Methemoglobin

Question 1

Methemoglobin (metHb) is hemoglobin in which the

Methemoglobin is incapable of carrying oxygen, and high levels:

Answer 1

ferrous (Fe2+) molecule
is oxidized to the ferric (Fe3+) form
> 20% can cause cellular hypoxia and shock

Question 2

Methemoglobin reductase deficiency is a rare condition in small animals that leads to

Answer 2

inefficient reduction of methemoglobin to hg

-may or may not lead to clinical signs of methemoglobinemia

Question 3

Clinical methemoglobinemia occurs when erythrocyte defense systems are overwhelmed and cannot ___ methemoglobin to hemoglobin fast enough to keep up with the oxidative damage

Answer 3

reduce

Question 4

Substances that can cause clinical methemoglobinemia in small animals include

Answer 4

acetaminophen
topical benzocaine formulations
phenazopyridine (a urinary tract analgesic)
nitrites, nitrates
hydroxycarbamide
skunk musk

Question 5

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

Answer 5

immune-mediated red blood cell destruction and anemia

Question 6

Tx for methemoglobinemia

Answer 6

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)

Question 7

MoA metHb

Answer 7

oxidative damage ferrous 2+ to ferric form Fe3+

oxidizes Fe2 to Fe 3

Question 8

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____

Answer 8

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

Question 9

What does MetHb do to oxyHg dissociation curve

Answer 9

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

Question 10

___% of total hemoglobin in normal dogs and cats

Answer 10

less than 3%

Question 11

ROS cause oxidative damage via:

Answer 11

transferring or extracting an unpaired e- to or from another molecule

Question 12

free radical scavengers and _____ agents that can _____ the unpaired electron from an oxidized molecule

Answer 12

reducing agents

remove the unpaired electron from an oxidized molecule

Question 13

RBC lack of organelle =
+ve
-ve

Answer 13

membrane deformability to navigate capillaries

anaerobic metabolism ad suscep oxidative damage

Question 14

Oxidants continuously generated in vivo include hydrogen peroxide:
superoxide free radicals:
hydroxyl radicals:

Answer 14

H2O2
O2−
OH−

Question 15

RBC protect themselves from oxidative damage:

Answer 15

superoxide dismutase
catalase
glutathione peroxidase
glutathione
metHb reductase (NADPH)

Question 16

Heinz bodies (HzBs)

Answer 16

aggregates of denatured, precipitated hemoglobin

Question 17

Oxidation of the SH groups of hemoglobin causes conformational changes in the globin chains that result in

Answer 17

precipitation of the denatured globin

Question 18

Feline hemoglobin is more susceptible to oxidative damage because

Answer 18

eight SH groups on the globin part of the molecule rather than four, as the canine counterpart does

Question 19

cats 8-SH groups on globin and less inability to remove Hz bodies =

Answer 19

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

Question 20

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

Answer 20

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

Question 21

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

Answer 21

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

Question 22

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:

Answer 22

drug metabolized by the cytochrome P450 system and an increase in the production of the toxic NAPQI

increased unconjugated NAPQI

Question 23

Cats, like dogs, also exhibit dose-dependent toxicokinetics, albeit with some important differences:

Answer 23

glucuronosyltransferase deficient
= diminished capacity to metabolize acetaminophen through the glucuronidation pathway
-more transformation through sulfation pathway

2. takes 1/10 the dose to saturate -dose dependency of biotransformation
3. 8 sulfahydral groups = more susceptible to oxidtive damage to RBCs

Question 24

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:

Answer 24

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

Question 25

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

Answer 25

para-aminophenol (PAP), contributes to the development of acetaminophen toxicity, specifically methemoglobinemia

enzyme N-acetyltransferase
more likely cause of methemoglobinemia than NAPQI

Question 26

C/S dogs

Answer 26

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

Question 27

C/S cats

Icterus may also develop, most commonly as a consequence:

Answer 27

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.

Question 28

The specific “antidote” for acetaminophen poisoning provides a source of:

N-acetylcysteine

Answer 28

glutathione precursors for repletion of cellular glutathione stores

hydrolyzed to cysteine - interacts directly with NAPQI to form non-toxic metabolite

Question 29

sources of sulfur donors
SAMe serves as an important intermediary in pathways that generate phospholipids, important for cell membrane function, and glutathione

Answer 29

sources of sulfur donors

Question 30

methylene blue (1 mg/kg IV of a 1 solution given every 2 to 3 hours for two to three treatments) MoA:

Cimetidine rationale

Answer 30

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

Question 31

px

Answer 31

cats poor if severe - pRBC transfusions help

dogs depends on degree - hepatic failure possible