Pharmacology antifungals, antivirals, antineoplastic Flashcards
Griseofulvin
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
Griseofulvin adverse effects
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)
Amphotericin B
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
Amphotericin B adverse effects
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”
Amphotericin B Drug interactions
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
Azole Antifungal Drugs Mechanism of Action, adverse rxns
Inhibits ergosterol synthesis
Fungistatic
Common adverse drug rxns – hepatotoxicity, not safe during pregnancy
Azole Spectrum
Dimorphic fungi
* Blastomyces
* Histoplasma
* Cryptococcus
* Sporothrix
Dermatophytes
Filamentous fungi (+/-)
* Aspergillus
* Fusarium
Ketoconazole absorbtion
Oral absorption is enhanced by food
Inhibited by antacids (pH dependent solubility)
Not absorbed in horses
Ketoconazole adverse effects
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)
Ketoconazole drug interactions
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
TRIAZOLES
Itraconazole, Fluconazole, Voriconazole
Better tolerated than ketoconazole
Less inhibition of CYP-450 enzymes/p-glycoprotein
Itraconazole>voriconazole>fluconazole
No endocrine effects
More expensive
Itraconazole adverse effects
Hepatic:
* Increased liver enzymes (10-43%)
* Hepatotoxicosis (10%)
GI: anorexia, vomiting (2-3%)
Congestive heart failure - people
Check for underlying disease
itraconazole pharmokinetics
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
Fluconazole differences from other Azoles
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
Fluconazole adverse effects
Minimal
Increased hepatic enzymes
Prolonged recovery (ketamine/midazolam)
Voriconazole
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!
Voriconazole and cats
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!
Terbinafine mechanism and spectrum
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
Terbinafine adverse effects
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
Antiherpetic drugs
Nucleoside analogs
Prodrugs
oral admin
Clinical use not usually recommended
Anti-influenza Drugs
Clinical use not recommended
prohibited in poultry
therapeutic targets of antineoplastic drugs
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)
antineoplastic drug toxicities
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”
antineoplastic drug toxicities
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”
resistance to antineoplastic drugs
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
antineoplastic protocols
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”
Cyclophosphamide adverse effects
Myelosuppression almost always occurs (Neutropenia and thrombocytopenia)
Nausea, vomiting
alopecia
neurotoxicity
Sterile necrotizing hemorrhagic cystitis
Vincristine adverse effects
Dose dependent leukopenia, usually mild
Thrombocytopenia, anemia are very rare
Peripheral neuropathy - tingling, intermittent sharp pains, clumsiness
IV only – vesicant (causes blisters)
Doxorubicin adverse effects
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
Doxorubicin adverse effects
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
L-asparaginase adverse effects
Anaphylaxis (immune/allergic - rare for first use)
Pancreatitis
Decrease clotting factors
Especially fibrinogen (decreased protein synthesis)
NOT myelosuppressive- Does not affect neutrophil count
anti neoplastic drug administration
Protective clothing
Gloves
Mask
Eye protection
