Antifungals Flashcards
What are the main drugs for antifungals?
- Amphotericin B
- Flucytosine
- Caspofungin
- Posaconazole
- Terbinafine
What is the delivery & mech of action of antifungals?
- liposome delivery
- ergosterol mech of action
What is Amphotericin B?
Amphotericin B (1st line therapy; then gets subbed by one not as astringent)
- for life-threatening disease
- binds to ergosterol
- forms pores
used against aspergillus & protozoa
What are the pharamokinetics for Amphotericin B?
- Poorly absorbed from GI tract; IV
- Insoluble in water
- Intrathecal in meningitis (CNS inf. With fungi)
- Delivered in liposomes – lower toxicity
What are the adverse effects for Amphotericin B?
- Low TI
Initial infusion
- Anaphylaxis & convulsions
- Fever
- Hypotension
Longer term tx
- RENAL IMPAIRMENT
- Anemia
- Neurological effects
What is Flucytosine (5-FC)?
- Enters via specific CYTOSINE PERMEASE – not in mammals
- Converted to 5’-fluorodeoxyuridine monophophate (5-FdUMP)
- False nucleotide inhibits THYMIDYLATE SYNTHASE
- Blocks thymidylic acid – needed for DNA
(therefore, decreased dTMP leads to inhibition of DNA synthesis & cell division)
- Synergy with amphotericin B
Subcutaneous & systemic myotic infection
What are the pharmacokinetics of Flucytosine?
- Water soluble
- Good BBB passage (*good for CNS inf.)
What are the adverse effects of Flucytosine?
Limited spectrum (Candida & some molds)
TOXIC METABOLITE – FLUOROURACIL
- Neutropenia
- Bone marrow depression
- Nausea, vomiting
- CI with renal impairment
What are Azoles – Posaconazole?
- Inhibits C-14 a-demethylase (cyt P450 enzyme)
- Blocks demethylation of lanosterol to ergosterol
- Disrupts membrane structure/function (leads to leakage & death of the fungi)
When are Azoles - Posaconazoles used?
- Synthetic triazole for systemic fungi inf.
- Oral with high absorption
- More specific than previous azoles (ex: Itraconazole) & imidazoles (ex: Ketoconazole)
- Wide fungi range – species of Candida & Aspergillus
Subcutaneous & systemic myotic infection
What are the pharmacokinetics of Azoles - Posaconazoles?
- Oral – gastric acid needed
- Major binding to plasma proteins
- Metabolized by liver
- Poor CNS penetration
What are the adverse effects of Azoles - Posaconazoles?
- Minor GI upset (not as serious as previous ones)
- Drug interaction – inhibition of cyt P450
What are Caspofungin:
Echinocandins
- Inhibit b-(1,3)-D-glycan (targeting cell wall b/c this is a component of cell wall)
- CELL WALL disruption & death
What are Caspofungin:
Echinocandins used for?
- Aspergillus & Candida
- T1/2 of 9-11 hr
- 2nd line therapy
Subcutaneous & systemic myotic infection
What is Terbinafine?
Inhibits squalene epoxidase & blocks ergosterol
Squalene build-up is toxic
What is Terbinafine used for?
- Dermatophytes - ‘ringworm’
- 3 month therapy
- Oral; 40% bioavailability
Drug for cutaneous mycotic infections
What are the adverse effects of Terbinafine?
- Accumulates in breast milk
- GI disturbance
What are the main Antiprotozoal drugs?
- Malaria = Chloroquine, Primaquine, Artemisinins
- Amebiasis = Metronidazole, Chloroquine
- Others = Stibogluconate, Melarsoprol, Nifurtimox
What are the drugs for Malaria?
Chloroquine, Primaquine, Artemisinins
What are the drugs for Amebiasis?
Metronidazole, Chloroquine
What are imp. about antiprotozoal drugs?
Eukaryotic – metabolism close to humans
Toxicity issues – esp. against metabolically active cells, ex: neurons, stem cells
Pregnant patients cannot be treated
What is Metronidazole?
- Kills E. histolytica trophozoites
- Anaerobic protozoa have FERRODOXIN-LIKE low redox potential electron transport proteins – nitro group of Metronidazole acts as electron acceptor
- Subsequent reduced compounds (that are produced) are cytotoxic
What are the pharmacokinetics & adverse effects for Metronidazole?
- Oral delivery – rapid absorption to all areas
- GI problems
What is Lodoquinol?
Cyst & trophozoite forms
- Target protozoa early in inf.
Luminal Amebicides
- Apply AFTER systemic treatment
- Asymptomatic colonization within intestine
(target protozoa early in inf)
What is Chloroquine?
Systemic Amebicides - target liver
Useful for liver abscess or intestinal wall infection
What does Malaria do?
cytotoxicity; high fever, orthostatic hypotension, erythrocytosis, capillary obstruction, anemia, raised intracranial pressure
What is Malaria’s Drug Therapy?
- An infected mosquito injects sporozoites
- Sporozoites migrate to the liver, where they form merozoites
(Drug effective against exoerythrocytic form: Primaquine) - Merozoites are released & invade RBCs
(Drugs effective against erythrocytic form: Artemisinin, Chloroquine, Quinine, Mefloquine, Pyrimethamine) - In the RBC, the merozoite becomes a trophozoite
- In the RBC, the trophozoite multiplies, producing new merozoites. These are relased when the RBC ruptures, & they can infect other RBCs
- Some merozoites become gametocytes
(Drug effective against gametocytes form: Primaquine) - The female mosquito picks up gametocytes from an infected human. The sexual cycle occurs in the mosquito, where sporozoites are formed
What is Primaquine?
- Primary/secondary EXOERYTHROCYTIC forms – mainly in liver
- Kills all gametocytic forms
- Does NOT affect erythrocyctic form (aka RBCs) - sued combined with schizonticide
- Effective in P. ovale & P. vivax forms (dormant liver form)
- Well absorbed; oral
EFFECTIVE AGAINST GAMETOCYTIC & EXOERYTHROCYTIC FORM (IN LIVER) (sufficient to know)
What are the adverse effects of Primaquine?
- Metabolites of Primaquine induce oxidative stress
- Drug-induced hemolytic anemia in pt’s with low G6PDH (imp. Metabolic pathway in RBC)
- CI in pregnancy
What is Chloroquine?
- The parasite digests the host cell’s hemoglobin to obtain essential AA’s
- The process releases large amounts of heme, which is toxic to the parasite
- To protect itself, the parasite ordinarily polymerizes the heme to nontoxic hemozoin which is sequesterd in the parasite’s food vacuole
- Chloroquine prevents the polymerization to hemozoin. The accumulation of heme results in lysis of both the parasite & the RBC
EFFECTIVE AGAINST ERYTHROCYTIC FORM (hopefully sufficient to know)
What is Chloroquine’s use?
- Mainstay of antimalarial therapy – except P. falciparum
- Blood schizonticide – erthyrocytic form
- Effective against systemic amebiosis
What is Chloroquine’s pharmacokinetics?
- Oral; rapid absorption; 4 days of therapy
- Large volume of distribution, long t1/2 (initial 3-5 days – terminal elimination 1-2 months)
- Persists in erythrocytes (& gives protection)
- *Crosses BBB & placenta
- Low doses well tolerated
- Resistance serious problem in P. falciparum
- Mutation (K76T) in PfCRT transporter in membrane food vacuole (FV) - induces release of chloroquine from FV
What is Chloroquine’s adverse effects?
CINCHONISM
- OVERDOSE of Chloroquine & related quinine-based drugs (blindness is reversible)
- Mild: reversible events incl. Flushing, ringing in ears, blurred vision, confusion, hearing loss & dizziness
- Severe: in most cases reversibel incl. Blindness, anaphylactic shock & heart arrhythmia (can lead to HF & death)
- Extreme: ‘blackwater fever’ resulting in KF & death
DUE TO LACK OF SUPERVISION & EDUCTION IN 3rd WORLD COUNTRIES
What is Artemisinins?
- Increase ROS in FV – via cleavage of endoperoxidase bridge
- Inhibit exported protein 1 (a glutathione-S-transferase) leading to reduced glutathione – plus various other targets
EFFECTIVE AGAINST ERYTHROCYTIC FORM (maybe sufficient to know)
- by lowering levels of Glutathione which leads to oxidative stress in FV (food vacuole) which is toxic to protozoa
What is Artemisinins use?
- Herbal remedies used in China – blood schizonticides
- **1st LINE therapy for Chloroquine & multi-drug resistant P. falciparum (& now resistant to vivax forms)
- Artemisinin combo therapy (ACT) - combined with mefloquinine o piperaquine
- **Well tolerated – SAFE in children – slow heart beat, allergy & low WBC count (big +, & therefore 1st line)
- Rapid absorption but short t1/2
- Rapidly metabolized - promiscuous targets
What is Melarsoprol?
- Reacts with SULFHYDRYL residues on enzymes (lead to suppression of metabolism of protozoa)
- Derivative of mersalyl oxide
- Late stage with CNS signs
What are the pharmacokinetics & adverse effects of Melarsoprol?
- Mammalian cells less permeable to drug (*can cause many S.E.’s but does kill the protozoa)
- IV; good levels in CSF; short t1/2
Adverse:
- CNS toxicity: encephalopathy; CI with influenza
- Hemolytic anemia
GETS IN CSF & REDUCES PROTOZOA
What is Nifurtimox & Suramin?
Nifurtimox; T. cruzi specific
- GENERATES ROS & KILLS PROTOTZOA (T.cruzi does not have catalase, *produce free radicals)
- Therefore ability to scavenge free radicals is impaired
Suramin; early tx; inhibits many enzymes
- Against American form
What is Sodium Stibogluconate?
Inhibits glycolysis
- Chemotherapy for Leishmaniasis (skin sores; longer term effects (yrs) - liver/spleen damage & anemia)
- 3 types: want to stop the VISCERAL (liver/spleen one b/c most deadly)
- Parenteral admin; extravascular compartment
