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pharmacology exam 3 > phenicols, sulfas, tetracyclines > Flashcards

phenicols, sulfas, tetracyclines Flashcards

1
Q

Florfenicol

A

FOOD ANIMAL PRODUCTS:
– Nuflor: injectable solution in cattle (IM/SC) & swine (IM)
* Cattle indications: Respiratory disease, footrot, pinkeye DONT USE FOR SIMPLE PINK EYE OR FOOTROT

– Resflor: florfenicol + flunixin (NSAID) injectable solution (SC)
– Zeleris: florfenicol + meloxicam (NSAID) injectable solution (SC

– Aquaflor: medicated premix for salmon
* Indications include Aeromonas & Vibrio infections

-small animal products:
– Osurnia, Claro: ear medications with terbinafine (antifungal) 1/week ear med

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2
Q

Chloramphenicol

A

– Chlor®Palm 250, Chlor-palmitate (oral suspensions)
* Label claim for various infections in dogs & cats
– Human generic formulations widely used as well
* Oral tablets and suspension
* Injectable (sodium succinate solutions
-banned in food animal, causes aplastic anemia in humans

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3
Q

Phenicols: Mechanism of Action

A
  • Binds to bacterial ribosomal 50S sub-unit
    – Causes incorrect tRNA translation
    – Disrupts bacterial protein synthesis

BUT: also inhibits mitochondrial protein synthesis in mammalian bone marrow
– Will impact blood cell production
– dose-dependent effect

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4
Q

Phenicols: Spectrum of Activity

A
  • Many Gram (+) species
    – Including some MRSA/P
  • Many Gram (-) bacteria (not gram neg enteric they are usually resistant)
  • Many anaerobes, protozia
  • Some Mycoplasma
  • Some Rickettsia & Chlamydia**
    -Enterococcus & E coli MICs may be too high for phenicols to work.
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5
Q

phenicols resistance

A

Enzymes adding acetyl group
– chloramphenicol acetyltransferases, CAT
– Prevents binding to ribosome 50S subunit
– FLOR less vulnerable to acetylation

  • Other resistance mechanisms:
    – ↓ phenicol permeability
    – ↑ efflux pumps (floR gene in Gram - enterics)
    – Mutations to 50S binding sites
  • Resistance genes are typically mobile
    – Plasmids, transposons, etc.
    Chlorampheicol
    Florfenicol
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6
Q

PK of phenicols bioavailability

A

Bioavailability:
* Chloramphenicol: Overall good oral
* Florfenicol:
– Prolonged (but variable) absorption after IM/SC
injection
– Flip-flop kinetics: slower rate of elimination but absorption still occurring during elimination phase.
-moderate/ high VD

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7
Q

phenicol’s elimination

A
  • Hepatic metabolism & glucuronide conjugation
    – Poor in cats! So longer half-life and dosing interval
    – Much longer T1/2 elim in young animals
  • Primarily renal excretion of inactive metabolites
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8
Q

phenicol pk-pd

A

Bacteriostatic:
* Very difficult to reach MBC (not safe)
* Considered “time-dependent”
– Limited proof?
– Recommended T>MIC for >50% of dosing interval

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9
Q

Phenicol Drug Interactions

A
  • May be antagonistic with other antibiotics. recommended not to be given with other antimicrobials

Hepatic metabolism interactions:
– Microsomal enzyme inhibitor (CYP)
* Can prolong barbiturate anesthesia (not relevant now)
* Can inhibit metabolism of phenobarb & other CYP-mediated
drugs

  • Florfenicol is not known to cause hepatic drug
    interactions
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10
Q

phenicols AE and warnings

A

Blood dyscrasias (aplastic anemia, pancytopenia)
* Decreased production of RBC, WBC, platelets
* Dose-dependent: Can be caused by CPHC or FLOR
– Cause: mitochrondrial protein inhibition in bone marrow
– Occurs in both humans & animal
Related to total phenicol exposure (AUC)
* Both dose and duration are important
– Cats more likely to develop toxicity

  • Dose-independent (idiosyncratic)
    – Humans – can be fatal

GI adverse events:
* Chloramphenicol: vomit, diarrhea, inappetence:
* FLOR:
– Change in GI normal flora, leads to diarrhea in calves
– Nuflor label: cause diarrhea, anal inflammation.

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11
Q

potentiated sulfonamides

A

Sulfadiazine (with trimethoprim – aka TMS)
* Uniprim (oral powders/granules)
– Indicated in horses for respiratory / soft tissue infections

Sulfadimethoxine (with ormetoprim)
* Romet 30 (medicated feed for furunculosis in salmon

  • Sulfaquinoxaline: oral solution coccidostat for poultry (not antibacterial use)
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12
Q

Sulfonamide Mechanism of Action

A

Sulfas:
* Structure similar to para-aminobenzoic
acid (PABA)
* Competitive inhibition for enzyme
dihydropteroate synthase (PABA
incorporation into folate pathway)

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13
Q

Diaminopyrimidines mechanism of action

A
  • Trimethoprim, ormetoprim,
    pyrimethamine
  • Inhibits dihydrofolate reductactase
    (next step in folate synthesis
    -End result: No folate, no bacterial DNA synthesis
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14
Q

Sulfonamides uses

A

-medicated feeds
-scour boluses
-water soluable preperations

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15
Q

Sulfonamide Mechanism of Action

A

Sulfas:
* Structure similar to para-aminobenzoic
acid (PABA)
* Competitive inhibition for enzyme
dihydropteroate synthase (PABA
incorporation into folate pathway)
End result: No folate, no bacterial DNA synthesis.
-bacteriastatic

-mammels need folate too but they can utilize dietary folate (vitamin B9) so sulfas arnt toxic to mammels.

-If lots of PABA present bacteria are resistant to sulfa drugs, ex abcesses

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16
Q

Diaminopyrimidines (added with sulfas) mechanism of action

A
  • Trimethoprim, ormetoprim,
    pyrimethamine
  • Inhibits dihydrofolate reductactase
    (next step in folate synthesis) blocks both steps, as synergism with sulfa drugs. very effective. bacteriacidal
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17
Q

Sulfonamides: Spectrum of Activity

A

Highly variable for individual isolates! labeled for many conditions but doesnt mean it will work.
-Gram Positives
-Gram negatives
-anarbobes
-protozoa, coccidia

18
Q

sulfa not/ less effective agaisnt

A

Resistance emerges rapidly in
many bacterial species
– Many/most Strep equi, E. coli,
Salmonella isolates now resistant
* Pseudomonas
* Enterococcus

19
Q

sulfas mechanisms of resistance

A

Very common!
* May be chromosomal or plasmid-mediated
* Hyper-production of PABA (or in environment)
* Altered dihydropteroic synthase (sulfa) or DHFR
(trimethoprim) enzymes
* Increased production of DHFR
* Reduced drug penetration into bacteria

Notes on resistance:
– Cross resistance between sulfas is typical
– Emerges more slowly with potentiated sulfas than with sulfas alone

20
Q

Sulfonamide PK

A

Not uniform between sulfa drugs and species!
* Generally good oral bioavailability
* Distributes into many tissues (Vd = 0.3 – 0.7 L/kg)
– Including CSF, synovial fluid, urine
* Differences in protein binding between sulfas & species

  • Elimination:
    – Hepatic metabolism (to inactive metabolites)
    – Renal excretion (glomerular filtration)
  • Tubular reabsorption can occur
  • ↓ reabsorption with alkaline urine (ion-trapping of acidic sulfa)
21
Q

PK between sulfas
and diaminopyrimidines!

A

significant differences in PK Makes optimizing the sulfa:TMP ratio challenging
* Makes C & S results more difficult to interpret
* Differences between vet & human formulations

22
Q

Sulfonamide Adverse Events hypersensitivity

A

. Hypersensitivity reactions: * N1 position: associated with type I
hypersensitivity (IgE) reactions
* N4 position: forms reactive metabolites
that can cause direct cytotoxicity or
stimulate an immunologic response

-different types are: blood dysrasisas (hemolytic anemia in horses), arthritis, skin eruptions, hepatic nectosis.

23
Q

Sulfonamide Adverse Events occular

A

Keratoconjunctivitis sicca (KCS)
* “Dry-eye” due to ↓ tear production
– Sulfa component toxic to lacrimal acinar cells
– Easy to confirm with Schirmer Tear Test
* Occurs in ~ 15% of dogs treated with sulfas
-resolves when therapy stops.

24
Q

Sulfonamide Adverse Events renal

A

Renal damage
* Sulfas are poorly soluble – can precipitate in urine
– Especially with ↓tubular flow (dehydration) or acidic
urine (↓ sulfa solubility)
* Can lead to crystalluria, hematuria, and tubule
blockage
* Not a big problem now, make sure patient is hydrated

25
Q

More Sulfonamide Adverse Events

A
  • Hypothyroidism – inhibition of thyroid enzyme activity
  • GI – diarrhea, vomiting, salivation
  • Anemia from chronic sulfa use (rare)
    – folate-related (as opposed to hypersensitivity-mediated)
    – ↓ folate production from intestinal bacteria
26
Q

Sulfonamide Adverse Events injection

A
  • Injection reactions:
    – Lesions after IM injection
    – Rapid IV injection has caused thrombophlebitis or
    anaphylaxis in horses
27
Q
  • Tetracycline (TC)
A

-Licensed in food animals & horses
– Water-soluble (oral) powders
– Oral / intrauterine boluses

28
Q

Oxytetracycline (OTC)

A

-Licensed in food animals only
– Oral: Feed premix or water soluble powder
– Intrauterine suspensions
– Injectable products
* Human TC & OTC oral capsules used extralabel in dogs/cats

29
Q

Chlortetracycline

A

Oral premixes & boluses for food animals

30
Q

Doxycycline

A

-Primarily used in small animals (and horses)
– Oral formulations: Human tablets or capsules used (100 mg)

31
Q

Tetracyclines: Mechanism of Action

A
  • Binds to bacterial ribosomal 30S sub-unit
    – Causes incorrect tRNA translation
    – Disrupts bacterial protein synthesis
  • Requires energy-dependent transport into
    bacterial cell to reach binding sites
    – Animal cells lack tetracycline transporters
  • TCs have multiple charges on functional groups
    – At physiological pH, mostly zwitterion form. neutral overall charge.
32
Q

Tetracyclines types of drug

A

-TCs are typically bacteriostatic, but can be
bactericidal at high concentrations

  • Considered time-dependent antimicrobials
    – Try for prolonged exposure, not high peak conc
33
Q

Tetracyclines: Spectrum of Activity

A

Potentially effective:
* Some Gram (+) species
* Some Gram (-) bacteria
– Respiratory pathogens
* Many anaerobes
* Some Mycoplasma
– In vitro – but clinical significance?
* Tick-borne bacteria, Chlamydia,
protozoa, and spirochetes
– Ehrlichiosis (Ehrlichia canis )
– Potomac horse fever (Neorickettsia)
– Rocky Mountain spotted fever (Rickettsia

34
Q

Tetracyclines less effective or dont work on

A

-Staphylococci often resistant
* Gram (-) enterics often resistant
* Pseudomonas
* Enterococcus
* Resistance emerges rapidly in
many bacterial species

35
Q

Tetracyclines:
Mechanisms of Resistance

A

-plasmid-mediated tet resistance genes
* ↓ tetracycline in bacterial cell
– Failure of active transport into bacterial cell
– Increased efflux from the cell
* Enzymatic inactivation of tetracycline
* Production of proteins that protect bacterial ribosome

36
Q

Tetracycline PK absorption

A

Absorption:
* CTC/OTC: Poor oral bioavailability (< 20%)
* Doxycycline: Much higher oral F (~ 50%)
– Oral F varies with feed status & formulation

  • Injectable OTC: high bioavailability
    – LA formulations = flip-flop kinetics
  • Slow absorption, drives rate of elimination
37
Q

tetracycline PK distribution

A

Distribution:
* Good distribution to most tissues & fluids
– Exception: don’t penetrate CSF well (P-gp substrates)
* Low/moderate protein binding Except DXC (~ 90%)
* TCs bind to Ca++/Mg+

38
Q

Tetracycline PK
Elimination

A
  • Metabolism - very little
  • Small amounts of TC excreted via:
    – Feces (biliary & intestinal P-gp)
  • enterohepatic circulation can occur (doxycycline excreted most in feces)
  • Unchanged TC excreted mainly by the kidneys
    (glomerular filtration)
    – High concentrations in urine (useful for UTI)
39
Q

Tetracycline family:
Adverse Effects

A
  • Nephrotoxicity (tubular necrosis) is possible, but
    very unlikely
    – Possible when very high doses used
    – Dehydration is a risk factor
  • Cardiovascular collapse with rapid IV injection. long acting productsare all IM/ SC
  • GI:
    – Vomit / diarrhea (oral capsules in small animals)
    – Enterocolitis / diarrhea in horses with oral OTC
  • Injection-site reactions (long-acting OTC)
40
Q

calcium and heavy metals with tetracyclines

A

-cause chelaltion
– Recommend to not administer oral tetracyclines
with dairy products or antacids
* ↓ TC oral bioavailability
– Administration in young animals = teeth staining

41
Q

Non-antimicrobial uses of tetracyclines

A

-horses born with contracted flexor tendons are treated with oxytetracycline which has musculoskeletal effects and relaxes tendons.
– High IV dose given to neonatal foals with angular limb deformity
(contracted tendons)
– Mechanism: Not an antimicrobial effect! Maybe inhibition of enzymes?
* Mild anti-inflammatory effects
(COX-2 inhibition?)

pharmacology exam 3 (8 decks)

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