6. Anti-fungal and Anti-protozoal Agents

Question 1

Classification of anti-fungal drugs

Answer 1

1. Drugs for subcutaneous and systemic mycotic infection

2. Drugs for cutaneous mycotic infections

Question 2

Types of drugs for subcutaneous and systemic mycotic infection

Answer 2

1. Amphotericin B
2. Antimetabolite antifungals: Flucytosine
3. Echinocandins: Caspofungin
4. Azole antifungals: Triazoles

Question 3

Types of drugs for cutaneous mycotic infection

Answer 3

1. Nystatin
2. Squalene epoxidase inhibitors: Terbinafine
3. Azole antifungals: Imidazoles

Question 4

MOA of amphotericin B

Answer 4

Binds to ergosterol in the plasma membrane of sensitive fungal cells → forms pores (channels) → disrupts membrane functions → allowing electrolytes (particularly potassium) and small molecules to leak from the cell → cell death

→ fungicidal or fungistatic depending on the organism and the conc. of the drug

Question 5

Indications for amphotericin B

Answer 5

1. Candida albicans (candidiasis)
2. Histoplasmosis
3. Crpytococcus neoformans
4. Aspergillus (Aspergillosis)

Question 6

Adverse effects of amphotericin B

Answer 6

1. Fever and chills
2. Nephrotoxicity
3. Hypotension
4. Thrombophlebitis
5. Bone marrow suppression
6. Ototoxicity

Question 7

MOA of 5-Flucytosine

Answer 7

5-Flucytosine enters the fungal cells through cytosine specific permeases and is then converted, by cytosine deaminase, to its metabolically active form 5-Fluorouracil (5-FU)

1. Conversion of 5-FU into 5-fluorouridine triphosphate (FUTP). FUTP is incorporated into fungal RNA in place of uridylic acid; and inhibits protein synthesis
2. Metabolism of 5-FU into 5-fluorodeoxyuridine monophosphate (FdUMP), a potent inhibitor of thymidylate synthase, which is a key enzyme of DNA synthesis

→ fungistatic

Question 8

Indications for 5-Flucytosine

Answer 8

effective in combination with amphotericin B for treating candidiasis and cryptococcosis (meningitis and pulmonary infections)

Question 9

Resistance to 5-Flucytosine

Answer 9

Decreased levels of any of the enzymes in the conversion of 5-FC to its metabolites and/or development of an increased synthesis of cytosine during therapy → not used as a single antimycotic drug, used in combination with amphotericin B which allows more 5-FC to penetrate the cell thus leading to synergistic anti-fungal effects and minimises resistance

Question 10

Adverse effects of 5-Flucytosine

Answer 10

1. GI effects
2. Bone marrow suppression
3. Hepatotoxicity

Question 11

Types of Echinocandins

Answer 11

1. caspofungin
2. micafungin
3. anidulafungin

Question 12

MOA of Echinocandins

Answer 12

Inhibit the activity of the glucan synthase complex → loss of structural integrity of the cell wall

Question 13

Indications for Echinocandins

Answer 13

1. First-line option for invasive candidiasis, including candidemia
2. Second-line option for aspergillosis (for those who have failed or cannot tolerate amphotericin B or an azole)

Question 14

Adverse effects of Echinocandins

Answer 14

1. GIT related symptoms
2. Fever
3. Chills
4. Rashes
5. Skin flushing
6. Thrombocytopenia

Question 15

Types of triazoles

Answer 15

1. Fluconazole
2. Itraconazole
3. Voriconazole

Question 16

MOA of triazoles

Answer 16

Inhibit C-14 alpha-demethylase (CYP450 enzyme) → blocking the demethylation of lanosterol to ergosterol → inhibition of ergosterol biosynthesis disrupts membrane structure and function → inhibits fungal cell growth

→ fungistatic

Question 17

Indications for fluconazole

Answer 17

1. Treatment of candidemia, and most forms of mucocutaneous candidiasis
2. Cryptococcal meningitis
3. Histoplasmosis
4. Blastomycosis
5. Single-dose oral treatment for vulvovaginal candidiasis
6. Most types of fungal meningitis

Question 18

Indications for itraconazole

Answer 18

1. Broad antifungal spectrum compared to fluconazole
2. Treatment of blastomycosis and aspergillosis in patients intolerant to amphotericin B
3. Onychomycosis in non-immunocompromised patients
4. Oral solution for esophageal and oropharyngeal candidiasis

Question 19

Indications for voriconazole

Answer 19

1. Broad-spectrum antifungal
2. Treatment of choice for invasive aspergillosis
3. Candida infections

Question 20

Adverse effects of triazoles

Answer 20

1. Nausea, vomiting, headache, and skin rashes
2. Hepatotoxicity
3. QT prolongation
4. Cardiotoxicity → Itraconzaole
5. Neurotoxicity → Voriconazole

Question 21

Resistance to triazoles

Answer 21

1. Mutations in the C-14 alpha-demethylase gene → decreased azole binding
2. Development of efflux pumps that pump the azole out of the cell

Question 22

Drug interactions with triazoles

Answer 22

1. Inhibit CYP450 3A4 isoenzyme to varying degree
2. Also interfere with CYP2C9 and CYP2C19
3. Enhance activity of drugs metabolised by CYP450 including warfarin, cyclosporine, oral hypoglycemic agents

Question 23

Contraindications to triazoles

Answer 23

Teratogenic → avoid in pregnancy

Question 24

Types of cutaneous anti fungal

Answer 24

Imidazoles

1. Clotrimazole
2. Miconazole

Question 25

Indications for imidazoles

Answer 25

1. Epidermophyton 2. Microsporum 3. Trichophyton 4. Candida → oropharyngeal and vulvovaginal candidiasis 5. Malassezia

Question 26

Adverse effects of imidazoles

Answer 26

Topical: 1. Contact dermatitis 2. Valvular irritation 3. Edema Oral: 1. GI disturbances 2. Elevated liver enzymes

Question 27

Indications for nystatin

Answer 27

Broad spectrum anti-fungal agent → used to treat oral or GI fungal infections and vulvovaginal candidiasis Commonly used for the treatment of cutaneous and oral candida infections

Question 28

Adverse effects of nystatin

Answer 28

Rare after oral administration | Topical and vaginal forms may cause skin infections

Question 29

MOA of terbinafine

Answer 29

1. Inhibiting squalene epoxidase → blocking its conversion to lanosterol and biosynthesis of ergosterol, an essential component of the fungal cell membrane 2. Accumulation of toxic amounts of squalene → increased membrane permeability and death of the fungal cell

Question 30

Indications for terbinafine

Answer 30

Trichophyton → causes tinea Oral → dermatophyte onychomycoses and tinea capitis Topical → tinea pedis, tinea corporis, tinea cruris

Question 31

Adverse effects of terbinafine

Answer 31

1. GI disturbances 2. Headaches 3. Rash 4. Hepatic failure 5. Exacerbation of autoimmune diseases (SLE)

Question 32

Drug interactions with terbinafine

Answer 32

1. Increase serum concentration with CYP450 inhibitors (azoles) 2. Inhibits CYP450 2D6 isoenzymes which is involved in the metabolism of beta-blockers, MAO inhibitors

Question 33

MOA of metronidazole

Answer 33

1. Amoebas possess electron transport protein that participate in metabolic electron removal reactions 2. Metronidazole → nitroimidazole 3. Nitro group of metronidazole is able to serve as an electron acceptor → forming reduced cytotoxic free radicals that result in protein and DNA damage → resulting in death of E. histolytica trophozoites

Question 34

Indications for metronidazole

Answer 34

1. Amebic infections → Protozoa including Entamoeba histolytica, Trichomonas vaginalis, Giardia lamblia 2. Anaerobes → Bacteriodes spp. and Clostridium difficile 3. H. Pylori 4. Surgical prophylaxis

Question 35

Adverse effects of metronidazole

Answer 35

1. GI: nausea, vomiting, epigastric distress, abdominal cramps 2. Unpleasant, metallic taste 3. Oral candidiasis 4. CNS and PNS effects: convulsive seizures, optic and peripheral neuropathy (rare). Discontinuation of drug. Avoid alcohol

Question 36

Drug interactions with metronidazole

Answer 36

Potentiate the effects of warfarin

Question 37

Contraindications with metronidazole

Answer 37

First trimester pregnancy