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Clinical Pharmacology II > Antifungal & Antiparasitic > Flashcards

Antifungal & Antiparasitic Flashcards

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1
Q

What are the four major families of Antifungal’s ?

A
  • Polyene Macrolides
    Natural Antifungals
  • Azole Drugs
    Synthetic Antifungals
  • Echinocandins
    Semisynthetic Antifungals
  • Allylamines
    Synthetic Antifungals
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2
Q

What does the fungal cell membrane have and what is its function?

A
  • Ergosterol

- Strength and Fluidity

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3
Q

What does the Fungal cell wall have and what is it’s function?

A
  • B1,3 and B1,6 Glucans
    Strength and Rigidity
  • Glucans
    Link glucose molecules
  • Mannoproteins
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4
Q

What are the two targets for Antifungal agents?

A

1) Ergosterol Syn

2) Glucan Synthesis

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5
Q

What antifngal targets the enzyme Squalene Epoxidase in the fungal cell membrane?

A
  • Terbinafine
    (Allylamines)
  • Prevents Squalene from becoming Squalene Epoxide
  • Prevents Ergosterol Syn
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6
Q

What antifungal targets the CYP450 in fungus in the fungal cell membrane?

A
  • Fluconazole
    (Azoles)
  • Prevents Ergosterol Syn
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7
Q

What antifungal interferes with Ergosterol in the Fungal cell membrane?

A
  • Amphotericin B & Nystatin
    (Polyene Macrolides)
  • Interferes with Ergosterol in cell membrane
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8
Q

What antifungal targets fungal cell wall Beta Glucan syn ?

A
  • Caspofungin

Echinocandins

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9
Q

MOA for Amphotericin B?

A
  • Forms membrane pores via interaction with Ergosterol

- Causes leakage of cellular contents killing the fungi

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10
Q

T of F

Amphotericin B has poor GI absorption?

A
  • True

- Very poor PO GI (Exploited to treat GI infections)

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11
Q

The half life of Amphotericin B is ?

A
  • Long half-life
  • T1/2 > 15 days (2 weeks)
  • Slow kidney excretion
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12
Q

T or F

You can give Amphotericin B IV or Intrathecally?

A
  • True

- Treats CNS infections (Fungal Meningitis)

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13
Q

T or F

Amphotericin B has no impact on Renal or Hepatic impairment?

A
  • True

- 90% serum protein bound

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14
Q

What antifungal has the widest spectrum of coverage and is the initial therapy or empiric therapy for life threatening infections?

A
  • Amphotericin B
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15
Q

What does Amphotericin B treat?

A
  • Pathogenic yeast (Candida; Cryptococcus)
  • Dermatophytes (Dermal / Topical infections)
  • Pathogenic Molds Aspergillis
  • Endemic mycoses for FL and SW US are blastomycosis, coccidiodomycosis, histoplasmosis, and sporotrichoisis
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16
Q

T or F

Amphotericin B can form pores in human cells as well?

A
  • True

- Fungicidal & relatively selectively Toxic (Can form pores in human cells too)

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17
Q

Amphotericin B has a lot of toxicities most common is?

A
  • Infusion Related Reaction (Common)
Chills
Muscle spasms
Vomiting
HA
Hypotension
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18
Q

How do you prevent Amphotericin B infusion toxicities?

A
  • Test Dose Before

or

  • Pretreatments with Antipyretics. Antihistamine, Corticosteroids
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19
Q

How can you minimize Amphotericin B infusion reactions?

A
  • Slow infusion

- Minimize the dosage

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20
Q

What is the Major and Limiting Toxicity of Amphotericin B

A
  • Irreversible Nephrotoxicity
  • Due to Prolonged/High Dose

Hypokalemia
Hypomagnesemia
Renal Tubular Acidosis

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21
Q

The precursor to Ergosterol is lanosterol and it is blocked by Azole drugs by targeting what in the fungus?

A
  • CYP450

- Disrupting Strength and Fluidity

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22
Q

What group of antifugal medications have a Imidazole (2N) 5 member or Triazole (3N) 5 member ring?

A
  • Azole drugs
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23
Q

What are Imidazole (2n) used as?

A
  • Topical Antifungals
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24
Q

What are Triazoles (3n) used as ?

A
  • Systemic Antifungals
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25
Metabolism of Azoles is important because it can also inhibit human CYP450, which ones exactly? Why is it important?
- CYP3A4 (moderate) 75% of FDA approved drugs - CYP2C9 (moderate) - CYP2D19 (strong) - CYP2C19 (strong) - A lot of Drug Drug interactions
26
What is Fluconazole used to treat?
- Yeasts Candida Cryptococcus - Dermatophytes Ringworm Jock itch Athlete’s foot
27
T or F Fluconazole treats Pathogenic Molds as well?
- False - Does not treat Mucormycosis Aspergillus Fusarium
28
T of F Azole drugs like Fluconazole inhibit CYP450 in fungas but it can inhibit it in humans as well, why is that important?
- True - Inhibits 17-alpha-hydroxylase (CYP450c17) - Blocks Sex hormone Testosterone, Estrogen - Blocks Glucocorticoids Drying and Thinning skin - Mineralcorticoids remain intact or elevated
29
MOA for Caspofungin (Echinocandin)?
- Inhibits the synthesis of β1-3-glucan to prevent cell wall biogenesis - Cell wall formation
30
T or F Caspofungin (Echinocandin) needs to be dose adjusted for hepatic insufficiency?
- True - Extensively metabolized in the liver - Peptide hydrolysis - N-acetylation
31
What is the major concern with toxicity with Caspofungin ?
- Hepatotoxcitiy Drug Drug reactions - Especially with Cyclosporine (Immunosuppressant) - Hepatotoxicity
32
What is Caspofungin ONLY approved to treat?
- Aspergillosis - In pt’s who failed to respond to Amphotericin B - Treats yeast and mold
33
Caspofungin treats Cryptococcus? T or F
- False
34
MOA of Terinafine?
- Inhibitor of squalene epoxidase (Fungus Enzyme) 1) Accumulation of toxic squalene 2) Inhibition of ergosterol formation to kill fungi
35
What antifugal is Keratinophilic, Only builds up in the cells with Keratine?
- Terbinafine (Lamisil) - Effective only against Dermatophytes in the Nails Skin Hiar
36
What does Terbinafine (Lamisil) treat?
Dermatophytes - Tenia Pedis - Athletes Foot - Jock itch
37
T or F Large doses of Terbinafine can cause Hepatotoxicity ?
- True | - No Drug Drug interacts
38
Which antifungal would be the best choice for empiric treatment of a life-threatening systemic infection?
- Amphotericin B | - Broadest spectrum of activity
39
Which antifungal(s) would be the best choice for treatment of Tinea pedis (athlete’s foot)?
``` - Terbinafine Topical imidazole (such as miconazole/Micatin®) ```
40
Which antifungal(s) would be the best choice for a systemic Candida infection?
- Fluconazole (Cheaper) | - Caspofungin
41
What does a mosquito bite produce?
- Sporozoites
42
What does the Exoerythrocytic stage produce?
-Sporozoites infecting the liver hepatocytes
43
Infected hepatocytes are now called ?
- Tissue Schizonts
44
Infected Hepatocytes rupture and release what?
- Merozoites
45
What is the Erythrocytic stage?
- Merozoites infecting RBC's in the blood called now | - Blood Schizonts aka Erythrocytic Schizonts
46
- Blood Schizonts aka Erythrocytic Schizonts have two possibilities now, what are they?
1) Produce more Blood Schizonts from infected RBC's or 2) Produce Gametocytes that can be taken up by mosquitoes
47
What are the three antimalarial drugs ?
1) Liver Schizonticide 2) Blood Schizonticides 3) Gametocides
48
T or F A signal agent can eliminate all forms of parasites ?
- False
49
Where do most antimalarial drugs target?
- Blood Schizonts
50
Liver Schizonticides act where?
- Act on the RBC's parasite which are rapidly dividing (Active disease) - Where most drugs target
51
Where do liver Schizonticides act?
- Interfere with production of Merozites
52
Where do gametocides act?
- Kills gametocytes or - Prevents transmission to mosquito
53
Most common parasitic Malarial causing organism in humans?
- Plasmodium Faciparum
54
T or F Antimalarial drugs can be Chemoprophylaxis or for used for treatment?
- True
55
T or F Tonic contains Quinine, and Quinine is an Antimalarial?
- True
56
Quinine is a rapid acting, highly active schizonticide against all five species, especially for Falciparum Malaria? T or F
- True, Blood Schizonticide for all five species - Gametocidal only against P. Vavax P. Ovale - Not a Liver Schizonticide for any species
57
What is the definition of Radical Cure?
- CLEARING ALL forms of the parasites to effectively clear the parasites and eradicate the disease
58
What is Quinine, and what is it used for?
- Natural Antimalarial - Blood Shizonticide (All 5) - Gametocidal (Only P. Vivax & P. Ovale) - No Liver Scizonticide activity
59
How do antimalarial agents work?
- Prevention of heme polymerization to kill off erythrocytic parasites - Accumulate in food vacuole inside the parasite - Have extremely large volumes of distribution - Long Half life
60
Most common antimalarial used ?
- Quinine
61
Quinine adverse effects?
- Cinchonism = Poisoning due to excessive ingestion of cinchona alkaloids ``` S&S of Cinchonism Tinnitus Nausea Flushing Visual disturbances Double vision ```
62
T or F Quinine needs to be used with caution in G6PD deficiency?
- True | - Will cause Hemolysis
63
What is Chloroquine ?
- Syn Quinine
64
MOA Chloroquine antimalarial?
- Chloroquine gets protonated inside food vaculole with low ph - Prevents biocrystallization of Ferriprotoporphyrin (toxic heme) into Hemozoin (Nontoxic heme)
65
Chloroquine is the drug of choice for treatment of?
- Non Malarial resistance - Treats Non Falciparum Malaria & Falciparum Malaria
66
What causes Falciparum resistance?
- Mutations in transporter of Choloquine | - Mutated PfCRT transporter
67
T or F Chloroquine can treat liver dormant parasites?
- False | - Only Blood Schizonticide
68
What does the Plasmodium Parasite (Inside RBC) depends on?
- Breakdown of hemoglobin from RBC’s for their amino acids to continue their life cycle
69
What kind of HEME is toxic to Plasmodium?
- Ferriprotoporphyrin Heme
70
What impairs the absorption of Chloroquine?
- Absorption impaired by Ca2+ or Mg2+ containing antacids | - Because its a Phosphate Salt
71
True or False Cholorquine has a HUGE volume of distribution (70,000 liters)
- True | - All in the food vacule of the plasmodium
72
T or F Cholorquine has a very long half life?
- Very Slow | - t/12 = 1 to 2 months
73
Common Adverse effects of Cholorquine?
- African descent = Pruritus (itchy skin) | - Hemolysis in G6PD deficiency
74
Chloroquine is contraindicated in what pt conditions?
- Psoriasis (Africans) | - Pt's predisposed to accumulation of heme or precursors/metabolites (Porphyria)
75
Mefloquine MOA?
- Inhibition of HEME polymerization | - Ferriprotoporphyrin Heme toxic heme builds up
76
Mefloquine is a strong blood schizonticidal agent? T or F
- True | - Not active against Liver Scizonts or Gametocytes
77
Mefloquine has a long half life? T or F
- True | - Trapped inside food vacuoles
78
Mefloquine is consider safe for Infants / children and pregnant women? T or F
- True
79
Mefloquine can be used as a __________ and against _______ diseases?
- Prophylaxis (Once a week) | - Active Malarial diseases (Single Dose)
80
What is the black box warning for Mefloquine?
- Potential Neuropsychiatric reactions | - Manic Monday in the military
81
Mefloquine is contraindicated in ?
- Pt's with Neuropsychiatric disorders - Seizures - Psychosis - Arrhythmias
82
T of F Mefloquine is given orally because of severe local skin irritations with IM ?
- True
83
What is the liver enzyme in the liver that process Mefloquine?
- CYP3A4
84
Mefloquine half live is ?
- 3 weeks | - Long half life
85
What is Atovaquone + Proguanil (Malarone) and what are they used for?
- Atovaquone Electron transport chain inhibitor - Proguanil DHFR inhibitor - Antimalarial
86
Atovaquone + Proguanil (Malarone) can be used for _____________ and _______________.
- Chemoprophylaxis | - Treatment
87
Why is Atovaquone not used alone but instead in combination with Proquanil?
- Rapid resistance | - Powerful activity in combination
88
What does Proguanil (Prodrug) require?
- CYP3A4 activation into Cycloguanil (DHFR inhibitor) Dihydrofolate reductase (DHFR) catalyzes the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate - Potentiates Atovaquone
89
Atovaquone is low and erratic when given PO, must be given with?
- Fatty food to slow down absorption
90
Atovaquone + Proguanil treats what ?
- Liver Schizonts and Blood Schizonts | - 1 week treatment for Chemoprophylactic treatment
91
Atovaquone is heavily protein-bound causing most drug to remain in what compartment?
- Central compartment (Plasma)
92
What do Plasmodium parasite require?
- ETC to produce ATP | - To maintain mitochondrial membrane potential
93
MOA of Atovaquone ?
- Mimics Ubiquinone in Complex III aka - Cytochrome Bc1 - coQ (Cytochrome C Oxidoreductase) - But can not carry electrons
94
Atovaquone can carry electrons ? T or F
- False - Can not carry electrons causing Mitochondrial membrane potential collapse - NO ATP = Cell death
95
How does Proguanil help Potentiates Atovaquone ?
- Inhibits DHFR
96
What are some important drug drug interactions with Atovaquone + Proguanil ?
- Plasma concentrations of Atovaquone are reduced by 50% when given with; - Tetracycline's - Ripampin
97
What causes Amoebiasis ?
- Entamoeba Histolytica - Ingestion of Cyst (Food or Water) - Cysts hatch in GI tract and release Amoebas - Amoebas divide into Trophozoites - Invade other parts of body
98
T or F Asymptomatic Amoebiasis are not generally treated in Endemic Areas?
- True | - Treated depending on clinical presentation
99
Metronidazole (Flagyl) treats ?
- Protozoa (Amoebas) Drug of Choice & - Bacteria In anaerobic conditions ONLY
100
Metronidazole (Flagyl) MOA?
- Formation of a nitro radical (Electrophillic) wants to react with (N, Sulfur or O2) - Nitro radical causes damage to nucleophilic biomolecules - DNA protein thiols (Anaerobic Amoeba) - Host is protected by oxygen-mediated radical detoxification - Oxygen in host cells absorbs the radical = No damage
101
T or F Metronidazole (Flagyl) must be adjusted for Liver and Kidney dysfunction?
- True
102
T or F Mild to Moderate, Severe and Extraintestinal Amoebas infections are all treated the same?
- True - Metronidazole (Flagyl) - 750 mg 3xd for 10 days
103
What are some common adverse effects of Metronidazole (Flagyl) ?
- Metallic taste - Nausea - Dry mouth - HA - Disulfiram Effect
104
The Disulfiram effect that Metronidazole induces is caused by drinking _______ and causes what S&S?
- Alcohol - Hot flashes - Flushing - Lightheaded - Increased body temp - Due to Increase of Acetaldehyde (Toxic by product)
105
What does Metronidazole inhibit in the liver?
- CYP2C9 | - Caution with pts taking Warfarin
106
T or F Metronidazole (Flagyl) is a Teratogen?
- True | - Avoid in pregnancy and nursing
107
What can you substitute Metronidazole for in a Pregnant pt or a pt with Hepatic or Renal Disease to treat Amoebas when there is no other option?
Antimicrobial Agents - Rifampin - Tetracycline - Amphotericin B
108
What are the three drugs that treat Helminthic infections in the US?
- Albendazole (Benazoles) - Ivermectin ( Avermectins) - Praziquantel
109
Albendazole (Benazoles) MOA ?
- Inhibit microtubule polymerization | - Component of the Cytoskeleton
110
Ivermectin ( Avermectins) MOA?
- Agonist of Glutamate - Activated channels that paralyze invertebrates
111
- Praziquantel
- Causes increased permiability of Helminthic cell membranes to Ca2+ - Triggering hyperpolarization - Subsequent paralysis
112
Dynamic polymerization and Depolymerization allows for cytoskeleton remodeling allows for _________ and controls cell _________.
- Mitosis | - Cells polarity
113
Albendazole is a microtubule destabilizers, they bind where?
- Bind to Colchicine site on Beta Tubulin - Prevents polymerization - Binds parasite > human tubulin - Relatively selective toxic
114
Once Albendazole binds Beta Tubulin in a parasite what happens?
- Disrupts EGG development (Disruption of Spindle) No eggs hatching - Disrupts polarity of Adult parasite cells Decreased nutrient glucose uptake Eventually death
115
T or F Albendazole leads to impaired uptake of glucose by the larval and adult stages of the susceptible parasites, and depletes their glycogen stores
- True
116
T or F Albendazole also prevents the formation of spindle fibers needed for cell division, which in turn blocks egg production and development; existing eggs are prevented from hatching.
- True
117
What other effects does the impairment of Beta Tubulin do to parasites?
- Cell motility - Maintenance of cell shape - Intracellular transport are also disrupted
118
T or F Taking Albendazole with a fatty meal increases its absorption?
- True increases PO x 5 | - Bad PO absorption
119
Albendazole can reach all tissue to include the CNS T or F
- True | - Its lipophillic
120
Albendazole is a CYP1A2 inducer and substrate meaning?
- Albendazole is a prodrug that is activated by the liver CYP1A2 - Its activated into it's primary active substrate (Active Drug) Albendazole Suloxide
121
What will inhibitors of CYP1A2 do to concentrations of Albendazole in the plasma ?
- Reduce plasma concentrations of its active substrate - Decreasing the therapy of the pt - Can cause Liver damage
122
What medications will inhibit CYP1A2 decreasing the effects of Albendazole ?
- Phenytoin - Dexamethasone - Praziquantel - Ritonavir
123
T or F Albendazole should not be given to pt's with Cirrhosis and if Pregnant ?
- True
124
What must be monitored in pt's taking Albendazole?
- Blood counts | - LFT's
125
What is Ivermectin an agonist of?
- Glutamate Gated Chloride Channel (GluCl) | - In invertebrates
126
T or F Humans have GluCl channels ?
- False | - But Ivermectin has off target affinity to GABAergic receptors
127
What invertebrates have GLucl channels which Ivermectin can target?
- Strongyloidiasis (DOC) - Onchocerciasis (River blindness) Kills larva (Microfilaria) NOT ADULT worms - Roundworms (Nematodes) - Scabies - Lice - Bed Bugs - Fleas - Tics - Heartworms
128
Ivermectin MOA?
- Forces the opening of GluCl - Causes hyperpolarization of nerve and muscle cells - Flooding the cells with Chloride - leads to paralysis and death for parasites
129
What are the Toxicities of Ivermectin (not produced by the drug)
- Result from rapid killing of microfilariae (larva) | - Due to pt’s having a high parasite burden
130
S&S of the Ivermectin induced toxicity?
- Fever - Lymphadenitis - Lymphangitis - Hypotension - Tachycardia - Peripheral edema
131
How can you counter the Ivermectin induced toxicity?
- Corticosteroids and Control immune response
132
T or F Ivermectin is taken on an empty stomach?
- True
133
What are some off target effects (Contraindications) of Ivermectin due to it enhancing its effect?
- Off-target activity against vertebrate GABA channels - Contraindicated in pts taking GABA agonists - Barbiturates - Valium - Benzodiazepines - Valproic acid (anticonvulsant)
134
Praziquantel is the DOC for ?
- All Schistosome infections (Blood Fluke Trematodes) - Effective against Larva and Adult stages - Very safe even for children
135
T or F Praziquantel is very safe and highly effective with just one dose?
- True
136
Praziquantel MOA?
- Causes increased permeability of helminthic cell membranes to Ca2+ - Triggering hyperpolarization and subsequent paralysis
137
What are the two ways to affect Praziquantel absorption?
- High-Carb meal Increases plasma concentrations - Antiepileptics Decrease bioavailabilty
138
Metabolism of Praziquantel can be affected during first pass because?
- Praziuantel is a CYP3A4 substrate | - Inducers of CYP3A4 are contraindicated, reduces Praziuantel serum concentration
139
What are some CYP3A4 inducers that are contraindicated with Praziquantel CYP3A4 substrate ?
- St. Johns Worth - Barbiturates - Phenytoin - Rifampin
140
T or F Pts taking Praziquantel can drive very easily after taking medication?
- False - Causes drowsiness and dizziness - Pts should not drive
141
Adverse side effects of Praziquantel?
- Immune response - Results from killing of worms - Fever, lymphadenitis, lymphangitis, hypotension, tachycardia, peripheral edema.
142
Praziquantel immune response can be counter with ?
- Corticosteroids | - Even though corticosteroids reduce plasma levels ≈ 50%

Clinical Pharmacology II (5 decks)

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