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DWT exam 3 > Pharmacology 50s and nucleic acid inhibitors > Flashcards

Pharmacology 50s and nucleic acid inhibitors Flashcards

1
Q

50S inhibition drugs

A

Plasma concentrations not always predictive of treatment success
Concentrate INTRACELLULARLY!
Reach high concentrations in ABSCESSES!

Bacteriostatic
Inhibit protein synthesis
Moderate post-antibiotic effects

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2
Q

drug interactions with 50S inhibitors

A

Co-administration not recommended
* Competitive inhibition at the site of action
* May decrease the effectiveness of each other

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3
Q

50S inhibitors classes

A

Phenicols
Macrolides
Lincosamides

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4
Q

Phenicols

A

50S inhibitor
Companion animal use (dogs, cats, horses)
* Chloramphenicol (oral)

Food animal use: Florfenicol
* Cattle (injectable)
* Swine (feed)
* Fish (water)

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5
Q

Phenicol spectrum

A

50S inhibitor
Broad spectrum with activity against
Gram-positive and gram-negative bacteria
Aerobes and anaerobes
* Rickettsia
* Chlamydia
* Mycoplasma
Activity against Gram-negative enteric bacteria is unpredictable
Activity against Pseudomonas is poor
Florfenicol treats BRDC

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6
Q

Chloramphenicol

A

50S inhibitor, phenicol
Moderately well absorbed following oral administration
* Formulation matters!
* Example: chloramphenicol palmitate in cats; poor absorption

Distributes very well to most tissues of the body
* Concentrations persist longer in tissues than plasma
* Distributes well to protected sites
* Abscesses!!!

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7
Q

Chloramphenicol metabolism

A

Metabolized by the liver
Extensive!!!
Metabolism is deficient in cats and very young animals (any species)
* Conjugation
* Prolonged half-life and increased risk of toxicity

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8
Q

Chloramphenicol adverse effects

A

Dose-dependent hematologic toxicity
* Inhibition of mitochondrial protein synthesis in the bone marrow
* Cats most susceptible
* Rare neutropenia and aplastic anemia have been reported in dogs

Idiosyncratic and irreversible aplastic anemia in people!
* 1 in 10,000 to 30,000 people
* Prohibited from Use in Food Animals!!!
* Client Education!!!
* Wear gloves
* Dissolve don’t crush
* Proper restraint

Anorexia, diarrhea, vomiting, depression (overdose)
Taste

Caution
Cats
Chloramphenicol

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9
Q

Chloramphenicol in food animals

A

Prohibited from Use in Food Animals!!!

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10
Q

Chloramphenicol drug interactions

A

Inhibitor of hepatic microsomal enzyme inhibitor
* May decrease clearance/metabolism of some drugs
* Phenobarbital, phenytoin, propofol

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11
Q

Florfenicol adverse effects

A

50S inhibitor, phenicol

Lacks the para-nitro group responsible for bone marrow toxicity
* Use and ELDU in FA is permissible
* Dose-dependent, reversible bone marrow toxicty still seen

Horses
* Injection site reactions
* Diarrhea
* Fewer Drug interactions

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12
Q

Phenicols resistance mechanisms

A

Acetylation and inactivation by bacterial enzymes
Cross-resistance does not always occur
Florfenicol more resistant to bacterial enzymes

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13
Q

Macrolides

A

50S inhibitor

Dogs, cats, foals
* Erythromycin
* Clarithromycin
* Azithromycin

Food animals
* Erythromycin (poultry)
* Tulathromycin
* Tilmicosin
* Gamithromycin
* Tildipirosin

most end in -mycin

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14
Q

macrolides spectrum

A

50S inhibitor
Gram-positive aerobes
* R. equi, streptococci, staphylococci

Some activity against anaerobes (azithromycin)
Gram-negative activity limited to BRD pathogens (Pasteurella)
Mycoplasma

Gram-positives, BRD, Mycoplasma

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15
Q

macrolides pharmokinetics

absorption, distribution, metabolism, elimination

A

Absorption
* Moderate oral absorption (F = 30-40%)

Distribution
* Wide!!!
* Vd 12-13 L/kg
* MILK/CELLS/LUNGS
* Cmax in cells 200x higher than plasma!!! Detectable 4 days longer

Metabolism
* Liver
* Few active metabolites

Elimination
* Mainly hepatic/biliary
* Half-life: 1-2 hours (erythromycin) to 1-2 days
* Dose intervals
* Q6-8h (erythromycin)
* Q48h (azithromycin)
* Once (tulathromycin)

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16
Q

macrolides adverse effects

A

Gastrointestinal
* Vomiting and diarrhea (dogs and cats)
* Severe, potentially fatal colitis in adult horses and rabbits
* Erythromycin most common (motilin receptors)

Hyperthermia
* Foals
* Anhidrosis

Injection site reactions

Cardiotoxicity
* Tilmicosin
DO NOT GIVE IV in any species
Do not use in cats, dogs, horses
Humans!!!

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17
Q

Macrolidea drug interactions

A

Inhibition of CYP450 enzymes
* Erythromycin
* May increase plasma concentrations/toxicity of other drugs

Co-administration with rifampin
* Decreases bioavailability of the macrolide
* P-glycoprotein interaction
* Still used together – synergism

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18
Q

lincosamides drugs

A

50S inhibitor
Lincomycin – food animals
Clindamycin – small animals

19
Q

Lincosamides spectrum

A

Active against gram positive organisms
Active against anaerobes (Clindamycin > lincomycin)

20
Q

lincosamides pharmokinetics

absorption, distribution, metabolism, elimination

A

Well absorbed orally in dogs and cats
Widely distributed!
* Effective in pyothorax and lung abscesses
* Reaches high concentrations in abscesses!
* Accumulate within leukocytes

Poor penetration into CNS
Hepatic metabolism and elimination

21
Q

Lincosamides adverse effects

A

Fatal antibiotic-induced diarrhea in Horses and rabbits!!!
C. difficile pseudomembranous colitis in humans
* At least one report in a dog

Common cause of anorexia and vomiting in dogs
Pain and irritation at the injection site
* IM or SC administration

22
Q

Fluoroquinolones drugs

A

Four labeled for dogs
* Enrofloxacin (Baytril®)
* Marbofloxacin (Zeniquin®)
* Orbifloxacin (Orbax®)
* Difloxacin (Dicural®)
* Ciprofloxacin is used off-label

Three labeled for cats
* Marbofloxacin (Zeniquin®)
* Orbifloxacin (Orbax®)
* Pradofloxacin (Veraflox®)

Extralabel drug use prohibited in food animals!!!
Two labeled for cattle
* Enrofloxacin (Baytril®)
* Danofloxacin (Advocin®)

One labeled for swine
* Enrofloxacin

Poultry products pulled from the market

Off-label use in horses
* Enrofloxacin
* Marbofloxacin – occ.

end in -floxacin

23
Q

Fluoroquinolones mechanism of action

A

Inhibition of DNA gyrase (aka topoisomerase II)
* Required for bacterial DNA replication, transcription, repair, recombination

Newer generation FQs also inhibit topoisomerase IV
* Pradofloxacin

Bactericidal
Post-antibiotic effect

24
Q

Fluoroquinolones spectrum

A

Treatment of gram-negative aerobic infections (enteric/BRDC)
Staphylococci
Some activity against Pseudomonas sp. – use with caution
* Higher doses are often needed (topical); resistance can develop during treatment

Brucella, Legionella, Chlamydia, Leptospira and sometimes Mycobacteria
Activity is poor against streptococci, not active against enterococci
Pradofloxacin has best activity against anaerobes

Similar spectrum to aminoglycosides but safer in azotemic patients

25
Q

Fluoroquinolones absorption

A

Well absorbed orally in monogastrics
* Exception – ciprofloxacin
* Poorly absorbed in cats
* Really poorly absorbed in horses

Exception – enrofloxacin
* Oral in kittens – chelation on milk diet

26
Q

Fluoroquinolones distribution

A

Distribute well to the tissues
Penetrate well intracellularly
* Enrofloxacin reaches the highest concentration in the cells
* Highest lipid solubility and volume of distribution

27
Q

Fluoroquinolones metabolism and elimination

A

Enrofloxacin is metabolized in vivo to ciprofloxacin
* Active metabolite
* Metabolism is species and age dependent
* 41% cattle, 36% dogs, 17% horses
* 0% foal, 16% kittens

Elimination mainly via the kidney
* EXCEPTION - Pradofloxacin - hepatic elimination
* Highly effective for treating resistant UTIs
* Activity is pH dependent (reduced in acidic environments)

Half-life is moderate
* Once daily dosing due to PAE
* Exception: twice daily ciprofloxacin in dogs

28
Q

Fluoroquinolones adverse effects

A

Cartilage toxicity – severe!
* Chelation of Mg++ in cartilage decreases adherence of chondrocytes
* Lesions exacerbated by weight-bearing = more severe
* Dogs and FOALS most susceptible, cats and calves resistant

Ocular toxicity
* Cats
* Enrofloxacin #1
* Dose dependent
* Retinal degeneration, blindness

29
Q

Fluoroquinolones drug interactions

A

May inhibit the clearance of some drugs (ie theophylline)
Chelation
* Antacids, sucralfate, and multiple vitamins (iron)
* Should not be administered orally at the same time as a FQ (prevent absorption)

30
Q

Fluoroquinolones mechanisms of resistance

A

Alteration of target enzyme (DNA gyrase)
* Not plasmid mediated

Reduced access through altered porins
* Pseudomonas
* Resistance may develop during treatment (esp enro)
* Not recommended as a systemic treatment (topical OK)

31
Q

sulfonamides

A

sulfa drugs
Extralabel use prohibited in adult dairy cattle!!!
bacteriostatic

32
Q

potentiated sulfonamides

A

Sulfonamide (bacteriostatic) plus dihydrofolate reductase inhibitor (bacteriostatic)= bacteriocidal
synnergism
Ruminants don’t absorb DHFRIs (use just sulfas alone)

33
Q

sulfonamides and DHFRI mechanism of action

A

inhibit folic acid synthesis at 2 different stages (bacteria must produce their own folic acid)
Broad Spectrum
* First line choice for pyodermas, UTIs and soft tissue infections (If caused by susceptible bacteria)
* Resistance to these combinations is increasing
* May be effective in some cases of MRSA/MRSP

Effective against protozoa
NOT against Anaerobes

34
Q

Potentiated Sulfonamides absorption, distribution, metabolism

A

Well absorbed orally
Good tissue distribution (extracellular and intracellular)
* Sulfadiazine and pyrimethamine best
* Includes CNS, prostate

Extensive metabolism in the liver
* Moderate half-life, allowing for once or twice daily dosing

Mainly renal elimination
Time-dependent

35
Q

Potentiated Sulfonamides adverse effects

A

Minimal in horses (Occasional diarrhea)
Minimal in cats (Taste and difficulty pilling, SLOBBERS!!!)
Safe in ruminants
Safe in swine
Numerous in dogs
* Altered metabolism
* Breed susceptibility
* Incidence 0.25%

36
Q

Potentiated Sulfonamides dogs adverse effects

A

Lack of N-acetyltransferase
* Detoxifying enzyme
* Without it, toxic metabolites produced
* Dobermans, Rottweilers

Allergic/immune
* polyarthritis, lymphadenopathy, fever, Glomerulonephropathy
* REVERSIBLE

Cutaneous
* ulcerations
* REVERSIBLE

Hepatopathy and Thrombocytopenia
* lower recovery rate

Keratoconjunctivitis sicca
* aka dry eye
* not reversible

Hypothyroidism
* Block formation of thyroxine and thyronine
* Reversible

Bone marrow supression (rare)
Urine crystal formation

36
Q

Potentiated Sulfonamides dogs adverse effects

A

Lack of N-acetyltransferase
* Detoxifying enzyme
* Without it, toxic metabolites produced
* Dobermans, Rottweilers

Allergic/immune
* polyarthritis, lymphadenopathy, fever, Glomerulonephropathy
* REVERSIBLE

Cutaneous
* ulcerations
* REVERSIBLE

Hepatopathy and Thrombocytopenia
* lower recovery rate

Keratoconjunctivitis sicca
* aka dry eye
* not reversible

Hypothyroidism
* Block formation of thyroxine and thyronine
* Reversible

Bone marrow supression (rare)
Urine crystal formation

37
Q

Potentiated Sulfonamides mechanisms of resistance

A

Sulfonamides
* Increased synthesis of PABA ( competes for target)
* PABA produced in abscesses
* Procaine in PPG metabolized to PABA (TMS-PPG DDI?)
* Low affinity or resistant DHP synthetase (plasmid)

DHFRIs
* Increased production of normal DHFR
* Low affinity or resistant DHFR synthetase (plasmid)

38
Q

Nitroimidazoles

A

Metronidazole, ronidazole, tinidazole
Use prohibited in food animals!!!

39
Q

Nitroimidazoles mechanism of action

A
  • Absorbed into bacterial cell (lipophilic)
  • Reduction of antibiotic by nitroreductases
  • Formation of highly reactive metabolites
  • Disruption of bacterial DNA
  • Bacterial cell death (bactericidal)

Only active in anaerobic conditions
* Oxygen competes with antibiotic for electrons necessary for nitroreductase rxn

40
Q

Nitroimidazoles spectrum

A

Only active in anaerobic conditions
* Oxygen competes with antibiotic for electrons necessary for nitroreductase rxn
* ANAEROBES!

41
Q

metronidazole absorption, distribution, spectrum, etc

A

Well absorbed orally
Well distributed into tissues
* Including CNS and abscesses

Rapid onset, bactericidal
Excellent activity against Bacteroides and Clostridium
Less active against Actinomyces and Proprionobacterium
Most common use – “Giardia”

Nitroimidazole

42
Q

Nitroimidazoles adverse effects

A

Neurotoxicity
* Severe ataxia, vertical or rotary nystagmus, seizures
* Signs are often preceded by anorexia and vomiting
* Typically reversible
* High doses, chronic dosing, rapid IV administration, neonates
* Ronidazole in cats

May be mutagenic/carcinogenic: Use prohibited in food animals!!
Anorexia (tastes bad!)

43
Q

Rifampin (rifampicin) spectrum, mechanism, distribution, uses, toxicity

A

Spectrum: Gram-positive and Gram-negative bacteria
Mechanism: inhibits bacterial DNA-dependent RNA polymerase
Mostly bacteriostatic (can be bactericidal)
Noted for intracellular activity (Abscesses!)
Low incidence of resistance currently
Noted for creating resistance DURING use

Sometimes used as a monotherapy for treatment of MRSP pyoderma (Culture dependent)
* Nearly always combined with second drug in horses
* Macrolide plus rifampin for treatment of R. equi in foals
* Co-administration of rifampin decreases clarithromycin bioavailability 90%!
* Still effective (synergism) and still used…for now
Low order of toxicity

Dogs – hepatic enzymes and hepatotoxicity an increasing concern
Turns urine, sweat, and tears a red or orange color

DWT exam 3 (14 decks)

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