Transcript 7-Antiparasitic Chemotherapy

Reading assignments:
Katzung’s Basic & Clinical Pharmacology,
13th Edi ,Ch-52&53,p886-917;
Dr.Sanjib Das
• IV.Antiparasitic Chemotherapy:
• A.Basic Principles of Antiparasitic Chemotherapy
• B.Antiprotozoal Chemotherapy
• 1. Antimalarials
– Know the infectious cycles of the Plasmodia and which
stages are susceptible to different antimalarials
– Understand the effect of drug resistance on the clinical
use of antimalarials
• 2. Other antiprotozoal drugs
– Know the mechanism of action, clinical uses, and
adverse effects associated with these drugs
• C. Anthelminthic Agents
– Know mechanisms of action against intestinal and
extra-intestinal parasites
– Know drugs used clinically in North America (limit to
infections by Ascaris, pinworm, hookworm, tapeworm)
1. Antimalarials
ARTEMISININ
CHLOROQUINE
MEFLOQUINE
PRIMAQUINE
PYRIMETHAMINE-SULFADOXINE
(FANSIDAR)
2. Anti-protozoal drugs
METRONIDAZOLE
TRIMETHOPRIM-SULFAMETHOXAZOLE
PYRIMETHAMINE-SULFONAMIDE
PENTAMIDINE
Anti-Parasitic Chemotherapy: AntiMalarials
Four species of
protozoan-–
–
–
–
Plasmodium falciparum
Plasmodium malariae
Plasmodium vivax
Plasmodium ovale
• First two single cycle,
second two multiple
cycles
• Key point-- Several
drugs affect blood
schizonts, only
primaquine affects
tissue schizonts
Life cycle of malaria parasites
https://www.youtube.com/watch?v=qMNmOsl5_e4
Anti-Malarials: Chloroquine
Mechanism
• Alters metabolism of hemoglobin by parasite, also blocks nucleic acid synthesis
Pharmacokinetics
• Oral or parenteral
•
Rapid, complete absorption; wide distribution
•
Excreted in urine, 25% as metabolite
•
Loading dose necessary for acute treatment
Clinical Uses
• "Highly effective blood schizonticide“
•
Acute-- Clears parasitemia from all four Plasmodia
– Curative for P. malariae and P. falciparum
– Used with primaquine for P. vivax and P. ovale
•
Prophylactic-- Begin 1 week before travel, continue four weeks after return
– Preferred drug for prophylaxis against all four species
Chloroquine
Adverse Effects-• Generally well tolerated
• GI, mild headache; may exacerbate psoriasis or porphyria
• Visual impairment occurs with long-term or high-dose
therapy
Resistance-• Widespread in South America, Africa, Asia
• "P-glycoprotein" pumping mechanism
• Block with verapamil in vitro
Anti-Malarial Chemotherapy
Mefloquine
Mechanism unknown
Pharmacokinetics
• Only oral-- too irritating for parenteral
• Well absorbed and distributed
• Metabolized in liver, excreted in feces
Adverse effects—CNS, possible psychotropic effects
Clinical Uses-• Chloroquine-resistant malaria
Fansidar (Pyrimethamine-Sulfadoxine)-•
Anti-folate combination, typical effects
Pharmacokinetics
• Well absorbed and distributed, Excreted in urine
Clinical Use-• Effective blood schizonticide for P. falciparum
• Slow-acting; cannot be used alone for acute attacks
Multi-drug resistance to fansidar and chloroquine common
Anti-Malarial Chemotherapy
•
Atovaquone plus proguanil
– Mechanism of action
(1) Atovaquone selectively inhibits parasite mitochondrial electron transport
(2) Proguanil’s metabolite cycloguanil, inhibits dihydrofolate reductase
– Used to prevent or treat acute, uncomplicated P. falciparum malaria
– Adverse effects
(1) GI distress
(2) Increased hepatic transaminase
(3) Headache
(4) Dizziness
•
Quinine and Quinidine
– Still used to treat uncomplicated chloroquine-resistant P. falciparum malaria
– Cinchonism
(1) Overdose of quinine or its natural source, cinchona bark
(2) Symptoms
(a) Flushed and sweaty skin
(b) Ringing of the ears (tinnitus)
(c) Blurred vision
(d) Impaired hearing
(e) Confusion
Anti-Malarial Chemotherapy: Tissue
Schizonticides
Primaquine-• Tissue schizonticide
•
Oral, well absorbed and distributed, extensively metabolized
•
Metabolites are intracellular oxidants
•
Used in combination with chloroquine for prophylaxis or cure of P. vivax, P.
ovale
•
GI distress, hemolytic anemia in G6PDH deficiency
Artemisinin—
• Traditional Chinese medicine
•
Oral, very short t ½
•
Activated by oxidative metabolism—free radicals, alkylation
•
Rapidly-acting blood schizonticide—particularly useful for multi-drug
resistant P. falciparum
Other Anti-Protozoal Drugs:
Metronidazole
&
Tinidazole
Mechanism
•
•
•
Tissue amebicide
Nitroimidazole-- activated by electron donation & produce free radicals as MOA.
Particularly effective for anaerobic/hypoxic sites
Pharmacokinetics
• Oral or IV
• Well absorbed and distributed, including CNS, bone
• Cleared in urine following hepatic metabolism
Protozoa
Clinical Uses
• Urogenital trichomoniasis (Trichomonas vaginalis)
Bacteria
• Giardiasis (Giardia)
• Amebiasis (Entamoeba histolytica)
• Aspiration pneumonia
• Anaerobic bacterial infections below diaphragm (including Clostridium difficile,
Bacteroides fragilis ,Gardinella vaginalis & Acne Rosacea).
• H. Pylori {used with bismuth & amoxycillin (or tetracycline) as ‘triple therapy’}.
Adverse Effects
• Nausea, headache, Dry mouth,
• Stomatitis, metallic taste, leukopenia, cystitis, Reversible peripheral neuropathy (free
redical injury)
• Disulfiram effect
A 21-year-old female is taking medication for a
recently diagnosed medical problem. While at a
college party, she develops facial flushing,
headache, nausea, vomiting, and abdominal
cramps immediately after having an alcoholic
drink. This patient is most likely being treated for
which conditions?
Other Anti-Protozoal Drugs:
Pentamidine
Mechanism -- unknown
Pharmacokinetics
• IV, IM or aerosol
• Concentrates in liver, spleen, kidneys
• Slowly released from those sites
• Doesn't enter CNS
Clinical Use
• Aerosol used for treatment/prophylaxis against
Pneumocystis pneumonia (PCP)
Adverse Effects
• Can cause respiratory stimulation followed by depression;
hypotension, anemia
• Adverse effects less common with aerosol administration
Other Anti-Protozoal Drugs:
• Iodoquinol
– Used for the local treatment of acute and
chronic intestinal amebiasis
– Used for asymptomatic cyst passers
• Paromomycin
– An aminoglycoside
– Acts locally on ameba
– Used to treat acute and chronic intestinal
amebiasis
3. Anthelminthic drugs
ALBENDAZOLE
IVERMECTIN
PRAZIQUANTEL
THIABENDAZOLE
MEBENDAZOLE
PYRANTEL PAMOATE
Anti-Helmintic Chemotherapy
• Target is multi-cellular organism
• Mobility/contractile systems in parasites are important targets
Mebendazole-• Wide spectrum anti-helmintic
• Given orally, less than 10% absorbed
• Rapidly metabolized, excreted in urine
• Mechanism-- Blocks microtubule synthesis, blocks vesicle and
organelle movement
• Effective against pinworm, hookworm, Ascaris
• Dose limited by GI effects; Possibly embryotoxic
Anti-Helmintic Chemotherapy
Albendazole-•
Wide spectrum anti-helmintic
•
Rapidly and completely metabolized in liver, conjugates excreted in urine
•
Interferes with microtubule aggregation, alters glucose uptake
Praziquantel-•
Effective treatment for all schistosomes, some trematodes and cestodes
•
80% bioavailability after oral dosing
•
Rapidly and extensively metabolized, cleared in urine
•
Parent is active species
•
Increases membrane permeability to Ca2+,resulting in contraction and
paralysis
•
Headache, dizziness, drowsiness may occur
Anti-Helmintic Chemotherapy
Thiabendazole and mebendazole
• Mechanism of action: block microtubule
formation
• Uses
– Thiabendazole (broad spectrum):, cutaneous larva
migrans, strongyloidiasis (alternative drug)
– Mebendazole: ascariasis, trichuriasis, hookworm,
pinworm (Enterobius vermicularis), cysticercosis
(Taenia solium), Echinococcus infestations
• Adverse effects: abdominal pain, diarrhea
Anti-Helmintic Chemotherapy
Pyrantel pamoate
• Mechanism of action
– Acts as a depolarizing neuromuscular blocking agent on the
nicotinic receptor
– Increases the effects of acetylcholine and inhibits cholinesterase in
the worm
• Uses: ascariasis, pinworm (E. vermicularis), hookworm,
whipworm (Trichuris trichiura), Trichostrongylus
• Adverse effects: nausea, vomiting, diarrhea, anorexia
Ivermectin
• Mechanism of action: increases chloride permeability,
thus polarizing cells, which leads to paralysis
• Uses: strongyloidiasis, onchocerciasis
Chemotherapeutic agents
Antibacterial agents
Antifungal agents
Antiparasitic agents
Antitumor agents
Antiviral agents
Amphotericin B
Liposomal Ampho-B
Flucytosine
Antimalarials
Ketoconazole
Fluconazole
Itraconazole
Chloroquine
Mefloquine
Primaquine
Anthelmintic drugs
GABA Ivermectin strongyloidiasis
 tremetodes &
Ca Praziquantel
cestodes
Tub Thiabendazole
Tub Mebendazole
Ach Pyrantel pamoate
Griseofulvin
Terbinafine
Antiprotozoal drugs
Metronidazole
TrimethoprimSulfamethoxazole
PyrimethamineSulfadoxine
Pentamidine
PCP
A 55-year-old construction worker had
a mild respiratory infection with flu-like
symptoms that resolved in less than 2
weeks. Two months later, a chest
radiograph revealed numerous diffuse
calcific densities confirming a diagnosis of
primary histoplasmosis. Which of the
following binds to ergosterol and would be
appropriate for treating this patient?
A.
B.
C.
D.
E.
Amphotericin B
Flucytosine
Itraconazole
Nystatin
Terbinafine
Answer: A
Amphotericin B & nystatin
bind to ergosterol;
toxicity due to binding to
cholesterol in host cells
A 39-year-old woman has dermatis and
pneumonitis with eosinophilia caused by
Strongyloides stercoralis (strongyloidiasis).
Which of the following medications will
paralyze the worm by intensifying GABAmediated transmission in the worm and
would be appropriate for treating the
condition of this patient?
A.
B.
C.
D.
E.
Chloroquine
Ivermectin
Praziquantel
Primaquine
Thiabendazole
Answer: B
Ivermectin paralyzes worms
by increasing chloride permeability
PowerPoint Slides
 Several of the PowerPoint slides are Copyright © 2002-04,
the American Society for Pharmacology and Experimental
Therapeutics (ASPET). All rights reserved.
 Some of slides in this session are from the above mentioned format
and are free for use by members of ASPET.
 Some others are from various sources like text book, recommended
books, slides of Dr. S. Akbar (ex. professor, Pharmacology ,MUA).
 Core concepts of various USMLE High yield review series like
Kaplan ,BRS etc. are thoroughly explored & integrated whenever
necessary