Antifungal Agent: Nystatin and Griseofulvin

Antifungal Agent: Nystatin and Griseofulvin:- 

Fig:- Antifungal Agent 

INTRODUCTION ABOUT ANTIFUNGAL AGENTS:-

1. An antifungal medication is also known as Antimycotic medication is a pharmaceutical fungicide used to treat and prevent mycosis such as athlate foot, ringworm, candidiasis, serious systemic infection such as cryptococcal meningitis and others.
2. The antifungal agents are mostly used in treatment of infection of the hairs, nails mucous membranes, nails or skin by fungi of the genera candida and epidermophyton.
3. Such drugs as usually obtained by a doctor’s prescription but few are available OTC (over the counter).
4. An antifungal agent is a drug that selectively eliminates fungal pathogens from a host with minimal toxicity to the host.
5. Fatty acids and some aromatic acids have been known      to possess antifungal agents. The other important category of antifungal substance belongs to the antibiotic class.

INTRODUCTIONS ABOUT NYSTATIN:-

1. Nystatin, sold under the brand name: Mycostatin among others,
2. It is an antifungal medication.
3. It is used to treat Candida infections of the skin including diaper rash, thrush, esophageal candidiasis, and vaginal yeast infections.
4. It may also be used to prevent candidiasis in those who are at high risk. Nystatin may be used by mouth, in the vagina, or applied to the skin.
5. Nystatin was discovered in 1950 by Rachel Fuller Brown and Elizabeth Lee Hazen.
6. It was the first polyene macrolide.
7. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.
8.  It is available has a generic medication.
9.  It is made from the bacterium Streptomyces noursei.
10. Structure:-
11. Formula of Nystatin is = C₄₇H₇₅NO₁₇

Structure of NYSTATIN:- 

 Mechanism of action of Nystatin:-

1. Nystatin firstly binds to fungal cell membrane ERGOSTEROL.
2. Then it can be changed the transition temperature.
3. As a result membrane becomes more fluid in nature.
4. Then it can be lead to the formation of transmembrane channels.
5. The leakage of monovalent ions takes place ( K, Na, Cl  ions ).
6. The ions imbalance should be occur and the death of fungal cell .
7. Like the amphotericin B, Nystatin binds to the ERGOSTEROL , a major components of fungal cell membrane.
8. When present in sufficient concentration, it forms pores in the membrane that lead to the K+ leakage, acidification and death of the fungus.
9. Ergosterol is a sterol unique to fungi ,so the drug does not have such catastrophic effect on animal or plants.

Medical uses:- 

1. Skin, vaginal, mouth, and esophageal Candida infections usually respond well to treatment with nystatin.
2. 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 people receiving chemotherapy.
3. It has been investigated for use in patients after liver transplantation, but fluconazole was found to be much more
4. effective for preventing colonization, invasive infection, and death.
5.  It is effective in treating oral candidasis in elderly people who wear dentures.
6. It is also used in very low birth-weight (less than 1500 g or 3 lb 5oz o) infants to prevent invasive fungal infections.
7. In the UK, its license for treating neonatal oral thrush is restricted to those over the age of one month.
8. It is not absorbed from the gut ,it is fairly safe for oral use and does not have  problems of drug interactions.
9. Nystatin is also known as Mycostatin polyene macrolide which is not absorbed when it is given by mouth and it is too toxic for partental use.
10. It is active against the number of yeast and fungi but is principally used for candida albicans infections.
11. The oral dose in adults for oral oesophageal candidiasis is 5 lakh to 1 billion units or 3-4 times a day .
12. Nystatin ointment, creams, drops and vaginal tablets contain ore lakh units of drug.

SIDE EFFECTS OF NYSTATIN :-

1. Bitter taste and nausea are more common than most other adverse effects.
2. Common side effects include Diarrhea
3. Abdominal pain
4. Rarely, tachycardia, bronchospasm, facial swelling, muscle aches
5. Both the oral suspension and the topical form can cause:
6. Hypersensitivity reactions, including Stevens-Johnson syndrom in  some cases 
7. Rash, itching, burning and acute generalized exanthematouspustulosis.

INTRODUCTIONS ABOUT GRISEOFULVIN:-

1. Griseofulvin is an antifungal medication used to treat a number of types of dermatophytoses (ringworm).
2. This includes fungal infections of the nails and scalp, as well as the skin when antifungal creams have not worked.
3.  It is taken by mouth.
4. Griseofulvin is discovered in 1939 from a type of penecillium mold.
5. Griseofulvin works by interfering with fungal mitosis.

STRUCTURE of GRISEOFULVIN:-

BIOSYNTHESIS OF GRISEOFULVIN:-

1. It is produced industrially by fermenting the fungus Penicillium griseofulvum.
2. The first step in the biosynthesis of griseofulvin by P. griseofulvin is the synthesis of the 14-carbon poly-β-keto chain by a type I iterative polyketide synthase (PKS) via iterative addition of 6 malonyl-CoA to an acyl-CoA starter unit.
3. The 14-carbon poly-β-keto chain undergoes cyclization/aromatization, using cyclase/aromatase, respectively, through a Claisen and aldol condensation to form the benzophenone intermediate.
4. The benzophenone intermediate is then methylated via S-adenosyl methionine (SAM) twice to yield griseophenone C.
5. The griseophenone C is then halogenated at the activated site ortho to the phenol group on the left aromatic ring to form griseophenone B.
6. The halogenated species then undergoes a single phenolic oxidation in both rings forming the two oxygen diradical species.
7. The right oxygen radical shifts alpha to the carbonyl via resonance allowing for a stereospecific radical coupling by the oxygen radical on the left ring forming a tetrahydrofuranogriseopheno
8. The newly formed Grison skeleton with a Spiro centre is then O-methylated by SAM to generate dehydrogriseofulvin.
9. Ultimately, a stereoselective reduction of the olefin on dehydrogriseofulvin by NADPH affords griseofulvin.

MECHANISM OF ACTION:-

1. The drug binds to tubulin, interfering with microtubules function, thus inhibiting the mitosis.
2. It binds to keratin in keratin precursors cells and makes them resistance to fungal infections.
3. The drug reaches its site of action only when hair or skin is relpaced by the keratin – griseofulvin complex.
4. Griseofulvin then enters the dermatophytes through energy dependent transport process and bind to fungal microtubules.
5. This alters the processing for mitosis and also underlying information for deposition of fungal cell walls.
6.  Keratin precursor’s cell + griseofulvin
7. Formation of keratin griseofulvin complex
8. When the skin is replaced with this complex griseofulvin enters into the fungal cell.
9. Bind to fungal cell tubulin .
10. Tubulin cannot polymerised into the microtubules. 
11. As a result spindle fibers are not form. 
12. As a result spindle fiber unable to attach kinatocore.
13. Suppression of chromosome is arrested .
14. These alter the cell division.
15. Death of fungal cell occurs.
16. It is selectively concern in keratin and it is drug for widespread or interaction dermatophytes.
17. It is poorly soluble in water.

GRISEOFULVIN POTENTIAL FOR CANCER TREATMENT:- 

1. When cancer cells divide, exact genetic material get copied and transferred to each new daughter cell and each further undergo division to form tumour.
2. Laboratory experiments at German cancer research center shows that griseofulvin cause cancer cells fail to divide the chromosome correctly which eventually leads  to tumor cell death .
3. It doesn’t interfere with cell division in healthy cells.
4. It may combine with other treatments to improve its affectivness and may leads to the development of more effective future drug treatment with very low side effects.

MEDICAL USES OF GRISEOFULVIN:-

1. Griseofulvin is used orally only for dermatophytosis. It is ineffective topically. It is reserved for cases with nail, hair, or large body surface involvement.
2. Terbinafine given for 2 to 4 weeks is at least as effective as griseofulvin given for 6 to 8 weeks for treatment of Trichophyton scalp infections. However, griseofulvin is more effective than terbinafine for treatment of Microsporum scalp infections.

SIDE EFFECTS OF GRISEOFULVIN:-

1. Loss of taste sensation, nausea , confusion, diarrhoea
2. Considered unsafe for those with porphyria, fatigue, and headache.
3. Oral thrush (yeast infections of the mouth), sensitivity to Alcohol, with a disulfiram like reaction.
4. Phototoxicity, urticaria,skin rashes , itching.
5. Impairment of liver enzymatic activity ,upper abdominal pain etc.
6. Side effects are although uncommon each may cause photosensitivity reaction.

DOSES:-

1. It is use in a dose of 0.1 to 1 gm daily in divided doses.
2. In children the recommended dose is 10 mg / kg daily in divided doses.
3. It is used in the treatment of mitotic diseases of nails, hair’s and skin .
4. It is also highly effective in athlete’s foot.