WEEK 4: ANTI-FUNGAL AND ANTI-PARASITIC DRUGS Flashcards
State the 2 main classes of drugs used as anti-fungal treatment and examples under each class.
- POLYENES: MOA of polyenes is the formation of pores in the fungal cell membrane, which allows leakage of cellular contents, ultimately leading to cell lysis.
*Amphotericin B
*Nystatin
- MACROLIDES: Macrolides are a class of antibiotics that are primarily used to treat bacterial infections. They work by inhibiting protein synthesis in bacteria.
*Macrolides, such as erythromycin, clarithromycin, and azithromycin
Outline diseases which can be treated using amphotericin B.
Aspergillus
Blastomyces
Cryptococcus
Candida
Coccidioides
Histoplasma
Leishmania
Trypanosome
Describe the MOA of amphotericin B.
How do fungi develop resistance against it?
Work by binding to ergosterol in the fungal cell membrane, causing the cell membrane to become permeable and allowing essential cellular components to leak out.
Resistance
↓ ergosterol content of the fungal membrane.
Efflux Pumps: Fungi can develop efflux pumps that actively pump out Amphotericin B from the fungal cell, preventing it from reaching effective concentrations within the cell.
Cell Wall Modifications: Some fungi may develop changes in their cell wall structure, which can reduce the drug’s ability to access the cell membrane.
Biofilm Formation: In some cases, fungi can form biofilms that act as protective barriers, making it difficult for the drug to penetrate and reach the fungal cells.
Reduction in Uptake: Fungi can downregulate or reduce the expression of proteins responsible for Amphotericin B uptake.
Outline characteristics of amphotericin B.
*Poorly absorbed across the gut
* Oral drug good only for infection within the gut
*Injectable preparations require addition of sodium deoxycholate
soluble colloidal dispersion
Insoluble in water
High Intravenous doses
Poorly crosses the BBB
State the infusion related toxicity of amphotericin B symptoms.
What is infusion rate?
What premedication can be given to prevent the toxic reaction?
Fever, chills, headache, and hypotension.
Infusion rate refers to the rate at which a fluid, medication, or solution is administered intravenously (through an IV or intravenous line) into a patient’s bloodstream.
It is typically measured in units of volume per unit of time, such as milliliters per hour (mL/hr) or drops per minute (gtts/min).
Administer a small test dose to gauge the severity of the reaction.
Slowing the infusion rate
Premedication with antihistamines and steroids
Amphotericin B results in nephrotoxicity.
Outline 3 signs which are related to this.
CUMULATIVE TOXICITY (NEPHROTOXITY)
Azotemia
Azotemia is a medical term that refers to an elevated level of nitrogen-containing compounds, particularly urea and creatinine, in the blood. These compounds are waste products that are normally excreted by the kidneys.
RTA
Renal Tubular Acidosis (RTA): Renal tubular acidosis is a medical condition that involves the kidney’s inability to effectively remove excess acid from the bloodstream and excrete it in the urine.
Potassium & Magnesium wasting.
Potassium wasting, also known as hypokalemia, refers to a condition in which there is a significant depletion of potassium in the body.
Magnesium wasting, also called hypomagnesemia, is a condition characterized by abnormally low levels of magnesium in the blood.
Salt loading may prevent and even reverse amphotericin B-induced azotemia by an unknown
mechanism.
Overall Toxicity:
Liposomal amphotericin B is often considered a less toxic alternative to conventional amphotericin B and is preferred when the risk of kidney toxicity needs to be minimized, especially in patients with underlying kidney disease.
State other polyene macrolides
OTHER POLYENE MACROLIDES
- AMPHOTERICIN A
Not used clinically.
Experimental drug - NYSTATIN
Poorly absorbed across the membranes.
Its mainly used for local candida infection.
Vomiting and local irritation
What are azoles?
State the 2 types of azoles and their examples.
They work by inhibiting the synthesis of ergosterol, a crucial component of the fungal cell membrane. Azoles are fungistatic, meaning they inhibit the growth and reproduction of fungi rather than killing them directly
Imidazoles
Ketoconazole
Miconazole
Clotrimazole
Triazoles
Itraconazole
Voriconazole
Fluconazole
Describe characteristics of KETOCONAZOLE
Unlike AmphoB: Not active against Aspergillus
Oral & topical formulation
Oral ketoconazole has largely been replaced by triazoles
Topical drug: Dermatophytes
Mucocutaneous candidiasis
Seborrheic dermatitis
Outline side effects of ketoconazole.
Nausea, anorexia, and vomiting
Hepatotoxicity
CP450 Inhibitor
Antiandrogen effects
Teratogenic
Describe characteristics of MICONAZOLE & CLOTRIMAZOLE.
Topical Imidazoles
Poorly absorbed orally
Widely used topically in the treatment of dermatophyte and
Candida infections.
Local irritation (i.e., stinging & burning sensation)
State the 3 triazoles.
Describe them
ITRACONAZOLE
Itraconazole is the drug of choice for the treatment of dimorphic fungi.
Rarely used for treatment of infections due to Candida and Aspergillus species because of the availability of newer and more effective agents.
Poor permeability of the blood–brain
barrier (BBB)
FLUCONAZOLE
High oral bioavailability (nearly 100%)
Very good CSF penetration
Azole of choice for systemic candidiasis & cryptococcal meningitis
No Activity against aspergillus
Nausea, vomiting, and rashes
VORICONAZOLE
* Candida
* Aspergillus
* Crosses the BBB
State 4 examples of dimorphic fungi.
Dimorphic fungi
Blastomycosis, Sporotrichosis, Paracoccidioidomycosis, and Histoplasmosis.
State the 4 other fungal drugs.
Flucytosine
Caspofungin
Griseofulvin
Terbinafine
Pyrimidine antimetabolite
Resistance due to decreased levels of any
of the enzymes
It is effective in combination with
amphotericin B for treating candidiasis or
cryptococcosis.
Bone marrow suppression
What drug is described above?
Flucytosine