What is anti-fungal,how it occur, types,Drugs,Prevention,Latest information

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Anti-Fungal Drug
Md. Shariful Islam
International Islamic University Chittagong

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What is Fungus?
Definition: A fungus is any member of the group of eukaryotic organisms that includes unicellular
microorganisms such as yeasts and molds, as well as multicellular fungi that produce familiar fruiting forms
known as mushrooms.
Characteristics
• Most fungi grow as tubular filaments called hyphae. An interwoven mass of hyphae is called a
mycelium.
• The walls of hyphae are often strengthened with chitin, a polymer of N-acetylglucosamine.
• Fungi disperse themselves by releasing spores, usually windblown.
• Fungi are heterotrophic.

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Morphology
Microscopic structures
Most fungi grow as hyphae, which are cylindrical, thread-like structures 2–10 µm in
diameter and up to several centimeters in length. Hyphae grow at their tips (apices); new
hyphae are typically formed by emergence of new tips along existing hyphae by a process
called branching, or occasionally growing hyphal tips fork, giving rise to two parallel-
growing hyphae.
Macroscopic structures
Fungal mycelia can become visible to the naked eye, for example, on various surfaces and
substrates, such as damp walls and spoiled food, where they are commonly called molds.
Mycelia grown on solid agar media in laboratory petri dishes are usually referred to as
colonies. These colonies can exhibit growth shapes and colors (due to spores or
pigmentation) that can be used as diagnostic features in the identification of species or
groups

4. Types of Fungal Diseases
Fungi are everywhere. There are approximately 1.5 million different species of fungi on Earth, but only about
300 of those are known to make people sick. Fungal diseases are often caused by fungi that are common in
the environment. Fungi live outdoors in soil and on plants and trees as well as on many indoor surfaces and
on human skin. Most fungi are not dangerous, but some types can be harmful to health.
Aspergillosis is an infection caused by Aspergillus, a
common mold (a type of fungus) that lives indoors and
outdoors. Most people breathe in Aspergillus spores every
day without getting sick. However, people with weakened
immune systems or lung diseases are at a higher risk of
developing health problems due to Aspergillus. The types
of health problems caused by Aspergillus include allergic
reactions, lung infections, and infections in other organs.
Aspergillosis

5. Blastomycosis:
Blastomycosis is a disease caused by the fungus Blastomyces dermatitidis. The fungus lives
in moist soil and in association with decomposing organic matter such as wood and
leaves. Lung infection can occur after a person inhales airborne, microscopic fungal
spores from the environment; however, many people who inhale the spores do not get
sick. The symptoms of blastomycosis are similar to flu symptoms, and the infection can
sometimes become serious if it is not treated.
Candidiasis
Candidiasis is a fungal infection caused by yeasts that belong to the genus Candida. There
are over 20 species of Candida yeasts that can cause infection in humans, the most
common of which is Candida albicans. Candida yeasts normally live on the skin and
mucous membranes without causing infection; however, overgrowth of these organisms
can cause symptoms to develop. Symptoms of candidiasis vary depending on the area of
the body that is infected.
Candidiasis that develops in the mouth or throat is called “thrush” or oropharyngeal
candidiasis. Candidiasis in the vagina is commonly referred to as a “yeast infection.”
invasive candidiasis occurs when Candida species enter the bloodstream and spread
throughout the body. Click the links below for more information on the different types of
Candida infections.
Types of Fungal Diseases cont……

6. Types of Fungal Diseases cont……
Ringworm
Ringworm is a common skin infection that is caused by a fungus. It’s called “ringworm” because it can cause a
circular rash (shaped like a ring) that is usually red and itchy. Anyone can get ringworm. The fungi that cause this
infection can live on skin, surfaces, and on household items such as clothing, towels, and bedding.
Pneumocystis pneumonia
Pneumocystis pneumonia (PCP) is a serious illness caused by the fungus Pneumocystis jirovecii. PCP is one of the
most frequent and severe opportunistic infections in people with weakened immune systems, particularly people
with HIV/AIDS. Although people with HIV/AIDS are less likely to get PCP today than in recent years, PCP is still a
significant public health problem.
Histopathology showing
Pneumocystis cysts in the lung of a
patient with AIDS

7. Fungi may be classified as yeast or moulds.
Classification
Yeast like pathogenic
• Histoplasmosis
• Coccidioidomycosis
• Blastomycosis
• Cryptococcosis
• Candida
Mould group of pathogenic
 Aspergillosis
 Dermatophytes
 Mucormicosis
 Candida Spp. and Pneumocyst carinii are not pathogenic
 pathogenic in immuno compromised patients OPPORTUNISTIC
INFECTION.

8. What Are Superficial Fungal Infections?
Superficial fungal infections attack tissues on the surface of the body, which
include the skin, nails, or hair. Some common examples are ringworm, athlete's
foot, jock itch, and yeast infections. Candida yeast * infections are usually found
on the skin, in the mouth, in the vagina, on the head of the penis, or around
the nails. Superficial fungal infections are somewhat contagious and pass from
person to person through direct contact or, less commonly, through clothes or
contact with surfaces of other objects in the environment.
Most common: Dermatophytoses
Encouraged by hot (Hygiene)and humid environment
Dermatophytoses classified according to body site
Tinea manuum(Hand) Tinea unguium(Nails)
Tinea barbae
Tenia capitis(Scalp)
Tinea corporis(Body)
Tinea pedis(Foot)

9. How Do Doctors Diagnose and Treat Superficial Fungal
Infections?
Skin infections
Superficial fungal infections are often diagnosed on the basis of their appearance and their location on the body.
Most skin infections respond well to topical antifungal creams, some of which are available over the counter, which
means they do not require a doctor's prescription. Other skin infections, however, do not respond to such
treatment. They require a doctor's attention and systemic treatment with prescription antifungal medications.
Candidiasis
Candida yeast infections are diagnosed by staining specimens of sputum or urine, or scrapings from the skin or
the lining of the mouth or vagina, and by examining them under a microscope. People with vaginal yeast
infections can be effectively treated with medications. Occasionally, repeated courses of treatment may be
required.

10. What Are Systemic Fungal Infections?
Some fungi are normally present in the body, kept under control by the body's immune system. If the immune
system is abnormally weak, however, the fungi can grow out of control and cause illnesses. These are termed
opportunistic infections. Among the most common opportunistic fungal infections that affect people are:
candidiasis
aspergillosis
phycomycosis
cryptococcosis
People with AIDS (acquired immune deficiency syndrome), people with leukemia (cancer of the blood cells), and
people with Hodgkin's disease or other kinds of lymphoma (cancer of the immune system) are at risk for
opportunistic fungal infections because their immune systems have been weakened. Such infections may also
occur in people who are receiving radiation therapy or chemotherapy, or who are taking corticosteroids * or
immunosupressant * drugs, such as the drugs a person takes after an organ transplant.

11. What Are the Symptoms of Systemic Fungal Infections?
Systemic fungal infections often are chronic * and develop slowly, taking weeks or months to become a problem.
Symptoms are sometimes similar to those of the common cold, but sometimes, especially in people with
weakened immune systems, symptoms may be sudden and severe, requiring hospitalization. Symptoms may
include cough, fever, chills, night sweats, anorexia (loss of appetite), weight loss, general fatigue, and depression.
If the infection spreads from the lungs to other organs, it may be particularly severe, especially if the patient has a
weakened immune system. For example, cryptococcosis (krip-to-ko-KO-sis) may lead to meningitis (men-in-JY-tis),
which causes inflammation and swelling of the lining around the brain and spinal cord.

12. How Do Doctors Diagnose and Treat Systemic Fungal Infections?
Diagnosis
Diagnosing and treating systemic fungal infections can be a challenge for a doctor. Many of the symptoms are
mild and vary greatly from person to person. Blood or skin tests exist for only a few of these infections and often
are inconclusive or fail to find a fungus that really is there, a result called a false negative. Chest x-rays may show
abnormalities in the lungs as fuzzy white spots on the black x-ray film, but the spots do not identify the specific
cause.
A diagnosis of systemic fungal infection usually is confirmed when a fungus is cultured, or grown, in a laboratory
dish from a sample of the patient's sputum, bone marrow, urine, blood, cerebrospinal (ser-e-bro-SPY-nel) fluid, or
other tissue.
• chronic (KRON-ik) means continuing for a long period of time.
Treatment
Treatment varies, depending on which fungus is causing the condition and how severe the symptoms are.
Doctors usually prescribe antifungal medications, with drug therapy sometimes continuing for several weeks. In
some cases, particularly if the immune system is weak, drug treatment may fail, or the doctor may recommend
surgery to remove infected tissues.

14. Fungal cell structure

15. • Fungal cell structure and function is essential for understanding the pharmacology
of antifungal agents.
• Four targets in fungal pathogens:
• Fungal Cell Wall
• Fungal Cell Membrane
• DNA/RNA Synthesis
• Inhibition of fungal mitosis
Fungal cell structure cont…

17. • Fungal Cell Wall contain β- 1,3-D-
glucan
• Depletion of glucan  Leads to
death

18. • Ergosterol is the predominant
sterol in many pathogenic fungi.

20. Squalene
Terbinafine
squalene 2,3 epoxide
Lanosterol
Ergosterol
Membrane synthesis
14-demethylase
Azoles

21.  Inhibits DNA synthesis by blocking the
functions of a key enzyme in DNA
replication- thymidylate synthetase.
 Fungal cell mitosis by disrupting
mitotic spindle formation-a critical
step in cellular division.

22. Classes
Polyene antifungals:
A polyene is a molecule with multiple conjugated double bonds. A polyene antifungal is a
macrocyclic polyene with a heavily hydroxylated region on the ring opposite the conjugated
system. This makes polyene antifungals amphiphilic. The polyene antimycotics bind with
sterols in the fungal cell membrane, principally ergosterol. This changes the transition
temperature (Tg) of the cell membrane, thereby placing the membrane in a less fluid, more
crystalline state. (In ordinary circumstances membrane sterols increase the packing of the
phospholipid bilayer making the plasma membrane more dense.) As a result, the cell's
contents including monovalent ions (K+, Na+, H+, and Cl−), small organic molecules leak and
this is regarded one of the primary ways cell dies. Animal cells contain cholesterol instead of
ergosterol and so they are much less susceptible. However, at therapeutic doses, some
amphotericin B may bind to animal membrane cholesterol, increasing the risk of human
toxicity. Amphotericin B is nephrotoxic when given intravenously. As a polyene's hydrophobic
chain is shortened, its sterol binding activity is increased. Therefore, further reduction of the
hydrophobic chain may result in it binding to cholesterol, making it toxic to animals.

23. •Amphotericin B
•Candicidin
•Filipin – 35 carbons, binds to cholesterol (toxic)
•Hamycin
•Natamycin – 33 carbons, binds well to ergosterol
•Nystatin
•Rimocidin
Polyene antifungals:

24. Imidazole, triazole, and thiazole antifungals
Imidazoles
•Bifonazole
•Butoconazole
•Clotrimazole
•Econazole
•Fenticonazole
•Isoconazole
•Ketoconazole
•Luliconazole
•Miconazole
•Omoconazole
•Oxiconazole
•Sertaconazole
•Sulconazole
•Tioconazol
Triazoles
•Albaconazole
•Efinaconazole
•Epoxiconazole
•Fluconazole
•Isavuconazole
•Itraconazole
•Posaconazole
•Propiconazole
•Ravuconazole
•Terconazole
•Voriconazole
Thiazoles
Abafungin
(Azole antifungal drugs (except for abafungin) inhibit the enzyme lanosterol 14 α-demethylase; the
enzyme necessary to convert lanosterol to ergosterol. Depletion of ergosterol in fungal membrane
disrupts the structure and many functions of fungal membrane leading to inhibition of fungal
growth.)

25. Allylamines:
Allylamines inhibit squalene epoxidase, another enzyme required for ergosterol synthesis. Examples include
Amorolfin, Butenafine, Naftifine, and Terbinafine.
Echinocandins
Echinocandins may be used for systemic fungal infections in immunocompromised patients, they inhibit the
synthesis of glucan in the cell wall via the enzyme 1,3-β-glucan synthase:
•Anidulafungin
•Caspofungin
•Micafungin
Echinocandins are poorly absorbed when administered orally. When administered by injection they will reach
most tissues and organs with concentrations sufficient to treat localized and systemic fungal infections

26. Others
•Benzoic acid – has antifungal properties, but must be combined with a keratolytic agent such as in
Whitfield's ointment
•Ciclopirox – (ciclopirox olamine) – is a hydroxypyridone antifungal that interferes with active
membrane transport, cell membrane integrity, and fungal respiratory processes. It is most useful
against tinea versicolour.
•Flucytosine or 5-fluorocytosine – an antimetabolite pyrimidine analog
•Griseofulvin – binds to polymerized microtubules and inhibits fungal mitosis
•Haloprogin – discontinued due to the emergence of more modern antifungals with fewer side
effects
•Tolnaftate – a thiocarbamate antifungal, which inhibits fungal squalene epoxidase (similar
mechanism to allylamines like terbinafine)
•Undecylenic acid – an unsaturated fatty acid derived from natural castor oil; fungistatic,
antibacterial, antiviral, and inhibits Candida morphogenesis
•Crystal violet – a triarylmethane dye, it has antibacterial, antifungal, and anthelmintic properties
and was formerly important as a topical antiseptic.
•Balsam of Peru has antifungal properties

27. Adverse effects
Apart from side-effects like liver damage or affecting estrogen levels,many antifungal medicines can cause
allergic reactions in people. For example, the azole group of drugs is known to have caused anaphylaxis.
There are also many drug interactions. Patients must read in detail the enclosed data sheet(s) of the medicine.
For example, the azole antifungals such as ketoconazole or itraconazole can be both substrates and inhibitors
of the P-glycoprotein, which (among other functions) excretes toxins and drugs into the intestines.Azole
antifungals also are both substrates and inhibitors of the cytochrome P450 family CYP3A4, causing increased
concentration when administering, for example, calcium channel blockers, immunosuppressants,
chemotherapeutic drugs, benzodiazepines, tricyclic antidepressants, macrolides and SSRIs.
Before oral antifungal therapies are used to treat nail disease, a confirmation of the fungal infection should be
made. Approximately half of suspected cases of fungal infection in nails have a non-fungal cause.The side
effects of oral treatment are significant and people without an infection should not take these drugs.

28. Classification based on Mechanism of action
Inhibitor of cell wall
synthesis:
• Caspofungin
Drugs altering membrane
permeability
• Amphotericin-B,
• Nystatin,
• Hamycin
Inhibit nucleic acid
Synthesis
• 5 Flucytosine
Disruption of mitotic
spindle
• Griseofulvin
Drugs altering membrane
synthesis
• Inhibition of ergosterol
Trimidazoles
• Fluconazle,
• Itraconazole,
• Voriconazole
Imidazoles
• Ketoconazole,
• Miconazole,
• Clotrimazole.
• Inhibition of ergosterol+
lanosterol
• Terbinafine

29. Inhibitor of cell wall
synthesis:
Caspofungin (INN) (brand name Cancidas worldwide) is a lipopeptide antifungal drug from Merck & Co.,
Inc. discovered by James Balkovec, Regina Black and Frances A. Bouffard. It is a member of a new class of
antifungals termed the echinocandins. It works by inhibiting the enzyme (1→3)-β-D-glucan synthase and thereby
disturbing the integrity of the fungal cell wall. Caspofungin was the first inhibitor of fungal (1→3)-β-D-glucan
synthesis to be approved by the United States Food and Drug Administration.[3] Caspofungin is administered
intravenously.
Indications
Its currently approved therapeutic indications by both organisations include the empirical therapy of presumed
fungal infections in febrile, neutropenic adult patients and the treatment of invasive aspergillosis in adult
patients whose disease is refractory to, or who are intolerant of, other antifungal agents (i.e., conventional or
lipid formulations of amphotericin B and/or itraconazole). Additionally, the FDA approval includes indication for
the treatment of candidemia and some specific Candida infections (intra-abdominal abscesses, peritonitis,
pleural cavity infections, and esophagitis) and the EMEA approval includes indication for the treatment of
general invasive candidiasis in adult patients.

30. Pharmacology
Mechanism of Action
Echinocandin; inhibits fungal cell wall synthesis
Distribution
Protein Bound: 97% to albumin
Metabolism
Slowly, via hydrolysis and N-acetylation as well as by spontaneous degradation with subsequent metabolism
to component amino acids
Elimination
Half-life: 9-11 hr (beta phase); 40-50 hr (gamma phase)
Excretion: 41% urine; 35% feces

31. Contraindications
Hypersensitivity to caspofungin acetate or any other ingredient contained in the formulation contraindicate
its use.
Side effects
•Gastrointestinal system: nausea, vomiting, abdominal pain, and diarrhea
•Central nervous system: headache
•Whole body: fever, phlebitis or thrombophlebitis, complications at the
intravenous cannulation site (e.g. induration), unspecified pain, flu-like
syndrome, myalgia, chills, and paresthesia
•Respiratory: dyspnea
•Renal: increased plasma creatinine
•Hematological: anemia
•Electrolytes: hypokalemia
•Liver: increased liver enzymes (asymptomatic)
•Hypersensitivity: rash, facial edema, pruritus
•Other: tachycardia

32. Dosage
Initial dose of 70 mg by intravenous infusion is given followed by 50 mg intravenous daily. If no
response is seen or if inducers of caspofungin clearance (see above) are coadministered the daily dose
may be increased to 70 mg. An infusion should take approximately 1 hour.

33. Drugs altering membrane
permeability
Polyenes, such as Amphotericin B, are important drugs for treating systemic fungal infections. They attack
ergosterol, injuring fungal membranes. Amphotericin B is an ingredient in topical preparations to treat
thrush, which is a yeast infection in the mouth. Remember that when a drug is used topically it means that
it is only used on a small region of the body. In contrast, giving a drug systemically means that the drug is
distributed throughout the whole body. Amphotericin B is pretty harmless when used just in the mouth,
but when given systemically as an IV, this drug is very toxic, especially to the kidneys and liver. It's so
toxic that it is sometimes nicknamed 'Amphoterrible'. This drug is given as an IV only in extreme cases, for
example systemic fungal infections.

34. Pharmacology

35. Adverse Effects
>10%
Anorexia
Chills
Diarrhea
Fever
Headache
Hypokalemia
Hypomagnesemia
Hypotension
Malaise
Nausea
Pain (generalized)
Pain at injection site
Renal function abnormalities
Tachypnea
Vomiting
1-10%
Arachnoiditis
Delerium
Flushing
Hypertension
Leukocytosis
Lumbar nerve pain
Paresthesia
Urinary retention
<1%
Agranulocytosis
Anuria
Bone marrow suppression
Cardiac arrest
Coagulation defects
Convulsions
Dyspnea
Hearing loss
Leukopenia
Maculopapular rash
Renal failure
Thrombocytopenia
Vision changes

36. Dosing & Uses

37. Nystatin
Nystatin (originally named Fungicidin) is a polyene antifungal medication that is derived from a bacterium,
Streptomyces noursei. It was discovered by Rachel Fuller Brown and Elizabeth Lee Hazen in 1950. Many mold
and yeast infections are sensitive to nystatin, most notably Candida. It is used primarily for infections
involving the skin, mouth, esophagus, and vagina
Uses
Cutaneous, vaginal, mucosal, and esophageal Candida infections usually respond well to treatment with
nystatin. It is available in many forms. Oral nystatin is often used as a preventive treatment in people who
are at risk for fungal infections, such as AIDS patients with a low CD4+ count and patients receiving
chemotherapy. It has been investigated for use in patients after liver transplantation, but fluconazole was
found to be much more effective for preventing colonization, invasive infection, and death

38. Nystatin binds to ergosterol, a major component of the fungal cell membrane. When present in sufficient
concentrations, it forms pores in the membrane that lead to K+ leakage, acidification, and death of the fungus
Mechanism of action
Adverse effects
The oral suspension form produces a number of adverse effects including but not limited to
• Diarrhea
• Abdominal pain
• Rarely, tachycardia, bronchospasm, facial swelling, muscle aches

39. Brand names
•Nyamyc
•Pedi-Dri
•Pediaderm AF Complete
•Candistatin
•Nyaderm
•Bio-Statin
•PMS-Nystatin

40. Inhibit nucleic acid
Synthesis
Flucytosine, or 5-fluorocytosine, a fluorinated pyrimidine analogue, is a synthetic antimycotic drug.
It is structurally related to the cytostatic fluorouracil and to floxuridine. It is available in oral and in some
countries also in injectable form. A common brand name is Ancobon. Flucytosine was first synthesized in
1957 but its antifungal properties were discovered in 1964. The drug is dispensed in capsules of 250 mg
and 500 mg strength. The injectable form is diluted in 250 mL saline solution to contain 2.5 g total
(10 mg/mL). The solution is physically incompatible with other drugs including amphotericin B

41. Pharmacology
Mechanisms of action
Competitive inhibition of purine, pyrimidine uptake.
Two major mechanisms of action have been elucidated:
•Flucytosine is intrafungally converted into the cytostatic fluorouracil which undergoes further steps of
activation and finally interacts as 5-fluorouridinetriphosphate with RNA biosynthesis thus disturbing the
building of certain essential proteins.
•Flucytosine also undergoes conversion into 5-fluorodeoxyuridinemonophosphate which inhibits fungal DNA
synthesis.

42. Pharmacokinetics
Absorption: 75-90%
Distribution: into CSF, aqueous humor, joints, peritoneal
fluid, & bronchial secretions
Protein Bound: 2-4%
Half-life elimination: 3-8 hr; anuria: up to 200 hr; end-
stage renal disease: 75-200 hr
Peak Plasma Time: 2-6 hr
Metabolism: minimally hepatic
Excretion: urine (75-90% as unchanged drug)

43. Adverse Effects
Confusion
Headache
Hallucinations
Dizziness
Drowsiness
Psychosis
Parkinsonism
Ataxia
Sedation
Rash
Photosensitivity
Pruritus
Urticaria
Temporary growth failure
Hypoglycemia
Hypokalemia
Nausea
Vomiting
Diarrhea
Abdominal pain
Loss of appetite
Bone marrow suppression
Anemia
Leukopenia
Thrombocytopenia
Elevated liver enzymes
Hepatitis
Azotemia
Peripheral neuropathy
Paresthesia
Weakness
Hearing loss
Elevated BUN and serum creatinine
Renal failure
Respiratory arrest
Anaphylaxis

44. Disruption of mitotic
spindle
Griseofulvin (marketed under the proprietary name Grifulvin V by Orthoneutrogena Labs,
according to FDA orange book) is an orally administered antifungal drug. It is used both in animals
and humans, to treat fungal infections of the skin (commonly known as ringworm) and nails.

45. Pharmacology
Mechanism of Action
Fungistatic; deposited in keratin precursor cells and is tightly bound to new keratin,
and this increases resistance to fungal invasion
Absorption
Absorption of ultramicrosize griseofulvin absorption is almost complete; absorption
of microsize griseofulvin is variable (25-70% of oral dose); enhanced by ingestion of
fatty meal (GI absorption of ultramicrosize is 1.5 times that of microsize)
Distribution
Drug crosses placenta
Metabolism
Extensively metabolized by liver; hepatic CYP3A4 induced
Elimination
Half-life: 9-22 hr
Excretion: Urine (<1% as unchanged drug), feces

46. Adverse Effects
Rash (most common)
Urticaria (most common)
Headache
Fatigue
Dizziness
Insomnia
Mental confusion
Photosensitivity
Nausea
Vomiting
Epigastric distress
Diarrhea
GI bleeding
Leukopenia
Hepatotoxicity
Proteinuria
Nephrosis
Oral thrush
Angioneurotic edema (rare)
Drug-induced lupuslike syndrome (rare)
Menstrual irregularities (rare)
Paresthesia (rare)

47. Dosing & Uses

48. Inhibition of ergosterol(Azoles)
Azoles are used as antifungal drugs, inhibiting the fungal enzyme 14α-
demethylase which produces ergosterol (an important component of the
fungal plasma membrane).

49. Azoles,These drugs inhibit the synthesis of ergosterol, which means they block the synthesis of the fungal plasma
membrane. A couple of these drugs, like clotrimazole and miconazole are mainly used topically, for example, in
creams to treat athlete's foot and yeast infections. Another related drug, ketoconazole can be used systemically
and is often used as an alternative to the more toxic Amphotericin B. Finally, fluconazole is even less toxic and
even more water-soluble. That means it is easier and more effective for systemic fungal infections.
Azoles

50. Adverse Effects
1-10%
Diarrhea (6%)
Nausea (4.6%)
Headache (5%)
Dysgeusia (2.9%)
Upper abdominal pain (2.5%)
Vomiting (2.5%)

51. Penicillin of antifungals
Echinocandins are antifungal drugs that inhibit the synthesis of glucan in the cell wall, via
noncompetitive inhibition of the enzyme 1,3-β glucan synthase and are thus called "penicillin of
antifungals"
Medical uses
Drugs and drug candidates in this class are fungicidal against some yeasts (most species of Candida, but not
against Cryptococcus, Trichosporon, and Rhodotorula). Echinocandins also have displayed activity against
Candida biofilms, especially in synergistic activity with amphotericin B and additive activity with fluconazole.
Echinocandins are fungistatic against some molds (Aspergillus, but not Fusarium and Rhizopus), and modestly
or minimally active against dimorphic fungi (Blastomyces and Histoplasma). These have some activity against
the spores of the fungus Pneumocystis carinii.

52. Mechanism of action
Echinocandins noncompetitively inhibit beta-1,3-D-glucan synthase enzyme complex in susceptible fungi to
disturb fungal cell glucan synthesis. Beta-glucan destruction prevents resistance against osmotic forces,
which leads to cell lysis. They have fungistatic activity against Aspergillus species. and fungicidal activity
against most Candida spp., including strains that are fluconazole-resistant. In vitro and mouse models show
echinocandins may also enhance host immune responses by exposing highly antigenic beta-glucan
epitopes that can accelerating host cellular recognition and inflammatory response.

53. Side effects
Echinocandin toxicity is uncommon. Its use has been associated with elevated aminotransferases and
alkaline phosphatase levels
Advantages
•broad range (especially against all Candida), thus can be given empirically in febrile neutropenia and stem cell
transplant
•can be used in case of azole-resistant Candida or use as a second-line agent for refractory aspergillosis
•long half-life (polyphasic elimination: alpha phase 1–2 hours + beta phase 9–11 hours + gamma phase 40–50
hours)
•low toxicity: only histamine release (3%), fever (2.9%), nausea and vomiting (2.9%), and phlebitis at the
injection site (2.9%), very rarely allergy and anaphylaxis
•not an inhibitor, inducer, or substrate of the cytochrome P450 system, or P-glycoprotein, thus minimal drug
interactions
•lack of interference from renal failure and hemodialysis
•no dose adjustment is necessary based on age, gender, race
•better (or no less effective) than amphotericin B and fluconazole against yeast infections

54. Disadvantages
•Embryotoxic (category C) thus should be avoided if possible in pregnancy
•needs dose adjustment in liver disease
•poor ocular penetration in fungal endophthalmitis

55. Inhibition of ergosterol+ lanosterol
Terbinafine hydrochloride, also known under the trade name Lamisil, is a synthetic allylamine
antifungal developed by Novartis. It is highly hydrophobic in nature and tends to accumulate in skin,
nails, and fatty tissues
Terbinafine is mainly effective on the dermatophyte group of fungi.
As a 1% cream or powder, it is used topically for superficial skin infections such as jock itch (tinea cruris),
athlete's foot (tinea pedis), and other types of ringworm (tinea corporis). Terbinafine cream works in about
half the time required by other antifungals.
Indications

56. FDA approval
Terbinafine first became available in Europe in 1991 and in the United States in 1996. The U.S. Food and
Drug Administration has approved the first generic versions of prescription Lamisil (terbinafine
hydrochloride) tablets. The remaining patent or exclusivity for Lamisil expired on June 30, 2007.
On September 28, 2007, the FDA stated that Lamisil (terbinafine hydrochloride, by Novartis AG) is a new
treatment approved for use by children age four and up. The antifungal granules can be sprinkled on a
child's food to treat ringworm of the scalp, tinea capitis

57. Pharmacology
Mechanism of Action
Inhibits squalene epoxidase, reducing cell membrane
ergosterol synthesis, causing inhibition of fungal cell-wall
synthesis and subsequently fungal cell death
Absorption
Absorption >70%
Bioavailability: 40% (Adults); 36-64% (children)
Peak plasma time: 1-2 hr
Peak plasma concentration (250-mg dose): 1 mcg/mL
Distribution
Predominantly distributed to sebum and skin
Protein bound: >99%
Vd: 2000 L
Metabolism
Metabolized in liver by several CYP450 enzymes;
first-pass effect (40%)
Metabolites: Inactive
Enzymes inhibited: CYP2D6
Elimination
Half-life: 36 hr (drug released very slowly from skin
and adipose tissues)
Excretion: Urine (~70%)

58. Brand name and dosages form

59. Side effects
>10%
Headache (13%)
1-10%
Rash (6%)
Pruritus (3%)
Nausea (3%)
Diarrhea (6%)
Dyspepsia (4%)
Abdominal pain (2%)
Taste disturbance (3%)
Elevated liver function test results (3%)
Visual disturbance (1%)