Re: ANTIFUNGAL AGENTS/TYPES

[Guest guest]

Hi dee, Thanks for your antifungal info. I printed it out so i can study it.

ellen

ANTIFUNGAL AGENTS/TYPES

http://www.vet.purdue.edu/bms/courses/bms514/chmrx/antifung.htm

Hi all, thought some of you might be interested in this on the various types

of antifungals. Warmest, Dee dtroll@...

ANTIFUNGAL AGENTS

Copyright, Purdue Research Foundation, 1996

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| BMS 445 Intro | | Drug Groups | | Slides / Graphics | | Address | | E-mail

| | Brief |

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Antifungal therapy can be divided into two categories; treatment of serious

systemic (deep) mycosis and superficial mycosis involving skin and mucous

membranes. The superficial mycoses may be subdivided into dermatophytic

infections and Candidosis. Dermatophytic infections, which affect the skin,

hair, and nails, are caused by such organisms as Epidermophyton sppi,

Trichophyton spp., and Microsporum spp.\i. Candidosis, which affects moist skin

and mucous membranes (e.g., gastrointestinal tract and vagina), is usually

associated with Candida albicans.

Key characteristics of is ergosterol. Vertebrates are also eukaryotic, but

they do not have cell walls. Their major membrane lipid is cholesterol. It is

apparent that drugs that affect synthesis and function of cell walls or of

hydroxylated glycerols and ergosterol might be more damaging to bacteria and/or

fungi than to vertebrates. Examples of these can be found among the antifungals.

Systemic Mycoses

Sytemic mycoses tend to be serious and chronic

Many effective drugs are extremely toxic

Major drugs come primarily from one of three families: polyenes; imidazoles;

and antimetabolites. Amphotericin B [Fungizone] is a polyene (so is nystatin,

but it is not used for systemic infections). Ketoconazole and miconazole are

imidazoles. Thiabendazole, the anthelmintic that has antifungal activity is also

a member of this group. Flucytosine is an antimetabolite.

Typical infections and drugs frequently used are as follows: (key =

amphotericin B, Amph; flucytosine, Flu; ketoconazole, Keto; and miconazole,

Mic.)

Systemic candidiasis -- Amph and/or Flu, Keto, Mic, Fluconazole

Cryptococcosis (meningitis) -- Amph + Flu, Mic, Fluconazole better

Systemic aspergillosis -- Amph and/or Flu

Aspergillosis -- sinusitis in dogs -- Emlkonazole (Bowersock95)

Blastomycosis -- Amph, Keto, Itraconazole

Histoplasmosis -- Amph, Keto, Fluconazole

Coccidioidomycosis - Amph, Keto, Itraconazole

Paracoccidioidomycosis -- Ampho, Keto, Itraconazole

Other drugs that have been used are iodides and hydroxystilbamidine

isethionate.

LIST OF DRUGS:

From USPDI95 plus others

Systemic

a.. Amphotericin B

b.. Dapsone

c.. Fluconazole

d.. Flucytosine

e.. Griseofulvin

f.. Itraconazole

g.. Ketoconazole

h.. Miconazole

i.. KI

Topical

a.. Amphotericin B

b.. Carbol-Fuchsin

c.. Ciclopirox

d.. Clotrimzole

e.. Econazole

f.. Haloprogin

g.. Ketoconazole

h.. Mafenide

i.. Miconazole

j.. Naftifine

k.. Nystatin

l.. Oxiconazole

m.. Silver Sulfadiazine

n.. Sulconazole

o.. Terbinafine

p.. Tioconazole

q.. Tolnaftate

r.. Undecylenic acid

Vaginal

a.. Butoconazle

b.. Clotrimazole

c.. Econazole

d.. Gentian Violet

e.. Miconazole

f.. Nystatin

g.. Terconazole

h.. Tioconazole

Amphotericin B [FungizoneR]

Amphotericin B is a polyene antibiotic isolated from Streptomyces nodosus.

It contains a macrolide ring and an aminosugar, mycosamine.

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Structure and chemical characteristics

It is poorly water soluble, but is sufficiently soluble that it is

administered by IV infusion (0.1 mg/ml) or (0.3 mg/ml) in 5% dextrose. It is

extremely unstable in solution, particularly in normal saline.

Mechanism of action

Apparently has an affinity for membranes that have higher content of

ERGOSTEROL. It forms a channel through the membrane that allows the passage of

potassium and other small molecules. The fungus is unable to maintain its

internal environment.

Resistance is rare and slow to develop.

Pharmacokinetics

The drug crosses cell membranes very poorly, therefore, it is poorly

absorbed from the gut and has poor penetration into the eye, CSF, and joint

capsules. For treatment of meningitis, it must be given intrathecally.

It is given only via IV injection or intrathecally. Some authorities feel

its topical use is no longer justified because of the availability of superior

products.

Adverse Effects

The drug has MANY adverse effects, some serious. It must be given in a

hospital setting.

It is noted for its renal toxicity that is both predictable and dose

related. Fortunately it is usually reversible. Renal function must be monitored

and the drug is usually given in cycles or courses of therapy, e.g., 7 days on,

7 days off. Treatment may last for 6 to more than 24 weeks.

Flucytosine [AncobonR]

Flucytosine is a synthetic agent chemically related to fluorouracil and

floxuridine, both anticancer drugs. It is an antimetabolite.

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Mechanism of Action

It is converted to 5-fluorouracil (5-FU) which inhibits thymidylate

synthetase. Thymidine is required for DNA synthesis. Vertebrate cells have

little of the enzyme required to convert flucytosine to the active

antimetabolite, 5-FU. It may be noted that 5-FU is an anticancer drug,

therefore, the toxicity of flucytosine could be expected to be similar to that

of antimetabolite anticancer drugs. Pharmacokinetics

A major characteristic of this drug is its rapid and complete absorption

after oral administration. It distributes widely throughout the body fluids,

including the CSF. As a result it is included in therapy of meningitis caused by

susceptible organisms, usually Candida and Cryptococcus species..

Half-life in humans is 2.5 to 6.0 hours, but this is extended to 12 to 250

hours if renal function is impaired. This is consistent with the fact that 80 to

90% of the drug is eliminated in the urine unchanged.

Adverse Effects

This drug is much less toxic than amphotericin B. Nonetheless, as might be

expected from a drug that can be converted to 5-FU, it causes bone marrow

depression and gastrointestinal disturbances Bone marrow depression includes

leukopenia, anemia, and thrombocytopenia. Gastrointestinal disturbances include

nausea, vomiting, and diarrhea.

Flucytosine also causes CNS toxicity that may be manifest as headache,

drowsiness, confusion, vertigo, and hallucinations.

Clinical applications

In addition to being used to treat meninigitis caused by susceptible Candida

and Cryptococcus species, it is also used to treat pneumonia, septicemia, and

urinary tract infections caused by susceptible organisms. It is also recommended

for systemic candidiasis & aspergillosis.

A major drawback to this drug is the high proportion of strains that are

resistant to the drug and the rapid development of resistance during therapy. It

IS NOT used as a single agent because of this.

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Azole Derivatives

The azole derivatives can be subdivided into two categories: imidazoles and

triazoles. Ketoconazole and miconazole are the imidazoles used to treat systemic

fungal infections. Itraconazole and Fluconazole are triazoles.

Ketoconazole was the first of these drugs to be used widely to treat

systemic fungal infections. It was a major step forward in decreasing dependence

on amphotericin B. Miconazole offered some useful systemic antifungal activity

with less desirable pharmacokinetic properties. Itraconazole and econazole cause

fewer side effects and have better pharmacokinetic properties.

Mechanism of action

The azoles inhibit cytochrome-P450 activity which has many ramifications.

With respect to antifungal activity, this decreases conversion of

14-alpha-methylsterols to ergosterol, an important membrane component in fungi.

Failure of ergosterol synthesis causes altered membrane permeability leading to

loss of ability to maintain a normal intracellular environment.

The azole antifungals inhibit transformation of blastospores into invasive

mycelial form in Candida albicans.

The inhibition of cytochrome function may also be the basis of their

interference with steroid biosynthesis. Ketoconazole is particularly noted for

inhibition of adrenal corticosteroid and testosterone synthesis. At higher

doses, this can result in hypoadrenal cortical activity and reduced libido. In

fact, the effect has been used therapeutically at doses higher than those used

to treat fungal diseases. Adrenal hyperplasia and cancer have been treated with

high dose ketoconazole. The effects are reversible. Testosterone and adrenal

corticosteroid concentrations in plasma return to normal upon cessation of

therapy

Itraconazole and fluconazole have a very weak, non-competitive inhibitory

effect on liver (and presumably adrenal cortical and testicular) cytochrome-P450

activity, but retain high affinity for the fungal cytochrome-P450. This

difference gives these drugs a greater margin of safety. However, reduction of

cortisol concentration was associated with a daily dose of 600 mg of

itraconazole (normal dose is 200 to 400 mg/day).

Ketoconazole [NizoralR]

This is a relatively new drug and offers the promise that it is much less

toxic than amphotericin B. It can also be used orally as well as parenterally

for systemic infections.

Pharmacokinetics

This weakly dibasic drug is best absorbed from solutions that have low pH.

Note that this is opposite from what one would expect from the " Law of Non-ionic

Diffusion. " The effect is caused by the increased rate of dissolution of the

dose form in the acidic solutions. Once in solution, the drug is rapidly

absorbed and distributed uniformly throughout the body.

The drug shows interesting dose-related kinetics consistent with transient

saturation of its biotransforming enzymes. The half-lives after administration

of varying oral doses are as follows: 100 mg tablet - 6.5 h; 200 mg tablet - 8.1

h; and 300 mg table - 9.6 h.

Adverse effects

The list of precautions that should be observed with the use of ketoconazole

is quite lengthy and includes, especially concurrent use of other potentially

hepatotoxic drugs or alcohol.

Hepatotoxicity

Hepatocellular type, has been reported in 1 of 10,000 patients. It is

usually reversible.

Adrenocortical suppression

With high doses, an unintended side effect may be depression of

adrenocortical function. Conversely, one may actually use the drug for this

purpose. Serum testosterone levels may also decrease during therapy. No specific

mention of effect on estrogen or progesterone synthesis, although menstrual

irregularities would be consistent with this. Depression of testosterone and

adrenal steroid synthesis in males may lead to gynecomastia.

Miconazole [Monistat i.v.]

Is similar to ketoconzole, but less able to cross membranes and more toxic.

Heavily advertized as a topical antifungal.

Must be used by infusion for systemic effects. Apparently does not cause

hepatotoxicity, but is associated with frequent occurrence of hypersensitivity

(fever and chills, skin rash or itching), and phlebitis (redness, swelling, or

pain at injection site).

Itraconazole [sporanox]

is another imidazole that has been introduced recently for use in human

medicine. It has also been used in veterinary medicine (Dallman et. al., 1992)

Potassium Iodide

Potassium iodide is an old drug that is still the drug of choice for

cutaneous-lymphatic sporotrichosis. (AMADE2:12). Veterinarians also use the drug

for actinomycosis. It may be used p.o. as a saturated solution (1 mg/ml). Most

textbooks classify KI as an expectorant. It increases secretions in the

respiratory tract in approximately 30 min. Adverse effects include

hypothyroidism and Iodism. Signs include brassy taste, rhinitis, coryza,

salivation, lacrimation, sneezing, burning of mouth and throat, ocular

irritation, sialadenitis, and dermal lesions.

Superficial fungal infections (Dermatophytes)

Superficial fungal infections are treated either orally (for effect in the

gastrointestinal tract) or topically. Drugs include imidazoles mentioned earlier

plus clotrimazole and econazole. In fact, there are a whole host of new

imidazoles intended for use against topical fungal infections, e.g.,

butaconazole nitrate [Femstat], econazole nitrate Spectazole], oxiconazole

[Oxistat], and Sulconazole [Exelderm]. Thiabendazole is a benzimidazole

anthelmintic that has some antifungal activity. It is used in some veterinary

otic preparations. A new class of compounds include the Triazoles typified by

Terconazole [Terazol 3, Terazol 7]. Tolnaftate and desenex are used topically

for dermatophytes (athletes foot and jock itch). Miconazole, too. Amphotericin B

and nystatin [Mycostatin] are polyene antibiotics that are used topically.

Haloprogin [Halotex] is used for superficial dermatophytic infections and

candidal infections. Another new antifungal class, the synthetic allylamines, is

represented by naftifine hydrochloride [Naftin].

Griseofulvin [FulvicinR

Griseofulvin is interesting in that it is a systemic antifungal used to

treat Topical ringworm infections, e.g., onychomycosis, Tinea capitis, Tinea

pedis, etc. Many Trichophyton spp., Microsporum spp. and Epidermophyton spp. are

susceptible.

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Structure and chemistry

Griseofulvin is derived from Penicillium griseofulvum. It is poorly water

soluble and requires bile salts for solubiliization in the gut.

Mechanism of Action

Griseofulin disrupts mitotic spindle structure to lead to metaphase arrest.

It concentrates in newly formed cells of skin, hair, and nails and is carried

with them as they continue their life history into keratinized structures. This

concentration is sufficient to inhibit growth of fungi (drug is static),

preventing them from invading. As the skin, hair, or nail is replaced, the

fungus is shed.

As a result of the mechanism of action, it is apparent that very long

courses of therapy may be required: hair covered skin -- 3 to 4 weeks; nails --

3 to 4 months.

Pharmacokinetics

Used orally. Absorption is best with high fat meals to aid in solubilizing

the drug. Unabsorbed drug is eliminated in the feces. Most absorbed drug is

biotransformed. A small amount is shed in dead skin and hair.

Adverse Effects

Griseofulvin causes hepatomas in mice and thyroid tumors rats, but there is

no direct evidence of tumorigenic activity in other species. Nonetheless, casual

use should be avoided.

Adverse effects are not common, but include confusion, hypersensitivity

(skin rash, hives, or itching), oral thrush (soreness or irritation of mouth or

tongue), and photosenstivity.

Rare effects seen more with high doses or prolonged therapy include

hepatitis, granulocytopenia or leukopenia, and peripheral neuritis (numbness,

tingling, pain, or weakness in hands or feet).

Ciclopirox [LoproxR]

Ciclopirox is a broad-spectrum antifungal with a spectru similar to that of

the imidazoles. Its use is indicated for topical candidiasis and various

ringworms as mentioned above.

Only rarely are adverse efects asociated with its topical use. These include

local iritation (burning, itching, rednes, sweling).

Tolnaftate [Tinactin and others, OTC]

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This synthetic drug was developed in the 1970s. It is poorly soluble in

dipolar solvents. It is effective topically against Trichophyton, Microsporum,

and Epidermophyton spp. It is not useful for bacterial and candidal infections.

Chronic, hyperkeratotic lesions may not respond well. Use of a keratolytic

(e.g., Whitfield's ointment) may help. One may also combine local tolnaftate

treatment with orally administered griseofulvin in refractory cases. Treatment

of susceptible cases may require 1 to 10 weeks for cure. Affected areas must be

kept clean and rug. Tolnaftate is " cidal " as opposed to undecylenic acid

[Desenex], another widely used OTC drug that is " static " .

Tolnaftate is not significantly absorbed from topical applications and no

confirmed adverse systemic reactions have been reported. Cream or liquid should

be used for active infections; powders for maintenance of remission. Must apply

treatment q12h.

Clotrimazole [Lotrimin, Gyne-Lotrimin, Mycelex, Mycelex-G]

Clotrimazole is a heavily advertised imidazole antifungal intended for

topical use. It is toxic when given systemically. It is useful for dermatophytic

infections, cutaneous candidiasis, and candidal infections of mucous membranes

and mucocutaneous junctions (i.e., perianal, intertriginous, and vulvovaginal

areas. Treatment may require two to four weeks. For vaginal candidiasis poor

compliance with complex, long regimens has led to using very high doses for one

to three treatments. Erythema, urticaria, pruritus, stinging, and blistering may

be seen. Use of the Troche form may require monitoring of hepatic function.

Whitfield's Ointment

Whitfield's ointment represents keratolytic agents which are often important

in treatment of topical fungal infections. Whitfield's ointment consists of 3%

salicylic acid plus 6% benzoic acid. It has no significant antifungal activity,

but helps remove keratinous layer to aid penetration of antifungals.

References

a.. USPDI11th91

b.. Heit/Riviere95-95: Heit, M.C., and J.E. Riviere, 1995,

Antifungal and Antiviral Drugs, Ch 44, in Veterinary Pharmacology and

Therapeutics, 7th ed, ed. H. , Iowa State University Press, Ames,

IA, pp. 855-869

c.. AMADE Section 14, Chapter 2: Topical drugs used in ear, skin, and

mucous membrane infections. Updated quarterly. 1992.

d.. AMADE Section 15, Chapter 2: Drugs used for systemic mycoses.

Updated quarterly, 1992.

e.. Rang & Dale87: Pharmacology. H.P. Rang and M.M. Dale, Churchill

Livingstone, New York, 1987.

f.. Dallman, M.J., et. al. 1992. Disseminated aspergillosis in a dog

with disk spondylitis and neurologic deficits. JAVMA 200(4): 511-513.

g.. Old GLC notes

h.. Frontiers in Biotechnology -- Resistance to Antibiotics. Special

section in Science 264(5157):15 April, 1994. Series of articles including News

Reports, Policy Forum, Perspectives, Scientific Articles. pp 359-393.

a.. Georgopapadakou, N.H., and T.J. Walsh, Human Mycoses: Drugs and

Targets for Emerging Pathogens p371... Has MOAs and nice illustrations of many

drugs acting on fungi

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| Drug Groups | | top |

Gordon L. Coppoc, DVM, PhD

Professor of Veterinary Pharmacology

Head, Department of Basic Medical Sciences

School of Veterinary Medicine

Purdue University

West Lafayette, IN 47907-1246

Tel: Fax:

Email: coppoc@...

Last modified 10:05 AM on 4/17/96 GLC