Pharmacology antifungals, antivirals, antineoplastic

Question 1

Griseofulvin

Answer 1

Spectrum of activity
* Microsporum spp.
* Trichophyton spp.

Mechanism of Action: Inhibits mitosis of fungal cells (Fungistatic)
Basically, not good for anything but ringworm

Oral absorption:
* enhanced with meal
* micronized preparations-25-70%
* ultramicronized-100%

Distribution to skin
* Deposits in stratum corneum by 48-72 hr and persists for weeks

Question 2

Griseofulvin adverse effects

Answer 2

Cats
* Bone marrow suppression, especially cats with FeLv
* Teratogenic in pregnant animals (Cranial/skeletal malformations; ocular, intestinal and cardiac problems)

Horses
* Has been reported to be teratogenic in early pregnancy (2 months)

Question 3

Amphotericin B

Answer 3

Mechanism of Action
* Binds to sterols in fungal cell membrane.
* Cell membrane becomes more permeable
* Fungicidal
* Can also bind to cholesterol in mammalian cells, leading to toxicity

Spectrum of Activity
* Broad spectrum antifungal
* Other – Leishmania, protothecosis
* Use limited to severe systemic infections due to potential adverse effects

Question 4

Amphotericin B adverse effects

Answer 4

Fever
Thrombophlebitis
Nausea, vomiting, anorexia
Anemia
Renal injury
* Acute injury – altered blood flow, azotemia
* Chronic (cumulative) injury – ischemia, cell death

Strategies to Decrease Toxicity
* Pretreatment fluid administration
* Slow IV infusion (60 min)
* Subcutaneous administration
* Liposomal formulations
Decrease transfer of drug to cholesterol-containing mammalian membranes
^ therapeutic index = higher doses

“amphoterrible on the kidneys”

Question 5

Amphotericin B Drug interactions

Answer 5

Amphotericin B and flucytosine
* Synergistic
* Treatment of refractory CNS Cryptococcus infections
* May be able to decrease the dose (therefore the toxicity) of amphotericin

Amphotericin B and azole antifungals
* Treatment with AmpB first – no change in efficacy of either
* Concurrent administration – no benefit, may interfere
* Azole administered first – decreased efficacy of AmpB
Azoles bind to and alter the receptor site on ergosterol
AmpB cannot subsequently bind

Question 6

Azole Antifungal Drugs Mechanism of Action, adverse rxns

Answer 6

Inhibits ergosterol synthesis
Fungistatic
Common adverse drug rxns – hepatotoxicity, not safe during pregnancy

Question 7

Azole Spectrum

Answer 7

Dimorphic fungi
* Blastomyces
* Histoplasma
* Cryptococcus
* Sporothrix

Dermatophytes
Filamentous fungi (+/-)
* Aspergillus
* Fusarium

Question 8

Ketoconazole absorbtion

Answer 8

Oral absorption is enhanced by food
Inhibited by antacids (pH dependent solubility)
Not absorbed in horses

Question 9

Ketoconazole adverse effects

Answer 9

Nausea, vomiting, diarrhea
Hepatotoxicosis
Cataracts
Fetal death

Inhibits steroid synthesis (CYP450 mediated)
* Decreases testosterone and cortisol (Used for the short term management of Cushing’s disease)

Question 10

Ketoconazole drug interactions

Answer 10

Inhibits CYP450 enzymes (CYP 3A4)
* Inhibits metabolism of drugs
* Cyclosporine A in dogs and cats
* Used clinically to decrease the dose/cost of CsA treatment

Inhibit p-glycoprotein efflux pumps
* Increased concentrations of drugs in CNS, eye, plasma

Question 11

TRIAZOLES

Answer 11

Itraconazole, Fluconazole, Voriconazole
Better tolerated than ketoconazole
Less inhibition of CYP-450 enzymes/p-glycoprotein
Itraconazole>voriconazole>fluconazole
No endocrine effects
More expensive

Question 12

Itraconazole adverse effects

Answer 12

Hepatic:
* Increased liver enzymes (10-43%)
* Hepatotoxicosis (10%)

GI: anorexia, vomiting (2-3%)
Congestive heart failure - people
Check for underlying disease

Question 13

itraconazole pharmokinetics

Answer 13

Highly lipophilic
* Concentrates in tissues and persists for 2 - 4 weeks
* High protein binding

Absorption
* Absorption of capsules increased by food in dogs and cats
* Decreased in horses (hay)
* pH dependent solubility
* Oral solution not affected by food

Question 14

Fluconazole differences from other Azoles

Answer 14

Most hydrophilic – but still pretty lipophilic
Low protein binding
High concentrations in:
* Urine
* CSF
* Aqueous humor

High oral absorption (even in horses)
Absorption not affected by antacids, feed or formulation

Question 15

Fluconazole adverse effects

Answer 15

Minimal
Increased hepatic enzymes
Prolonged recovery (ketamine/midazolam)

Question 16

Voriconazole

Answer 16

broad spectrum antifungal
Intermediate lipo/hydrophilicity
Intermediate protein binding
Excellent oral absorption (>100%)
Excellent penetration into the CNS and eye
Dogs, horses, birds
Not cats!

Question 17

Voriconazole and cats

Answer 17

Possible toxicity
* Ataxia, paraplegia of the hind limbs
* Mydriasis, decreased PLRs, decreased menace
* Hypokalemia, arrhythmias
* Inappetance, lethargy, weight loss
* Azotemia, cutaneous drug reaction, ataxia, paresis

t1/2 of 4 days!

Question 18

Terbinafine mechanism and spectrum

Answer 18

Lamisil®
Inhibits ergosterol synthesis through inhibition of squalene epoxidase
Fungicidal

Spectrum
* Dermatophytes
* Yeasts
* Dimorphic and some filamentous fungi
* Includes some Aspergillus strains
* Does not include Fusarium
* Protozoa - Toxoplasma

Question 19

Terbinafine adverse effects

Answer 19

No inhibition of Cyp450 enzymes
Adverse effects in people include vomiting and anorexia

Cats
* Vomiting during treatment - 4/10
* Intense facial pruritus – 2/10
* Followed by skin reaction 7-14 days after the discontinuation

Rare incidence of hepatitis and loss of taste in people
* Mild-moderate elevations in hepatic enzymes in dogs
* NOT teratogenic in people

Question 20

Antiherpetic drugs

Answer 20

Nucleoside analogs
Prodrugs
oral admin
Clinical use not usually recommended

Question 21

Anti-influenza Drugs

Answer 21

Clinical use not recommended
prohibited in poultry

Question 22

therapeutic targets of antineoplastic drugs

Answer 22

Rapidly dividing cancer cells
Improve recovery rates of normal cells
* G-CSF

Cancer cell-specific antigens
(CD20 on human lymphocytes)

Atypical biochemistry of certain cancer cells
* Tyrosine kinase permanently switched on (leukemia)

Question 23

antineoplastic drug toxicities

Answer 23

Most cytotoxic drugs produce myelosuppression
* Neutrophils (mostly) - neutropenia
* Platelets (sometimes) - thrombocytopenia
* Anemia (unlikely)

Mucosal cells of the GI tract
* Diarrhea
* Vomiting
* Ulceration

Hair loss: Less in dogs than people, Continuously growing hair (e.g. poodles)

Agent specific:
* Nausea- Varies by agent
* Phlebitis
* Cellulitis and necrosis (extravasation)
* Nephrotoxicity (especially ‘platins)
* Peripheral neuritis
* Acute tumor lysis “syndrome”

Question 24

antineoplastic drug toxicities

Answer 24

Most cytotoxic drugs produce myelosuppression
* Neutrophils (mostly) - neutropenia
* Platelets (sometimes) - thrombocytopenia
* Anemia (unlikely)

Mucosal cells of the GI tract
* Diarrhea
* Vomiting
* Ulceration

Hair loss: Less in dogs than people, Continuously growing hair (e.g. poodles)

Agent specific:
* Nausea- Varies by agent
* Phlebitis
* Cellulitis and necrosis (extravasation)
* Nephrotoxicity (especially ‘platins)
* Peripheral neuritis
* Acute tumor lysis “syndrome”

Question 25

resistance to antineoplastic drugs

Answer 25

Similar to antibiotic resistance
* Genetically altered target (mutation)
* Reduced cellular uptake, increased efflux (p-glycoprotein, MDR1)
* Drug inactivation by cancer cells
* Decreased activation of prodrugs
* Decreased rate of cell division
* Increase in DNA repair systems

Question 26

antineoplastic protocols

Answer 26

Most cancers treated with combination drug protocols
* Attack multiple targets- Reduce or delay the onset of drug resistance
* Alternate week therapy- Reduce adverse effects (of any ONE drug)

Protocols based on studying clinical outcomes
* Survival curves not “cure rates”

Question 27

Cyclophosphamide adverse effects

Answer 27

Myelosuppression almost always occurs (Neutropenia and thrombocytopenia)
Nausea, vomiting
alopecia
neurotoxicity
Sterile necrotizing hemorrhagic cystitis

Question 28

Vincristine adverse effects

Answer 28

Dose dependent leukopenia, usually mild
Thrombocytopenia, anemia are very rare
Peripheral neuropathy - tingling, intermittent sharp pains, clumsiness
IV only – vesicant (causes blisters)

Question 29

Doxorubicin adverse effects

Answer 29

Acute toxicity
* EKG changes, cardiac arrest (usually brief)

Short term
* Weight loss, anorexia, diarrhea, vomiting
* Myelotoxic
* Neutropenia
* Bone marrow hypoplasia
* Poikilocytosis in cats
* Lymphoid atrophy

Chronic toxicity
* Hair loss
* Testicular atrophy
* Dose dependent Cardiac toxicity

Question 29

Doxorubicin adverse effects

Answer 29

Acute toxicity
* EKG changes, cardiac arrest (usually brief)

Short term
* Weight loss, anorexia, diarrhea, vomiting
* Myelotoxic
* Neutropenia
* Bone marrow hypoplasia
* Poikilocytosis in cats
* Lymphoid atrophy

Chronic toxicity
* Hair loss
* Testicular atrophy
* Dose dependent Cardiac toxicity

Question 30

L-asparaginase adverse effects

Answer 30

Anaphylaxis (immune/allergic - rare for first use)
Pancreatitis
Decrease clotting factors
Especially fibrinogen (decreased protein synthesis)
NOT myelosuppressive- Does not affect neutrophil count

Question 31

anti neoplastic drug administration

Answer 31

Protective clothing
Gloves
Mask
Eye protection