Pharmacology - Antimebics And Antihelminthics

Front 1

Define Ambiasis

Back 1

- intestinal tract infection by Entamoeba histolytica
- disease can be acute or chronic
- no sx --> mild diarrhea --> fulminating dysentry

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3 Types of Antiamebics

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1. Luminal
- act on parasite in bowel lumen

2. Systemic
- active both in intestinal wall and liver

3. Mixed
- active against both luminal and systemic disease

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Mixed Antiamebics

Back 3

Metronidazole and tinidazole

Front 4

Metronidazole - Clinical Applications

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-MIXED AMEBICIDE OF CHOICE - used w/ a luminal amebicide

- also used in tx of infections by Giardia lamblia, Trichomonas vaginalis and is used in comb regiments for H. pylori tx

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Metronidazole - MOA / PK / AE

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- Metronidazole's nitro group acts as an electron acceptor --> reduced cytotoxic compounds (bind to proteins and DNA) --> cell death

PK: Oral, well dist, undergoes hepatic oxidation and glucouronidation (CYP 450)

AE: GI (nausea, vomiting, abd pain), unpleasant metallic taste, oral moniliasis, dark urine

Front 6

Tinidazole

Back 6

- 2nd generation nitroimidazole; similar to metronidazole but better tolerated

Clinical app: tx of amebiasis, amebic liver abscess, giardiasis + trichomoniasis

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Luminal Antiamebics

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Iodoquinol
Diloxanide furoate
Paromomycin

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Iodoquinol

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- orally active against E. hystolytica (alternative to diloxanide for mild-severe infections)
- AE: rash, diarrhea, peripheral neuropathy, avoid long-term use

Front 9

Diloxanide Furoate

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- used as sole agent for Tx of ASYMPTOMATIC AMEBIASIS

- AE: mild

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Paromomycin

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- effective ONLY against luminal forms of E. histolytica and tapeworm
- alternative for cryptosporidiosis in AIDS pts

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Paromomycin - MOA/AE

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MOA
- amebicidal (causes cell membranes to leak)
- reduces intestinal flora population

AE
- GI distress, diarrhea, systemic absorption may lead to headaches, dizziness, rashes, and arthralgia

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Systemic Antiamebics

Back 12

Chloroquine
Emetine
Dehydroemetine

Front 13

Chloroquine

Back 13

- used in comb w/ metronidazole and diloxanide furoate
- MOA: eleminates trophozoites in liver abscesses

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Emetine and Dehydroemetine

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- BACKUP drugs for tx of severe intestinal or hepatic amebiasis + luminal agent
- MOA: inhibit protein synthesis by blocking ribosomal movement along mRNA

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Emetine and Dehydroemetine - PK / AE

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PK
- IM (preferred), SC
- conc in liver (persists for 1 month)
- slowly met and eliminated

AE
- pain at injection site, transietnt nausea, cardiotoxicity, neuromuscular weakness, dizziness, rash

Front 16

Review: Tx of Asymptomatic intestinal infection

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Diloxanide furoate

alternative: Iodoquinol, paromomycin

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Review: Tx of Mild-moderate intestinal infection

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Metronidazole + luminal agent

alternative: Tinidazole, tetracycline, or erythromycin + luminal agent

Front 18

Review: Tx of Severe intestinal infection

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Metronidazole or Tinidazole + luminal agent

alternative: tetracycline, emetine, or dihydroemetine + luminal agent

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Review: Tx of Hepatic abscess and other extra-intestinal diseases

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Metronidazole or Tinidazole + luminal agent

alternative: emetine or dihydroemetine + choloroquine + luminal agent

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Benzimidazoles

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- Albendazole
- Mebendazole
- Thiabendazole

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Albendazole

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- tx of cestodal infestations such as CYSTICERCOSIS (Taenia solium), and HYDATID disease (Echinococcus granulosis)
- MOA: inhibits microtubule synthesis + glucose intake

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Albendazole - PK/AE

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PK
- oral (erratically abs, high fat meal)
- extensive first pass met --> active metabolite

AE
- Short course therapy: mild and transient headaches/nausea
- Hydatid therapy (3months): hepatotoxicity, agranulocytosis or pancytopenia
- CONRA. in PREGNANCY and CHILDREN <2 y/o

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Mebendazole

Back 23

DOC for infections by:
- WHIPWORM (Trichuris trichiura)
- PIN WORM (Enterobius vermicularis)
- HOOKWORMS (Necator americanus + Ancylostoma duodenale)
- ROUNDWORM (Ascariasis lumbricoides)

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Mebendazole - MOA

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Binds to and interferes w/ assembly of parasites' MICROTUBULES

Decreased glucose uptake

Affected parasites expelled w/ feces

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Mebendazole - PK/AE

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Oral (chewable) - nearly insoluble in aqueous solution (take w/ high fat meal); undergoes first-pass met --> INACTIVE compounds

AE:
abd pain, diarrhea
CONTRA. IN PREGNANCY
use w/ caution in children <2 and pts w/ cirrhosis

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Thiabendazole

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- tx of STRONGYLOIDIASIS caused by Strongyloides stercoralis (threadworm), cutaneous larva migrans, and early stages of trichinosis

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Thiabendazole - MOA/PK

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MOA
- affects MICROTUBULAR aggregation

PK
- oral (readily absorbed, nearly insoluble in water)

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Thiabendazole - AE

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- MORE TOXIC than over benzimidazoles
- Erythema multiforme + Stevens-Johnson
- CONTRA in PREGNANCY
- SHOULD NOT BE USED IN PRESENCE OF LIVER AND KIDNEY DISEASE

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Ivermectin

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- DOC for tx of ONCHOCERCIASIS (Onchocerca volvulus) [River blindness]
"IVERmectin for rIVER blindness"
- MOA: GABA agonist; Cl influx increases --> hyperpolarization --> paralysis
- does NOT cross BBB
- AE: Mazotti-like rxns (fever, dizziness, somnolence, hypotension)
- CONTRA in PREGNANCY and in MENINGITIS (can cross BBB)
- Avoid: ivermectin + other GABA agonists (barbiturates, benzodiazepines, etc)

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Piperazine

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- alt tx of ascariasis
- GABA agonist; Cl influx increases --> hyperpolarization --> paralysis --> expulsion of worm by peristalsis
- CI: pts w/ SEIZURE DISORDERS

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Pyrantel Pamoate

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- tx of infections by Roundworms, pinworms, and hookworms
- MOA: depolarizing, neuromuscular-blocking agent (persistent activation of parasite's nicotinic receports by relase of ACh + inhibition of cholinesterase)
- PK - poorly abs orally (effects on intestinal tract)
- AE: mild

Front 32

Diethylcarbamazine

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- DOC for LYMPHATIC FILRIASIS, LOIASIS, and TROPICAL EOSINOPHILIA
- replaced by IVERMECTIN for onchocerciasis

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Diethylcarbamazine - MOA/PK/AE

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MOA
- immobilizes microfilariae
- renders them susceptible to host defense mechs

PK
- Oral; excreted in urine

AE
- LEUKOCYTOSIS; antihistamines or steroids can be coadministered

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Doxycycline

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- Macrofilaricidal activity against Wuchereria bancrofti
- MOA: indirectly by killing Wolbachia (inctracellular bacterial symbiont of filarial parasites)
- PK: oral; excreted in urine

Front 35

Praziquantel

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DOC for ALL FORMS OF SCHISTOSOMIASIS and MOST TREMATODE and CESTODE INFECTIONS

Cysticercosis - albendazole is DOC

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Praziquantel: MOA/PK/AE

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MOA: increases permeability of cell mem to Ca --> contracture + paralysis of parasite

PK: oral, well dist, short half-life b/c of extensive met (CYPs), inactive met excreted in urine and bile

AE: Drug interactions (CYP P450); CONTRA in PREGNANCY AND NURSING MOTHERS and for tx of OCULAR CYSTICERCOSIS

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Bithionol

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DOC for FASCIOLOSIS (sheep liver fluke)
alt for pulmonary paragonimiasis

MOA: inhibition of helminths electron transport chain

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Niclosamide

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- 2nd line for tx of cestode infections
- not avail in US
- MOA: inhibition of parasites mitochondrial phosphorylation of ADP. Anaerobic met also inhibited. Drug is lethal for cestode's scolex and segments of cestodes but NOT for the ova

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Niclosamide: PK

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- laxative given before niclosamide to purge bowel of all dead segments in order to preclude digestions and liberations of ova (can lead to cysticercosis)
- avoid alcohol w/in 1 day of dose