Methemoglobin Flashcards
Methemoglobin (metHb) is hemoglobin in which the
Methemoglobin is incapable of carrying oxygen, and high levels:
ferrous (Fe2+) molecule
is oxidized to the ferric (Fe3+) form
> 20% can cause cellular hypoxia and shock
Methemoglobin reductase deficiency is a rare condition in small animals that leads to
inefficient reduction of methemoglobin to hg
-may or may not lead to clinical signs of methemoglobinemia
Clinical methemoglobinemia occurs when erythrocyte defense systems are overwhelmed and cannot ___ methemoglobin to hemoglobin fast enough to keep up with the oxidative damage
reduce
Substances that can cause clinical methemoglobinemia in small animals include
acetaminophen topical benzocaine formulations phenazopyridine (a urinary tract analgesic) nitrites, nitrates hydroxycarbamide skunk musk
many substances that cause methemoglobinemia also can cause the body to form clinically significant numbers of Heinz bodies (HzBs), aggregations of denatured hemoglobin that can lead to
immune-mediated red blood cell destruction and anemia
Tx for methemoglobinemia
augmentation of endogenous glutathione levels with N-acetylcysteine (NAC)
methylene blue administration (in severe cases)
antioxidant therapy
increased clearance or decreased metabolism of any toxins present
blood transfusions (if required)
MoA metHb
oxidative damage ferrous 2+ to ferric form Fe3+
oxidizes Fe2 to Fe 3
four polypeptide chains (globins) - each is attached to a heme molecule
Heme is made up of a tetrapyrrole with a central iron molecule
iron molecule must be maintained in the ferrous (Fe2+) state for the hemoglobin to bind oxygen
Methemoglobin (MetHb) is an inactive form of hemoglobin created when the iron molecule of hemoglobin is____
oxidized to the ferric (Fe3+) state because of oxidative damage within the red blood cell
lazy co-worker doesnt carry O2 and then also causes the other three Fe2 to hold onto O2 tighter
What does MetHb do to oxyHg dissociation curve
MetHb increases the affinity for oxygen in the remaining ferrous moieties of the hemoglobin molecule, decreasing release of oxygen to the tissues and shifting the oxyhemoglobin dissociation curve to the left
___% of total hemoglobin in normal dogs and cats
less than 3%
ROS cause oxidative damage via:
transferring or extracting an unpaired e- to or from another molecule
free radical scavengers and _____ agents that can _____ the unpaired electron from an oxidized molecule
reducing agents
remove the unpaired electron from an oxidized molecule
RBC lack of organelle =
+ve
-ve
membrane deformability to navigate capillaries
anaerobic metabolism ad suscep oxidative damage
Oxidants continuously generated in vivo include hydrogen peroxide:
superoxide free radicals:
hydroxyl radicals:
H2O2
O2−
OH−
RBC protect themselves from oxidative damage:
superoxide dismutase catalase glutathione peroxidase glutathione metHb reductase (NADPH)
Heinz bodies (HzBs)
aggregates of denatured, precipitated hemoglobin
Oxidation of the SH groups of hemoglobin causes conformational changes in the globin chains that result in
precipitation of the denatured globin
Feline hemoglobin is more susceptible to oxidative damage because
eight SH groups on the globin part of the molecule rather than four, as the canine counterpart does
cats 8-SH groups on globin and less inability to remove Hz bodies =
healthy cats often have notable HzBs in circulation (with reports up to 96%).
The reasons are still unknown why some cats undergo hemolysis with HzB percentages lower than 96%, but other cats have no clinical signs with most of their erythrocytes affected
acetominophen
Expected single toxic doses of acetaminophen range from ____ (cats) to ____mg/kg (dogs). Toxicity may be observed with lower doses, particularly with chronic exposure.
Clinical signs of toxicity usually reflect:
Diagnosis
The mainstay of therapy is
50 to 100 mg/kg (cats)
600 mg/kg (dogs)
hepatic injury or failure (dogs)
hemolytic anemia from methemoglobinemia (cats)
history of exposure coupled with compatible clinical and laboratory findings.
N-acetylcysteine
S-adenosylmethionine (SAMe) may also be therapeutic for intoxicated animals
IV fluids and blood, are necessary in many cases
After ingestion, the drug is rapidly absorbed into the:
and metabolized in the liver by (3):
dogs, metabolized primarily through:
amount of acetaminophen metabolized through the cytochrome P450 pathway is usually small, but the:
toxic effects of NAPQI are normally limited by
portal circulation and metabolized in the liver by
glucuronidation
sulfation
cytochrome P450-mediated pathways
glucuronidation and sulfation pathways
product of this metabolic pathway,
N-acetyl-p-benzoquinone imine (NAPQI) is toxic
its conjugation with glutathione, a compound essential for cellular protection against oxidative injury, to form nontoxic:
cysteine
mercapturic acid conjugate
metabolism of acetaminophen by glucuronidation and sulfation pathways is capacity limited, increasing doses of acetaminophen lead to an increased proportion of:
Cellular stores of glutathione become depleted during conjugation of the increased amounts of NAPQI. In addition, synthesis of glutathione is suppressed in the face of high concentrations of acetaminophen. The end result is:
drug metabolized by the cytochrome P450 system and an increase in the production of the toxic NAPQI
increased unconjugated NAPQI
Cats, like dogs, also exhibit dose-dependent toxicokinetics, albeit with some important differences:
glucuronosyltransferase deficient
= diminished capacity to metabolize acetaminophen through the glucuronidation pathway
-more transformation through sulfation pathway
- takes 1/10 the dose to saturate -dose dependency of biotransformation
- 8 sulfahydral groups = more susceptible to oxidtive damage to RBCs
ROS and hemolytic anemia/hepatotoxicity:
MoA;
=increased concentrations of NAPQI accumulate
MoA NAPQI toxicity:
also, glutathione depletion renders cells:
dogs the:
in cats the:
reasons for the differences in tissue affected:
depletion of cellular glutathione
electrophilic properties, NAPQI covalently binds to cellular proteins (e.g., enzymes, structural and regulatory proteins), thereby
- disrupting protein function
- damaging cellular membranes via lipid peroxidation
oxidative injury that contributes to loss of mitochondrial function, depletion of adenosine triphosphate, and cell necrosis
liver is more susceptible to the toxicity of acetaminophen (it is estimated that 70% of hepatic glutathione must be depleted before hepatotoxicity occurs)
red blood cell is most susceptible to oxidative injury
Feline hemoglobin = 8 sulfhydryl groups
= much more prone to oxidative injury
= making the development of methemoglobinemia a much earlier and more prominent feature of toxicosis in cats than in dogs
recent study has suggested that another metabolite:
generation of para-aminophenol in dogs and cats is bc deficiency of the enzyme _________ as compared with other species and may be the _______ of methemoglobinemia than NAPQI
para-aminophenol (PAP), contributes to the development of acetaminophen toxicity, specifically methemoglobinemia
enzyme N-acetyltransferase
more likely cause of methemoglobinemia than NAPQI
C/S dogs
Vomiting, lethargy, trembling, chemosis, anorexia, tachycardia, and tachypnea are most often described
may be abdominal pain and icterus. If methemoglobinemia is present, cyanosis, hemoglobinuria, and hematuria may also be observed. Facial and paw edema are commonly reported
C/S cats
Icterus may also develop, most commonly as a consequence:
cats do not develop hepatotoxicosis as readily
most common C/S reported include cyanosis or muddy mucous membranes, methemoglobinemia, lethargy, anorexia, respiratory distress, edema of the face and paws, hypothermia, and vomiting
hemolysis. Signs associated with hepatotoxicosis in cats are more commonly seen in high-dose exposures and in males.
The specific “antidote” for acetaminophen poisoning provides a source of:
N-acetylcysteine
glutathione precursors for repletion of cellular glutathione stores
hydrolyzed to cysteine - interacts directly with NAPQI to form non-toxic metabolite
sources of sulfur donors
SAMe serves as an important intermediary in pathways that generate phospholipids, important for cell membrane function, and glutathione
sources of sulfur donors
methylene blue (1 mg/kg IV of a 1 solution given every 2 to 3 hours for two to three treatments) MoA:
Cimetidine rationale
reduce methemoglobin to hemoglobin
via >NADPH dehydrogenase
in a study of limited numbers of experimentally intoxicated cats, combination therapy with methylene blue and N-acetylcysteine offered little advantage over N-acetylcysteine alone
Methylene blue was shown not to be toxic to cats
inhibitor of the cytochrome P450 system
inhibit metabolism of acetaminophen into toxic compounds
but need 10X dose
px
cats poor if severe - pRBC transfusions help
dogs depends on degree - hepatic failure possible
