Pharmacology/Toxicology: 4 Flashcards
Administration rate of potassium
How much potassium is in RL?
(in form of potassium chloride)
<0.5mEq/kg/HOUR
in Liège: Braun KCl 14.9% amp.20ml –> 2mEq/ml K+
for a 500kg horse: 250mEq/HOUR –> 125ml/HOUR -> 6amp/HOUR
Attention if adding to RL: already 20mEq in a 5L bag
fluid composition of Lactated Ringer’s Solution
difference to Plasmalyte and Normosol?
LRS: Na 130 K 4 Cl 109 Ca 3 pH 6.5
Plasma Lyte A: Na 140 K 5 Cl 98 Mg 3 pH 7.4
Normosol - R: Na 140 K 5 Cl 98 Mg 3 pH 6.6
LRS contains lactate (metabolized by liver and kidney)
whereas the other two contain acetate and gluconate (by a number of tissues)
Mechanism of action of Misoprostol
side effects
= synthetic analogue of PGE1 (5µg/kg PO BID)
= Cytotec 200-mcg in Liège: 12comprimés BID pour cheval de 500kg
Prostaglandin E2 and prostacyclin (PGI2) are the major PGs synthetized by the gastric mucosa
–> bind to EP3 Receptors on parietal cells and stimulate the Gi pathway –>
- decreasing intracellular cyclic AMP and gastric acid secretion
- ups mucin and bicarbonate secretion and
- increase mucosal blood flow
side effects: ABORTION, abdomial cramping, diarrhea, sweating
dose of heparin for sepsis and types of heparin
heparin 20-80IU/kg IV or SC every 6-12hrs
high molecular weight heparin causes anemia by inducing aggregation of red blood cells, which is undesirable in sepsis
low molecular weight heparins appears to be less likely to have that effect
Mechanism of action of benzimidazoles
f.e. fenbendazole
inhibition of microtubule polymerization by by binding to beta tubulin, also reduction of energy metabolism
-> flaccid paralysis
negligable side effects
Mechanism of action of macrocyclic lactones
Side effects?
fe eavermectins: immobilization of affected organisms by inducing tonic paralysis of the musculature by activating ligand gated Cl channels (only present in invertebraes) causing Cl influx and hyperpolarization
also stimulates synptic excretion of GABA in the mamalian brain –> open chloride channels –> membrane hyperpolarisation
–> causes ataxia and blindness in overdose or potentially foals <4months
Mechanism of action of Biosponge
Biosponge = Di Tri Octahedral Smectite, binding Clostridum toxins in vitro
difference between ionized and non ionized drugs?
- ionized drug is hydrophilic and poorly lipid soluble.
- nonionized drug is lipophilic and can cross biologic membranes.
depends on the environment
f.e. Weak acids such as penicillins and cephalosporins are highly ionized in plasma and therefore do not penetrate into the mammary gland very well, so these are most effective when administered by local infusion into the udder, where the extremely high local concentrations negate local pH effects.
Difference between Pharmako-kinetics and -dynamics in antimicrobials
Pharmacokinetics is what the body does to a drug; the processes of absorption, distribution to the various organs and tissues, metabolism, and elimination.
Pharmacodynamics is what the antimicrobial does to the bacteria.
It describes the drug action and responses of the bacteria.
Define MIC and MBC
MIC: The lowest drug concentration that inhibits bacterial growth. Often expressed as the concentration that inhibits 50% (MIC50) or 90% (MIC90) of the bacterial growth.
=> based on safely achievable plasma concentrations. This does not necessarily take into account extremely high concentrations of antimicrobials achieved in organs and fluids of excretion (kidney, urine, bile) or with local administration of high drug concentrations (e.g., ophthalmic ointments).
f.e. Macrolide antimicrobials are characterized by negligible plasma concentrations despite very high lung and intracellular concentrations
Minimum bactericidal concentration (MBC): The lowest drug concentration that kills 99.9% of bacteria.
What are breakpoints? What is the problem in equine medicine?
A breakpoint is a chosen concentration (mg/L) of an antibiotic which defines whether a species of bacteria is susceptible or resistant to the antibiotic.
If the MIC is less than or equal to the susceptibility breakpoint the bacteria is considered susceptible to the antibiotic. If the MIC is greater than this value the bacteria is considered intermediate or resistant to the antibiotic.
Problem: only ceftiofur, ampicillin, amikacin, and gentamicin have CLSI-approved breakpoints for equine pathogens - the rest is derived from human medicine
What is the postantibiotic effect?
for some ABs; bacterial growth remains suppressed for a period after drug concentration has decreased below the MIC.
This postantibiotic effect (PAE) may be the reason that dosage regimens that fail to maintain drug concentration above the MIC are still efficacious. The PAE depends on the antimicrobial and the bacterial pathogen.
Classify the antibiotic classes into bactericidal and bacteriostatic
BACTERICIDAL
- Aminoglycosides
- β-lactams
- Fluoroquinolones
- Trimethoprim/sulfonamides
BACTERIOSTATIC
- Chloramphenicol
- Macrolides
- Sulfonamides
- Tetracyclines
Classify the antibiotic classes into concentration- or time-dependant
CONCENTRATION-DEPENDENT ANTIMICROBIALS
Aminoglycosides
Fluoroquinolones
Metronidazole
TIME-DEPENDENT ANTIMICROBIALS
Cephalosporins
Chloramphenicol
Macrolides
Penicillins
Sulfonamides
Tetracyclines
Name drugs with a postantibiotic effect of over 3hours
Gram positive: Fluoroquinolones, Macrolides, Chloramphenicol, Tetracycline
Gram negative: Fluoroquinolones, Aminoglycosides
Anaerobes: Metronidazole
Combination of Chloramphenicol and Macrolide
= antagonistic combination both
these classes of drugs competitively bind to the same binding
site on bacterial ribosomes, thus effectively battling each other
for the site of action.
β-lactam antibiotics
- include …
- activity against
- time/dose? static/cidial?
- binds to
- distribution
- excretion
- half life
- include the penicillins, cephalosporins, and carbapenems.
- excellent activity against most gram-positive bacteria and very few associated side effects.
- bactericidal and time dependent.
- low plasma protein binding,
- distribute well to the ECF in most tissues, but do not distribute well to protected sites, such as the central nervous system, the eye…
- excreted renally
- short half-life and require frequent dosing.
Mechanism of action of β-lactam antibiotics. Spectrum is defined by..?
β-Lactam antibiotics bind irreversably on penicillin-binding proteins (PBPs) responsible for building the bacterial cell wall. Therefore they are active only against rapidly multiplying organisms in which the binding of penicillin within the
cell wall interferes with production of cell wall peptidoglycans and results in cell lysis in a hypo-osmotic or iso-osmotic environment.
Differences in the spectrum and activity bc of relative affinity for different PBPs.
To bind to the PBPs, the β-lactam antibiotic must first diffuse through the bacterial cell wall. Gram-negative organisms have an additional lipopolysaccharide layer that decreases antibiotic penetration. => gram-positive bacteria more susceptible
poor penetratation in mammalian cells => ineffective for intracellular pathogens.
Name the resistance mechanisms against B-Lactams
- failure of the antibiotic to penetrate the outer bacterial cell layers
- alteration of PBPs that decrease the affinity of the PBP for the antibiotic. f.e. methicillin-resistant staphylococci (alterations of the PBPs to a low-affinity PBP2a - by gene mecA)
-
production of β-lactamase enzymes => hydrolyze the cyclic amide bond of the β-lactam ring and inactivate the antibiotic. f.e. Staphylococcal β-lactamases are produced by coagulase-positive Staphylococcus spp. The synthesis of these enzymes is plasmid encoded, and the enzymes are exocellular.
- => add inhibitors such as clavulanic acid and sulbactam
BENZYLPENICILLIN
- Spectrum
- ionized/non-ionized
- absorption
- excretion
- adverse effects
= Penicillin G
- Aerobic bacteria: β-hemolytic streptococci, β-lactamase–negative staphylococci, Actinomyces spp., some Bacillus anthracis, Corynebacterium
spp. Most species of anaerobes susceptible, excluding β-lactamase–producing
Bacteroides spp - Because penicillin is a weak acid with a pKa of 2.7, it is highly ionized in plasma.
- depending on product: Na/K Peni IV, Procain Peni IM, Benzathine penicillin G is the least soluble; very slowly absorbed, producing sustained but subtherapeutic plasma concentrations => not recommended in horses
- renal: glomerular filtration and active renal tubular secretion.
- immune-mediated hemolytic anemia (type II hypersensitivity) and anaphylaxis (type I hypersensitivity)
Difference between aminopenicillins and benzylpenicillin?
The aminopenicillins (zB Amoxicillin) are able to penetrate the outer layer of gram-negative bacteria better than benzylpenicillins (penicillin G)
therefore they have activity against many of the gram-negative bacteria (E. coli, Salmonella, Pasteurella spp.) as well as gram-positive bacteria.
Name anti-pseudomonal penicillins
Pseudomonas = gram neg
Carbenicillin, ticarcillin, and piperacillin
TICARCILLIN licensed intrauterin in horses
Aminoglycosides
- Examples
- Spectrum
- ionized/non-ionized
- -cidal/-static? concentration/time?
- ineffective under which circumstances?
- streptomycin, neomycin, gentamicin, amikacin, tobramycin,
- aerobic gramnegative bacteria and staphylococci.
- highly ionized at physiologic pHs; ; binds to and is inactivated by the nucleic acid material released by decaying white blood cells. (ineffective in the
acidic, hyperosmolar, anaerobic environment of abscesses) - bactericidal and concentration dependent.
- ineffective against anaerobic bacteria (penetration into the bacteria requires an oxygen-dependent transport mechanism) and against intracellular bac (f.e. Salmonella) and in puss
Mechanism of action of aminoglycosides
Susceptible, _aerobic gram-negative bacteria actively pump the aminoglycoside
into the cell (_oxygen-dependent interaction between the antibiotic cations and the negatively charged ions of the bacterial membrane lipopolysaccharides)
=> bind to the 30S ribosomal subunit and cause a misreading of the genetic code, interrupting normal bacterial protein synthesis.
=> changes the cell membrane permeability, resulting in additional antibiotic uptake, further cell disruption, and ultimately cell death
Mechanisms of aminoglycoside resistance
Plasmid-mediated resistance transferable between bacteria.
containing phosphotransferases, acetyltransferases, and adenyltransferases acting
internally to alter the aminoglycoside and prevent it from binding to ribosomes. Amikacin is least susceptible to enzyme inactivation.
Distribution of aminoglycosides
Elimination
- polar antibiotics; therefore distribution is limited to the ECF space:
penetrates into synovial, perilymph, pleural, peritoneal, and pericardial fluid.
not present in CSF, respiratory secretions, and ocular fluids. Gentamicin does not cross the placenta of late-term mares;
predominant site of drug accumulation is the renal cortex in most species.
- eliminated in urine by glomerular filtration
The administration of therapeutic fluids, colic surgery, or peritoneal lavage does
not significantly change the pharmacokinetics of concurrently administered gentamicin.
Mechanism of nephrotoxicity of aminoglycosides.
Risk reduction through supplementation of …
filtration through the glomerulus => renal tubule
=> carrier-mediated pinocytosis (with phospholipids) and translocatation into cytoplasmic vacuoles of renal tubular cells => fusion with lysosomes => sequestration => overloaded lysosomes swell and rupture.
=> Lysosomal enzymes, phospholipids, and the aminoglycoside are released into the cytosol of the proximal tubular cell, disrupting other organelles and causing cell death.
- supplementation of Calcium can reduce the risk of nephrotox
