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Pharmacology > Pharm of Protozoans and Helminths > Flashcards

Pharm of Protozoans and Helminths Flashcards

1
Q

what drugs are available for nematode infections?

A

benzimidazoles

Diethylcarbamazine

Ivermectin

Pyrantel pamoate

Doxycycline

anti-helminth

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2
Q

What are the types of Benzimidazoles?

A

Albendazole

Mebendazole

Thiabendazole

anti-helminth

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3
Q

MOA of Benzimidazoles

A

Binds beta-tubulin and inhibits polymerization of parasitic tubulin dimers into microtubules

other effects on the nematodes include - inhibition of mito fumerate reductase, decreased glucose transport causing depleted glycogen stores of larvae, uncoupling of ox-phos -> decreased energy production leads to parasite immobilization and death

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4
Q

Albendazole - PK and Adverse Effects

A

Benzimidazoles. poor absorption, distributes to CSF and hydatid cysts

hep metabolism w/ active metabolite, fecal excretion, half life 12 h

Adverse Effects - ab discomfort, diarrhea, rash, alopecia, dizziness

In high doses for Echinococcus Rx can cause hepatitis or myelosuppression

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5
Q

Albendazole - Therapeutic Uses

A

Broad Spectrum -
Intestinal nematodes,
Hydatid disease (echinococcus - cestode),
Neurocysticercosis
Lymphatic filariasis (combination with diethylcarbamezine or ivermectin)

high cure rates – Ascariasis (hookworm), Trichuras trichuria (whipworm), Necator, Ancylostoma, Enterobius vermicularis (pinworm), Trichinella spiralis (undercooked meat)

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6
Q

Mebendazole

A

Benzimidazoles, anti-helminthic, poor oral absorption, widely distributed with hepatic metabolism

fecal excretion, half life is 3 hours - does the job in the intestines as long as it’s in the intestines

Active against Intestinal nematodes only

Adverse effects are abdominal pain, distention, diarrhea in cases of massive infection&raquo_space; expulsion of GI worms

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7
Q

Thiabendazole

A

Benzimidazoles, anti-helminthic, rapidly absorbed

extensive hepatic metabolism with renal excretion of glucuronide and sulfate metabolites

short half life

Broad Spectrum - therapy is limited by toxicities

Used for cutaneous larva migrans - eruption of nematodal larvae

used for strongyloidiasis in the past but Ivermectin is now first line

Adverse effects in 50% + pts - diarrhea, headache, tinnitus, hypotension, bradycardia, allergic manifestations, crystallurai and abnormalities in liver function.

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8
Q

Diethylcarbamazine (DEC) - PK and MOA

A

Anti-helminthic, nematodal

oral with wide distribution, hepatic metabolism and renal excretion.

MOA in adult unknown, action against microfilaraie - inhibition of arachidonic acid metabolism on the surface of microfilariae, this causes the nematode to be immobile and more susceptible to the host immune response

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9
Q

Therapeutic Uses of Diethylcarbamazine (DEC)

A

Lymphatic filariasis: caused by Wuchereria bancrofti, Brugia malayi/timori

One dose mass treatment with ivermectin/albendazole

Loa loa - microfilariae and adult filariae

Mansonella streptocirca (adult and micro-filariae)

contraindication in onchocerciasis

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10
Q

Adverse Effects of Diethylcarbamazine (DEC)

A

anti-helminthic,

Anorexia, nausea, headache, vomiting (high dose)

Bancroftian, brugian filiariasis - lymphangitis, swelling and lymphoid abscess

Loiasis - skin wheals, heavy infections with severe side effects (retinal hemorrhages and severe encephalopathy)

Mazzotti reaction when rx Onchocerciasis – from killing of microfilariae – intense itching, papular rash, enlarged tender lymph nodes, tachycardia, arthralgia and headache. Ocular lesions.

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11
Q

Ivermectin

A

Anti-helminthic, nematodal

Oral, doesnt cross BBB, hepatic meta, fecal excretion, half life 18hr

MOA - induces tonic paralysis of parasite musculature by binding to glutamate-gated Cl- ion channels in invertebrate muscle and nerve cells ↑ permeability of the cell membrane causing hyperpolarization leads to the paralysis and death of the nematode

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12
Q

Ivermectin - Activity and Uses

A

Activity: anti-helminthic,

  • Microfilaria (not adults) of W. bancrofit, B. malayi, L. loa, Mansella ozzardi
  • A. lumbricoides, S. stercoralis, cutaneous larva migrans

Drug of choice for -

Onchocerciasis: aborts microfilariae from gravid female, decreases transmission

Strongyloidiasis: as effective as thiabendazole and better tolerated. More effective than albendazole

Contraindicated in meningitix

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13
Q

Adverse Effects of Ivermectin

A

Generally well tolerated

Mazzotti-like reaction due to killing of microfilariae but usually limited to mild itching and tender, swollen lymph nodes

seldom exacerbates oculra lesions

Loa encephalopathy with high loa microfilariae burden

not known to be safe in pregnancy or breast feeding

interacts with GABA drugs - benzos, barbituates and valproic acid

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14
Q

Doxycycline

A

Antibacterial that fights Wolbachia species (similar to Rickettsia) within filarial nematodes — Wuchereria and Oncocerca

Doxycycline x6 weeks causes sterility of the adult female

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15
Q

Pyrantel pamoate

A

anti-helminthic,

Treatment of pinworms caused by Enterobius vermicularis - nematodes - anti-helminthic

Poor oral absorption; Safe and effective

mechanism - Depolarizing NM blocking agent, activation of cholinergic nicotinic R in somatic muscles of nematodes causes a depolarizing blockade and paralysis

no marked effect on neuromuscular function

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16
Q

Praziquantel - Activity

A

anti-helminthic,

used against cestodes and flukes
- flat, segmented bodies that attach to host intestinal walls with hooks/suckers

Trematodes, parasitic flatworms (flukes)

Intestinal Cestodes - Taenia saginata (beef), Taenia solium (pork), Diphyllobothrium latum (broad fish), Hymenolepis nana (dwarf tapeworm)

Intestinal Trematode - Fasciolopsis buski (giant)

trematode tissue infections - Paragonimus westermani, Schistosoma mansoni (blood fluke), Schistosoma japonicum, and Schistosoma haematobium

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17
Q

Praziquantel - PK and MOA

A

anti-helminthic,

Oral; good bioavailability; CSF concentrations ~14-20% of plasma

plasma protein binding; extensive hepatic first-pass metabolism with renal excretion, short half life (1 - 4 hours)

MOA - increase cell permeability to Ca2_ whih increase muscular activity and causes spastic paralysis, causes detachment from blood vessel walls.

Damage exposes tegumental antigen - immune system activate

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18
Q

Adverse Effects of Praziquantel

A

anti-helminthic,

Generally safe - Abdominal pain, nausea, diarrhea, headache, dizziness, drowsiness - transient

Parasite destruction occasionally causes: fever, pruritus, urticaria, rashes, arthralgia, myalgia

In neurocysticercosis: there can be inflammatory reactions - meningismus, seizures, mental changes and CSY pleocytosis, delayed onset and last 2-3 days. Rx - analgesics and anticonvulsants

Safe in pregnancy

interacts with CYP3A4 induces

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19
Q

Triclabendazole

A

anti-helminthic

Drug of choice for the treatment of chronic fascioliasis in adults and children

Efficacy:
• Single dose
• Absence of adverse effects
• High tolerability
• High cure rate
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20
Q

What drugs are used to treat amoebiasis, giardiasis, and other intestinal protozoan infections?

A

Metronidazole - Tinidazole - Secnidazole:

Paromomycin

Nitazoxanide

21
Q

Metronidazole - PK and MOA

A

Oral, 100% bioavailability
-can be given IV, intravaginally, topically

wide distribution including abscessess, hepatic metabolism (oxidation and glucuronidation) with renal excretion.

MOA - radical-mediated killing, electron donated from ferredoxin, the drug is also catalytically recycled

22
Q

Resistance Mechanisms of Metronidazole

A

Impaired oxygen scavenging capabilities

An increase in local oxygen causes decreased reduction of metronidozole

leading to decreased PFOR and ferrodoxin levels

23
Q

Activity and Therapeutic Uses of Metronidazole

A

Kills E. hystolytica trophozoites - but not cysts

extra-intestinal infections - well absorbed + requires a liminal amebicide for full infectious Rx

Useful against - 
Amoebiasis
Trichomoniasis
Giardiasis
Bacterial infections - anaerobic bacteria
24
Q

Tinidazole and Secnidazole

A

Tinidazole - amoebiasis, giardiasis, trichomoniasis: better tolerated

Secnidazole - bacterial vaginosis

25
Q

Side Effects of Metronidazole

A

generally well tolerated

common are headache, nausea, dry mouth, and a metallic taste

occasional - vomiting, diarrhea, and abdominal distress, thrush, dark urine

dizziness, vetigo, rarely - encephalopathy, convulsions

Paresthesias of extremities

Disulfiram-like effect

Avoid in pregnancy in first semester

26
Q

Paromomycin - PK, MOA, AE’s

A

Luminal Antiamoebic Agent

PK: oral; poor absorption, 100% fecal excretion

MOA - protein synthesis inhibitor

Generally safe but can cause bowel lesions, ototoxicity and nephrotoxicity

27
Q

Paromomycin - Uses

A

Use - Acute and chronic intestinal amoebiasis after metronidazole treatment, E. histolytica

Adidtional uses against Dientamoeba fragilis, cryptosporidiosis, giardiasis, cutaneous leishmaniasis and resistant trichomoniasis

28
Q

Treatment of African trypanosomiasis

A

Melarsoprol (trivalent arsenical)

Eflornithine (fluorinated ornithine analog)

Suramin (polyanionic compound)

Pentamidine (aromatic diamidine)

29
Q

East African sleeping sickness

A

Trypanosoma brucei rhodesiense

Tanzania. Uganda, Malawi, Zambia

Melarsoprol - Meningoencephalitic stage

Suramin - Hemolymphatic stage

30
Q

West African sleeping sickness

A

Trypanosoma brucei gambiense

Central and West Africa, Democratic Republic of Congo, Angola, Sudan, Central African Republic, Chad and northern Uganda

Eflornithine - Meningoencephalitic stage

Pentamidine - Hemolymphatic stage

31
Q

Melarsoprol

A

East African sleeping sickness - Meningoencephalitic stage

Melarsen oxide reacts with sulfhydryl groups on biomolecules - inactivates

Slow IV infusion, intensely irritating, half like 35 h

Adverse Effects

  • reactive encephalopathy (5-10% pts, 50% fatal), cerebral edema, seizures, coma, death
  • Myocardial toxicity, renal, hepatic dysfunction, agranulocytosis, hypersensitivity reaction
32
Q

Suramin

A

East African sleeping sickness - Hemolymphatic stage

Reversibly complexes with various enzymes essential to parasite energy metabolism

IV (not absorbed), no CNS, 5 doses in 21 days

Adverse effects - Renal toxicity, Hypersensitivity reaction, hypotension, shock, (from the dying parasites)

33
Q

Eflornithine

A

West African sleeping sickness - Meningoencephalitic stage

Suicide inhibitor of ornithine decarboxylase, inhibits polyamine synthesis, cell growth and differentiation

IV every 6h x 14d, half life 3h

Adverse Effects - myelosupprion, ototoxicity, diarrhea, nausea, vomiting

34
Q

Pentamidine

A

West African sleeping sickness - Hemolymphatic stage

Interference with DNA, RNA, protein synthesis and metabolism

IV and IM, not absorbed, No CNS. Half life 5-8 hours

Adverse Effects - Nephrotoxicity; 
hypoglycemia; 
severe hypotension; 
QT interval prolongation;
anemia, 
neutropenia, 
thrombocytopenia;
GI effects
35
Q

Treatment of Chagas disease

A

AMERICAN trypanosomiasis

Nifurtimox
Benznidazole

36
Q

Nifurtimox

A

Oral; hepatic CYP metabolism, renal excretion

MOA - reduced by microbe enzyme to nitro anion radicals and superoxide radicals causes membrane injury, enzyme inactivation and DNA damage

Better effiicacy in acute disease

Adverse effects - nausea, vomiting, polyneuropathy, headache, dizziness, vertigo, insomnia

37
Q

Benznidazole

A

Oral; hepatic metabolism, excreted in urine/feces, half life 12 h

MOA - activated by trypanosomal nitroreductases making reactive superoxide radicals causing parasitic proteins and DNA

Better effiicacy in acute disease

Adverse Effects - generally well tolerated but pruritic rash and abdominal pain is sometimes experienced

38
Q

treatment of leishmaniasis

A

Sodium Stibogluconate / Meglumine Antimoniate

Amphotericin B

Miltefosine

39
Q

Leishmaniasis

A

spread by sand fly, obligate intra-macrophage protozoa

visceral, cutaneous or mucocutaneous leishmaniasis

general chemotherapy - first line: Sodium Stibogluconate [Pentosam]* and Meglumine antimoniate

alternatives - Pentamidine, Amphotericin B, Miltefosine*, Paromomycin + gentamicin

40
Q

Sodium Stibogluconate / Meglumine Antimonate

A

Used first like for leishmaniasis

Pentavalent antimonial Sb5+ converted into Sb3+ species - kills amastigotes in macrophages, by inhibiting trypanothione reductase

I.V. for treatment of cutaneous and visceral disease

cardiac toxicity; hepatotoxicity; pancreatitis; renal toxicity; muscle aches

41
Q

Amphotercin B

A

Leishmaniasis Rx (and probably more)

Complexes with sterol precursors in Leishmania cell and forms pores

I.V. for treatment of visceral leishmaniasis

Adverse Effects - Infusion reactions, nephrotoxicity, anemia and anaphylaxis

42
Q

Miltefosine

A

oral; visceral and cutaneous disease; vomiting, diarrhea, ↑ transaminases (reversible); MOA undefined

not starred

43
Q

Pentamidine:

A

I.M. for cutaneous leishmaniasis

alternate for visceral disease

hypotension; tachycardia; GI Sx; sterile abscesses; and pancreatic, liver, and kidney abnormalities

44
Q

treatment of toxoplasmosis

A

Spiramycin
Pyrimethamine + Atovaquone or Dapsone or Clindamycin

Toxoplasma gondii: cats are natural hosts, Acute, self-limiting illness, immunocompromised people at risk (encephalitis), also congenital toxoplasmosis

45
Q

Spiramycin

A

(<18 weeks gestation) acute acquired infection to prevent transmission to the fetus

46
Q

Treatment of cerebral toxoplasmosis

A

AIDS patients

Pyramethamine + sulfadiazine + folinic acid (leucovorin)

Clindamycin or atovaquone may be substituted if sulfonamide

Primary prophylaxis: trimethoprim-sulfamethoxazole

47
Q

Babesiosis:

A

Tick-borne zoonosis: erythrocyte invasion

protozoan

Clindamycin + Quinine

Atovaquone + Azithromycin (fewer AEs)

48
Q

Balantidiasis:

A

− Fecal-oral transmission: intestinal parasite

− Tetracycline

Pharmacology (23 decks)

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