Pharmacology 50s and nucleic acid inhibitors Flashcards
50S inhibition drugs
Plasma concentrations not always predictive of treatment success
Concentrate INTRACELLULARLY!
Reach high concentrations in ABSCESSES!
Bacteriostatic
Inhibit protein synthesis
Moderate post-antibiotic effects
drug interactions with 50S inhibitors
Co-administration not recommended
* Competitive inhibition at the site of action
* May decrease the effectiveness of each other
50S inhibitors classes
Phenicols
Macrolides
Lincosamides
Phenicols
50S inhibitor
Companion animal use (dogs, cats, horses)
* Chloramphenicol (oral)
Food animal use: Florfenicol
* Cattle (injectable)
* Swine (feed)
* Fish (water)
Phenicol spectrum
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
Chloramphenicol
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!!!
Chloramphenicol metabolism
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
Chloramphenicol adverse effects
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
Chloramphenicol in food animals
Prohibited from Use in Food Animals!!!
Chloramphenicol drug interactions
Inhibitor of hepatic microsomal enzyme inhibitor
* May decrease clearance/metabolism of some drugs
* Phenobarbital, phenytoin, propofol
Florfenicol adverse effects
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
Phenicols resistance mechanisms
Acetylation and inactivation by bacterial enzymes
Cross-resistance does not always occur
Florfenicol more resistant to bacterial enzymes
Macrolides
50S inhibitor
Dogs, cats, foals
* Erythromycin
* Clarithromycin
* Azithromycin
Food animals
* Erythromycin (poultry)
* Tulathromycin
* Tilmicosin
* Gamithromycin
* Tildipirosin
most end in -mycin
macrolides spectrum
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
macrolides pharmokinetics
absorption, distribution, metabolism, elimination
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)
macrolides adverse effects
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!!!
Macrolidea drug interactions
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
lincosamides drugs
50S inhibitor
Lincomycin – food animals
Clindamycin – small animals
Lincosamides spectrum
Active against gram positive organisms
Active against anaerobes (Clindamycin > lincomycin)
lincosamides pharmokinetics
absorption, distribution, metabolism, elimination
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
Lincosamides adverse effects
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
Fluoroquinolones drugs
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
Fluoroquinolones mechanism of action
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
Fluoroquinolones spectrum
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
Fluoroquinolones absorption
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
Fluoroquinolones distribution
Distribute well to the tissues
Penetrate well intracellularly
* Enrofloxacin reaches the highest concentration in the cells
* Highest lipid solubility and volume of distribution
Fluoroquinolones metabolism and elimination
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
Fluoroquinolones adverse effects
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
Fluoroquinolones drug interactions
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)
Fluoroquinolones mechanisms of resistance
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)
sulfonamides
sulfa drugs
Extralabel use prohibited in adult dairy cattle!!!
bacteriostatic
potentiated sulfonamides
Sulfonamide (bacteriostatic) plus dihydrofolate reductase inhibitor (bacteriostatic)= bacteriocidal
synnergism
Ruminants don’t absorb DHFRIs (use just sulfas alone)
sulfonamides and DHFRI mechanism of action
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
Potentiated Sulfonamides absorption, distribution, metabolism
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
Potentiated Sulfonamides adverse effects
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%
Potentiated Sulfonamides dogs adverse effects
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
Potentiated Sulfonamides dogs adverse effects
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
Potentiated Sulfonamides mechanisms of resistance
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)
Nitroimidazoles
Metronidazole, ronidazole, tinidazole
Use prohibited in food animals!!!
Nitroimidazoles mechanism of action
- 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
Nitroimidazoles spectrum
Only active in anaerobic conditions
* Oxygen competes with antibiotic for electrons necessary for nitroreductase rxn
* ANAEROBES!
metronidazole absorption, distribution, spectrum, etc
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
Nitroimidazoles adverse effects
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!)
Rifampin (rifampicin) spectrum, mechanism, distribution, uses, toxicity
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
