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Pharmacology > Lecture 14 - Antifungals > Flashcards

Lecture 14 - Antifungals Flashcards

1
Q

Eukaryotic - ______

A

mycoses

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2
Q

Cell membrane contains _______

A

ergosterol

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3
Q

Cell wall; ____ is a polymer of N-acetylglucosamine

A

chitin

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4
Q

Describe how Amphotericin B is used in “Subcutaneous and systemic mycotic infections”

A
  • Polyene macrolide
  • Produced by Streptomyces nodosus
  • For life threatening disease
  • Binds to ergosterol - not cholesterol
  • Forms pores
  • Wide range of fungi
  • Candida and blastomyces
  • Used against aspergillum and protozoa (leishmaniasis)
  • 1st line therapy and then substituted
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5
Q

Describe the pharmacokinetics of Amphotericin B

A
  • poorly absorbed from GI tract, intravenous
  • insoluble in water
  • intrathecal for meningitis
  • delivered in liposomes - lower toxicity
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6
Q

Adverse effects of Amphotericin B

A
  • low therapeutic index

- daily dose < 1.5 mg/kg

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7
Q

Effects that may happen after the initial infusion of amphotericin B?

A
  • anaphylaxis and convulsions
  • fever
  • hypotension
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8
Q

Effects that may happen after a longer term treatment of Amphotericin B?

A
  • renal impairment
  • anemia
  • neurological effects
  • thrombophlebitis (blood clot formation)
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9
Q

Describe Flucytosine (5-FC)

A
  • synthetic pyrimidine antimetabolite
  • enters via specific cytosine permeate - not in mammals
  • converted to 5’-fluorodeoxyuridine monophosphate (5-FdUMP)
  • false nucleotide inhibits thymidylate synthase
  • blocks thymidylic acid - needed for DNA
  • synergy with amphotericin B
  • limited spectrum (candida and some molds)
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10
Q

Resistance to Flucytosine

A

Target enzyme can be down-regulated and lead to resistance - need for combination therapy

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11
Q

Pharmacokinetics of Flucytosine

A
  • water soluble

- good BBB passage

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12
Q

Adverse effects of flucytosine ?

A
  • neutropenia (low neutrophil number)
  • bone marrow depression
  • nausea, vomiting
  • contraindicated with renal impairment
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13
Q

Toxic metabolite of flucytosine?

A

fluorouracil

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14
Q

Describe posaconazole

A
  • synthetic triazole for systemic fungi infection
  • inhibits C-14 alpha demethylase (cyt P450 enzyme)
  • blocks demethylation of lanosterol to ergosterol
  • disrupts membrane structure/function
  • oral with high absorption
  • more specific than previous azoles (itraconazole) and imidazole (ketoconazole)
  • wide fungi range - species of Candida and Aspergillus
  • Resistance becoming a problem in HIV patients
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15
Q

Pharmacokinetics of Posaconazole

A
  • oral: gastric acid needed
  • major binding to plasma proteins
  • metabolized by liver
  • poor CNS penetration
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16
Q

Adverse effects of Posaconazole

A

minor GI upset

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17
Q

Drug interactions with Posaconazole

A

Inhibition of Cyt P450 (rifampin an inducer)

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18
Q

Describe Caspofungin

A
  • new group of fungicides
  • echinocandins
  • inhibit B-1,3-D-glycan
  • cell wall disruption and death
  • Aspergillus and candida
  • T1/2 of 9-11 hour
  • 2nd line therapy
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19
Q

Drugs for cutaneous mycotic infections (dermatophytes - ringworm)

A

Terbinafine:

  • Inhibit squalene epoxidase and blocks ergosterol
  • Squalene build-up is toxic
  • 3 month therapy
  • Oral; 40% bioavailability
  • Accumulates in breast milk
  • Gastrointestinal disturbance
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20
Q

Problem with treating eukaryotes with antiprotozoal drugs?

A

metabolism close to humans

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21
Q

Toxicity issues with antiprotozoal drugs?

A

especially toxic against metabolically active cells (ex. neurons, stem cells)

22
Q

Can pregnant patients be treated with antiprotozoal drugs?

A

no

23
Q

Describe amebiasis - amebic dysentery

A
  • Entamoeba histolytica
  • Anaerobic protozoan
  • 50 million infected
  • Causes fulminating diarrhea
  • Liver abscess
  • Can be dormant
24
Q

Describe the life cycle of E. histolytica

A
  • Cysts: survive outside the body
  • Trophozoites
  • Ulcerate intestine
  • Feed off and kill host bacteria
25
Q

Metronidazole is a ??

A

mixed amebicide

26
Q

What does Metronidazole kill?

A

E. histolytic trophozoites

27
Q

Describe mixed amebicides

A
  • Anaerobic protozoa have ferrodoxin-like low redox potential electron transport proteins - nitro group of metronidazole acts as electron acceptor
  • Subsequent reduced compounds are cytotoxic
  • Oral delivery - rapid absorption to all areas
  • GI adverse effects
28
Q

Describe Luminal amebicides

A
  • apply after systemic treatment
  • asymptomatic colonization within intestine
  • Iodoquinol - cyst and trophozoite forms
29
Q

Describe systemic amebicides

A
  • useful for liver abscess or intestinal wall infection

- chloroquine (see malaria later)

30
Q

Describe chemotherapy for malaria

A
  • Plasmodium protozoan parasite
  • Plasmodium falciparum and Plasmodium vivax
  • Infective female Anopheles mosquito
  • 250 million cases each year
  • 1 million deaths
  • Could double in next 20 yrs
  • “Greenhouse effect” spread away from equator
31
Q

Symptoms of Malaria Cytotoxicity

A
  • high fever
  • orthostatic hypotension
  • erythrocytosis
  • capillary obstruction
  • anemia
  • raised intracranial pressure
32
Q

Describe malaria life cycle

A
  • sporozoites
  • infect liver within 30 min
  • dormant hypnozoites
  • invisible to immune system
  • form schizont
  • merozoites infect blood cells
33
Q

Malaria:

Drugs effective against erythrocytic form

A
  • Artemisinin
  • Chloroquine
  • Quinine
  • Mefloquine
  • Pyrimethamine
34
Q

Malaria:

Drug effective against exoerythrocytic form

A

-Primaquine

35
Q

Malaria:

Drug effective against gametocytic form

A

-Primaquine

36
Q

What drug is used against tissue schizonticide?

A

Primaquine

37
Q

Describe the use of Primaquine against tissue schizonticide

A
  • 8-aminoquinoline
  • primary/secondary exoerythrocytic forms - mainly in liver
  • kills all gametocytic forms
  • does not affect erythrocytic form - used combined with blood schizonticide
  • metabolites of primaquine induce oxidative stress
  • well absorbed; oral
  • drug-induced hemolytic anemia in patients with low G6PDH
  • contraindicated during pregnancy
38
Q

Describe Chloroquine

A
  • synthetic 4-aminoquinoline
  • mainstay of antimalarial therapy
  • blood schizonticide - erythrocytic form
  • effective against systemic amebiosis
39
Q

How does Chloroquine work?

A

1 - the parasite digests the host cells’ hemoglobin to obtain essential amino acids
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 sequestered in the parasites’ food vacuole
4 - Chloroquine prevents the polymerization to hemozoin. The accumulation of heme results in lysis of both the parasite and the red blood cell

40
Q

Describe chloroquine more

A
  • oral; rapid absorption; 4 days of therapy
  • large volume of distribution
  • persists in erythrocytes
  • crosses BBB and placenta
  • low doses well tolerated
  • resistance is a serious problem
  • not good for pregnant women
41
Q

Describe chemotherapy for Trypanosomiasis

A
  • Trypanosoma bruce gambiense or rhodiense - African sleeping sickness
  • 60 million affected
  • T. cruzi - American sleeping sickness
  • 20,000 killed per annum
  • Live/grow in blood cells - enter CNS and cause inflammation
42
Q

Describe Trypanosoma life cycle

A

Tsetse fly:
1: Tsetse fly takes a blood meal

Human:

2: injected metacyclic trypomastigotes transform into bloodstream trypomastigotes, which are carried to other sites
3: trypomastigotes multiply by binary fission in various body fluids (ex. blood, lymph, and spinal fluid)
4: trypomastigotes in blood

Tsetse fly:

5: Tsetse fly takes a blood meal
6: Bloodstream trypomastigotes transform into pro cyclic trypomastigotes in tsetse fly’s midgut. Procyclic tryposmastigotes multiply by binary fission
7: Procyclic trypomastigotes leave the midgut and transform into epimastigotes
8: Epimastigotes multiply in salivary gland. They transform into metacyclic trypomastigotes.

43
Q

Describe Melarsoprol

A
  • Derivative of mersalyl oxide
  • Late stage with CNS signs
  • Reacts with sulfhydryl residues on enzymes
  • Mammalian cells less permeable to drug
  • Intravenous; good levels in CSF; short t1/2
  • CNS toxicity; encephalopathy; contraindicated with influenza
  • Hemolytic anemia
44
Q

Nifurtimox is ____ specific

A

T. cruzi

45
Q

Suramin is for?

A

early treatment, inhibits many enzymes

46
Q

Nifurtimox generates ____

A

ROS (T. Cruzi does not have catalase)

47
Q

Nifurtimox is taken ____

A

orally

48
Q

List some other protozoan-related diseases

A
  • Leishmaniasis; skin sores; longer term effects (years) - liver/spleen damage and anemia
  • Toxoplasmosis
  • Giardiasis
49
Q

Describe the life cycle of Leishmania

A

Sandfly:
1: Sandly takes a blood meal

Human:

2: Promastigotes are phagocytized by macrophages
3: Promastigotes transform into amastigotes inside machrophages
4: Amastigotes multiply in cells (including macrophages) of various tissues

Sandfly:

5: Sandfly takes a blood meal
6: Ingestion of parasitized cell
7: Amastigotes transform into promastrigote stage in midgut
8: Divide in midgut and migrate to proboscis

50
Q

Describe chemotherapy for Leishmaniasis

A
  • 3 types; cutaneous, mucocutaneous, visceral (liver/spleen - deadly)
  • 12 million infected - 50,000 deaths PA
  • sodium stibogluconate (antimony)
  • inhibits glycolysis
  • parenteral administration; extravascular compartment
  • Amphotericin B - mechanism?

Pharmacology (21 decks)

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