TOPIC 2: ANTIFUNGAL AGENTS

Clinical Types of Fungal Agents

Superficial Infections
Cutaneous Infections
Subcutaneous Infections
Systemic Infections
Opportunistic Infections
- Dermatomycoses / Dermatophytoses
• Epidermophyton (skin and nails)
• Microsporum (skin and hair)
• Tricophyton (skin, hair, and nails)-
Dermatophytes
- refers to a group of fungal diseases in w/c both the
skin and subcutaneous tissues are involved/ mostly
caused by saprophytic fungi lives in soil
- have the ability to adapt to the internal
environment of the host; inhalation of fungal spores

Superficial Mycoses

Black Piedra/ Tinea nodosa CA: Piedrai hortae

White Piedra CA: Trichosporon asahii/ Trichosporon beigelii
Pityriasis/ Tinea versícolor CA: Malasezzia furfur
(ap-ap)
Tinea nigra - CA: Hortae werneckii

Locations on the Most Common Types of Ringworm

Tinea mannum Hands

Tinea cruris Groin
Tinea sycosis Beards
Tinea capitis Scalp
Tinea unguium Nails
Tinea corporis Trunk/body

SUBCUTANEOUS INFECTIONS
- refers to a group of fungal diseases in w/ both the skin and subcutaneous tissues are
involved/ mostly caused by saprophytic fungi lives in soil

Chromoblastomycoses - CM: Primary lesion are warty-like/ verrucous

appearance found along the draining lymphatics
Mycetoma - CA: Bacteria: Actinomycetes, Mycotic mycetoma
(Fungi)
- CM: Formation of draining sinuses with granules,
- Abscess formation
- Can spread to bones, muscles and nearby tissues
Sporotrichosis - CA: Sporothrix schenck
- CM: nodular lesions
Organic Medicinal Chemistry Kriszelle C. Mancera
 - Occupational disease of gardeners *
Phaeohyphomycoses - Caused by the dermataceous fungi
- CA:
• Exophiala jeanselmei,
• Phialaphora richardsiae
• Bipolaris spicifera
• Wangiella dermatitidis
• Exorhilum rostratum

Systemic Mycoses

Coccidioidomycoses - CM: Valley Fever/ Desert Rheumatis

Histoplasmosis - Most common respiratory infections
- CA: Histoplasma capsulatum
- CM: Spelunker's disease
South American - CA: Paracoccidioiodes brasiliensis
Blastomycoses
North American - CA: Blastomyces dermatitidis
Blastomycoses - More contagious

Opportunistic Fungal Infections

Candidiasis - Most common opportunistic mycoses in humans

- CA: Candida ablicans
Cryptococcosis - CA: Crytpococcus neoformans
- Dx: Staining technique employing the india ink
- CM: Meningitis
- Tx. Flucytosine + Amphotericin B
Pneumocystis jirovecii - Tx: Co-trimoxazole
Aspergillosis - CA: Aspergillus fumigatus (more common)
- Fungal balls visible in the lungs
- DOC: Voriconazole

Organic Medicinal Chemistry Kriszelle C. Mancera

 ANTI-FUNGAL AGENT
FATTY ACIDS

- all fatty acids and their salts have fungicidal properties

Propionic acid

- present in perspiration in low concentrations (around 0.01%)

Undecylenic Acid

- obtained from the destructive distillation of castor oil

NUCLEOSIDES

Flucytosine

- used only in combination with Amphotericin B for the treatment of systemic mycoses
and meningitis caused by Cryptococcus neoformans and Candida

ANTI FUNGAL ANTIBIOTICS

Polyenes
Amphotericin B (Fungizone®) - naturally occurring produced by Streptomyces
nodosus
- MOA: binds to ergosterol present in the cell
membrane disrupting membrane function,
allowing electrolytes to leak out from the cell
resulting in cell death
- Drug of Choice for systemic mycoses
Nystatin - Streptomyces noursei
- cereal like odor
- used for the treatment of candida * infections
- administered as an oral agent for the treatment
of oral candidiasis
- negligibly absorbed from the GIT tract so
adverse effects are rare
Natamycin - obtained from Streptomyces natalensis

ANTI-FUNGAL AGENT

Azoles - MOA: interacts with C-14 α-demethylase to block

Ketoconazole (Nizoral®)
Itraconazole (Sporanox®)
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demethylation of lanosterol t0 ergosterol, the
principal sterol of fungal membranes. This
inhibition disrupts membrane function & increases
permeability
- only administered orally for systemic infection
- inhibits CYP450 and adrenal steroid synthesis
- has endocrine effects: gynecosmastia,
decreased libido, impotence, menstrual
irregularities
- it lacks the endocrinologic effects of
ketoconazole
 Fluconazole (Diflucan)
Ketoconazole, Itraconazole,
Fluconazole
Clotrimazole, Miconazole,
Econazole
- administered orally and intravenously
- it has Excellent penetrability into the CSF
- Drug of Choice for cryptococcal meningitis
(Cryptococcus neoformans)
- for SC & Systemic mycoses
- for superficial mycoses

TOPOC 3: ANTI-PARASITIC AGENTS

Protozoal Infection

Disease Causative Agent

Amebiasis
Trichomoniasis
Giardiasis
Leishmaniasis
African Trypanosomiasis
Toxoplasmosis
Malaria

Organic Medicinal Chemistry Kriszelle C. Mancera

Metronidazole (Flagyl)

- Drugs of choice for infections:

• T – Trichomonas vaginalis
• A – Entamoeba histolytica
• G – Giargia intestinalis
• S- Spore formers (C. difficile)
- Unpleasant metallic taste is often experienced
- If taken with alcohol, a disulfiram-like effect occurs

Anti-Protozoal Drugs

Diloxanide - Asymptomatic E. histolytica carriers

8-hydroquinoline
Iodoquinol - DOC for asymptomatic amebiasis
Emetine and Dehydroemetine - Protoplasmic poison that (x) protein synthesizing
protozoal and mammalian cells by preventing
protein elongation
Pentamidine isethionate - Alternative treatment of PCP
- Alternative treatment of visceral leishmaniasis
(esp. when stibogluconate is unresponsive or
contraindicated)
- S/E: cough and bronchospasm(inhalation);
Hypertension and Hypoglycemia (injection)
- Prophylaxis and treatment of African
trypanosomiasis
Atovaquone - Original: P. falciparum (tolerated rapidly)
- Aletrnative: to TMP-SMX against PCP (treatment
and prophylaxis)
- Absorption is increased by fatty food
Eflornithine - West African Sleeping Sickness
- (Meningoencephalitic stage) (T. brucei var.
gambiense)
- Myelosuppressive ↑ incidence of anemia,
leukopenia and thrombocytopenia → CBC
counting monitor
Nifurtimox - T. cruzi (South American Sleeping Sickness) →
the only clinically proven regimen for both acute
and chronic forms of the disease
Benznidazole - Treatment of Chaga’s disease (Similat effect
with Nifurtimox)
Melarsoprol - Prepared by reduction of a corresponding
pentavalent arsanilate to the trivalent
arsenoxide followed by reaction of the latter
with BAL
- OLD DOC for txt of latter stages of African
trypanosomiasis
- Adv: excellent penetration into the CNS;
therefore, effective against
meningoencephalitis form
Organic Medicinal Chemistry Kriszelle C. Mancera
 Sodium stibogluconate - Pentavalent antimonial compound
- Schistosomiasis and other flukes
• Pentavalent → Trivalent
• Anti-Leishmaniasis (DOC),
Dimercaprol - 2,3-dimercapto-1-propanol
- Developed by the British during WWII; an
antidote to German Nazi’s Lewisite
- Antidote for As, Sb, Hg, Au and Pb toxicity
Suramin Sodium - Prophylaxis for Trypanosomiasis &
Onchocerciasis
- DOC for African Trypanosomiasis early stage
(but not Chaga's disease)
- not absorbed in the GIT & is given parenterally
- Early stage: Suramin alone; Late Stage (CNS
involvement) spoor penetration of suramin &
pentamidine, requires melarsoprol

ANTHELMINTIC AGENTS

Piperazine - MOA: blocks the response of the Ascaris muscle

to acetylcholine, causing flaccid paralysis
- Paralyses ascaris by acting as an agonist at
GABA receptors
Diethylcarbamazine Citrate - Immobilizes microfilariae by an unknown
mechanism, increasing their susceptibility to host
defense mechanisms
- DOC for Filariasis / Elephantiasis
• Causative agent:?
Pyrantel Pamoate - stimulates nicotinic receptors present at
neuromuscular junctions of nematodes →
contraction of a muscle occurs, followed by a
depolarization-induced paralysis
- The drug has no actions on flukes or ringworms
Mebendazole - Mebendazole irreversibly blocks glucose uptake
in susceptible helminths, thereby depleting
glycogen stored in the parasite
- KATZUNG: acts by selectively inhibiting
microtubule synthesis & glucose uptake in
nematodes
Thiabendazole - structural congener of mebendazole and has a
similar action on microtubules
- DOG for Threadworm infection
Albendazole - Arrest cell division in metaphase by interfering w/
microtubule assembly. They exhibit a high
affinity for tubular, the precursor protein of
microtubule synthesis
Niclosamide - MOA: uncoupling oxidative phosphorylation or
by activating ATPases
Bithionol - MOA: Unknown

Organic Medicinal Chemistry Kriszelle C. Mancera

 - co-Drug of Choice (Triclabendazole) for
treatment of fascioliasis (Sheep liver fluke)
Praziquantel - increases cell membrane permeability of
susceptible worms, resulting in loss of
extracellular Cal+ ions causing massive
contraction & ultimate paralysis
Ivermectin - Isolated from S. avermitilis
- Intensifies GABA mediated
neurotransmission in nematodes & causes
immobilization of parasites, facilitating their
removal by the reticuloendothelial system
- DOC for River blindness / Onchocerciasis

TOPIC 4: ANTIMALARIAL DRUG

MALARIAL SPECIES
- Plasmodium falciparum
- Plasmodium vivax
- Plasmodium ovale
- Plasmodium malaria
- Plasmodium knowlesi

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CHEMISTRY
- have one common structural feature-a-quinoline ring or a "quinoline with an
additional benzene added" (an acridine ring)

CINCHONA ALKALOIDS

QUININE

- reserved for malarial strains resistant to other agents

- Major adverse effect: Cinchonism
• Nausea, vomiting, tinnitus, vertigo
- General Protoplasm
- Quinoclidine ring
- Adverse Effect:
• Cinchonism
▪ Tinnitus, Visual disturbances, Flushing, Dizziness, Headache, Nausea
- Hypoglycaemia - insulin release & glucose consumption of parasite
- QT prolongation (IV Quinidine)
- Blackwater Fever

7-CHLORO-4-AMINOQUINOLINES

Chloroquine

- DOC in txt of erythrocytic malaria

- Anti-inflammatory action explains its occasional use in RA and SLE
- Prophylaxis (in areas with no resistance)

Amodiaquine

- highly suppressive in P. vivax & falciparum

- has curative activity against P. falciparum
- S/E: prolonged use pigmentation of the palate, nail & skin, agranulocytosis

8-AMINOQUINOLONES

Primaquine

- The only drug effective against exocrythrocytic stages of malaria

- only agent that can lead to “radical cures? of the P. vivid & ovale
- Gametocidal for all 4 plasmodia species

9-AMINOACRIDINES

Quinacrine - primarily used in txt of Giardiasis, but also

effective against tapeworm and malaria, and
topically against leishmaniasis ® should not be
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 given w/ primaquine because of increased
toxicity

Mefloquine - effective single agent for suppressing and

cutting multi-drug resistant forms of P. falciparum

Artemisinin, Artesunate, - Artemisinin (Quinghaosu) (PO)

Artemether - Artesunate (PO, IV, IM, Rectal)
- Artemether (PO, IM, Rectal)
• Very rapidly acting blood schizonticides
against all malaria parasites
• Rapidly metabolised to the active
metabolite Dihydroartemisinin
• A/E: N & V, Diarrhea
- Clinical Uses:
• treatment of multidrug-resistant P.
falciparum malaria
- only drugs reliably effective against Quinine-
resistant strains

Artesunate - treatment of severe malaria

- treatment of uncomplicated & severe
falciparum malaria
- treatment of highly resistant falciparum malaria
in Thailand (with Mefloquine)

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