Unit-II/Lecture-VI

Anti-fungal Drugs

By: Muhammad Aurangzeb

BSN, MSPH, MSN
Lecturer-INS/KMU
 Objectives

At the completion of this unit the students will be able to;

• Define the most commonly used categories of anti-fungal drugs
that are used to prevent and treat fungal infections.
• Briefly discuss action and effects of selected drug category

• List some of the most commonly used drugs for each drug
category
• Discuss the nursing measures/patient education which can be
taken if patient is using to treat and prevent infections.
 Fungal Infections

• Infectious diseases caused by fungi are called mycoses, and

they are often chronic in nature.
• Fungal infectious occur due to :

1- Abuse of broad spectrum antibiotics

2- Decrease in the patient immunity
 Fungal Cell

• They have rigid cell walls composed largely of a polymer of N-

acetylglucosamine rather than peptidoglycan (a characteristic
component of most bacterial cell walls).
• The fungal cell membrane contains ergosterol rather than the
cholesterol found in mammalian membranes.
• These chemical characteristics are useful in targeting
chemotherapeutic agents against fungal infections
 Cont…

• Human fungal infections have increased dramatically , owing

mainly to advances in surgery, cancer treatment, and critical
care accompanied by increases in use of broad-spectrum
antimicrobials and the HIV epidemic.
 Types of fungal infections

I. Mucocutaneous (superficial)
infections:
A. Dermatophytes:
• Cause infection of skin, hair,
and nails e.g. tinea capitis
(scalp), tinea cruris (groin),
tinea pedis (foot),
onychomycosis (nails).
 Types of Fungal Infections

B. Yeasts:
• Cause infections of moist skin
and mucous membranes e.g.
Candida albicans causing oral,
pharyngeal, vaginal, &
bladder infections

7
 Types of fungal infections

II. Systemic mycoses: are

fungal infections affecting
internal organs. It occurs in
immunocompromized
patients e.g. cryptococcosis,
and aspergillosis (lung).
 Polyenes (Disrupt membrane structure &
function)

Azoles inhibit

Flucytosine inhibits DNA synthesis

Caspofungin inhibits
cell wall synthesis
Sites of Actions of Antifungal Drugs
 Classification of Antifungal Agents
Antifungals

Caspofungin

ERGOSTEROL SYNTHESIS
INHIBITORS

Voriconazole
Itraconazole
Posaconazol
e
Fluconazole
 Classification of Antifungal Drugs
• Classification of Antifungal Drugs based on mechanism of
action
1. Fungal cell wall synthesis inhibition: Caspofungin.
2. Bind to fungal cell membrane ergosterol: Amphotericin-B,
Nystatin.
3. Inhibition of ergosterol synthesis: Azoles
4. Inhibition of lanosterol synthesis: Terbinafine
5. Disruption of mitotic spindle and inhibition of fungal
mitosis: Griseofulvin.
6. Nucleic Acid synthesis inhibitors: Flucytosine
 Amphotericin B

• Amphotericin B is a naturally occurring polyene antifungal

produced by Streptomyces nodosus. In spite of its toxic
potential, amphotericin B remains the drug of choice for the
treatment of several life-threatening mycoses.
• It is a macromolecule and consists of both lipophilic and
hydrophilic groups i.e., it is amphiphilic in nature
• The amphiphilicity of the drug is responsible for its unique
mechanism of action
 Pharmacokinetics

• Poorly absorbed orally, is effective for fungal infection of

gastrointestinal tract.
• For systemic infections given as slow I.V. Infusion.
• Highly bound to plasma protein .
• Poorly crossing BBB.
• Metabolized in liver
• Excreted slowly in urine over a period of several days.
• Half-life 16 days.
 Cont…

• Inflammation favors penetration into various body fluids, but

little of the drug is found in the CSF, vitreous humor, or
amniotic fluid. However, amphotericin B does cross the
placenta.
• Accumulates in renal cells causing nephrotoxicity leading to
Azotemia characterized by decreased GFR, Urinary output,
Creatinine clearance and increased Serum creatinine and
BUN
 Mechanism of Action
AMPHOTERICIN B

HYDROPHILIC PART LIPOPHILIC PART

Forms pores in the cell membrane Binds with ergosterol and bilipid
layer

Cell contents such as Na+ and K+ leak trough the

spores from the cytoplasm

FUNGICIDAL ACTION
 Mechanism of Action

• It is a selective fungicidal drug.

• Disrupt fungal cell membrane by binding to ergosterol , so
alters the permeability of the cell membrane leading to
leakage of intracellular ions & macromolecules (cell death ).
 Adverse Effects

1- Immediate reactions (Infusion –related toxicity).

• Fever, muscle spasm, vomiting, headache, hypotension. Can
be avoided by:
– Slowing the infusion
– Decreasing the daily dose
– Premedication with antipyretics, antihistamines or
corticosteroids.
– A test dose.
 Adverse Effects

2- Slower toxicity
• Most serious is renal toxicity (nearly in all patients ).
• Hypokalemia
• Hypomagnesaemia
• Impaired liver functions
• Thrombocytopenia
• Anemia
 Clinical uses

• Has a broad spectrum of activity & fungicidal action.

• The drug of choice for life-threatening mycotic infections.
• Also, for chronic therapy & preventive therapy of relapse.
• Intestinal candidiasis
• Topical candidiasis
• Febrile neutropenia
• Leishmaniasis – kala Azar
Liposomal preparations of Amphotericin B

• Amphotericin B is packaged in a lipid- associated delivery

system to reduce binding to human cell membrane , so
reducing:
• Nephrotoxicity
• Infusion toxicity
• Also, more effective
• More expensive
 Nystatin

• It is a polyene macrolide, similar in structure & mechanism to

amphotericin B.
• Too toxic for systemic use.
• Used only topically.
• It is available as creams, ointment, suppositories & other
preparations.
• Not significantly absorbed from skin, mucous membrane, GIT
 Clinical uses

• Prevent or treat superficial candidiasis of mouth, esophagus,

intestinal tract.
• Vaginal candidiasis
• Can be used in combination with antibacterial agents &
corticosteroids.
 Ergosterol Synthesis Inhibitors (Azoles)

• A group of synthetic fungistatic or fungicidal agents with a

broad spectrum of activity .
• Azoles are made up of two different classes of drugs

– Imidazole

– Triazoles

• Although these drugs have similar mechanisms of

action and spectra of activity, their pharmacokinetics and
therapeutic uses vary significantly.
 Azoles

Imidazoles Triazoles

Topical Systemic
Voriconazole
Clotrimazole Ketoconazole Itraconazole
Oxiconazole
Posaconazole
Moconazole
Fluconazole
Econazole
Butoconazole
 Azole Mechanism of Action

• Inhibit the fungal cytochrome P450 enzyme, (α-

demethylase) which is responsible for converting
lanosterol to ergosterol
Lanosterol

Lanosterol 14 demethylase
(CYP 450 enzyme)

Azoles

Ergosterol
 Imidazoles

• Imidazoles includes:
– Ketoconazole
– Miconazole
– Clotrimazole
• They lack selectivity, they inhibit human gonadal and steroid
synthesis leading to decrease testosterone & cortisol
production.
• Also, inhibit human P-450 hepatic enzyme.
 Ketoconazole

• Well absorbed orally

• Bioavailability is decreased with antacids, H2 blockers, proton
pump inhibitors & food .
• Cola drinks improve absorption in patients with achlorhydria.
• Half-life increases with the dose, it is (7-8 hrs).
• Inactivated in liver & excreted in bile (feces ) & urine.
• Does not cross BBB
 Ketoconazole Clinical Uses

• Used topically or systematic (oral route only ) to treat :

1. Oral & vaginal candidiasis

2. Dermatophytosis.

3. Systemic mycoses.
 Ketoconazole Adverse Effects

• Nausea, vomiting, anorexia

• Hepatotoxic
• Inhibits human P 450 enzymes
• Inhibits adrenal & gonadal steroids leading to:
– Menstrual irregularities
– Loss of libido
– Impotence
– Gynaecomastia in males
 Triazoles
• Triazoles includes:
– Fluconazole
– Itraconazole
– Voriconazole
• They are :
– Selective
– Resistant to degradation
– Causing less endocrine disturbance
 Itraconazole

• Lacks endocrine side effects

• Has a broad spectrum activity
• Given orally & IV
• Food increases its absorption
• Metabolized in liver to active metabolite
• Highly lipid soluble, well distributed to bone, sputum, adipose
tissues.
• Can not cross BBB
 Itraconazole (cont.)

• Half-life 30-40 hours

Clinical uses:
• Used orally in dermatophytosis & vulvo-vaginal candidiasis.
• IV only in serious infections.
• Effective in AIDS-associated histoplasmosis

Side effects:
• Nausea, vomiting, hypokalemia, hypertension, edema,
inhibits the metabolism of many drugs as oral anticoagulants
 Fluconazole

• Water soluble
• Completely absorbed from GIT
• Excellent bioavailability after oral administration
• Bioavailability is not affected by food or gastric PH
• Concentrated in plasma is same by oral or IV route
• Has the least effect on hepatic enzymes
 Fluconazole (cont.)

• Drug interactions are less common

• Penetrates well BBB so, it is the drug of choice of cryptococcal
meningitis
• Safely given in patients receiving bone marrow transplants
(reducing fungal infections)
• Excreted mainly through kidney
• Half-life 25-30 hours
• Resistance is not a problem
 Clinical uses

• Candidiasis (is effective in all forms of cutaneous candidiasis)

• Cryptococcus meningitis
• Histoplasmosis, blastomycosis, ring worm
 Side effects

• Nausea, vomiting, headache, skin rash, diarrhea,

abdominal pain, reversible alopecia.
• Hepatic failure may lead to death
• Highly Teratogenic ( as other azoles)
• Inhibit cytochrome P450
• No endocrine side effects
 Inhibition of Lanosterol Synthesis:
Terbinafine
• Mechanism of action:
• It inhibits squalene epoxidase thus blocking the biosynthesis
of ergosterol, an essential component of fungal cell
membranes.
• This inhibition also results in an accumulation of squalene,
result in the death of the fungal cell.
 Terbinafine

• Fungicidal ,its activity is limited to candida albicans &

dermatophytes.
• Effective for treatment of onychomycoses
• 6 weeks for finger nail infection & 12 weeks for toe nail
infections .
• Well absorbed orally , bioavailability decreases due to first
pass metabolism in liver.
 Therapeutic uses

• It is fungicidal and drug of choice for treating dermatophytoses

and, especially, onychomycoses (fungal infections of nails).
• It is better tolerated, requires shorter duration of therapy, and
is more effective than either itraconazole or griseofulvin
 Adverse effects

• The drug is well tolerated, with a low incidence of

gastrointestinal distress headache, or rash

• Contraindicated in pregnancy
 Nucleic Acid synthesis inhibitors
Flucytosine
• Flucytosine (5-FC) is a synthetic pyrimidine analog that is
often used in combination with amphotericin B.
• This combination of drugs is administered for the treatment
of systemic mycoses and for meningitis caused by
Cryptococcus neoformans and Candida albicans.
 Mechanism of Action

• Converted within the fungal cell to 5- fluorouracil (Not in

human cell), that inhibits thymidylate synthetase enzyme
that inhibits DNA synthesis.
• (Amphotericin B increases cell permeability , allowing more
5-FC to penetrate the cell, they are synergistic).
 Pharmacokinetics

• Rapidly & well absorbed orally

• Widely distributed including CSF.

• Mainly excreted unchanged through kidney

• Half-life 3-6 hours

 Clinical Uses

• Severe deep fungal infections as in meningitis

• Generally given with amphotericin B

• For cryptococcal meningitis in AIDS patients

 Adverse Effects

• Nausea, vomiting, diarrhea, severe enterocolitis

• Reversible neutropenia, thrombocytopenia, bone marrow
depression
• Alopecia
• Elevation in hepatic enzymes
 Fungal Cell Wall Synthesis Inhibitors
Caspofungin
• Inhibits the synthesis of fungal cell wall, leading to lysis & cell
death.
• Given by IV route only
• Highly bound to plasma proteins
• Half-life 9-11 hours
• Slowly metabolized by hydrolysis
• Elimination is nearly equal between the urinary & fecal
routes.
 Caspofungin Mechanism of Action

• Inhibit synthesis of glucan in the cell wall via noncompetitive

inhibition of enzyme 1,3-β glucan synthase

• Beta glucans are carbohydrate polymers that are cross-linked

with other fungal cell wall components .

 Clinical Uses

• Effective in aspergillus & candida infections.

• Second line for those who have failed or cannot tolerate
amphotericin B or itraconazole.
Adverse effects:
• Nausea, vomiting
• Flushing (release of histamine from mast cells)
 Anti- Mitotic (Griseofulvin)
• Fungistatic, has a narrow spectrum
• Given orally (Absorption increases with fatty meal)
• Half-life 26 hours
• Taken selectively by newly formed skin & concentrated in the
keratin.
• Should be given for 2-6weeks for skin & hair infections to
allow replacement of infected keratin by the resistant
structure
 Griseofulvin(cont.)
• MOA: Inhibits fungal mitosis by interfering with microtubule
function
• Clinical uses:
– Used to treat dermatophyte infections ( ring worm of skin,
hair, nails ).
– Highly effective in athlete's foot.
• Adverse effects:
– Peripheral neuritis, mental confusion, fatigue, vertigo,
– GIT upset, enzyme inducer, blurred vision.
 Nursing Considerations
• Assess for the contraindications
• Obtain a culture of the infected area
• Instruct patient for correct method of administration, to
improve effectiveness and decrease the risk of adverse effects
• Advise patient to stop the drug if a severe rash occurs
• Educate client on drug therapy to promote understanding and
compliance.
• Monitor patient response to therapy (resolution of fungal
infections).
• Monitor for adverse effects
 References

• Harvey, R.A and Champe, P.C. Lippincott’s Pharmacology.4th

edidtion.(2006)
• Katzung, B.G. and Masters, S.B. Basic and clinical
pharmacology 12th edition.(2012)
• Brunton.L, Chabner. B, and Knollman. B. Goodman and
Gillman’s The Pharmacological Basis of Therapeutics.12th
eidtion.(2011)