Theme Lecture : Block 1.

2
(04 Dec 2017, 8:30-9:20 AM)

Anti-parasitic & Anti-fungal Drugs

Dr. Girish M B
Associate Professor (Pharmacology)
College of Medicine, KFU
[email protected]
 Case Scenario

A 36-year-old man had diarrhea for six weeks

before consulting the health clinic. He is a
regular traveler and recently he traveled to
several different African countries a few weeks
prior. His symptoms included abdominal
cramps and frothy stools later progressed to
bloody diarrhea with mucus and sometimes
accompanied by systemic symptoms such as
headache, nausea and anorexia.
A stool specimen was submitted to the
reference laboratory for diagnostic evaluation.  What is your diagnosis? Based
After examining the smear-specimen it was on what criteria?
found that motile trophozoites containing red
blood cells as shown in the picture (below).  How to manage this clinical
condition?
 Learning objectives - Antiparasitic Drugs

 Understand the broad classification of anti-parasitic drugs

 Discuss the principal indications, adverse effects and contraindications

for the major drugs used in the treatment of following protozoal
infections a) Malaria, b) Amoebiasis, c) Giardiasis, d) Toxoplasmosis,
e) Leishmaniasis f) Pneumocystis

 What are the challenges encountering in the treatment of parasitic

infections?
Overview of Parasitic Infections

Parasite
 Anti-parasitic Drugs

Anti-parasitic Drugs

Anti-helminthic Anti-protozoal Anti-ectoparasitic

Drugs Drugs Drugs
E.g: Albendazole E.g: Permethrin,
Mebendazole Sulfur, Lindane,
Diethylcarbamazine Benzyl benzoate,
Ivermectin, Praziquantel Ivermectin
 Anti-protozoal Drugs
- Pyrimethamine
Malaria Amoebiasis Toxoplasmosis - Sulfadiazine
- Co-trimoxazole
- Chloroquine - Metronidazole - Azithromycin
- Artemisinin - Tinidazole
- Mefloquine - Diloxanide furoate - Metronidazole
- Primaquine Giardiasis - Tinidazole
- Quinine
- Pyrimethamine Pneumocystis
- Sulfadoxine
- Doxycycline - Sodium stibogluconate
- Co-trimoxazole - Amphotericin-B
Leishmaniasis
- Pentamidine - Miltefosine
 Anti-malarial Drugs
Life cycle of malarial parasite Site of action of drugs

1- Inject sporozoites into the blood

2- Entry of sporozoite into liver cell
6
3- Hypnozoite: for radical cure (P.vivax & P.ovale
only) e.g. Primaquine
4- Rupture & release of merozoites (liver cell):
for prophylaxis e.g. Chloroquine, mefloquine
5 5- Rupture & release of merozoites (red cell):
for the acute attack e.g. Chloroquine,
artemisinin, quinine
6- Development of male & female gametocytes
: to prevent transmission e.g. Primaquine
 Anti-malarial Drugs
Drug MOA Adverse effects Contraindication
Chloroquine Inhibits polymerization of haem Pruritus, hypotension, ----
to haemozoin retinopathy
Quinine Cinchonism, hypoglycemia, ----
“ “ “ black water fever, hypotension
cardiac arrhythmias, delirium
Mefloquine GI.disturbances, arrhythmias, Pregnancy
“ “ “ insomnia
Primaquine Interfere with electron transport Hemolysis (G6PD), cyanosis, Pregnancy,
in parasite methemoglobinemia G6PD deficiency
Artemisinin Generation of free radicals Leucopenia ----

Sulfadoxine Inhibits dihydropteroate synthase Hypersensitivity ----

Pyrimethamine Inhibits dihydrofolate reductase Megaloblastic ----

 Drug Treatment in Malaria

Malaria Chloroquine sensitive Chloroquine resistant

 Acute attack Chloroquine & Single drug: Quinine, mefloquine & artemisinin
uncomplicated (by primaquine (p.vivax & Combination: e.g. Pyrimethamine + Sulfadoxine,
oral route) p.ovale only) Artesunate + Mefloquine
 Severe complicated Chloroquine Quinine, artemisinin
(by parenteral route)
 Prophylaxis Chloroquine phosphate Mefloquine 250mg weekly
300mg base weekly Doxycycline 100mg daily
Anti-amoebic Drugs

Drug MOA & Indication ADR

Metronidazole Nitro group converted to Anorexia,
(MTZ) highly reactive radical Kills nausea,
trophozoites of E.histolytica- metallic taste,
Invasive amoebiasis interactions
with alcohol

Tinidazole Similar to MTZ in its action Better

tolerated &
lesser ADR
Diloxanide Destroys the trophozoites of G.I
E. histolytica that eventually disturbances
form into cysts-
Asymptomatic amoebiasis
Anti-giardial Drugs

 Metronidazole
 Tinidazole
(already discussed earlier)
Drugs used in Toxoplasmosis

Drugs MOA ADR

Pyrimethamine Interfere with Hypersentivity,
(PMT) + folate synthesis. megaloblastic
Sulfadiazine (SD) These agents are anemia
active against
tachyzoites & are
synergistic in
combination.
Trimethoprim + Similar to PMT & Hypersentivity,
Sulfamethoxazole SD combination GI disturbances
(Co-trimoxazole)
 Drugs used in Leishmaniasis

Drugs MOA & Indication ADR

Stibogluconate Increase production of
toxic oxygen free Hypotension,
radicals- VL bradycardia,
Pentamidine Inhibition of the pain at inj site
synthesis of DNA, RNA
& proteins- VL
Miltefosine Induces DNA G I disturbances
fragmentation &
apoptosis- CL, VL & MCL
Amphotericin B Inhibits binding of L. High fever, shaking
Cutaneous Leishmaniasis (CL) donovani promastigotes chills, hypotension
Mucocutaneous Leishmaniasis (MCL) to macrophages- VL & Kidney & liver
Visceral Leishmaniasis (VL) MCL damage,leukopenia
 Pneumocystis Carinii/ Jiroveci

• Precise classification is uncertain Group & Sulfonamides:

Drugs Trimethoprim/sulfamethoxazole
• It shares structural features of both
protozoa & fungi MOA It is bactericidal due to the
double inhibition of bacterial folic
• Recognized as opportunistic acid synthesis
infection in immunocompromised
pts (in AIDS). ADR Fever, skin rashes and
• Causes serious pneumonia bone marrow hypoplasia
Contra- Pregnancy, G6PDD, renal failure
indications
Challenges in the treatment of protozoal infections

 Difficult to make a conclusive diagnosis: e.g. Toxoplasmosis

 Laboratory diagnosis is notoriously difficult to establish
 Lack of effective drugs: e.g. Cryptosporidiosis
 Toxic adverse effects: e.g. Visceral leishmaniasis
 The emergence of drug resistance: e.g. Falciparum malaria
 Prevention

Done by the following steps

 Source reduction: to reduce the source of infection by treating all
infected patients
 Health education: to prevent the distribution of parasite
 Eradication of host reservoir and vector control
 Increase biological immunity against infection
 Control of hygiene and sanitation
Anti-fungal Drugs
 Case Scenario

• A 4-year-old preschool going boy is

brought to hospital by his mother
because he keeps scratching a spot on his
arm for several days and it appears that
the spot is growing larger. No one else at
home has anything similar. He has not
had a fever or any systemic signs of
illness. No history of recent exposures to
new foods, medications, lotions or soaps.
• On examination of his skin you see a
circular nickel sized ring on his right
forearm as shown in the picture (below). • What is your clinical diagnosis?
It has a red raised border and central • How to treat this clinical
clearing. The remainder of his skin exam condition?
and his general physical examination are
normal.
 LQ’s: Anti-fungal Drugs

 Discuss the general drug action, indications, adverse effects, precautions and
contraindications of anti-mycotic agents used in major types of fungal infections
(including superficial and systemic mycoses)
- Cryptococcus neoformans
- Candida albicans,
- Aspergillus fumigatus,
- Ringworm,
- Histoplasma capsulatum.
 Who Gets Fungal Infections..?

 People with weak immune systems – Opportunistic infections

 What weakens an immune system..?
 Born with weak immune system
 Immunocompromised states
 HIV/AIDS infected pts.
 Organ transplant pts.
 Cancer pts.
 Hospitalized pts.
 Medications that weaken the immunity (Corticosteroids etc.)
 Anti-fungal Drugs

 Polyenes : Amphotericin-B, Nystatin

 Azoles : Ketoconazole, Fluconazole, Itraconazole

 Antimetabolite : Flucytosine

 Other : Griseofulvin, Caspofungin

 Topical : Clotrimazole, Miconazole, Econazole, Turbinafine

Fungal cell wall & site of action of anti-fungal drugs
 Anti-fungal Drugs: Systemic mycoses

Group & Polyenes:

Drugs Amphotericin-B, Nystatin
MOA Disrupting cell membrane
ADR Nephrotoxicity, anemia,
acute reaction, hypokalemia
Indications Invasive aspergillosis,
histoplasmosis or
disseminated infections
Precautions In pts with renal damage
 Anti-fungal Drugs: Systemic mycoses

Group & Azoles: Ketoconazole,

Drugs Fluconazole

MOA Inhibit ergosterol synthesis

ADR Gynecomastia, liver damage,
menstrual irregularities

Indications Tineasis, athletes foot,

otomycosis, candidiasis,
dermatophytosis, systemic
mycoses
Precautions Drug interactions
(astemizole,rifampicin,antacids)
 Anti-fungal Drugs: Systemic mycoses

Group & Antimetabolite: Flucytosine

Drugs
MOA Inhibit nucleic acid synthesis

ADR Bone marrow depression

Indications With AMB- Cryptococcosis &

disseminated candidiasis

Precautions In pts with renal damage

 Anti-fungal Drugs: Systemic mycoses

Group & Others: Griseofulvin,

Drugs Caspofungin
MOA - Anti-mitotic
- Inhibit cell wall synthesis
ADR - Headache
- Diarrhea, skin rash
Indications - Systemic dermatophytosis
- Invasive aspergillosis
& Candidiasis
Precautions Pregnancy
 Anti-fungal Drugs: Superficial mycoses

Drugs (Topical Clotrimazole, Miconazole,

preparations) Econazole, Terbinafine etc.

MOA Ergosterol synthesis

inhibitors

Indications Ring worm dermatophytosis

,candidiasis, tinea versicolor,
fungal keratitis etc.
 Anti-fungal Drugs: Superficial mycoses

Drugs (Topical Amphotericin-B,

preparations) Nystatin

MOA Disrupting cell membrane

Indications Oropharngeal & cutaneous

candidiasis, mycotic corneal
ulcers
 Summary & Conclusion

• A wide array of parasites infect humans, causing some of the most prevalent
infectious diseases globally. Recent advances in the treatment of malaria &
leishmaniasis have brought needed improvements to the management of these
diseases.
• Despite a relatively narrow therapeutic pipeline for new antiparasitic drugs, there
have been significant improvements in the treatment of these widespread
infections in the past two decades.
• Different antifungals have different spectrums of antifungal coverage, for
superficial mycoses topical preparations and for deep mycoses systemic antifungal
agents are used respectively.
• Extensive work is being done to validate new targets & develop new drugs
Study resource: Rang & Dale’s, Text book of pharmacology – 8th Edition, Chapters:53 & 54,
Page no's: 653-669