Antifungals, antivirals, antiprotozoals,

and anthelmintics

Joseph K. Ritter, PhD Asst. Prof

Department of Pharmacology and
Toxicology
MSB Room 530
jritter@hsc.vcu.edu
Difficulties associated with treatment
of fungal infections
Infections increasingly common
High similarity to animal cells (resistant to
antibacterial agents)
Presence of cell wall
Slow growth rate
Infections often occur in poorly vascularized
tissues
 Classes of fungal infections
Systemic infections (meningitis,
pneumonia)
Aspergillus
Candida albicans
Cryptococcus neoformans
Blastomyces dermatitidis
Histoplasma capsulatum
Coccidioises immitis
Superficial infections
Candida albicans

Deeper superficial (dermatophytic)

infections
Epidermophyton
Microsporum
Trichopyton
Overview of classes of antifungal
drugs
Polyenes
Amphotericin B
Nystatin
Imidazoles/triazoles
Ketoconazole, Fluconazole,
Itraconazole
Miconazole, Clotrimazole
Nucleosides
Flucytosine
Griseofulvin
 Amphotericin B (Fungizone)

H OH OH
H3 C O
OH OH OH OH OH H
O
HO CH3 O COOH
NH2
OH O
H3 C
O
H
O CH3
Amphotericin B

polyene = conjugated double bonds

 Mechanism of polyene antifungals
P-lipid Membrane
Sterol Pore Amph B
H O NH2 H2N O H
O C OH HO C O
HO OH

OH HO

OH HO

OH HO

OH HO

OH HO

OH HO

HO OH
O C OH HO C O
H O NH
2 H2N O H
Effect of sterol on the ability of a particulate fraction
from Neurospora to bind nystatin

Particle treatment Reconstitution Nystatin bound

(ug/0.4 ml
particulate)

None None 13.3

Extracted None 0

Extracted Extract 10.1

Extracted Ergosterol 6.8

 Characteristics of amphotericin B

Spectrum: Broadest of all antifungals

Kinetics:
o High molecular weight, very insoluble in water, IV

formulations only
o Crosses membranes poorly

o Inject where needed

o Eliminated unchanged in urine

Toxicity: Extremely nephrotoxic

Uses: Serious systemic infections
 Imidazole/azole antifungal

Ketoconazole
Fluconazole
Itraconazole
Miconazole
Clotrimazole
Antifungal mechanism of imidazoles and triazoles
Acetate
CYP51
14 alpha-
sterol
demethylase
14alpha
Squalene methyl Ergosterol
sterol
(lanosterol)

OH OH OH

Ergosterol required for close

packing
of P-lipid fatty acid chains

OH OH OH OH
 Ketoconazole (Nizoral)

N
Cl
O CH2
Cl
O
H3 C C N N O C O
H2
 Ketoconazole (Nizoral)
Spectrum: Broad, includes Candida
Kinetics:
o Crosses membranes, oral absorption good but variable
o Good tissue penetration except CNS
o Elimination by CYP3A4 metabolism in liver
o Dose-dependent half life (6-12 hrs depending on dose)
Toxicities/drug interactions
o Common
o Gastrointestinal upset
o Gynecomastia
o Menstrual irregularities
o Drug interactions!!!!
o Rare
o Hepatotoxicity
Uses-systemic antifungal for oral and vaginal
candidiasis, adrenal hypercorticism
Ketoconazole inhibits P450s involved in human
steroidogenesis
Acetate
CYP51
Lanosterol 14
alpha-
14alphademethylase
Squalene methyl Cholesterol
sterol P450
SCC
Androgens P450 17,20-lyase
Androstene DHEA Pregnenolone
dione
Estrogens
Progesterone
Corticosterone, cortisol, aldosterone
 Itraconazole (Sporanox)
Mechanism: same as ketoconazole, higher
potency
Kinetics
Variable absorption, increased by meals
Wide distribution-high and prolonged tissue levels
Hepatic metabolism
Serum half life 17-25 hr
Side effects
Few
Uses: Systemic antifungal for oral candiasis
 Fluconazole (Diflucan)

Spectrum: Broad
Mechanism: same as ketoconazole but more
potent
Kinetics
Oral absorption (less affected by acid)
Distributes (high concentrations in CNS)
Elimination (90% by kidney)
Side effects (less P450 inhibition)
Uses: Systemic agent for Cryptococcal meningitis,
systemic and mucocutaneous Candida, prophylaxis in IC)
 Flucytosine
( 5-fluorocytosine)

5-FdUTP
NH2 OH
F N F Blocks DNA
N
synthesis
O N Cytosine O N
H deaminase H
5-FUTP
5-fluorocytosine 5-fluorouracil
5-FU
Extremely toxic Blocks RNA
Anticancer drug synthesis
 Flucytosine

Mechanism: blocks nucleic acid synthesis

Kinetics: >95% oral availability, distribution
into CSF, renal elimination (unchanged,
glomerular filt)
Toxicity: bone marrow suppression
Uses: serious systemic infections
(meningitis, etc.), combined with
amphotericin B
Drugs used exclusively for treating
superficial fungal infections
Nystatin (Nilstat)
Spectrum: Extremely Broad
Mechanism: see amphotericin B
Uses:
topical only
mucocutaneous Candida infections (oral,
vaginal, skin, GI)
Drugs used exclusively for treating
superficial fungal infections
Clotrimazole
Imidazole too toxic for systemic use
Mechanism: same as ketoconazole
Uses:
topical only
mucocutaneous Candida infections (oral,
vaginal, skin, GI
Precautions: best to avoid in alcoholics,
individuals with liver disease
 Drugs used exclusively for treating
dermatophytic fungal infections
Griseofulvin (Fulvicin)
Spectrum: Dermatophytes

Mechanism: interferes with fungal mitosis, static effect

Kinetics:
PO for topical infections
Concentrates in skin, hair, nails
Eliminated by liver metabolism

Uses: Infections of hair, nails, scalp

Problems with treating viral infections

Simple structure
Dependence on host cell enzymes for
replication
 Typical virus infection cycle

Synthesis of non-structural proteins

RNA/DNA Synthesis

Synthesis and processing of structural proteins

Assembly of virions
& release
 O
N
N

Acyclovir (Zovirax) H2 N N
H
N
H2
C O
HSV thymidine kinase HO C C
H2
(infected cells) H2

Acycloguanosine-P
Host enzyme

Acycloguanosine-P-P-P
Host enzyme

Inhibition of viral DNA synthesis

 Acyclovir (Zovirax)

Mechanism: Incorporates into DNA during

DNA synthesis and terminates synthesis
Kinetics
: PO use
Short T1/2
Renal excretion unchanged
Resistance: common
Toxicity:
Few side effects
Can be nephrotoxic at high doses

Use: Symptomatic relief of oral and genital

HSV infection
 Other agents related to acyclovir
available for treatment of HSV
Valacyclovir
better oral availability

Famciclovir
even better oral availability
much longer intracellular half life than either
acyclovir or valacyclovir
 Ganciclovir
More toxic cousin of other cyclovirs
Undergoes phosphorylation by CMV kinases to
form triphosphate which inhibits CMV DNA
polymerase
Used primarily for cytomegalovirus (CMV)
infections
Usually IV infusion (5-9% oral availability) for 2
weeks, urinary excretion
Resistance common during therapy
Toxicity: Anemia, leukopenia
 O
O
Foscarnet HO P C
OH
OH

Alternative for acyclovir-resistant herpes and

ganciclovir-resistant CMV
Inhibits herpes virus and CMV DNA synthesis
directly (no phosphorylation required)
Nephrotoxicity, Ca and PO4 imbalance
Topicals for herpes simplex eye
infections

Idoxuridine
cytarabine
trifluorothymidine
 Vidarabine

Alternative to acyclovir, foscarnet for resistant

HSV
Guanosine analogue, phosphorylated by
cellular kinases to inhibit DNA synthesis
Topical for herpes keratitis, intravenous for
severe systemic infections
Low toxicity
 Ribavirin
Guanosine analogue, interferes with
guanine monophosphate formation
(DNA synthesis)
Primary clinical use is for treatment of
respiratory syncytial virus infections in
neonates
Major toxicity: bone marrow
suppression
 Antiretroviral agents

Nucleoside analogue
Protease inhibitors
 AZT (Azidothymidine, zidovudine)

Anti-HIV drug, acts by inhibiting reverse

transcriptase
Good oral absorption, elimination by liver
metabolism
Resistance common when used as
monotherapy
Use associated with granulocytopenia,
anemia
 Didanosine
Dideoxyinosine
Dideoxycytidine
Mechanism: inhibits reverse
transcriptase
Resistance common (but no cross
resistance to each other)
Pancreatitis and polyneuropathy
 Protease inhibitors
HIV polypeptide

Protease required for cleavage of precursor

protein to release reverse transcriptase,
structural proteins, integrase, and the
protease itself
Ritonavir, saquinavir, indinavir
Resistance develops over long term
 Amantadine, rimantidine

Inhibit replication of flu virus

Mechanism is through inhibition of viral
uncoating following entry into cell
Neurotoxicity (hallucinations, seizures)
 Interferons
Recombinant (nonglycosylated)
versions of natural cytokines
Three forms
Mechanisms: inhibition of transcription,
translation, protein processing, and
virus maturation
Uses: genital warts, viral hepatitis (B
and C), cancers, multiple sclerosis
Limitation: toxicity