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Pharmacology (Fall) > Antifungals > Flashcards

Antifungals Flashcards

1
Q

What are the main drugs for antifungals?

A
  • Amphotericin B
  • Flucytosine
  • Caspofungin
  • Posaconazole
  • Terbinafine
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2
Q

What is the delivery & mech of action of antifungals?

A
  • liposome delivery
  • ergosterol mech of action
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3
Q

What is Amphotericin B?

A

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

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4
Q

What are the pharamokinetics for Amphotericin B?

A
  • Poorly absorbed from GI tract; IV
  • Insoluble in water
  • Intrathecal in meningitis (CNS inf. With fungi)
  • Delivered in liposomes – lower toxicity
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5
Q

What are the adverse effects for Amphotericin B?

A
  • Low TI

Initial infusion
- Anaphylaxis & convulsions
- Fever
- Hypotension

Longer term tx
- RENAL IMPAIRMENT
- Anemia
- Neurological effects

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6
Q

What is Flucytosine (5-FC)?

A
  1. Enters via specific CYTOSINE PERMEASE – not in mammals
  2. Converted to 5’-fluorodeoxyuridine monophophate (5-FdUMP)
  3. False nucleotide inhibits THYMIDYLATE SYNTHASE
  4. 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

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7
Q

What are the pharmacokinetics of Flucytosine?

A
  • Water soluble
  • Good BBB passage (*good for CNS inf.)
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8
Q

What are the adverse effects of Flucytosine?

A

Limited spectrum (Candida & some molds)

TOXIC METABOLITE – FLUOROURACIL
- Neutropenia
- Bone marrow depression
- Nausea, vomiting
- CI with renal impairment

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9
Q

What are Azoles – Posaconazole?

A
  1. Inhibits C-14 a-demethylase (cyt P450 enzyme)
  2. Blocks demethylation of lanosterol to ergosterol
  3. Disrupts membrane structure/function (leads to leakage & death of the fungi)
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10
Q

When are Azoles - Posaconazoles used?

A
  • 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

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11
Q

What are the pharmacokinetics of Azoles - Posaconazoles?

A
  • Oral – gastric acid needed
  • Major binding to plasma proteins
  • Metabolized by liver
  • Poor CNS penetration
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12
Q

What are the adverse effects of Azoles - Posaconazoles?

A
  • Minor GI upset (not as serious as previous ones)
  • Drug interaction – inhibition of cyt P450
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13
Q

What are Caspofungin:

Echinocandins

A
  1. Inhibit b-(1,3)-D-glycan (targeting cell wall b/c this is a component of cell wall)
  2. CELL WALL disruption & death
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14
Q

What are Caspofungin:

Echinocandins used for?

A
  • Aspergillus & Candida
  • T1/2 of 9-11 hr
  • 2nd line therapy

Subcutaneous & systemic myotic infection

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15
Q

What is Terbinafine?

A

Inhibits squalene epoxidase & blocks ergosterol
Squalene build-up is toxic

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16
Q

What is Terbinafine used for?

A
  • Dermatophytes - ‘ringworm’
  • 3 month therapy
  • Oral; 40% bioavailability

Drug for cutaneous mycotic infections

17
Q

What are the adverse effects of Terbinafine?

A
  • Accumulates in breast milk
  • GI disturbance
18
Q

What are the main Antiprotozoal drugs?

A
  • Malaria = Chloroquine, Primaquine, Artemisinins
  • Amebiasis = Metronidazole, Chloroquine
  • Others = Stibogluconate, Melarsoprol, Nifurtimox
19
Q

What are the drugs for Malaria?

A

Chloroquine, Primaquine, Artemisinins

20
Q

What are the drugs for Amebiasis?

A

Metronidazole, Chloroquine

21
Q

What are imp. about antiprotozoal drugs?

A

Eukaryotic – metabolism close to humans

Toxicity issues – esp. against metabolically active cells, ex: neurons, stem cells

Pregnant patients cannot be treated

22
Q

What is Metronidazole?

A
  • 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
23
Q

What are the pharmacokinetics & adverse effects for Metronidazole?

A
  • Oral delivery – rapid absorption to all areas
  • GI problems
24
Q

What is Lodoquinol?

A

Cyst & trophozoite forms
- Target protozoa early in inf.

Luminal Amebicides

  • Apply AFTER systemic treatment
  • Asymptomatic colonization within intestine

(target protozoa early in inf)

25
Q

What is Chloroquine?

A

Systemic Amebicides - target liver

Useful for liver abscess or intestinal wall infection

26
Q

What does Malaria do?

A

cytotoxicity; high fever, orthostatic hypotension, erythrocytosis, capillary obstruction, anemia, raised intracranial pressure

27
Q

What is Malaria’s Drug Therapy?

A
  1. An infected mosquito injects sporozoites
  2. Sporozoites migrate to the liver, where they form merozoites
    (Drug effective against exoerythrocytic form: Primaquine)
  3. Merozoites are released & invade RBCs
    (Drugs effective against erythrocytic form: Artemisinin, Chloroquine, Quinine, Mefloquine, Pyrimethamine)
  4. In the RBC, the merozoite becomes a trophozoite
  5. In the RBC, the trophozoite multiplies, producing new merozoites. These are relased when the RBC ruptures, & they can infect other RBCs
  6. Some merozoites become gametocytes
    (Drug effective against gametocytes form: Primaquine)
  7. The female mosquito picks up gametocytes from an infected human. The sexual cycle occurs in the mosquito, where sporozoites are formed
28
Q

What is Primaquine?

A
  • 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)

29
Q

What are the adverse effects of Primaquine?

A
  • Metabolites of Primaquine induce oxidative stress
  • Drug-induced hemolytic anemia in pt’s with low G6PDH (imp. Metabolic pathway in RBC)
  • CI in pregnancy
30
Q

What is Chloroquine?

A
  1. The parasite digests the host cell’s hemoglobin to obtain essential AA’s
  2. The process releases large amounts of heme, which is toxic to the parasite
  3. To protect itself, the parasite ordinarily polymerizes the heme to nontoxic hemozoin which is sequesterd in the parasite’s food vacuole
  4. 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)

31
Q

What is Chloroquine’s use?

A
  • Mainstay of antimalarial therapy – except P. falciparum
  • Blood schizonticide – erthyrocytic form
  • Effective against systemic amebiosis
32
Q

What is Chloroquine’s pharmacokinetics?

A
  • 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
33
Q

What is Chloroquine’s adverse effects?

A

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

34
Q

What is Artemisinins?

A
  • 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

35
Q

What is Artemisinins use?

A
  • 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
36
Q

What is Melarsoprol?

A
  • Reacts with SULFHYDRYL residues on enzymes (lead to suppression of metabolism of protozoa)
  • Derivative of mersalyl oxide
  • Late stage with CNS signs
37
Q

What are the pharmacokinetics & adverse effects of Melarsoprol?

A
  • 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

38
Q

What is Nifurtimox & Suramin?

A

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
39
Q

What is Sodium Stibogluconate?

A

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

Pharmacology (Fall) (28 decks)

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