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Nada Dwiri35

مبسم الله الرحمن الرحي

Fungal Cell Wall Synthesis Inhibitors

There is major fundamental differences between fungal cell wall and bacterial cell

wall in :

1) Structure : fungal cell wall is more rigid than bacterial cell wall .

2) Also the composition is difference:

Bacterial cell wall is composed from peptidoglycans precursors, but the fungal

cell wall is completely difference , it is composed of glucan and kitin precursors .

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Echinocandins

Antifungals 2

Lecture 35

Date : 30/12/2021

الأسود: كلام الدكتور

:السلايدالأزرق

Mechanism of action

• Inhibit the synthesis of β(1,3)-

D-glucan synthase → inhibit

β(1,3)-D-glucan synthesis →

inhibit cell wall synthesis

SCIENTIFIC TEAM 1 –الفريق العلمي

Echinocandins are cell wall synthesis Inhibitors

Glucan is usually make up the majority of the thickness of fungal cell wall .

Glucan is two types : beta (1,3) and beta (1,6) glucans.

The backbone of fungi consist of layer of kitins between cell wall and fungal

cell membrane .

Inhibit cell wall synthesis leading to fungal cell death.

الانزيم اللي بصنع الglucan هو عبارة عنtransmembranous enzyme وهوbeta 1,3

synthase بحول الglucan precursors الىbeta 1,3 glucans اللي بتكون ال cell wall .

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Caspofungin

Echinocandins are drugs that use to treat systemic infection fungal .

Caspofungin is first example of echinocandins

• First-line for patients with invasive candidiasis e.g., candidemia

Candidemia is systemic infection caused by candida

• Second-line for invasive aspergillosis

That means if there is a reason to prevent the use of voriconazole as a main treatment ,

we can switch to caspofungin .

• Must be administered by slow IV infusion because it can cause histamine-like reaction

The allergic reaction could be intense , so we are giving it slow IV infusion and this is

similar to another antifungal drugs that are given IV that can cause similar reactions

such as Amphotericin B

The caspofungin would required a loading dose .

. separatelyوبعدين بقدر اعطيها loadingعني اول جرعة بنعطيها ي

Caspofungin is metabolizing by cyp450 system.


Caspofungin is inhibition cyp450 , so if the other drugs (metabolize by the cyp450)

are given with Caspofungin , the caspofungin will decrease the metabolism for

these drugs due to Inhibit cyp450.

drug-drug interaction.

• MUST NOT be given with cyclosporine → hepatotoxicity

This problem (hepatotoxicity) will be bigger if the caspofungin combined with

other hepatotoxic drug such as cyclosporine .

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Micafungin and Anidulafungin

these are other example for echinocandins.

• First-line options for the treatment of invasive candidiasis e.g., candidema

Ex: in patients which have HIV (AIDS, immunodeficiency) they can develop an

esophageal infection by candida called esophageal candidiasis(yeast candida) this type

of disease doesn't have in patients with healthy immune system .

• Prophylaxis against candida infections in patients undergoing organ transplant and

may be AIDS and the patients who are receiving immunosuppressive therapy .

• No drug-drug interactions

Micafungin isn't giving as a loading dose , and it isn't metabolizing by liver this

there is no drug- drug interactions.

Drugs For Cutaneous Mycotic Infections

there is certain types of fungi that cause both systemic infections and cutaneous infections (localized

infection ) ex: candida can cause invasive candidiasis (candidemia) and can

cause localized infection ex: vaginal infections or skin infections or oral cavity

infections so cell wall synthesis Inhibitors are main (first line) treatment of

systemic invasive candidiasis , but aren’t the drug of choice to treat local or

cutaneous candidiasis .


so in this case we have a new category of drugs called cutaneous antimycotic drugs .

(used to treat fungal systemic infectionاللي اخذناهم قبل كانو )

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Drugs For Cutaneous Mycotic Infections

• Dermatophytes/tinea

Dermatophytes = infect the skin

We usually call a fungal infection of the skin and associated

tissue based on the location of infection.

• Classified according to affected site, e.g., tinea pedis

• Main fungal classes that cause cutaneous infections:

1. Trichophyton

2. Microsporum

3. Epidermophyton

There is another form of skin infection is called tinea versicolor caused by

species Malaysia.

ة . بس مزعجين وبرضو لازم يتعالجو لانه هاي الامراض معدي life threatening هما مش

Tinea capitis = الثعلبة

Tinea corporis (in trunk) this isn't ring worm disease , not caused by parasites.

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Squalene Epoxidase Inhibitors

First drugs that use to treat cutaneous fungal infections.

These drugs are interfere with activation or conversion of squalene to squalene -

2.3 epoxide .

malassezia


There is (لحد الآن يعني) two drugs that interfere within ergosterol synthesis but in

different step of pathway

. squaleneوال azolesاللي هما ال

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Squalene Epoxidase Inhibitors

Mechanism of action

• Inhibition of squalene epoxidase

The target of these drugs are squalene epoxidase .

two consequences for squalene Inhibitors :

1) Blocking the biosynthesis of ergosterol , so there isn't

enough ergosterol to form functional viable fungal cell

membrane.

2) Squalene accumulation affects membrane permeability

بتراكم squaleneفال ما الو دخل بالخطوة اللي بعده( squalene)ال squaleneهون نتيجة تثبيط تحول ال

and the squalene is known to be toxic if it starts accumulating at high levels (toxic

to fungal cells ) , the accumulation of squalene affects membrane permeability

that leads to leakage of fungal cellular constituents to outside.


Terbinafine (example of squalene inhibitor)

• Drug of choice for treating dermatophyte onychomycoses (in nails )

• More effective than itraconazole or griseofulvin for Trichophyton

لكن يعتبر ال (onychomycosesلعدوى ال)غم وجود اكثر من دوا لعلاج هذه ار

terbinafine لانه : رقم واحد

1. Better tolerated ( سميةناحية الن م )

2. Required short duration of therapy relatively with other drugs.

• Useful in the treatment of tinea capitis -oral terbinafine (topical ineffective)

بالعكس ، skinـعال بس ومش محدود locallyهي بالعادة ما بتكون بس cutaneous fungal infectionsال

... هو orallyيعني ادوية بنعطيها systemic drugsبتتعالج بال cutaneous fungal infectionsمعظم ال

. orallyلكن يفضل topicalموجود

-topical can be used with other types, e.g., pedis, corporis…

يعني ما بتتعالج systemic(orally)ما بنعاجلها الا tinea capitisانه الثعلبة ال exceptionفي عنا

locally ال ابدا ...locally . يستخدم في الحالات الاخرى

Terbinafine

Antifungal spectrum

Effective against all dermatophyte that cause skin in nail fungal

infection .

• Effective against: Trichophyton, Candida, Epidermophyton,

Scopulariopsis Pharmacokinetics

• Oral and topical

• Prolonged half-life (200-400 h). Why? (Very long)

• Extensively metabolized by CYP450(type of cyp450 system) and excreted renally

• Potent inhibitor of CYP2D6


خاصة اذا كان بصيرله لهذا الدوا dose adjusmentلازم نعمل terbinafineدوا ثاني مع ال اذا اعطينا

metabolize by CYP2D6 لانه الterbinafine بعملinhibition for CYP2D6 عناته بزيد ال م plasma

of drug concntration .

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Griseofulvin (the second example of squalene inhibitor)

• MOA: disruption of the mitotic spindle(M phase) and inhibition of fungal mitosis

Unique mechanism of action that interferes within

fungal cell division .

• Has been largely replaced by oral terbinafine for nail

infection (onychomycosis ) … griseofulvin doesn’t first

line for nail infection.

• Still used to treat dermatophytosis of the scalp and

hair(tinea capitis) .

• Fungistatic

• Requires long duration of treatment. Why? Because the duration of treatment is

dependent on formation new nail .

complete cureترة طويلة بس ال لف griseofulvinبنعطي ال effective therapy ا عني مشان يصير عني

of infection ( بصير لما يصيرreplacement of infected nail) وتعويضه بإظفر جديد وهاي الفترة بتاخذ

(replacement of infected nail)شهر فيعني فترة العلاج بتعتمد على ا

• INDUCES hepatic CYP450 activity

CYP450عن طريق ال metabolismللادوية اللي بحدثلها metabolismن عكس الباقي بزيد الوه

which means its lower plasma concentration

تاعه رح يكون سريع. metabolism فبنزيد الجرعة تاعته لانه ال dose adjusment ممكن نحتاجف

• Contraindicated in pregnancy and porphyria patients


Nystatin

• Polyene

• Very similar to amphotericin B

The defferences is very limited between amphotericin B and

nystatin , so they have the same mechanism of action

(identical ) , so Nystatin can make hydrophobic interactions

with ergosterol in fungal cell membrane leading to creation

of pores that leading to leakage of fungal intracellular

constituents mainly electrolytes specifically k+ which

disrupts fungal cell membrane potential leading fungal cell death, also Nystatin has the

same mechanism of resistance for amphotericin B .

amphotericin B for treatment of systemic fungalلما اخذناه مع ا nystatinلالسؤال انه ليش ا

infection لا، في سببين الى انهnystatin تصنف مع الادوية الcutaneous :

1) When Nystatin is given orally , it is poorly absorbed (not absorbed from GIT)

. orally(systemic)عني ما بنستفيد لما نعطيه ي

2) It is extremely toxic compound ( so we can't use IV ) and it is associated with

nephrotoxicity ( more severe than nephrotoxicity that caused by amphotericin B )

• Used for the treatment of oral and cutaneous Candida

• Routes:

❑No parenteral use (toxic)

❑Orally (“swish and swallow” or “swish and spit”)

It use if patient has local fungal infection in mucus membrane of oral cavity

عني للمضمضة فقط مش للبلع . ي

❑Intravaginally (vagina candidiasis)


❑topically (يستخدم موضعيا)

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Azole Antifungals :interfere with ergosterol synthesis .

Azole has two components : (the difference between them is very simplistic in structure)

1) Imidazole Antifungals

Are used to treat cutaneous fungal infections.

2) Triazole Antifungals

Treat systemic fungal infections (حكينا عنه قبل وعن العدوى اللي بعالجهم)

كن نستخدمهم لعلاج ( ممfungal systemic functionفي بعضهم بالاضافة انه بنستخدمهم ) triazoleال *

)مثال واحد( واللي هو : والمثال اللي عليهم والمفروض تعرفوه cutaneous fungal infectionال

Inraconazole is triazole antifungals , it is drug of choice to to treat systemic

blastomycosis, paracoccidiomycosis and histoplasmosis , so mainly used in

systemic fungal infections , and it can be used to treat cutaneous fungal

infections such as tinea capitis …etc , but itraconazole such as griseofulvin has

been largely replaced by terbinafine.

Imidazoles very big family of drugs.

• Drugs:

❑Butoconazole ❑Clotrimazole

❑Econazole ❑Ketoconazole

❑Miconazole ❑Oxiconazole

❑Sertaconazole ❑Sulconazole

❑Terconazole ❑Tioconazole


They all have similar uses for the treatment of cutaneous fungal infections and

different types of tinea.

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Imidazoles

• Wide range of antifungal activity

• Still used topically for the treatment of tinea corporis, tinea cruris, tinea

pedis, and oropharyngeal and vulvo-vaginal candidiasis

Usually imidazole use topically.

• Miconazole: available as a buccal tablet

. local بتنحط مش للبلع oral cavityفقط بال يعني حبوب بتنحط buccal tabletل ا

• Clotrimazole: available as throat lozenge

جل بنحط داخل التجويف الفموي مش للبلع برضو . throat lozengeل ا

terbinafineبالاضافة مع علاجها الحبوب ال tinea capitisبو لعلاج الثعلبة ال وفي منه متوفر على شكل شام

• Ketoconazole: historically used for systemic mycoses (highly toxic –causes severe liver

injury)

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Ciclopirox (cutaneous antifungals drugs)

• MOA: Inhibits transport of essential elements in the fungal cell

amino acid and)بدها metabolic processesعندها fungal cell: ال MOAال

nitrogenous bases) ع يدخلو عليها عشان تصن(proteins, RNA,DNA ) وبالتالي اذا

inhibition for transport of these important elements that canعملت

result in inhibition of fungal cell growth .

• Disrupts synthesis of DNA, RNA and proteins

• Available as a shampoo for seborrheic dermatitis


• Available as a gel/cream for Tinea pedis, tinea corporis, tinea cruris, cutaneous

candidiasis, and tinea versicolor

. للاستخدام الموضعيتوفرة هاي الادوية وبرضو م

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Tavaborole (the last example of cutaneous antifungal drugs)

Tavaborole is target protein synthesis ( this drugs is protein synthesis Inhibitors)

(activity against bacteria)ذا الدواء ما عنده ه

• MOA: inhibits fungal aminoacyltransfer ribonucleic acid synthetase (fungal ribosome)

→ inhibition of fungal protein synthesis

It active against variety of fungal species such as trichophyton species , candida albicans

that all cause cutaneous fungal infections.

• Can be used for the treatment of toenail onychomycosis (requires 48 weeks of

treatment)


You are a physician-scientist in a drug development company. You

are leading a research group investigating the development of

potent antifungal drugs. Due to decreased funding, the company

asked you to stop one of the undergoing projects by your team.

Which project will you stop?

(A) Development of drug A – a potent inhibitor of fungal DNA synthesis

(B) Development of drug B – activator of fungal CYP450 microsomal enzymes

(C) Development of drug C – inhibitor of fungal aminoacyl-transfer ribonucleic acid

synthetase

(D) Development of drug D – inhibitor of fungal β(1,3)-D-glucan synthase

(E) Development of drug E – inhibitor of chitin polymerization

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. . بالتوفيق .

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