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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?

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
Metronidazole is a ??
mixed amebicide
26
What does Metronidazole kill?
E. histolytic trophozoites
27
Describe mixed amebicides
- 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
Describe Luminal amebicides
- apply after systemic treatment - asymptomatic colonization within intestine - Iodoquinol - cyst and trophozoite forms
29
Describe systemic amebicides
- useful for liver abscess or intestinal wall infection | - chloroquine (see malaria later)
30
Describe chemotherapy for malaria
- 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
Symptoms of Malaria Cytotoxicity
- high fever - orthostatic hypotension - erythrocytosis - capillary obstruction - anemia - raised intracranial pressure
32
Describe malaria life cycle
- sporozoites - infect liver within 30 min - dormant hypnozoites - invisible to immune system - form schizont - merozoites infect blood cells
33
Malaria: | Drugs effective against erythrocytic form
- Artemisinin - Chloroquine - Quinine - Mefloquine - Pyrimethamine
34
Malaria: | Drug effective against exoerythrocytic form
-Primaquine
35
Malaria: | Drug effective against gametocytic form
-Primaquine
36
What drug is used against tissue schizonticide?
Primaquine
37
Describe the use of Primaquine against tissue schizonticide
- 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
Describe Chloroquine
- synthetic 4-aminoquinoline - mainstay of antimalarial therapy - blood schizonticide - erythrocytic form - effective against systemic amebiosis
39
How does Chloroquine work?
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
Describe chloroquine more
- 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
Describe chemotherapy for Trypanosomiasis
- 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
Describe Trypanosoma life cycle
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
Describe Melarsoprol
- 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
Nifurtimox is ____ specific
T. cruzi
45
Suramin is for?
early treatment, inhibits many enzymes
46
Nifurtimox generates ____
ROS (T. Cruzi does not have catalase)
47
Nifurtimox is taken ____
orally
48
List some other protozoan-related diseases
- Leishmaniasis; skin sores; longer term effects (years) - liver/spleen damage and anemia - Toxoplasmosis - Giardiasis
49
Describe the life cycle of Leishmania
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
Describe chemotherapy for Leishmaniasis
- 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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