteroids

• unknown
• different effects found
  • alter worm surface membrane, leading to enhanced killing by host immune system
  • stimulate plately aggregation around membrane damaged parasites
  • may alter arachadonic acid metabolism in host immune cells to promote immune response
  • worm organelle damage and apoptosis

• rapid absorption
• peak plasma levels within 1-2 hrs
• half life: 2-10 hrs
  • depends on urinary pH
  • alkalinzied urine leads to elevated plasma levels and prolonged half life, causing increased therapeutic effects
    • dosage adjust with persistant urinary alkalosis
• renal excretion
  • dose adjust in patients with renal dysfunction

• rarely sever if doses below 10 mg/kg/dL, but disapear with continued tx
  • anorexia
  • nausea
  • headache
  • vomitting
• major ones due to dying parasites- inflammatory reaction due to release of protiens of microfilaria and adult worms
  • retinal hemorrahge (onchoceriasis- tx with ivermectin and corticosteroids)
  • mazzotti like rxn
  • leukocytosis
  • reversible proteinuria
  • eosinophilia

• luminal parasites
  • pinworm (enterobius)
  • ascariasis (giant roundworm)
  • Trichostrongylus orientalis
• kill larvae and adult worms (no effect on egs or migratory stages into tissue)

• depolarizing neuromuscular blocker
  1. stimulate nicotinic receptors
  2. leads to depolarizing block of worm nicotinic receptors at neuromuscular junctions
  3. also cause release of ACh and inhibits cholinesterase
  4. leads to spastic paralysis (like praziquantil
  5. worm expelled from GI tract

• poorly absorbed
  • why its so good for GI infections
• eliminated in feces

• toxicity only at high doses
  • neuromuscular blockade in host
• transient symptoms
  • mild GI symptoms
  • headache
  • dizziness
  • rash
  • fever