1. Katzung’s Basic & Clinical Pharmacology,
Reading assignments:
Katzung’s Basic & Clinical Pharmacology,
13th Edi ,Ch-52&53,p ;
Dr.Sanjib Das

2. 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)

3. 1. Antimalarials 2. Anti-protozoal drugs ARTEMISININ CHLOROQUINE
MEFLOQUINE
PRIMAQUINE
PYRIMETHAMINE-SULFADOXINE (FANSIDAR)
2. Anti-protozoal drugs
METRONIDAZOLE
TRIMETHOPRIM-SULFAMETHOXAZOLE
PYRIMETHAMINE-SULFONAMIDE
PENTAMIDINE

4. Anti-Parasitic Chemotherapy: Anti-Malarials
Life cycle of malaria parasites
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

5. 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
The mechanism of action of chloroquine in Plasmodium falciparum malaria is elimination of
a. Secondary tissue schizonts
b. Exoerythrocytic schizonts
c. Erythrocytic stage
d. Asexual forms
e. Sporozoites
The answer is c. Chloroquine is a 4- aminoquinoline derivative that selectively concentrates in parasitized red blood cells. It is a weak base, and its alkalinizing effect on the acid vesicle of the parasite effectively destroys the viability of the parasite.

6. 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

7. 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
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

8. 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

9. 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
1. A 27-year-old female has just returned from a trip to Southeast Asia. In the past 24 hours, she has developed shaking, chills, and a temperature of 104?F. A blood smear reveals Plasmodium vivax. Which of the following agents should be used to eradicate the extraerythrocytic phase of the organism?
a. Primaquine
b. Pyrimethamine
c. Quinacrine
d. Chloroquine
e. Chloroguanide
The answer is a. (Hardman, pp 977–978.) Primaquine is effective against the extraerythrocytic forms of P. vivax and P. ovale and is thus of value in a radical cure of malarial infection. It also attacks the sexual forms of the parasite, rendering them incapable of maturation in the mosquito and making it valuable in preventing the spread of malarial infection.

10. 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
Clinical Uses
Urogenital trichomoniasis (Trichomonas vaginalis)
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
Protozoa
Bacteria
#H.Pylori responsible for 100% occurrence of duodenal ulcers ,75% occurrence of gastric ulcers
#H.Pylori responsible for 1.Recurrence 2.precipitation of Malignancy by increasing turn over of diff.types of Gastric cells.
#Economic Regimen :Bismuth+Metronidazole+Tetracycline
#Expensive Regimen:Clarithromycin+Amoxycillin+Omeprazole
An women previously diagnosed with a duodenal ulcer and is currently taking medication for her condition. developed profound nausea, vomiting, sweating, hyperventilation, tachycardia, and vertigo .after having few glasses of wine. Which of the following medications is most likely responsible for her latest symptoms? Or
A 35-year-old female complains of itching in the vulval area. Hangingdrop examination of the urine reveals trichomonads. What is the preferred treatment for trichomoniasis?
a. Doxycycline
b. Pyrimethamine
c. Pentamidine
d. Emetine
e. Metronidazole
2. The mechanism of action of metronizaole

11. 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?
Patients receiving metronidazole treatment commonly develop symptoms
like those described above shortly after ethanol consumption.
Metronidazole is commonly used to treat trichomonas vaginitis and
bacterial vaginosis. Metronidazole’s interaction with alcohol is
thought to result from its inhibition of alcohol oxidizing enzymes,
which causes acetaldehyde to accumulate and thus the unpleasant
effects. Disulfiram is an aldehyde dehydrogenase inhibitor that also
causes acetaldehyde accumulation and a similar adverse reaction with
ethanol consumption. Disulfiram is used in recovering alcoholics to
prevent them from relapsing to alcohol use.

13. 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

14. 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

15. 3. Anthelminthic drugs ALBENDAZOLE IVERMECTIN PRAZIQUANTEL
THIABENDAZOLE
MEBENDAZOLE
PYRANTEL PAMOATE

16. 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

17. 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
1.Drug useful in cestode & trematode infections

18. 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
1.Thiabendazole, a benzimidazole derivative, is an antihelminthic drug used primarily to treat infections caused by
a. Ascaris lumbricoides (roundworm)
b. N. americanus (hookworm)
c. Strongyloides
d. Enterobius vermicularis
e. Taenia saginata (flatworm)
The answer is c. Thiabendazole has been shown to be effective against Strongyloides, cutaneous larva migrans, and Trichuris. Adverse effects consist of nausea, vertigo, headache, and weakness. Treatment usually involves oral administration for several days. It has been found to be ineffective in Ascaris, N. americanus, E. vermicularis, and T. saginata.

19. 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
1.The mechanism of action by which pyrantel pamoate is effective for the treatment of Necator americanus (hookworm) disease is
a. Interference with cell-wall synthesis
b. Interference with cell division
c. Inhibition of neuromuscular transmission
d. Interference with protein synthesis
e. Depletion of membrane lipoproteins
The answer is c. Pyrantel pamoate is an antihelminthic that acts primarily as a depolarizing neuromuscular blocker. In certain worms, a spastic neuromuscular paralysis occurs, resulting in the
expulsion of the worms from the intestinal tract of the host. Pyrantel also exerts its effect against parasites via release of acetylcholine and inhibition of cholinesterase.

20. strongyloidiasis
tremetodes &
cestodes
PCP

21. 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?
Amphotericin B
Flucytosine
Itraconazole
Nystatin
Terbinafine
Answer: A
Amphotericin B & nystatin
bind to ergosterol;
toxicity due to binding to
cholesterol in host cells

22. 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 GABA-mediated transmission in the worm and would be appropriate for treating the condition of this patient?
Chloroquine
Ivermectin
Praziquantel
Primaquine
Thiabendazole
Answer: B
Ivermectin paralyzes worms
by increasing chloride permeability

23. PowerPoint Slides
Several of the PowerPoint slides are Copyright © , 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