Antifungal drugs -
antimycotics
(basic principles, main categories and
adverse events)
Antifungal drugs -
antimycotics
(basic principles, main categories and
adverse events)
Regina Demlova, MD, Ph.D.
Fungal Infection in Humans =
Mycosis
Fungal Infection in Humans =
Mycosis
• Major Types of Mycoses
– Superficial
– Systemic
– Opportunistic
• Symptoms vary from cosmetic to life threatening
Superficial mycosesSuperficial mycoses
Dermatophytosis (tinea)
trychophyton
epidermophytom
microsporum
Superficial candidiasis
Tinea pedisTinea pedis
Systemic mycosesSystemic mycoses
Pulmonary aspergillosis
Cryptococcal meningitis and endocarditis
Cerebral mukomycosis
Systemic candidiasis
Pulmonary aspergillosisPulmonary aspergillosis
Main categoriesMain categories
A. Polyene antimycotics
B. Azole-based antimycotics
C. Allylamines
D. Others (pyrimidines, griseofulvin)
Physiology – fungal cellPhysiology – fungal cell
A. polyenes : mechanism of
action
A. polyenes : mechanism of
action
the interaction of the antifungal with membrane sterol
results in the production of aqueous pores
this configuration gives rise to a pore
leading to altered permeability, leakage of vital
cytoplasmic components, and death of the organism
PolyenesPolyenes
PolyenesPolyenes
PolyenesPolyenes
Systemic (i.v. administration)
amphotericin B
Local (topical)
nystatin (MACMIROR)
natamycin (PIMAFUCORT)
Amphotericine BAmphotericine B
relatively poor penetration into tissues and fluids
penetration into the brain virtually zero
absorption from GI systém zero (i.v.!)
binding to protein 90-95% (+ erythrocytes +
cholesterol)
serum half-life of 18-24 hours, elimination half-life of
15 days
excreted unchanged in bile
Amphotericine BAmphotericine B
Aspergillosis (drug of 1st choice)
Serious systemic mycoses with organ involvement
(meningitis, endocarditis, pneumonia)
Coccidiomycosis, histoplasmosis, blastomycosis
Amphotericine BAmphotericine B
1. Acute symptoms:
fever, chills, rigor, nausea, vomiting, headache,
muscles, joints - production of PGE2, TNF and IL-1
1. Chronic symptoms:
nephrotoxicity !! (up to 80% of patients) - failure of
membrane cholesterol + vasoconstriction
normocytic normochromic anemia
thrombophlebitis
Amphotericine B - nephrotoxicityAmphotericine B - nephrotoxicity
Synergic effects with flucytosin - ↓ dose of amphotecine
B - ↓ nephrotoxicity
Liposomal forms : ABELCET i.v.
B. azole–based antimycotics:
mechanism of action
B. azole–based antimycotics:
mechanism of action
Inhibition of ergosterol synthesis
Inhibitors of cytochrome P-450-dependent 14a-sterol
demethylase
azole–based antimycoticsazole–based antimycotics
Azole-based antimycotic agentsAzole-based antimycotic agents
Systemic – p.o. or topical
ketoconazol (NIZORAL)
flukonazol (DIFLUCAN, MYCOMAX)
Azole-based antimycotic agentsAzole-based antimycotic agents
Systemic – i.v. (immunocompromised patients ) –
broader spectrum
itraconazol (SPORANOX)
voriconazol (VFEND)
posaconazol (NOXAFIL)
Azole-based antimycotic agentsAzole-based antimycotic agents
Local (topical)
clotrimazon (CANESTEN) – topical treatment
mikonazol (LORAMYC) – local orophacial candidosis
3. Allyamines : mechanism of
action
3. Allyamines : mechanism of
action
Allylamines act by inhibiting early steps of ergosterol
biosynthesis
allylamine inhibition of sterol synthesis occurs at the
point of squalene epoxidation, a reaction catalyzed
by squalene epoxidase
AllyaminesAllyamines
3. Allyamines3. Allyamines
Terbinafin (LAMISIL – topical or oral)
Indication : dermatophytes
4. Others – 5-flucytosin (5-FC)4. Others – 5-flucytosin (5-FC)
5-FC enters fungal cells aided by a permease
enzyme. Once inside, it is converted to 5-fluorouracil
(5FU) - RNA, DNA synthesis
Indication : Candida and Cryptococcus neoformans
Synergic effects with amphotericin B
4. Others – griseofulvin4. Others – griseofulvin
Obsolent, not used in daily practice
Development of antifungalsDevelopment of antifungals
mod. nach R. Lewis, ICAAC 2002
Amphotericin B
Abelcet Amphotec
liposomales
Nystatin
Ketoconazol
Fluconazol
Voriconazol
PosaconazolRavuconazol
AmBisome
5-Flucytosin
Itraconazol
Micafungin
Caspofungin
Nystatin
PyrimidinanalogaPolyene Azole Echinocandine
Anidulafungin
Amphotericin B
Abelcet Amphotec
liposomales
Nystatin
Ketoconazol
Fluconazol
PosaconazolRavuconazol
AmBisome
5-Flucytosin
Micafungin
Nystatin
PyrimidinanalogaPolyenes Azoles Echinocandins
Anidulafungin
Antiviral drugsAntiviral drugs
Understanding Viruses intracellular
parasites
Understanding Viruses intracellular
parasites
Viral replication
• Small inefective agents (20-30 nm)
• Incapable of reproduction outside their host cells
• It must attach to and enter a host cell
• It then uses the host cell’s energy to synthesize protein,
DNA, and RNA
Key characteristics of antiviral
drugs
Key characteristics of antiviral
drugs
Some drugs interfere with ability of virus to bind to cells
Able to enter the cells infected with virus
Interfere with viral nucleic acid synthesis and/or regulation
Some drugs stimulate the body’s immune system
Best responses to antiviral drugs are in patients with competent
immune systems
A healthy immune system works synergistically with the drug to
eliminate or suppress viral activity
Viruses controlled by current
antiviral therapy
Viruses controlled by current
antiviral therapy
• Influenza viruses (the “flu”)
• Cytomegalovirus (CMV)
• Hepatitis viruses
• Herpes viruses
• Human immunodeficiency virus (HIV)
• Influenza viruses (the “flu”)
• Respiratory syncytial virus (RSV)
Viral InfectionsViral Infections
Competent immune system:
Best response to viral infections
A well-functioning immune system will eliminate or effectively
destroy virus replication
Immunocompromised patients have frequent viral infections
Cancer patients, especially leukemia or lymphoma
Transplant patients, due to pharmacologic therapy
AIDS patients, disease attacks immune system
Viral InfectionsViral Infections
Opportunistic infections
Occur in immunocompromised patients
Infections that would not normally harm an immunocompetent
person
Require long-term prophylaxis and anti-infective drug therapy
Can be other viruses, fungi, bacteria, or protozoa
Type of antivirotics therapyType of antivirotics therapy
1. Antiviral drugs
– Used to treat infections caused by viruses
other than HIV
2. Antiretroviral drugs
– Used to treat infections caused by HIV, the
virus that causes AIDS
Type of antivirotics therapyType of antivirotics therapy
1. Antiviral drugs
A. herpetic infection
B. Influenza
C. Cytomegaloviruses
Antivirals used for treatment of
a. herpetic infection
Antivirals used for treatment of
a. herpetic infection
Aciclovir /ZOVIRAX/ – DNA polymerase inhibitor
active in triphosphate form, acts as false substrate for
specific viral DNA polymerase of the virus.
Administration: local, orally (20%) or i.v.
Indications: skin and systemic infections caused by
herpes simplex, zoster.
Antivirals used for treatment of
herpetic infection
Antivirals used for treatment of
herpetic infection
Valaciclovir – prodrug, converted to aciclovir
Pencyclovir – prodrug famciclovir
Vidarabin (adenin arabinosid) : competitive inhibition
od DNA-polymerase
ADRs: neurotoxicity
Herpes zoster-systemic
Herpes simplex-locally (cornea)
Antivirals used for treatment of
b. influenza
Antivirals used for treatment of
b. influenza
Amantadine: also for the treatment of Parkinson
disease
It inhibits the replication of influenza type A nucleic acid,
used as systemic prophylaxy
Zanamivir: against influenza virus types A and B
it inhibits the viral neuraminidase
Local inhalation, intranasal application.
Antivirals used for treatment of
c. cytomegaloviruses
Antivirals used for treatment of
c. cytomegaloviruses
Ganciclovir: in the triphosate-form inhibits viral DNA
systhesis.
Selectivity is not only to viruses, damage.
hematopoiesis, fertility
Cidofovir: a derivative of cytidine
Foscarnet: inhibition of viral DNA polymerase and
influence of reverse transcriptase.
Indication: viruses resistent to aciclovir
InterferonesInterferones
antiviral, immunomodulatory and antiproliferative effects
Interferon-α: produced by human lymphocytes
I: inf. hepatitis B, C
IFN-β: formed by fibroblasts.
I: Hepatitis B, C
Interferon-γ: in lymphocytes after stimulation with
mitogens.
Type of antivirotics therapyType of antivirotics therapy
2. Antiretroviral drugs
– Used to treat infections caused by HIV, the
virus that causes AIDS
HIVHIV
Human immunodeficiency virus infection
ELISA (enzyme-linked immunosorbent assay)
Detects HIV exposure based on presence of human antibodies to the virus in the
blood
RNA retrovirus, that contains ensyme reverse transkriptase - RT
Transmitted by:
Sexual activity, intravenous drug use, perinatally from mother to child
Five Stages of HIV Infection
Stage 1: asymptomatic infection
Stage 2: early, general symptoms of disease
Stage 3: moderate symptoms
Stage 4: severe symptoms, often leading to death
WHO model stages
1.HIV kills infected lymfocyte, because after
replication it is released by budding and lysis
of the host cell
2.Infected and noninfected cell unify and
form nets and syncytia of non functionnal
lymfocytes
3 Immunocompetent cells do not recognise
infected cells, which are foreign for them
and they kill them
Depression of T cell quantity
Antiretroviral DrugsAntiretroviral Drugs
HAART - Highly active antiretroviral
therapy
• Includes at least three medications
– “cocktails”
• These medications work in different ways
to reduce the viral load
Antiretroviral DrugsAntiretroviral Drugs
• Reverse transcriptase inhibitors (RTIs)
– Block activity of the enzyme reverse transcriptase, preventing
production of new viral DNA
• Examples
abacavir (Ziagen) delavirdine (Rescriptor)
didanosine (Videx) lamivudine (Epivir)
stavudine (Zerit) tenofovir (Viread)
Antiretroviral DrugsAntiretroviral Drugs
• Protease inhibitors (PIs)
– Inhibit the protease retroviral enzyme, preventing viral
replication
– Examples:
amprenavir (Agenerase)
indinavir (Crixivan)
nelfinavir (Viracept)
ritonavir (Norvir)
saquinavir (Invirase)
Antiretroviral DrugsAntiretroviral Drugs
• Fusion inhibitors
– Inhibit viral fusion, preventing viral replication
– Newest class of antiretroviral drugs
– Example: enfuvirtide (Fuzeon)
Antiretroviral Drugs:
Adverse Effects
Antiretroviral Drugs:
Adverse Effects
• Numerous and vary with each drug
• Drug therapy may need to be modified because of
• adverse effects
• Goal is to find the regimen that will best control
the infection with a tolerable adverse effect
profile
• Medication regimens change during the
course of the illness