L-28 Antifungal Agents: Imidazoles and Triazoles

Antifungal Agents

• Work to treat superficial fungal infections
• Tinea refers to cutaneous fungal infections of a dermatophyte
• Dermatophytes include Microsporum, Trichophyton, and Epidermophyton

Subtypes of dermatophyte

• Tinea corporis occurs on body surfaces excluding feet, scalp, nails, and groin. Generally ringworm
• Tinea pedis mostly occurs on the foot. Athlete's foot
• Tinea cruris occurs in the groin, generally jock itch
• Tinea unguium occurs on finger or toenails. Onychomycosis
• Tinea capitis occurs on head and scalp
• Tinea faciei occurs on the face
• Majocci granuloma is the term for when dermatophyte infections penetrate the hair follicle and involve the dermis

Imidazoles

• Clotrimazole
• Miconazole
• Ketoconazole
• Econazole
• Sulconizole
• Oxiconazole
• Sertaconazole

Triazoles

• Itraconazole
• Fluconazole

Mechanism of Action for Imidazoles and Triazoles

• These inhibit fungal sterol/ ergosterol synthesis by inhibiting the enzyme cytochrome P-450, which converts lanosterol to ergosterol

Important note

• Topical azoles aren't effective against hair or nail fungal infections

Clotrimazole and Miconazole facts

• These are topical therapy, and over the counter medications
• Used for dermatophyte infections such as tinea pedis, tinea cruris, and tinea corporis
• Can also treat tinea versicolor, and tinea nigra
• Side effects consist of irritation, burning/stinging, erythema, pruritus, and contact dermatitis
• Other topical agents effective against dermatophytes treat infections such as tinea pedis, tinea cruris, tinea corporis, tinea versicolor, and cutaneous candidiasis

Topical agents that are effective against dermatophytes

• Econazole
• Oxiconazole
• Sulconazole
• Sertaconazole

Ketoconazole facts

• Topical and oral options are available
• Treats dermatophytic infections including tinea pedis, tinea cruris, and tinea corporis
• Also treats tinea versicolor, and seborrheic dermatitis
• Orally, it treats chromomycosis and paracoccidioidomycosis
• Also treats cutaneous candidiasis
• Oral dose side effects: hepatotoxicity, gynecomastia, and QT interval prolongation
• Systemic ketoconazole shouldn't be used for skin and nail infections
• Should only use for systemic fungal infections when no other medication is available

Adverse effects of Itraconazole

• Hepatotoxicity
• Should not be used with congestive heart failure, CHF, or a history of CHF or ventricular dysfunction
• Contraindicated in pregnant women or women considering pregnancy
• US Boxed Warning says itraconazole can cause or exacerbate congestive heart failure

Itraconazole

• Orally therapeutic
• Treats, dermatomycoses, tinea pedis, tinea cruris, tinea corporis, and tinea versicolor
• Treats tinea capitis, onychomycosis, and cutaneous candidiasis.

Fluconazole

• Orally therapeutic
• Only for serious fungal infections when no other antifungal therapies are available
• Treats dermatomycoses, tinea pedis, tinea cruris, tinea corporis, tinea versicolor and tinea capitis
• Treats onychomycosis as well as cutaneous candidiasis
• Side effects consist of rare hepatotoxicity; must monitor liver toxicity with long term use

Allylamines

• Terbinafine
• Naftifine

Benzylamines

• Butenafine

Mechanism of Action for Allylamines and Benzylamines

• Inhibit fungal squalene epoxidase to reduce synthesis of ergosterol
• Leads to accumulation of squalene which then leads to increased membrane permeability and cell death
• The accumulation of toxic metabolite squalene can make fungal cells fungicidal in most situations
• In general, they are more effective than topical azole agents against common dermatophytes and tinea infections
• However, topical terbinafine and butenafine are less effective than topical azoles against candida skin infections

Terbinafine

• Both topical and oral
• Is an allylamine. Has a prolonged terminal half-life of 200 to 400 hours reflecting slow release from tissues.
• Treats tinea pedis, tinea cruris, and tinea corporis topically
• Orally, treats tinea capitis, and chromoblastomycosis, and is especially effective for onychomycosis
• Better tolerated and can be more effective than either itraconazole or griseofulvin
• Prolonged therapy of generally 3 months but considerably shorter than griseofulvin
• Side effects are hepatotoxicity and dysgeusia alongside gastrointestinal upset
• Should not be recommended with patients in renal, hepatic failure, or pregnant women

Naftifine

• Topical allylamine
• Treats tinea pedis, tinea cruris, and tinea corporis
• Adverse effects: skin irritation, burning sensation of skin, xeroderma, erythema, and agranulocytosis.

Butenafine

• Topical treatment using benzylamine
• Treats tinea pedis, tinea cruris, tinea corporis, as well as tinea versicolor
• Adverse effects: Skin irritation, burning sensation of skin, and erythema

Griseofulvin

• Oral benzofurans
• Mechanism of action: Binds to keratin precursor cells to accumulate in keratin-rich tissues (nails/hair)
• Enters the fungal cell and disrupts fungal mitosis and microtubules
• Treats tinea capitis as an oral treatment
• Treats onychomycosis that is largely replaced by oral terbinafine.
• Is fungistatic that requires a long duration of treatment of about 6 to 12 months for onychomycosis,
• It is important to continue until infected skin, hair, or nail is completely replaced by normal tissue
• Adverse effects: hepatotoxicity and teratogenicity along with CNS disturbances, increased cytochrome P-450 and warfarin metabolism
• Should not be used with pregnancy, breastfeeding, porphyria and liver/hepatic failure

Ciclopirox

• Is a topical pyridone antimycotic agent
• Inhibits transmembrane transport of essential substrates to disrupt synthesis of DNA, RNA, and protein
• Treats tinea pedis, tinea cruris, tinea corporis, onychomycosis, cutaneous candidiasis, and seborrheic dermatitis

Tolnaftate

• Topical thiocarbamate
• Reversible and noncompetitive inhibitor of fungal squalene epoxidase
• Treats tinea pedis, tinea cruris. Tinea corporis. But is not effective against candida infections.
• Side effects include contact dermatitis, pruritus, and stinging of the skin.

Warts

• Molluscum Contagiosum
• Herpes Simplex Virus Infections
  • Herpes gingivostomatitis
  • Herpes labialis
  • Cutaneous herpes infections
  • Eczema herpeticum
  • Neonatal herpes simplex

Imiquimod

• Topical
• Mechanism of action: Binds toll-like receptor 7 of macrophages, monocytes, and dendritic cells
• It is a topical antitumor immune response modifier
• Treats anogenital warts, and actinic keratosis. Side effects itch and burn at the site of application as well as rashes

Cimetidine

• Is an oral histamine H2 antagonist that has an immunomodulatory effect
• Treats warts and molluscum contagiosum. Side effects: skin irritation, superficial erosion/crusting, and burning sensation

Warts Management

• Topical Salicylic Acid Preparations exfoliate the hyperkeratotic dead skin of warts and induces inflammation
• Topical Retinoids: Are antiproliferative and anti-inflammatory.
• They treat flat warts more efficiently, though used for common warts as an adjunct treatment
• Topical Chemotherapy: 5-Fluorouracil is a chemotherapeutic agent that promotes cell replication
• Used for recalcitrant warts

Molluscum Treatment

• No gold standard or FDA-approved
• The best treatment depends on age of the patient, the number of legions, and location of the lesions
• Some approved includes Imiquimod cream, cimetidine, as well as tretinoin and potassium hydroxide

Mucocutaneous Herpes Infection Management

• Guanine analogs inhibit viral DNA polymerase to cause chain termination
• Reduces treatment goals shortening duration of eruption and preventing dehydration
• Systemic treatments: acyclovir and valacyclovir that shortens diseases length within 1 to 2 days of symptoms
• Topical Treatments: acyclovir, penciclovir, docosanol, acyclovir and hydrocortisone reduces effect better than systemic treatments
• Pain control: lidocaine containing creams

Antiparasitic Agents

• Lindane. Topical
• Directly absorbs parasites and ova through exoskeleton to stimulate the nervous system to cause seizures and ultimately arthropod death
• Treats scabies, and head lice and crab lice infestation
• Adverse effects: contact dermatitis, eczematous rash, aplastic anemia, and CNS issues
• Should be used among infants, children, and pregnant women

Other Antiparasitic Agents

• Crotamiton
• Crotamiton has scabicidal activity against Sarcoptes scabiei, but the mechanism is unknown
• Antipruritic effects come from inhibition of histamine, serotonin, and protease-activated receptors
• Treats scabies and head lice infestation as well as pruritus
• Can cause localized warm feeling

Permethrin

• Blocks Na channels so depolarization of membranes, ultimately paralyzing the parasites.
• Adverse effects consist of pruritus, skin rash and edema

Ivermectin

• Topical and oral: a semisynthetic anthelminthic agent, that enhances neuro transmission and chloride channels to cause cell hyperpolarization and cell death
• Topically, used to treat head lice infestations with limited use against adult onchocerca volvulus parasites as side effects show abdominal and joint pain.

Praziquantel

• Oral.
• Used to treat infections caused by schistosoma but not to developing schistosomula but is more effective against adult schistosomas.
• Adverse effects: diarrhea and headaches

Immunotherapy for Melanoma

• Immunotherapy treats certain cancers by working with your immune system
• Can cause the immune system to attack organs and tissues, causing damage, or death
• The attack and damage is serious and can happen any time during or after treatment
• Serious problems are pneumonitis, colitis, hepatitis, hormone gland problems as well as skin problems
• Ipilimumab is an anti- CTLA-4 antibody
• Pembrolizumab as well as nivolumab are anti- PD-1 antibodies
• T-Vec is an oncolytic virus therapy,
• Aldesleukin is an Interleukin-2 (IL-2) treatment

Pembrolizumab

• It is an anti-PD-1 antibody that binds to PD-1 receptor found on T-cells and stops ligands 1-2 on tumor cells
• With treatment risk of autoimmunity can occur and is used to treat melanoma with lymph node involvement or cancer, postresection.

Nivolumab

• Binds to PD-1 that blocks cell interactions
• It helps with the autoimmune issue side effects. Used in patients with metastasis

Mechanism of action of Ipilimumab

• Humanized antigen one IgG1 helps lymphocytes and cell function down regulation
• This down regulation helps by treating metastatic melanoma. side effects for pneumonitis and rash come in effect.
• Box warnings with fatal reaction due to dermatitis, endocrinopathy and neropathy

Aldesleukin

• IL-2
• Promotes differentiation and proliferation of B and T cells
• Treats the patient w/ tumor necrosis and loss of tone and the extraversion loss in vascular system and proteins

Talimogene laherparepvec

• Weakened form of herpes simples that works to inject and directly impact melanoma tumors, cancer immunity cycle helps destroy cancerous cells.
• Approved by the FDA approved for treating cancer in the skin and nodes.
• Common side effects included tiredness or chills

Targeted Therapy for Melanoma

• The treatment works to block molecules and regulate the molecules growth and stop with the use of Encorafenib and MEK
• This may stimulate cancerous growth.

Encorafenib

• Oral w/ treatment side affects such as drug hypo sensitivity
• It's an inhibitor to help help the pathway of enzymes for the RAS
• Helps with patients or with metastasis

Cobimetinib

• Used with vermurfenib with kinase inhibitor that effects with two kinases in that ERK pathway
• This reversible combination effect helps unresectable patients
• Side effects highpertension, rash and visual impair

Nonmelanoma

• Squamous cell Carcinomas
• Surgery is the main treatment.
• PDT may be needed following treatment.
• Systemic Therapies involved: Chemo, Immune or targeted therapy.

Chemotherapy

• With dicoflenac and fluorouracil and mebutate
• Topical Imiquimod: with basal cells

Vismodegib and Sonidegib

• The are inhibitors that target Hedgehog pathways and blocks this genetic growth of basal cell carcinoma
• The therapies effect BCCS if cancer is recurrent in the skin.

Immunotherapy

• Immune system checkpoint
• The therapy stops tumors but with long term life threatening side effects.