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Flucytosine, Griseofulvin, and Terbinafine

In addition to the 3 other major classes of antifungal Antifungal Azoles agents ( azoles Azoles Azoles are a widely used class of antifungal medications inhibiting the production of ergosterol, a critical component in the fungal cell membrane. The 2 primary subclasses of azoles are the imidazoles, older agents typically only used for topical applications, and the triazoles, newer agents with a wide spectrum of uses. Azoles, polyenes Polyenes Polyenes are a class of fungicidal agents that consist of 2 primary drugs in current use, namely, nystatin and amphotericin B. Both these drugs exert their effects by binding to ergosterol (a critical component of fungal cell membranes) and creating pores in the membrane, leading to the leakage of intracellular components and ultimately cell lysis. Polyenes, and echinocandins Echinocandins Echinocandins are a group of fungicidal agents that target the fungal cell wall. Echinocandins inhibit β-glucan synthase, which in turn inhibits the production of β-glucan, a key structural component of fungal cell walls. The 3 primary drugs in this class include caspofungin, micafungin, and anidulafungin. Echinocandins), several other clinically important antifungal Antifungal Azoles agents are used, including flucytosine, griseofulvin, and terbinafine. Each drug has a distinct mechanism of action and unique characteristics and indications. Flucytosine is a pyrimidine analog that disrupts fungal DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure and RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR). Flucytosine is always used in combination with other antifungal Antifungal Azoles agents and is primarily used to treat cryptococcal meningitis Cryptococcal meningitis Meningeal inflammation produced by cryptococcus neoformans, an encapsulated yeast that tends to infect individuals with acquired immunodeficiency syndrome and other immunocompromised states. The organism enters the body through the respiratory tract, but symptomatic infections are usually limited to the lungs and nervous system. The organism may also produce parenchymal brain lesions (torulomas). Clinically, the course is subacute and may feature headache; nausea; photophobia; focal neurologic deficits; seizures; cranial neuropathies; and hydrocephalus. Cryptococcus/Cryptococcosis. Both griseofulvin and terbinafine act within the stratum corneum Stratum corneum Skin: Structure and Functions of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions and are used to treat dermatophyte infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions, hair, and nails.

Last updated: 29 Mar, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Classification and Chemistry

Classification

In addition to the 3 major classes of antifungal Antifungal Azoles agents ( azoles Azoles Azoles are a widely used class of antifungal medications inhibiting the production of ergosterol, a critical component in the fungal cell membrane. The 2 primary subclasses of azoles are the imidazoles, older agents typically only used for topical applications, and the triazoles, newer agents with a wide spectrum of uses. Azoles, polyenes Polyenes Polyenes are a class of fungicidal agents that consist of 2 primary drugs in current use, namely, nystatin and amphotericin B. Both these drugs exert their effects by binding to ergosterol (a critical component of fungal cell membranes) and creating pores in the membrane, leading to the leakage of intracellular components and ultimately cell lysis. Polyenes, and echinocandins Echinocandins Echinocandins are a group of fungicidal agents that target the fungal cell wall. Echinocandins inhibit β-glucan synthase, which in turn inhibits the production of β-glucan, a key structural component of fungal cell walls. The 3 primary drugs in this class include caspofungin, micafungin, and anidulafungin. Echinocandins), there are several other clinically important antifungals agents. These drugs include:

  • Flucytosine (also known as 5-fluorocytosine (5- FC Fc Crystallizable fragments composed of the carboxy-terminal halves of both immunoglobulin heavy chains linked to each other by disulfide bonds. Fc fragments contain the carboxy-terminal parts of the heavy chain constant regions that are responsible for the effector functions of an immunoglobulin (complement fixation, binding to the cell membrane via fc receptors, and placental transport). This fragment can be obtained by digestion of immunoglobulins with the proteolytic enzyme papain. Immunoglobulins: Types and Functions))
  • Griseofulvin
  • Terbinafine

Chemical structures

  • Flucytosine: a pyrimidine analog
  • Griseofulvin: an oxaspiro compound (a cyclic structure in which 1 of the ring components is an oxygen molecule)
  • Terbinafine:
    • An allylamine: contains a nitrogen Nitrogen An element with the atomic symbol n, atomic number 7, and atomic weight [14. 00643; 14. 00728]. Nitrogen exists as a diatomic gas and makes up about 78% of the earth’s atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. Urea Cycle atom and carbon-carbon double bond
    • Contains an alkynyl functional group (carbon-carbon triple bond)

Pharmacodynamics: Mechanisms of Action

Flucytosine

Flucytosine is a pyrimidine analog that disrupts both DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure and RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR).

  • Enters fungal cells via a protein known as cytosine Cytosine A pyrimidine base that is a fundamental unit of nucleic acids. Nucleic Acids permease
  • Inside the fungal cell, flucytosine is converted to its active form 5-fluorouracil 5-Fluorouracil A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. Antimetabolite Chemotherapy ( 5-FU 5-FU A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. Antimetabolite Chemotherapy) by the enzyme cytosine Cytosine A pyrimidine base that is a fundamental unit of nucleic acids. Nucleic Acids deaminase.
    • Mammals lack cytosine Cytosine A pyrimidine base that is a fundamental unit of nucleic acids. Nucleic Acids deaminase → selective effects on microbial cells
    • Conversion to 5-FU 5-FU A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. Antimetabolite Chemotherapy by intestinal flora is thought to be responsible for toxicity Toxicity Dosage Calculation in humans.
  • 5-FU 5-FU A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. Antimetabolite Chemotherapy:
    • Competes with uracil Uracil One of four nucleotide bases in the nucleic acid RNA. Nucleic Acids → incorporated into RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure strands, disrupting RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR) → inhibits fungal protein synthesis Synthesis Polymerase Chain Reaction (PCR)
    • Irreversibly inhibits thymidylate synthases → inhibition of thymine Thymine One of four constituent bases of DNA. Nucleic Acids production → inability to synthesize or correct DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure damage
  • May exert fungistatic Fungistatic Azoles or fungicidal Fungicidal Polyenes effects depending on the organism
  • Synergistic effects with amphotericin B Amphotericin B Macrolide antifungal antibiotic produced by streptomyces nodosus obtained from soil of the orinoco river region of venezuela. Polyenes and azoles Azoles Azoles are a widely used class of antifungal medications inhibiting the production of ergosterol, a critical component in the fungal cell membrane. The 2 primary subclasses of azoles are the imidazoles, older agents typically only used for topical applications, and the triazoles, newer agents with a wide spectrum of uses. Azoles
  • Resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing:
    • Primary/intrinsic resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing: due to mutations in cytosine Cytosine A pyrimidine base that is a fundamental unit of nucleic acids. Nucleic Acids permease → ↓ 5- FC Fc Crystallizable fragments composed of the carboxy-terminal halves of both immunoglobulin heavy chains linked to each other by disulfide bonds. Fc fragments contain the carboxy-terminal parts of the heavy chain constant regions that are responsible for the effector functions of an immunoglobulin (complement fixation, binding to the cell membrane via fc receptors, and placental transport). This fragment can be obtained by digestion of immunoglobulins with the proteolytic enzyme papain. Immunoglobulins: Types and Functions uptake into fungal cells
    • Secondary/acquired resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing:
      • Due to mutations in cytosine Cytosine A pyrimidine base that is a fundamental unit of nucleic acids. Nucleic Acids deaminase
      • Resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing is significant when flucytosine is used as monotherapy.
    • Resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing among C. albicans: approximately 10%
Antifungal agents and mechanisms of action

Antifungal Antifungal Azoles agents and mechanisms of action

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Griseofulvin

The exact mechanisms of griseofulvin are not completely understood, but 2 general mechanisms of action have been suggested:

  • Binds to keratin Keratin A class of fibrous proteins or scleroproteins that represents the principal constituent of epidermis; hair; nails; horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms a coiled-coil alpha helical structure consisting of type I keratin and a type II keratin, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. Alpha-keratins have been classified into at least 20 subtypes. In addition multiple isoforms of subtypes have been found which may be due to gene duplication. Seborrheic Keratosis in newly forming skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions, rendering new human cells resistant to invasion
    • Prevents infection of new skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions structures → fungistatic Fungistatic Azoles agent
    • Over time (weeks to months), the new, uninfected hair/ skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions/nail structures will have replaced the old, infected ones.
  • Inhibits cell replication in dermatophytes Dermatophytes Tinea infections are a group of diseases caused by fungi infecting keratinized tissue (hair, nails, and skin). These infections are termed dermatomycoses and are caused by the dermatophyte fungi. There are approximately 40 dermatophyte fungi that are part of 3 genera, including Trichophyton, Epidermophyton, and Microsporum. These infections can affect any part of the body but occur most often in warm, moist regions like the groin and the feet. Dermatophytes/Tinea Infections:
    • Binds to tubulin, inhibiting microtubule assembly Assembly The assembly of viral structural proteins and nucleic acid (viral DNA or viral RNA) to form a virus particle. Virology 
    • Leads to inhibition of the formation of the mitotic spindle → prevention of mitosis Mitosis A type of cell nucleus division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. Cell Cycle at metaphase Metaphase The phase of cell nucleus division following prometaphase, in which the chromosomes line up across the equatorial plane of the spindle apparatus prior to separation. Cell Cycle

Terbinafine

Terbinafine exerts its effects by causing deterioration of the fungal cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane by inhibiting the production of squalene Squalene A natural 30-carbon triterpene. Cholesterol Metabolism epoxide, a precursor to ergosterol Ergosterol A steroid occurring in fungi. Irradiation with ultraviolet rays results in formation of ergocalciferol (vitamin d2). Azoles.

  • Ergosterol Ergosterol A steroid occurring in fungi. Irradiation with ultraviolet rays results in formation of ergocalciferol (vitamin d2). Azoles synthesis Synthesis Polymerase Chain Reaction (PCR):
    • Squalene Squalene A natural 30-carbon triterpene. Cholesterol Metabolism is converted to squalene Squalene A natural 30-carbon triterpene. Cholesterol Metabolism epoxide by the enzyme squalene Squalene A natural 30-carbon triterpene. Cholesterol Metabolism epoxidase.
    • Squalene Squalene A natural 30-carbon triterpene. Cholesterol Metabolism epoxide is converted to lanosterol Lanosterol A triterpene that derives from the chair-boat-chair-boat folding of 2, 3-oxidosqualene. It is metabolized to cholesterol and cucurbitacins. Cholesterol Metabolism.
    • Lanosterol Lanosterol A triterpene that derives from the chair-boat-chair-boat folding of 2, 3-oxidosqualene. It is metabolized to cholesterol and cucurbitacins. Cholesterol Metabolism is converted to ergosterol Ergosterol A steroid occurring in fungi. Irradiation with ultraviolet rays results in formation of ergocalciferol (vitamin d2). Azoles by the enzyme lanosterol Lanosterol A triterpene that derives from the chair-boat-chair-boat folding of 2, 3-oxidosqualene. It is metabolized to cholesterol and cucurbitacins. Cholesterol Metabolism 14-α-demethylase (14-α-demethylase is inhibited by azoles Azoles Azoles are a widely used class of antifungal medications inhibiting the production of ergosterol, a critical component in the fungal cell membrane. The 2 primary subclasses of azoles are the imidazoles, older agents typically only used for topical applications, and the triazoles, newer agents with a wide spectrum of uses. Azoles).
  • Terbinafine noncompetitively inhibits squalene Squalene A natural 30-carbon triterpene. Cholesterol Metabolism epoxidase.
  • Effects include:
    • Squalene Squalene A natural 30-carbon triterpene. Cholesterol Metabolism epoxide production → ↓ ergosterol Ergosterol A steroid occurring in fungi. Irradiation with ultraviolet rays results in formation of ergocalciferol (vitamin d2). Azoles
    • Fungi Fungi A kingdom of eukaryotic, heterotrophic organisms that live parasitically as saprobes, including mushrooms; yeasts; smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi, commonly known as molds, refer to those that grow as multicellular colonies. Mycology are unable to synthesize or maintain their cell membranes without ergosterol Ergosterol A steroid occurring in fungi. Irradiation with ultraviolet rays results in formation of ergocalciferol (vitamin d2). Azoles.
    • ↑ Fungal cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane permeability → cell lysis
  • Terbinafine exerts fungicidal Fungicidal Polyenes effects in dermatophytes Dermatophytes Tinea infections are a group of diseases caused by fungi infecting keratinized tissue (hair, nails, and skin). These infections are termed dermatomycoses and are caused by the dermatophyte fungi. There are approximately 40 dermatophyte fungi that are part of 3 genera, including Trichophyton, Epidermophyton, and Microsporum. These infections can affect any part of the body but occur most often in warm, moist regions like the groin and the feet. Dermatophytes/Tinea Infections.

Pharmacokinetics

Table: Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics of azoles Azoles Azoles are a widely used class of antifungal medications inhibiting the production of ergosterol, a critical component in the fungal cell membrane. The 2 primary subclasses of azoles are the imidazoles, older agents typically only used for topical applications, and the triazoles, newer agents with a wide spectrum of uses. Azoles
Drugs Flucytosine Griseofulvin Terbinafine
Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption
  • Not absorbed topically
  • Very poor water solubility
  • Improved oral absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption with fatty foods
Distribution
  • Minimal protein binding
  • Penetrates well into all body fluid compartments Body fluid compartments The adult human body is made up of 60% water and is divided into extracellular and intracellular fluid compartments. Extracellular fluid is present outside the cells and makes up two-thirds of the total body water. Intracellular fluid is present inside the cells and makes up two-thirds of the total body water. Body Fluid Compartments, including CSF
  • Stratum corneum Stratum corneum Skin: Structure and Functions ( keratin Keratin A class of fibrous proteins or scleroproteins that represents the principal constituent of epidermis; hair; nails; horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms a coiled-coil alpha helical structure consisting of type I keratin and a type II keratin, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. Alpha-keratins have been classified into at least 20 subtypes. In addition multiple isoforms of subtypes have been found which may be due to gene duplication. Seborrheic Keratosis layer) of skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions, hair and nails
  • Also concentrates in:
    • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy
    • Fat
    • Skeletal muscle
Metabolism Metabolized intracellularly by yeasts to its active form, 5-FU 5-FU A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. Antimetabolite Chemotherapy
  • Extensive hepatic metabolism
  • CYP450 inducer (drug-drug interactions)
  • Hepatic metabolism via CYP450 enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes to inactive metabolites
  • Moderate inhibitor of CYP2D6
Excretion
  • Renal elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy via glomerular filtration Glomerular filtration The kidneys are primarily in charge of the maintenance of water and solute homeostasis through the processes of filtration, reabsorption, secretion, and excretion. Glomerular filtration is the process of converting the systemic blood supply into a filtrate, which will ultimately become the urine. Glomerular Filtration, primarily as unchanged drug
  • T1/2: 3‒6 hours
  • Adjust dose in renal impairment.
  • Elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy:
    • Fecal (33%)
    • Perspiration
  • T1/2: 9‒24 hours
  • Elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy:
  • Effective T1/2: approximately 36 hours
  • Terminal T1/2: 200‒400 hours (very slow drug release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology from skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions and adipose tissue Adipose tissue Adipose tissue is a specialized type of connective tissue that has both structural and highly complex metabolic functions, including energy storage, glucose homeostasis, and a multitude of endocrine capabilities. There are three types of adipose tissue, white adipose tissue, brown adipose tissue, and beige or “brite” adipose tissue, which is a transitional form. Adipose Tissue: Histology)
CYP450: cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-induced Liver Injury
5-FU 5-FU A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. Antimetabolite Chemotherapy: 5-fluorouracil 5-Fluorouracil A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the thymidylate synthetase conversion of deoxyuridylic acid to thymidylic acid. Antimetabolite Chemotherapy
T1/2: half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics
Layers of the skin

Layers of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions:
Griseofulvin and terbinafine are distributed to the stratum corneum Stratum corneum Skin: Structure and Functions.

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Flucytosine

Indications

Flucytosine has a narrow spectrum of activity. Owing to its demonstrated synergy with other antifungal Antifungal Azoles agents and the high risk for secondary resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing when used as monotherapy, flucytosine is not used as a single agent.

  • Active against:
    • Cryptococcus Cryptococcus Cryptococcosis is an opportunistic, fungal infection caused by the Cryptococcus species. The principal pathogens in humans are C. neoformans (primary) and C. gattii. Cryptococcus neoformans is typically found in pigeon droppings and acquired by inhaling dust from contaminated soil. The majority of affected patients are immunocompromised. Cryptococcus/Cryptococcosis neoformans
    • Some Candida Candida Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis spp.
    • Chromoblastomycosis
  • Not active against:
    • Endemic mycoses Mycoses Diseases caused by fungi. Mycology: Histoplasma Histoplasma Histoplasmosis is an infection caused by Histoplasma capsulatum, a dimorphic fungus. The fungus exists as a mold at low temperatures and as yeast at high temperatures. H. capsulatum is the most common endemic fungal infection in the US and is most prevalent in the midwestern and central states along the Ohio and Mississippi River valleys. Histoplasma/Histoplasmosis, Blastomyces Blastomyces Blastomycosis is an infection caused by inhalation of the spores of the fungus, Blastomyces. Blastomyces species thrive in moist soil and decaying material and are common in the Ohio and Mississippi River valleys and the Great Lakes regions of the United States and Canada. Although most patients are asymptomatic, some can develop pneumonia. Blastomyces/Blastomycosis, Coccidioides Coccidioides Coccidioidomycosis, commonly known as San Joaquin Valley fever, is a fungal disease caused by Coccidioides immitis or Coccidioides posadasii. When Coccidioides spores are inhaled, they transform into spherules that result in infection. Coccidioidomycosis is also a common cause of community-acquired pneumonia and can cause severe disease in the immunocompromised. Coccidioides/Coccidioidomycosis
    • Aspergillus Aspergillus A genus of mitosporic fungi containing about 100 species and eleven different teleomorphs in the family trichocomaceae. Echinocandins
    • Zyomycetes
    • Most dermatophytes Dermatophytes Tinea infections are a group of diseases caused by fungi infecting keratinized tissue (hair, nails, and skin). These infections are termed dermatomycoses and are caused by the dermatophyte fungi. There are approximately 40 dermatophyte fungi that are part of 3 genera, including Trichophyton, Epidermophyton, and Microsporum. These infections can affect any part of the body but occur most often in warm, moist regions like the groin and the feet. Dermatophytes/Tinea Infections
  • Clinical uses:
    • Used in combination with amphotericin B Amphotericin B Macrolide antifungal antibiotic produced by streptomyces nodosus obtained from soil of the orinoco river region of venezuela. Polyenes to treat cryptococcal meningitis Cryptococcal meningitis Meningeal inflammation produced by cryptococcus neoformans, an encapsulated yeast that tends to infect individuals with acquired immunodeficiency syndrome and other immunocompromised states. The organism enters the body through the respiratory tract, but symptomatic infections are usually limited to the lungs and nervous system. The organism may also produce parenchymal brain lesions (torulomas). Clinically, the course is subacute and may feature headache; nausea; photophobia; focal neurologic deficits; seizures; cranial neuropathies; and hydrocephalus. Cryptococcus/Cryptococcosis and pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia (primary use)
    • Used in combination with itraconazole Itraconazole A triazole antifungal agent that inhibits cytochrome p-450-dependent enzymes required for ergosterol synthesis. Azoles to treat chromoblastomycosis
    • Used in combination with other agents for systemic, susceptible fungal infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, including:
      • Septicemia
      • Endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis
      • Urinary tract infections Urinary tract infections Urinary tract infections (UTIs) represent a wide spectrum of diseases, from self-limiting simple cystitis to severe pyelonephritis that can result in sepsis and death. Urinary tract infections are most commonly caused by Escherichia coli, but may also be caused by other bacteria and fungi. Urinary tract infections (UTIs)
      • Peritonitis Peritonitis Inflammation of the peritoneum lining the abdominal cavity as the result of infectious, autoimmune, or chemical processes. Primary peritonitis is due to infection of the peritoneal cavity via hematogenous or lymphatic spread and without intra-abdominal source. Secondary peritonitis arises from the abdominal cavity itself through rupture or abscess of intra-abdominal organs. Penetrating Abdominal Injury
      • Pulmonary infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease

Adverse effects

Flucytosine is often administered with the highly nephrotoxic agent amphotericin B Amphotericin B Macrolide antifungal antibiotic produced by streptomyces nodosus obtained from soil of the orinoco river region of venezuela. Polyenes Amphotericin B Amphotericin B Macrolide antifungal antibiotic produced by streptomyces nodosus obtained from soil of the orinoco river region of venezuela. Polyenes-induced renal impairment can lead to the accumulation of 5- FC Fc Crystallizable fragments composed of the carboxy-terminal halves of both immunoglobulin heavy chains linked to each other by disulfide bonds. Fc fragments contain the carboxy-terminal parts of the heavy chain constant regions that are responsible for the effector functions of an immunoglobulin (complement fixation, binding to the cell membrane via fc receptors, and placental transport). This fragment can be obtained by digestion of immunoglobulins with the proteolytic enzyme papain. Immunoglobulins: Types and Functions (which is renally cleared) and direct 5- FC Fc Crystallizable fragments composed of the carboxy-terminal halves of both immunoglobulin heavy chains linked to each other by disulfide bonds. Fc fragments contain the carboxy-terminal parts of the heavy chain constant regions that are responsible for the effector functions of an immunoglobulin (complement fixation, binding to the cell membrane via fc receptors, and placental transport). This fragment can be obtained by digestion of immunoglobulins with the proteolytic enzyme papain. Immunoglobulins: Types and Functions toxicity Toxicity Dosage Calculation, which includes:

  • Hematologic effects: due to bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis toxicity Toxicity Dosage Calculation
    • Leukopenia
    • Thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
  • GI and hepatic effects:
    • GI distress (6% of individuals): nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, and/or diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
    • ↑ Serum transaminases Transaminases A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Autoimmune Hepatitis
    • Hepatic necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage has been reported, but is rare.

Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation

  • Hypersensitivity to flucytosine (only absolute contraindication)
  • Use with extreme caution in individuals with:
    • Bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis depression
    • Hepatic impairment
    • Renal impairment
  • Avoid use as monotherapy.

Monitoring

  • CBC with differential: to monitor for signs of hematologic toxicity Toxicity Dosage Calculation
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy function tests: to monitor for signs of hepatotoxicity Hepatotoxicity Acetaminophen
  • BUN and creatinine: to monitor for signs of renal dysfunction, which may necessitate dosing adjustments
  • Serum flucytosine concentrations: narrow therapeutic window Therapeutic Window Dosage Calculation

Griseofulvin

Indications

Griseofulvin is primarily used to treat dermatophyte infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease of the hair, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions, or nails. However, griseofulvin is being replaced by newer agents such as terbinafine or itraconazole Itraconazole A triazole antifungal agent that inhibits cytochrome p-450-dependent enzymes required for ergosterol synthesis. Azoles for many of its indications.

  • Active against:
    • Trichophyton Trichophyton A mitosporic fungal genus and an anamorphic form of arthroderma. Various species attack the skin, nails, and hair. Dermatophytes/Tinea Infections spp.
    • Microsporum Microsporum A mitosporic oxygenales fungal genus causing various diseases of the skin and hair. The species microsporum canis produces tinea capitis and tinea corporis, which usually are acquired from domestic cats and dogs. Teleomorphs includes arthroderma (nannizzia). Dermatophytes/Tinea Infections spp.
    • Epidermophyton Epidermophyton A fungal genus which grows in the epidermis and is the cause of tinea. Dermatophytes/Tinea Infections floccosum
  • Clinical indications:
    • Tinea pedis Tinea pedis Dermatological pruritic lesion in the feet, caused by Trichophyton rubrum, T. mentagrophytes, or Epidermophyton floccosum. Dermatophytes/Tinea Infections: “athlete’s foot Foot The foot is the terminal portion of the lower limb, whose primary function is to bear weight and facilitate locomotion. The foot comprises 26 bones, including the tarsal bones, metatarsal bones, and phalanges. The bones of the foot form longitudinal and transverse arches and are supported by various muscles, ligaments, and tendons. Foot: Anatomy
    • Tinea cruris Tinea cruris Fungal infection of the groin. The main causative fungus is Trichophyton. Dermatophytes/Tinea Infections: “jock itch,” typically affecting the groin Groin The external junctural region between the lower part of the abdomen and the thigh. Male Genitourinary Examination
    • Tinea corporis Tinea corporis Dermatophytes/Tinea Infections: “ ringworm Ringworm Dermatophytes/Tinea Infections,” anywhere on the body
    • Tinea barbae: an infection of the beard and mustached areas of the face, typically seen in adult men
    • Tinea capitis Tinea capitis Ringworm of the scalp and associated hair mainly caused by species of Microsporum; Trichophyton; and Epidermophyton, which may occasionally involve the eyebrows and eyelashes. Dermatophytes/Tinea Infections: infection of the scalp and hair shaft
      • Efficacy is improved when combined with a shampoo containing selenium Selenium An element with the atomic symbol se, atomic number 34, and atomic weight 78. 97. It is an essential micronutrient for mammals and other animals but is toxic in large amounts. Selenium protects intracellular structures against oxidative damage. It is an essential component of glutathione peroxidase. Trace Elements sulfide.
    • Tinea unguium Tinea unguium A fungal infection of the nail, usually caused by dermatophytes; yeasts; or nondermatophyte molds. Dermatophytes/Tinea Infections (onychomycosis): infection of the nails
  • Note: Griseofulvin is not effective for the treatment of tinea versicolor Tinea versicolor A common chronic, noninflammatory and usually symptomless disorder, characterized by the occurrence of multiple macular patches of all sizes and shapes, and varying in pigmentation from fawn-colored to brown. It is seen most frequently in hot, humid, tropical regions and is mostly caused by Malassezia furfur (formerly Pityrosporum orbiculare). Malassezia Fungi.

Adverse effects

Overall, griseofulvin has a relatively low level of toxicity Toxicity Dosage Calculation. Adverse effects may include:

  • GI symptoms: nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, and/or diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Headaches
  • Histamine reactions:
    • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
    • Rash Rash Rocky Mountain Spotted Fever
    • Flushing
  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions reactions:
  • Porphyria crisis
  • Systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus ( SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus) exacerbation
  • Hepatotoxicity Hepatotoxicity Acetaminophen (rare, but may be severe)
  • Possible cross-allergenicity with penicillins Penicillins Beta-lactam antibiotics contain a beta-lactam ring as a part of their chemical structure. Drugs in this class include penicillin G and V, penicillinase-sensitive and penicillinase-resistant penicillins, cephalosporins, carbapenems, and aztreonam. Penicillins
  • Leukopenia

Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation

  • Hypersensitivity to griseofulvin
  • Hepatic failure Hepatic failure Severe inability of the liver to perform its normal metabolic functions, as evidenced by severe jaundice and abnormal serum levels of ammonia; bilirubin; alkaline phosphatase; aspartate aminotransferase; lactate dehydrogenases; and albumin/globulin ratio. Autoimmune Hepatitis
  • Porphyria
  • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care

Terbinafine

Indications

  • Dermatophyte infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, especially onychomycosis
  • More effective than griseofulvin or itraconazole Itraconazole A triazole antifungal agent that inhibits cytochrome p-450-dependent enzymes required for ergosterol synthesis. Azoles for onychomycosis
  • Available in both oral and topical forms (unlike griseofulvin, which is only available as an oral formulation)

Adverse effects

Adverse effects are usually mild and self-limiting Self-Limiting Meningitis in Children.

  • GI distress: nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, and/or diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Histamine reactions:
    • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
    • Rash Rash Rocky Mountain Spotted Fever
    • Flushing
  • SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus exacerbation
  • Rare cases of hepatic and hematologic toxicity Toxicity Dosage Calculation have been reported.

Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation

  • Hypersensitivity to terbinafine or other allylamines (e.g., naftifine)
  • Chronic or active liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease
  • Use with caution in individuals with renal impairment.

Comparison of Antifungal Medications

Table: Comparison of antifungal Antifungal Azoles medications
Drug class (examples) Mechanism of action Clinical relevance
Azoles Azoles Azoles are a widely used class of antifungal medications inhibiting the production of ergosterol, a critical component in the fungal cell membrane. The 2 primary subclasses of azoles are the imidazoles, older agents typically only used for topical applications, and the triazoles, newer agents with a wide spectrum of uses. Azoles ( Fluconazole Fluconazole Triazole antifungal agent that is used to treat oropharyngeal candidiasis and cryptococcal meningitis in aids. Azoles, Voriconazole Voriconazole A triazole antifungal agent that specifically inhibits sterol 14-alpha-demethylase and cytochrome p-450 cyp3a. Azoles) Inhibits the production of ergosterol Ergosterol A steroid occurring in fungi. Irradiation with ultraviolet rays results in formation of ergocalciferol (vitamin d2). Azoles (a critical component of the fungal cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane) by blocking the lanosterol Lanosterol A triterpene that derives from the chair-boat-chair-boat folding of 2, 3-oxidosqualene. It is metabolized to cholesterol and cucurbitacins. Cholesterol Metabolism 14-α-demethylase enzyme
Polyenes Polyenes Polyenes are a class of fungicidal agents that consist of 2 primary drugs in current use, namely, nystatin and amphotericin B. Both these drugs exert their effects by binding to ergosterol (a critical component of fungal cell membranes) and creating pores in the membrane, leading to the leakage of intracellular components and ultimately cell lysis. Polyenes ( Amphotericin B Amphotericin B Macrolide antifungal antibiotic produced by streptomyces nodosus obtained from soil of the orinoco river region of venezuela. Polyenes, Nystatin Nystatin Macrolide antifungal antibiotic complex produced by streptomyces noursei, s. Aureus, and other streptomyces species. The biologically active components of the complex are nystatin a1, a2, and a3. Polyenes) Binds to ergosterol Ergosterol A steroid occurring in fungi. Irradiation with ultraviolet rays results in formation of ergocalciferol (vitamin d2). Azoles in the fungal cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane creating artificial pores in the membrane → results in leakage of cellular components and leads to cell lysis (death) Amphotericin B Amphotericin B Macrolide antifungal antibiotic produced by streptomyces nodosus obtained from soil of the orinoco river region of venezuela. Polyenes:
Nystatin Nystatin Macrolide antifungal antibiotic complex produced by streptomyces noursei, s. Aureus, and other streptomyces species. The biologically active components of the complex are nystatin a1, a2, and a3. Polyenes:
  • Topical use only: skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions, mucous membranes, GI lumen
Echinocandins Echinocandins Echinocandins are a group of fungicidal agents that target the fungal cell wall. Echinocandins inhibit β-glucan synthase, which in turn inhibits the production of β-glucan, a key structural component of fungal cell walls. The 3 primary drugs in this class include caspofungin, micafungin, and anidulafungin. Echinocandins ( Caspofungin Caspofungin A cyclic lipopeptide echinocandin and beta-(1, 3)-d-glucan synthase inhibitor that is used to treat internal or systemic mycoses. Echinocandins, Micafungin Micafungin A cyclic lipo-hexapeptide echinocandin antifungal agent that is used for the treatment and prevention of candidiasis. Echinocandins, Anidulafungin Anidulafungin Echinocandin antifungal agent that is used in the treatment of candidemia and candidiasis. Echinocandins) Inhibits β-glucan synthase (the enzyme synthesizing β-glucan and an important structural component of the fungal cell wall Fungal Cell Wall Echinocandins) → weakened cell wall Cell wall The outermost layer of a cell in most plants; bacteria; fungi; and algae. The cell wall is usually a rigid structure that lies external to the cell membrane, and provides a protective barrier against physical or chemical agents. Cell Types: Eukaryotic versus Prokaryotic → cell lysis
  • Treats Candida Candida Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis and Aspergillus Aspergillus A genus of mitosporic fungi containing about 100 species and eleven different teleomorphs in the family trichocomaceae. Echinocandins infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease in critically ill and neutropenic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
  • Minimal toxicity Toxicity Dosage Calculation
  • Minimal drug-to-drug interactions
Griseofulvin
  • Binds to the keratin Keratin A class of fibrous proteins or scleroproteins that represents the principal constituent of epidermis; hair; nails; horny tissues, and the organic matrix of tooth enamel. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms a coiled-coil alpha helical structure consisting of type I keratin and a type II keratin, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. Alpha-keratins have been classified into at least 20 subtypes. In addition multiple isoforms of subtypes have been found which may be due to gene duplication. Seborrheic Keratosis in newly forming skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions, making the human cells resistant to invasion → over time the new, uninfected hair/ skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions/nail structures replace the old, infected structures
  • Inhibits the assembly Assembly The assembly of viral structural proteins and nucleic acid (viral DNA or viral RNA) to form a virus particle. Virology of microtubules Microtubules Slender, cylindrical filaments found in the cytoskeleton of plant and animal cells. They are composed of the protein tubulin and are influenced by tubulin modulators. The Cell: Cytosol and Cytoskeleton in dermatophytes Dermatophytes Tinea infections are a group of diseases caused by fungi infecting keratinized tissue (hair, nails, and skin). These infections are termed dermatomycoses and are caused by the dermatophyte fungi. There are approximately 40 dermatophyte fungi that are part of 3 genera, including Trichophyton, Epidermophyton, and Microsporum. These infections can affect any part of the body but occur most often in warm, moist regions like the groin and the feet. Dermatophytes/Tinea Infections → inhibits fungal cell replication
  • Treats dermatophyte infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease of the hair, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions, and nails
  • Oral medication only (not topically active)
  • Affects the CYP450 system (more drug-to-drug interactions)
  • Largely replaced by newer agents (e.g., terbinafine)
Terbinafine Inhibits the squalene Squalene A natural 30-carbon triterpene. Cholesterol Metabolism epoxidase enzyme → blocks the production of squalene Squalene A natural 30-carbon triterpene. Cholesterol Metabolism epoxide, which is a precursor to ergosterol Ergosterol A steroid occurring in fungi. Irradiation with ultraviolet rays results in formation of ergocalciferol (vitamin d2). Azoles and a critical component of the cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane
  • Treats dermatophyte infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease of the hair, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions, and nails
  • Agent of choice for onychomycosis
  • Relatively low toxicity Toxicity Dosage Calculation
Flucytosine A pyrimidine analog with metabolites:
  • Competing with uracil Uracil One of four nucleotide bases in the nucleic acid RNA. Nucleic Acids and disrupting RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure synthesis Synthesis Polymerase Chain Reaction (PCR)
  • Irreversibly inhibiting thymidylate synthase Thymidylate synthase An enzyme of the transferase class that catalyzes the reaction 5, 10-methylenetetrahydrofolate and dump to dihydrofolate and dtmp in the synthesis of thymidine triphosphate. Purine and Pyrimidine Metabolism → fungus is unable to synthesize or correct DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure
  • Always used in combination with other agents due to:
    • Positive synergistic effects
    • Resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing with monotherapy
  • Major indications:
    • Cryptococcal meningitis Cryptococcal meningitis Meningeal inflammation produced by cryptococcus neoformans, an encapsulated yeast that tends to infect individuals with acquired immunodeficiency syndrome and other immunocompromised states. The organism enters the body through the respiratory tract, but symptomatic infections are usually limited to the lungs and nervous system. The organism may also produce parenchymal brain lesions (torulomas). Clinically, the course is subacute and may feature headache; nausea; photophobia; focal neurologic deficits; seizures; cranial neuropathies; and hydrocephalus. Cryptococcus/Cryptococcosis
    • Chromoblastomycosis
  • Toxicity Toxicity Dosage Calculation: myelosuppression Myelosuppression Oxazolidinones

References

  1. Sheppard, D., Lampiris, H.W. (2012). Antifungal agents. In Katzung, B.G., Masters, S.B., and Trevor, A.J. (Eds.), Basic and Clinical Pharmacology, 12th Ed., pp. 852‒853, 855‒856.
  2. Drew, R.H. (2020). Pharmacology of flucytosine (5-FC). In Bogorodskaya, M (Ed.), UpToDate. Retrieved July 23, 2021, from https://www.uptodate.com/contents/pharmacology-of-flucytosine-5-fc 
  3. Nivoix, Y., Ledoux, M., Herbrecht, R. (2020). Antifungal therapy: New and evolving therapies. Semin Respir Crit Care Med. 2020, 41, 158-174. Retrieved July 23, 2021, from https://www.medscape.com/viewarticle/924712_7 
  4. Padda, I. (2021). Flucytosine. In StatPearls. Retrieved July 23, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/21829/ 
  5. Olson, J. (2020). Griseofulvin. In StatPearls. Retrieved July 23, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/22435/ 
  6. Maxfield, L. (2021). Terbinafine. In StatPearls. Retrieved July 23, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/42970/ 
  7. Lexicomp Drug Information Sheets (2021). In UpToDate. Retrieved July 22, 2021, from:

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