Pharmacology 9% Flashcards
1
Q
Ceftazidime
A
- Third generation injectable cephalosporin for gram-negative infections
- Considered an “anti-pseudomonas” cephalosporin
- bactericidal; inhibits enzymes responsible for bacterial cell wall synthesis
- Much expanded gram-negative activity than first and second generation
- Excreted via renal excretion, may accumulate in patients with impaired renal function
2
Q
Imiquimod
A
- Synthetic ligand of Toll-like receptors and induces secretion of antiviral cytokines, such as IFNs
3
Q
List 10 drugs that can inhibit P450 enzymes
A
1) Ketoconazole
2) Itraconazole
3) Fluconazole
4) Erythromycin
5) Furosemide
6) Calcium channel blockers (diltiazem and verapamil)
7) Metoclopramide
8) Methylprednisolone
9) Doxycycline
10) Allopurinol
4
Q
What are cutaneous manifestations of babesiosis (caused by B. canis and B. gibsoni)?
A
- oral and cutaneous petechial/ecchymotic hemorrhages associated with thrombocytopenia or DIC
- Other skin lesions are due to subjacent leukocytoclastic vasculitis with or without vascular necrosis -> edema, ecchymosis, ulceration and necrosis on the pinnae, axillae, groin, limbs or scrotum
5
Q
Describe the effects of EDTA?
A
When incorporated into a topical, can decrease the MIC of an organism by making the bacterial cell wall more permeable.
6
Q
What are the most common bacteria that cause skin infections in cats?
A
- Pasteurella multocida
- Beta hemolytic streptococci
7
Q
What percentage of the cardiac output of blood reaches the skin?
A
4%
8
Q
Methicillin resistance is associated with what?
A
Associated with resistance to all beta-lactam antibiotics, including the penicillins and cephalosporins
9
Q
Staphylococcus schleferei has two subspecies. What are they and how do they differ from one another?
A
S. schleiferi has 2 distinct subspecies, which are known as S schleiferi subsp schleiferi and S schleiferi subsp coagulans. They can be distinguished by activity of tube coagulase and urease. S schleiferi subsp schleiferi is tube coagulase and urease negative, whereas S schleiferi subsp coagulans is tube coagulase and urease positive
10
Q
What is the difference between time-dependant vs. concentration-dependant antibiotics?
A
Time-dependent drugs must be given at their specified interval of administration for maximal efficacy. The total dose administered is more important for the concentration-dependent drugs.
11
Q
Sulfonamides
A
- With chronic use, can result in KCS, clinical hypothyroidism and adverse cutaneous drug reactions
12
Q
List 6 drugs that have been used as immunomodulators to help prevent canine recurrent idiopathic pyoderma in cases of immunodeficiency ?
A
1) Levamisole
2) Cimetidine - H2 receptor antagonist, may inhibit histamine-influenced immunosuppresion
3) Recombinant human interferon alpha 2b
4) S. aureus bacterin (i.e. Staphage lysate) - initially 0.5 ml given SQ twice weekly for 10-12 weeks
5) Bacterin using P. acnes (called Immunoregulin) - given via IV injection every 3 - 4 th day for 2 weeks then once weekly thereafter until condition stablizes or goes into remission; if given SQ of IM, can cause a necrotizing dermatitis.
6) Autogenous staphylococcal vaccine
* 4 and 5 most often prescribed, mechanisms of action of 4 or 5 are unknown, thought to improve cell-mediated immunity with subsequent impact on humoral and non-specific immunity.
13
Q
What does keratolytic mean?
A
These agents facilitate decreased cohesion among corneocytes, desquamation and shedding, resulting in a softening of the stratum corner with easy removal of scale
14
Q
What does keratoplastic mean?
A
These agents attempt to renormalize the keratinization and abnormal epithelialization that is present in keratinization disorders; the complete mechanism of these effects is unknown; it is believe that some keratoplastic agents (especially tar) decrease DNA production with a resultant decrease in the mitotic index of the epidermal basal cells
15
Q
What does follicular flushing mean?
A
Term used to describe agents that help remove follicular secretions and bacteria and decrease follicular hyperkeratosis.
16
Q
Sulfur
A
Mechanism of action associated with interaction between sulfur with cysteine in keratinocytes.
- Mild follicular flushing agent; not a good degreased
- antibacterial, antifungal and anti parasitic
- Actions attributed to the formation of pentathionic acid and hydrogen sulfide
- Keratoplastic: Deeper action of sulfur on the basal layer of the epidermis and by the formation of cystine.
- Keratolytic: from superficial effect on the horny layer and the formation of hydrogen sulfide
- Always in associated with salicylic acid due to synergistic effects
17
Q
Salicylic acid
A
Keratoplastic (0.1-2%) and externs a favorable influence on the new formation of the keratinous layer
- mildly antipruritic and bacteriostatic
- At [3-6%], solubilizes the intercellular cement, acting as a keratolytic agent, causing shedding and softening of the stratum corneum
- When combined with sulfur, believed to have synergistic effects
18
Q
Tar
A
- Products derived from destructive distillation of bituminous coal or wood
- Coal tar solution contains only 20% of the coal tar present in coal tar extract or refined tar
- Most pharmaceutical preparations have been refined to decrease the staining effect and strong odor
- Cats are sensitive to coal tar
- All tars are odiferous, potentially irritation, photosensitizing and carcinogenic
- Tar shampoos are keratolytic, keratoplastic and mildly degreasing
- Usually incorporated with sulfur and salicylic acid
19
Q
Benzoyl peroxide (2.5-5%)
A
- Keratolytic, antibacterial, degreasing, antipruritic, follicular flushing
- metabolized in the skin to benzoic acid, which lyses intercellular substance in the horny layer to account for its keratolytic effect
- Can be drying, can induce a contact dermatitis, bleaches hair, clothing and furniture
- Potent degreasing action, excessively dire out normal skin with prolonged use, contraindicated in the presence of dry skin or significant irritation or both.
20
Q
Selenium sulfide
A
- Alters epidermal turnover rate and interferes with hydrogen bond formation in keratin
- Keratolytic, keratoplastic and very degreasing
- Antiyeast
- Causes irritation in some dogs and should not be used in cats
21
Q
Emollients
A
Agents that soften or soothe the skin
- Occlusive emollients are mostly oils (safflower, sesame, mineral oil) or contain lanolin; these decrease trans epidermal water loss and cause moisturization; work best if applied immediately after saturation of the stratum corneum with water
- Non-occlusive emollients are relatively ineffective in retaining moisture.
- Examples: vegetable oils (olive, cottonseen, corn, peanut oil), animal oils (lard, whale oil, anhydrous lanolin and lanolin 25-50% water), silicones, hydrocarbons (paraffin and petrolatum) and waxes
22
Q
Moisturizers
A
Agents that increase the water content of the stratum corneum
23
Q
Hydroscopic (humectant) agents
A
Moisturizers that work by being incorporated into the stratum corny and attacking water; draw water from the deep epidermis and dermis and from the environment if the relative humidity is greater than 70%
- Propylene glycol, glycerin, colloidal oatmeal, urea, sodium lactate and lactic acid
24
Q
What is a retinoid?
A
All the chemicals, natural or synthetic, that have vitamin A activity.
- Synthetic retinoids: retinol, retinoic acid, retinal derivatives or analogs; more than 1500 synthetic retinoids have been developed and evaluated.
- Biological effects are numerous and diverse but their ability to regulate proliferation, growth and differentiation of epithelial tissues is their major benefit
- Also effect proteases, prostaglandins, humoral and cellular immunity and cellular adhesion and communication
- All retinoids are potent teratogens
25
Q
Vitamin A
A
- an alcohol, all-trans retinol
- Oxidized in the body to retinol and retinoic acid
- Both important in the induction and maintenance of normal growth and differentiation of keratinocytes
- Only retinol has all the known functions of vitamin A
26
Q
Isotretinoin (13-cis-retinoic acid)
A
- Synthesized as a natural metabolite of retinrol
- One of the most commonly prescribed retinoids in veterinary medicine
- Side effects in dogs: conjunctivitis, hypertriglyceridemia, hypercholesterolemia, increases levels of ALT, AST, ALP.
- Side effects in cats: conjunctivitis, diarrhea, anorexia, vomiting
- With long-term use, skeletal abnormalities including cortical hyperostosis, periosteal calcification, long-bone demineralization are a concern.
- Potent teratogen
27
Q
Etretinate
A
One of the most commonly prescribed retinoids
- a synthetic retinoid, no longer available
28
Q
Vitamin D analogs
A
- Inhibit keratinocyte proliferation, induce terminal differentiation of keratinocytes and decrease immunologic reactivity
29
Q
What are the proposed mechanisms of action when using topical n acetylcysteine in an ear cleaner?
A
NAC is a known mucolytic (breaks down biofilm?)
- Proposed to completely inhibit the uptake of amino acids such as cysteine by bacterial cells or to react with bacterial cell proteins with its own sulfhydryl group
30
Q
Are azole antifungals fungistatic or fungicidal?
A
Fungistatic
31
Q
What is the mechanism of action of azole antifungals?
A
Azole antifungal drugs inhibit sterol 14-alpha demethylase, a cytochrome P450-dependant fungal enzyme involved in synthesis of ergosterol from lanosterol
- Ergosterol is a key component of the fungal cell wall
- The result is an accumulation of 14-alpha methyl sterols which disrupt the fungal cell membrane
- All azole antifungals have the potential to be teratogenic
- Some azole antifungals used in humans for treatment of leishmaniasis (ex. fluconazole).
- Azoles inhibit the cytochrome P450 enzyme lanoesterol 14-demethylase; inhibits conversion of lanosterol to ergosterol, causing accumulation of C14 methylated sterolds
- also inhibit intracellular triglyceride, phospholipid synthesis, cell wall chitin synthesis and inhibition of oxidative and peroxidative enzymes
32
Q
What is an imidazole vs. triazole and what are examples of each?
A
Azole antifungals that have either two nitrogen molecules (i.e. an imidazole) or three nitrogen units (i.e. triazole) in their azole ring
- Imidazole: ketoconazole, econazole, enilconazole, clotrimazole, miconazole
- Triazole: itraconazole, fluconazole. voriconazole, posaconazole, ravuconazole
- Triazoles and allylamines are liphophilic and kertainophilic, shorter durations of therapy and pulse therapy are feasible.
33
Q
Ketoconazole
A
- Imidazole antifungal
- large
34
Q
What are different mechanisms of resistance to azole antifungals?
A
- Mutations in the gene encoding the demethylase enzyme
- Increased production of C-14 alpha demethylase
- Increased azole efflux by fungal cell membrane transporters
35
Q
What are X drugs that can interfere with P-glycoprotein transport?
A
- Ketoconazole
- Itraconazole
- Spinosad
36
Q
Ketoconazole
A
- Imidazole antifungal
- General inhibitor of P450 enzymes
- at higher concentrations KCZ may have a direct physicochemical effect on the fungal cell membrane, leading to fungicidal action.
- ALSO blocks 11-hydroxylase; blocks transformation of deoxycorticosterone to corticosterone; also inhibits the transformation of progersterone to pregnenolone
- inhibit yeast transforming into mycelial form
- Absorption best when given with food, inhibited when given with antacids
- Greater toxicity relative to triazole antifungals
- Can cause vomiting, diarrhea, lethargy and diarrhea
- Mild increases in transaminases can occur
- Can cause hepatitis (anorexia, lethargy, increasing ALT, ALP, hyperbilirubinemia)
- Pruritus and cutaneous erythema reported in small number of dogs
- Lightening of the hair coat associated with loss of guard hairs and cataract formation can occur
- Potent inhibitor of mammalian cytochrome P450 enzymes and efflux transporter proteins, such as P-glycoprotein
- Inhibits the metabolism of cyclosporine
- Inhibits testosterone and cortisol synthesis
- give with fats to increase absorption
- Metabolized by liver to inactive metabolite
- Less effect against aspergillus and sporotrichosis
- NOT recommended for feline dermatophytosis
- NOT a first choice for animals with fungal infection involving the CNS or ocular disease
- Increases concentrations of drugs metabolized by P450 enzymes.
- Cats experience alot of side effects (inappetence, weight loss, hepatotoxicity); do not use i cats.
- ALT, ALP, bilirubin and bile acids should be monitored before and during therapy (i.e. every 2-4 weeks)
- NOT approved for use in cats or dogs in the USA
37
Q
Itraconazole
A
- Synthetic triazole antifungal
- Binds weakly to mammalian P450 enzymes
- Concentrated in lipophilic tissues and keratin; secreted in sebum
- Persists in skin 2-4 weeks after discontinuation
- Does not penetrate well into CNS or ocular tissues
- Metabolized by liver into inactive metabolites that are excreted in bile and urine
- Given with food, absorption decreased when given with antacids
- Compounded versions have very poor absorption, stability etc.
- Inhibits metabolism of mammalian P450 enzymes; does not interfere with cortisol synhtesis
- Inhibits metabolism of other P450 dependant drugs (cisapride, diazepam, cyclosporin).
- Only triazole converted to an active metabolite
- Adverse effects: vomiting and transient lethargy
- Mild to moderate increase in ALT
- Significant hepatotoxicity less likely to occur than ketoconazole
- Ulcerative skin lesions occur when especially when doses of 10 mg/kg/day or more are used from cutaneous vasculitis
- Does not suppress adrenal and testicular function
- Variable efficacy against Pythium
- DO NOT administer with ketoconazole, cisapride, or terfenadine - fatal cardiac arrhythmias can occur
- Prolongs the effects and increases the toxicity of benzodiazepines, cyclosporine, glucocorticoids, antihistamines, quinidine, digoxin, vincritine, warfarin, sulfonylureas.
- Concurrent antacids, H2 blocks and anticholinergics are contraindicated
38
Q
Fluconazole
A
- A bis-triazole antifungal
- higher affinity for fungal enzymes than mammalian enzymes.
- Penetrated well into ocular and CNS independant of inflammation
- Least active azole antifungal with narrowest spectrum
- More water soluble and stable than itraconazole
- Diffuses better into body tissues (saliva, urine, synovial fluid, and CSF)
- Absorption unaffected by gastric acidity
- Primarily excreted via kidneys; reduce dosage in animals with underlying kidney disease and avoid in pregnant animals
- Not extensively metabolizes
- Side effects uncommon and similar to itra.
- Excellent spectrum of activity for yeasts
- Potentiates the effects of anticoagulants, thiazide diuretics, rifampin, cyclosporine, glipizide, antihistamines, diphenyldantoin and theophylline
- Does not suppress adrenal or sex hormones
- Evaluate liver enzymes prior to and during therapy.
- The most fungal-enzyme specific azole antifungal
- Thought to be less effective than other azole antifungals with treating dermatophytosis
39
Q
Voriconazole
A
- Second-generation triazole
- Derived from fluconazole
- Used to treat disseminated mold infections; not affective against Sporothrix or zygomycetes
- Good CNS penetration
- Of all triazoles, it is the most potent inhibitor of P450 enzymes
- Cats extremely sensitive to adverse effects: inappetence, ocular and CNS signs including ataxia, pelvic limb paresis, mydriasis, apparent blindness, decreased PLR’s, decreased menace, cardiac arrhythmias and hypokalemia
40
Q
Posaconazole
A
- Itraconazole analogue
- Good efficacy for refractory deep mycoses
- Broadest spectrum of all azole antifungals
- Spectrum similar to voriconazole
- Absorption improve with fatty meal
- Gastric acid suppression can reduce bioavailability of posaconazole
41
Q
List X P450 dependant drugs
A
- Ketoconazole
- Itraconazole
- Cyclosporin
- Cisapride
- Diazepam
- Digoxin
- vinca alkaloids
42
Q
What azole antifungal has been associated with the development of cutaneous ulcerations when used at a dose equal to, or greater than, 10 mg/kg/day?
A
Itraconazole
43
Q
Amphotericin B
A
- polyene macrolide antibiotic
- Produced by Streptomyces nodosus
- Closely related to nystatin
- Irreversibly binds sterols (primarily ergosterol; to a lesser degree cholesterol) in fungal cell membranes, forming pores or channels with subsequent leakage of ions
- Generally considered fungistatic, can be fungicidal at high doses
- Immunomodulatory effects: activated macrophages, and enhances macrophage killing capacity; stimulates lymphocytes, neutrophil function and induces production of TNF-alpha
- Active against all important small animal fungal pathogens; also has activity against leishmania
- Treatment of choice for visceral leishmaniasis; Thought to bind to ergosterol in the protozoal leishmania membrane and block the ability of Leishmania to bind and enter macrophages; WHO recommends against the use of AMB for treating canine leishmaniasis.
- mechanism of resistance is not well understood but believed to be secondary to decreased cell wall ergosterol content
- IV infusion in lyophilized form
- Nephrotoxicity is the major adverse effect that is dose dependent and transient if detected early; loading sodium before the infusion may decrease severity of nephrotoxicity
- Fever, vomiting and inappetence can occur in some dogs
- Phlebitis can occur at injection site
- Newer lipid formulations are taken up by macrophages and carried to the sites of fungal induced inflammation
- Poor penetration into CSF, bones, brain
- primarily indicated for the treatment of severe systemic mycotic infections
- NOT effective against dermatophytes
44
Q
5-Flucytosine
A
- fluorinared pyrimindine related to fluorouracil
- Has activity ONLY against cryptococcus and Candida; also used for Aspergillus and some fungi associated with phaeohyphomycosis; NOT affective against dermatophytes or filamentous fungi
- Fungal cells only susceptible if they contain the enzyme cytosine permease which allows flucytosine to be taken in by the fungal cell
- After taken up, 5-fluorcytosine is then deaminated by cytosine deaminase to 5-fluoro-21-deoxyuridic acid; these substances inhibit thymidylate synthetase and DNA synthesis
- These fungi deaminate flucytosine to 5-fluorouracil so toxicity in mammalian cells is limited
- resistance occurs during treatment, always pair it with a different antifungal (most commonly AMB)
- Resistance to this drug results from modifications in fungal enzymes that required for flucytosine uptake and metabolism
- Excellent penetraction into CSF and aqueous humor.
- Excreted unchanged in the urine; adverse effects (myelosuppression and and GI upset) increased in animals with kidney disease
- Avoid use in dogs; consider in cats with refractory cryptococcosis
- contraindicated in animals with renal disease, neonates, pregnancy and preexisting myelosuppression
- Dogs develope a severe and reversible drug eruption wihtin 2-3 weeks of starting treatment.
- Evaluate CBC and biochemical profile prior to and every 2 weeks during treatment
45
Q
Griseofulvin
A
- oral antifungal derived from Penicillium griseofulvum
- Binds to fungal tubulin leading to impaired microtubule function and mitotic arrest; inhibits nucleic acid synthesis and cell mitosis by arresting division at metaphase
- also has antiinflammatory properties: known to suppress delayed-type hypersensitivity reactions and irritant reactions in the skin
- Rapidly deposited in keratin precursor cells in the skin and hair; disappears from stratum corneum within 48-72 hours; concentrates in newly formed keratinized epithelium and concentrates in the dermis and appendanges
- Metabolized by the liver to inactive compounds
- Fungistatic with limited spectrum of activity; ONLY ACTIVE AGAINST DERMATOPHYTOSIS
- Very effective against dermatophytes but expensive and can cause GI upset and myelosuppression
- Used primarily to treat dermatophytosis, also has efficacy against yeasts including Malassezia and Candida; NOT EFFECTIVE AT TREATING MALASSEZIA
- Resistance mechanism believed to be due to altered tubulin in some dermatophytes
- Potent induce of P450 enzymes; so decreases the efficacy of other drugs that are metabolized to inactive metabolites by P450 enzymes
- Teratogenic! Do not use in pregnant animals, or animals with hepatic dysfunction; feline retroviral infections, anemia or leukopenia
- Can cause neurotoxicity in overdoses
- Interferes with spermatogensis
- inappetence, vomiting, diarrhea
- cats: myelosuppression; more likely in FIV+ cats
- Persians, Siamese, Abyssinians may be predisposed to side effects
- Monitor CBC every 2 weeks
- Drug carried to stratum corneum by diffusion, sweating, and transepidermal fluid loss
46
Q
What are potent inducers of P450 enzymes
A
- decrease efficacy of other drugs that are metabolized o inactive metabolites by P450 enzymes
- Griseofulvin
47
Q
Terbinafine
A
- Synthetic allylamine
- Inhibits fungal squalene epoxidase; blocks fungal lanoesterol and ergosterol synthesis and leads to accumulation of toxic squalene with resultant fungcal cell lysis
- fungistatic and fungicidal
- Fungicidal against dermatophytes, aspergillus, sporothrix; less effective against yeast or dimorphic fungi; active against malassezia and candida
- Drug delivered to stratum corneum via sebum
- Has some effect against pythium (when combined with ITZ)
- Reduce dosage with renal or hepatic insufficiency
- May be used in pregnancy
- Cimetidine increases blood concentration, rifampin decreases blood concentration
- Not inhibitory to most P450 enzymes
- Most effective for dermatphytes; also useful for Malassezia
- Resistance in dermatophytes reported as a result of altered squalene epoxidase
- accumulated in hair, skin, claws and fat and persists weeks after medication is discontinued
- GI signs (vomiting and increased liver enzymes) occur uncommonly; facial pruritus has been reported in cats
- Evaluate liver enzymes prior to and every 2 - 4 weeks through therapy
- Adverse effects: vomiting, anorexia, diarrhea, abdominal pain, hepatotoxicity (biliary stasis, increased ALP and ALT), neutropenia, pancytopenia
48
Q
Caspofungin
A
- An “echinocandin” lipopeptide antifungal
- A cyclic hexapeptide that inhibits the formation of beta-1, 3-D-glucans in the fungal cell wall; blocks cell wall synthesis
- Inhibits hyphen growth and branching, converts mycelium to small clumps
- Fungicidal against Candida spp. and fungistatic against Aspergillus species.
- Active against dermatophytes, Sporothrix and some yeasts
- Given IV; has been used to treat aspergillosis in humans that do not respond to AMB and azaleas
- infusion-related urticaria, pruritus, hepatotoxicity
49
Q
Famciclovir
A
- A prodrug, metabolized into penciclovir
- A guanosine (i.e. nucleoside) analogue; use of nucleoside analogues during viral replication leads to the formation of abnormal nucleic acids or termination of nucleic acid synthesis
- Activate by the herpesviral enzyme thymidine kinase (TK) which phosphorylates the drug into a monophosphate form
- Host cell enzymes then phosphorylate these drugs further to triphosphate forms, which concentrate in virus-infected cells and interfere with viral DNA replication via inhibition of the viral DNA polymerase enzyme
- Drug resistance occurs from reduced viral TK activity, altered viral TK or altered viral DNA polymerase
- Potent inhibitor or FHV-1 replication
50
Q
Lysine
A
- Amino acid that interferes with herpes viral replication by poorly understood mechanisms
- Antagonism of arginine may somehow be involved because a high lysine to arginine ratio appears to be important
51
Q
What are type I interferons?
A
- Cytokines with antiviral properties produced by leukocytes and fibroblasts
- IFN-a (alpha)
- IFN-b (beta)
- IFN-w (omega)
- Activate natural killer cells, increase expression of MHC class I molecules and have anti-tumor activity
52
Q
What are type II interferons?
A
IFN-y (i.e. gamma); the only type of type II interferon and produced by T lymphocytes and NK cells in response to antigenic stimulation
- Plays important role in clearing of intracellular pathogens by macrophages.
53
Q
Interferon alpha
A
- A group of more than 20 molecules that differe slightly
- Inhibit vial nucleic acid and protein synthesis
- Human recombinant IFN-alpha has been administered to cats for treatment of retroviral infections, feline upper respiratory viral infections and FIP
- Inhibits replication of FeLV, FIV, FHV-1 and feline coronavirus in vitro.
- Parenteral administration can lead to the development of neutralizing antibodies and apparent loss of activity after 3-7 weeks
- Oral administration controversial due to presumed proteolytic degradation by gastric acid; can still benefit if absorbed through mucosa
54
Q
Feline recombinant interferon-omega
A
- Type 1 interferon closely related to IFN-alpha
- Secreted by virus-infected leukocytes
- Precise mechanism of action is not known
- In dogs: increases macrophage and NK cell activity
- Antiviral effects against several feline viruses in vitro (FeLV, FHV-1, feline calicivirus, canine and feline parvovirus, feline coronavirus)
- Also has anti-tumour activity
- Recombinant feline IFN-w produced by silkworms available in Eu and Canada.
- Similar effect in both canine and feline cells
- Transient lethargy, fever, vomiting, mild diarrhea and anorexia have been documented in some cats
- Mild neutropenia, eosinophilia and reversible increases in the activity of serum AST have also been described following treatment
55
Q
Meglumine antimoniate
A
- derived from the heavy metal antimony (i.e. “Sb”)
- A pentavalent antimondy compound because they contain Sb atoms with give electrons in their outer shell
- Recommended as first choice for treatment of leishmanisis
- Mechanism of action not completetly clear; suspected that pentavalent antimony goes under reduction to the more toxic trivalent antimony, possibly within macrophage phagolysosomes or within the parasite itself
- Trivalent antimony inhibits protozoal enzymes and damages protozoal DNA
- Elimination of the parasite does not always occur
- Resistance to antimonials is an increasing problem in humans with leishmaniasis.
- Administered subcutaneously
- Typically combined with allopurinol for canines
- 80% eliminated by kidneys ; can result in lethargy, vomiting, diarrhea, inappetenace and increased serum liver enzyme activity more likley to occur in the presence of kidney disease
- Can cause renal tubular necrosis in healthy dogs
56
Q
Allopurinol
A
- A purine analogue
- In parasites, metabolized to derivatives that are incorporated into RNA which leads to impaired RNA synthesis
- Resistance can occur from reduced activity of purine transporters and a reduced ability to accumulate purine
- Most commonly combined with meglumine or miltefosine.
- Rarely causes side effects in dogd
- Inhibits mammalian xanthine oxidase, which results in decreased uric acid production from xanthine; long-term use can result in xanthine urolithiasis
- Serious adverse effects occur when combined with azathioprine
57
Q
Miltefosine
A
- Effective alternative to pentavalent antimonials
- A phospholipid analogue that activates cellular proteases in Leishmania spp. which result in apoptosis.
- First highly active oral drug for treatment of leishmaniasis
- Elimination of the parasite does not always occur
- Resistance can result from increased P-glycoprotein-mediated drug efflux and decreased drug uptake
- WHO recommends decreasing use of this drug to prevent resistance
- Does not contribute to renal pathology in dogs.
58
Q
What drug class is Naftifine in?
A
- allylamine
59
Q
Chlorhexidine
A
- synthetic biguanide
-
60
Q
What drugs do azole antifungals interact with?
A
- Cyclosporine
- Certain antihistamines (terfenadine, astemizole)
- GI motility agents (cisapride)
- Benzodiazepines
- Calcium channel blocksers
- Anticonvulsants
- antimycobacterial agents
61
Q
Iodides
A
- Inorganic halogens
- exact anti fungal action unknown; may facilitate phagocyte killing of fungal cells; have no effect against fungal organisms in vitro
- Enhance the halide-peroxidase killing system of phagocytic cells
- Anti-inflammatory: quench toxic oxygen metabolites and inhibit neutrophil chemotaxis
- Used to treat sporothrix, basidiobolus, subcutaneous phycomycosis, rhinosporidiosis
- Do not use in animals with thyroid disease, iodide hypersensitivity, renal failure, dehydration, pregnancy
- Give orally
- Adverse effects: anorexia, hyper salivation, vomiting, muscle twitching, cardiomyopathy, heart failure, death, ocular/nasal discharge, scaling, dry hair coat, hypothyroidism thyroid goiters and/or adenomas
- Highly effective in treating sporotrichosis
62
Q
Lufenuron
A
- a benzoylphenyl urea; an insect growth regulator that acts by inhibiting chitin synthesis, polymerization and deposition
- Proposed to interfere with formation of fungal cell wall and insect exoskeleton
- Controversial for use for treating fungal infections
63
Q
Oclacitinib
A
- A non selective janus kinase inhibitor (i.e. a “JAKinib”) with most potent effects on JAK1 associated with the intracellular portion of type I and type II cytokine receptors
- Blocks the transmission of interleukins 2, 4, 6, 13, 31
- Blocking of the cytokine signal prevents gene transcription and protein production mediated by these cytokines.
64
Q
Lokivetmab
A
- A caninized Monoclonal antibody that binds and neutralized IL-31
65
Q
What is the mechanism of action of beta-lactam antibiotics?
A
- Have a beta-lactam ring in their molecular structure
- Includes penicillins, cephalosporins, monobactams and carbapenams
- Bactericidal
- Covalently bind and inhibit pencillin binding proteins (i.e. PBP’s); PBP’s are needed to catalyze the cross-linking (or transpeptidaiton) or the peptidoglycan layer of bacterial cell walls.
- When penicillin binding proteins are inactivated by Beta lactam antibiodics, bacterial enzymes that hydrolyse the peptidoglycan cross-links continue to function and break down the cell wall further
- Accumulation of peptidoglycan precursors triggers activation of cell wall hydrolases, which further digest intact peptidoglycan
- Results in bacterial rupture
66
Q
What are the methods of resistance against beta-lactam antibiotics?
A
- Results primarily from beta-lactamase production
- Production of altered penicillin binding proteins (such as PBP2a)
67
Q
Are beta-lactam antibiotics concentration or time dependent antibiotics?
A
time-dependent pharmacodynamics
68
Q
Penicillins
A
- An inhibitor of cell wall synthesis
- derived from penicillium molds
- Categorized as
1) naturally occurring pencillins (i.e. Penicillin g; aka benzyl penicillin);
2) semisynthetic aminopenicillins (ampicillin, amoxicillin), 3) penicillinase-resistant pencillins (methicillin, oxacillin, cloxacillin,),
4) extended-spectrum penicillins (i.e. antipseudomonal penicllins like ticarcillin). - Typically distributed in the extracellular fluid of most tissues
- low penetration across the blood-brain barrier and blood-ocular barrier
- Rapid renal excretion and concentrated in the urine
69
Q
Amoxicillin
A
- A semisynthetic aminopenicillin
- Activity against gram positive aerobic bacteria (cocci and bacilli) and anaerobes, some susceptible gram negative bacteria
- Commonly combined with clavulanic acid, a beta-lactamase inhibitor
70
Q
Ticarcillin
A
- An extended spectrum carboxypenicillin
- Increased activity against suspectible gram-negative aerobes, including Pseudomonas aeruginosa, Proteus, Klebsiella and anaerobes
- Some reduction in gram positive spectrum
- Destroyed by beta-lactamases, often combined with a beta lactamase inhibitor such as clavulanate
- Typically given parenterally or formulated topically
71
Q
Piperacillin
A
- A Ureidopencillin
- Covers suscpetible gram-positive and gram-negative aerobes including Pseudomonas aeruginosa. Some loss of anaerobic spectrum
- Destroyed by beta-lactamases, often combined with tazobactam (a beta-lactamase inhibitor)
72
Q
Cephalosporins
A
- An inhibitor of cell wall synthesis
- A group of beta-lactam antibiotics
- Originally derived from Acemonium spp.
- Broadly grouped into 1st, 2nd, 3rd and 4th generation based on spectrum of activity
- As the generation increases, there is more gram negative coverage
- Cephalosporings are resistant to staphylococcal beta-lactamases
- extended-spectrum third generation cephalosporins are also resistant to many gram-negative beta lactamases
- Extended-spectrum beta-lactamase enzymes can hydrlolyze even third-generation cephalosporings and present an important therapeutic challenge.
- Using third generation cephalosporins can promote ESBL e.coli
- Adverse effects: GI upset and hypersensitivity reactions; cross-sensitivity can occur between penincillins and cephalosporins.
73
Q
Carbapenams
A
- A group of beta-lactam antibiotics
- An inhibitor of cell wall synthesis
- Highly resistant to almost all beta-lactamases
- Include imipenem, meropenem, ertapenem and doripenem
- Penetrate the outer membrane of gram negative bacteria more effectively than any other kind of beta-lactam
- Bind to a wide number of penicillin binding proteins, leads to rapid lysis of a broad spectrum of bacteria
- In contrast to other beta-lactams, carbapenams have a post antibiotic effect similar to aminoglycosides and flouroquinolones
- Reserved for treatment of serious, multiple drug resistant gram-negative infections especially E.coli, Klebsiella pneumoniae and P. aeruginosa that are resistant to other antibioitics
- METHICILLIN-RESISTANT BACTERIA ARE RESISTANT TO CARBAPENEMS
- Imipenem is metabolized by dehydropeptidase-1, a brush border enzyme in the proximal renal tubules, to an inactive metabolite that is nephrotoxic; imipenem is typically administered with cilastatin which inhibits the dehydropeptidase 1 enzyme
74
Q
Vancomycin
A
- An inhibitor of cell wall synthesis
- A glycopeptide, i.e. a cyclic glycosylated peptide antimicrobial
- Bactericidal
- inhibit the synthesis of peptidoglycan by binding to amino acids (D-alanyl-D-alanine) in the cell wall, preventing the addition of new units.
- Other glycopeptides include teicoplanin, decaplanin
- Not absorbed orally, IV infusion required
- Useful for treating MDR gram positive bacterial infections such as MR Staph infections, resistant enterococcal infections, encrusting cystitis.
- Resistance is extremely rare to this antimicrobial
- Resistance occurs from bacterial alteration of the terminal amino acid to which vancomycin binds
75
Q
What is the mechanism of action of the fluoroquinolone?
A
- A nucleic acid inhibitor
- Bind to DNA gyrase (also known as topoisomerase II) and topoisomerase IV; these are enzymes that cleave DNA during DNA replication
- CONCENTRATION DEPENDANT ANTIBIOTICS, best administered as a single high dose.
- Poor absorption occurs when given with antacids or supplements containing aluminum, calcium, iron and zinc.
- Results in disruption of bacterial DNA and protein synthesis
- For the veterinary fluoroquinolones (marbofloxacin, enrofloxacin, orbifloxacin), DNA gyrase is the primary target for gram-negative bacteria; topoisomerase IV is the primary target for gram-positive bacteria
- Created by the addition of a fluorine group to nalidixic acid
- Newer-generation fluoroquinolone inhibit both DNA gyrase and topoisomerase IV in gram-positive bacteria leading to enhanced activity for treatment of gram-positive bacteria and anaerobic bacterial infections and decreasing selection for resistant strains.
- 3rd generation fluoroquinolone: pradofloxacin, moxifloxacin, levofloxacin, gatifloxacin
- Most valuable for treating gram-negative infections as well as staphylococci, although Staph tend to have a higher MIC than gram negative bacteria for fluoroquinolone
- Enrofloxacin is metabolized to ciprofloxacin
- Ciprofloxacin’s bioavailability is not the same as humans.
- Most concentrated in the urine
- Obtain high intracellular concentrations and can be used to treat infections by intracellular pathogens such as Mycoplasma and mycobacterium.
76
Q
What are the mechanisms resistance to fluoroquinolone antibiotics?
A
- DNA gyrase mutations
- decreased bacterial permeability
- Increased drug efflux
- Pradofloxacin and ciprofloxacin have higher in vitro efficacy against pseudomonas aeruginosa than other fluorquinolones.
77
Q
What are adverse side effects of fluoroquinolones
A
- Cats can go blind with enrofloxacin (>5 mg/kg/day) due to acute retinal degeneration; results from a functional defect in fluoroquinolone transport protein in the cat with accumulation of photo reactive drug in the retina.
- Orbifloxacin can also cause retinal degeneration in cats but the dose needed to do so is much higher than what is used therapeutically.
- Allegedley no retinal degeneration with marbofloxacin or pradofloxacin unless there is a disease (i.e. renal disease) that impairs clearance.
- Because they inhibit proteoglycan synthesis and chelate magnesium, can cause cartilage and joint toxicity in young animals;
- avoid fluoroquinolines for longer than 7 days in animals ages 1 month - 7 months; this is a period of rapid growth.
- Cats thought to be more resistant to cartilage toxicity
- In dogs, >10mg/kg/day or Prado has been associated with myelosuppression.
- Fluoroquinolone inhibit some cytochrome P450 enzymes which decrease metabolism of other drugs.
