BIOCHEMISTRY: BOARDS AND BEYOND Flashcards
Removes the amine group from adenosine and converts into inosine (a amanation reaction). This enzime is dysfunctional or deficient in many cases of severe combined immunodeficiency syndrome.
Adenosine deaminase
Treatment of gout
Inhibit xanthine oxidase (allopurinol)
Metabolized by xanthine oxidase, caution with allopurinol. May boost effects and increase toxicity.
Azathioprine and 6-MP
Lesch-Nyhan syndrome
Absence of the HGPRT enzyme. Purines cant be saved and are shunted into uric acid. JUVENILE GOUT. Increase of novo purine synthesis (+ PRPP, + IMP), Neurologic impairment: chorea, hypotonia, self mutilating behavior,
This enzyme converts inosine monophosphate (IMP) to guanosine monophosphate (GMP).
IMP deshydrogenase
An inhibitor of IMP dehydrogenase
Ribavirin
Is an X-linked recessive enzyme deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) characterized by hyperuricemia, self-mutilation/aggression, dystonia, and intellectual impairment. HGPRT is an enzyme in the purine salvage pathway necessary for the conversion of hypoxanthine and PRPP into IMP, as well as the conversion of guanine and PRPP into GMP.
Lesch-Nyhan syndrome
HGPRT enzyme activity less than 1.5% of normal is diagnostic for
Lesch-Nyhan syndrome
This enzyme catalyzes the rate limiting step in synthesis of pyrimidine nucleotides. Found in the cytosol. This enzime is inhibited by uridine triphosphate (UTP).
Carbomoyl phosphate synthetase II
Made of 2 N and 4 C
Pyrimidine ring
Sources of the ring of pyrimidines
Carbamoyl phosphate and aspartate
Autosomal recessive, defect in UMP synthase. Orotic acid in urine. Megaloblastic anemia (no response to B12/folate), growth retardation. Treatment: uridine
Orotic aciduria
Key urea cicle enzime, combines carbamoyl phosphate with ornithine to make citrulline
Ornithine transcarbamylase (OTC)
High nevels of carbamoil phophate get converted to orotic acid. High nevels of ammonia (urea cycle dysfunctional) = encephalopathy
OTC deficiency
Chamotherapy agent, converted to araCTP, mimics dCTP and inhibits DNA polymerase.
ARA-C (Cytarabine or cytosine arabinoside)
Sinthesized from deoxyuridine (converted by ribonucleotide reductase), deoxythymidine is only required nucleotide.
Thymidine
Inhibits ribonucleotide reductase, blocks formation of deoxynucleotides. Can be used in polycitemia vera, essential thrombocytosis, sickle cell anemia (increase in fetal Hb).
Hydroxyurea
Converts dUMP in dTMP (adding 1 C), involves use of N5,N10 tetrahydrofolate
Thymidylate synthase
Converts DHF to THF
Dihydrofolate reductase
Chemotherapy agent mimics uracil. Inhibits thymidylase synthase. Thymidylase death.
5-FU (5-fluorouracil)
Chemotherapy agent, immunosupressent. Mimics DHF, inhibits dihydrofolate reductase = blocks synthesis of dTMP. Bone marrow can be rescued with leucovorin (folinic acid, converted to THF).
Metrotrexate
Competitors inhibitors of Dihydropteroate synthase, Mimics PABA (paraaminobenzoic acid that is used for bacteria to create THF). No effect in human cells (dietary folate).
Sulfonamide antibiotics
Blocks bacteria dihydrofolate reductase. No THF.
Trimethoprim
Loss in dTMP production. Macrocytic anemia (fewer but larger RBCs). Neural tube defects in pregnancy.
Folate deficiency
Required to regenerate THF from N5-Methyl THF. (Deficiency Methyl folate trap), loss of dTMP synthesis (megaloblastic anemia), neurological dysfunction (demyelination)
Vitamin B12
Elevated ? in vitamin B12 and folate deficiency
Homocysteine
Elevated MMA level (no convertion to succynil CoA)
B12 Deficiency
Low crit, large RBC (increased MCV, mean corpuscular volume), hypersegmented neutrophils, caused by defective DNA production.
Megaloblastic anemia
Causes of megaloblastic anemia
Folate deficiency
B12 (neuro symptoms, MMA)
Orotic aciduria
Drugs (MTX, 5-FU, hydroxyurea)
Zidovudine (HIV NRTIs)
Classically presents as a pearly nodule with rolled borders and central ulceration. Treatment can include 5-Fluorouracil (5-FU). This drug is a pyrimidine analog that is activated to 5-fluoro-deoxy-uridine monophosphate (5-FdUMP) which binds N5, N10-tetrahydrofolate and inhibits thymidylate synthase.
Basal cell carcinoma
Inhibition of thymidylate synthase by 5-FU decreases intracellular thymidine and increases
Intracellular uridine
Is a myeloproliferative disorder of megakaryocyte proliferation leading to elevated platelet counts. One of the symptoms that may occur is erythromelalgia, or redness and burning pain of the hands and feet (this syndrome may also be seen in polycythemia vera). Low-risk cases can be observed without treatment. High-risk cases are treated with drug therapy to prevent complications such as thrombosis or bleeding.
Essential thrombocytosis (ET)
Reduces the platelet count in ET. In clinical trials, it has been shown to reduce rates of thrombosis. Inhibits pyrimidine synthesis via inhibition of the enzyme ribonucleotide reductase. When pyrimidine synthesis is inhibited, DNA production is limited. This leads to megaloblastic anemia, including a low red cell count and high mean corpuscular volume. In fact, a rise in the MCV can be used to establish that patients are taking the medicine, and that the therapy is exerting a biologic effect.
Hydroxyurea
Two nucleotides, carries electrons.
NADH (Nicotinamide adenine dinucleotide)
Accepts electrons
NAD+
Donate electrons, can donate to electron transport chain = ATP.
NADH
At this stage of glycolylis, the glucose molecule is split into two three carbon molecules
Glyceraldehyde-3-phosphate
Reactions not reversible in glycolysis.
Glucose to glucose-6-phosphate.
Glucose 6-phosphate to Fructose-1,6-biphosphate.
Phosphoenolpyruvate to pyruvate.
Low km, quickly reach Vm (relatively low Vm compared to glucokinase)
Hexokinase
Found in liver and pancreas, not inhibited by G6P. Induced by insulin (it promotes transcription). Inhibited by F6P (overcome by glucose).
Glucokinase
Enzime inactive when low glucose and high F6P. The liver favor gluconeogenesis. High Km (rate varies with glucose). Sigmoidal curve (cooperativity)
Glucokinase
Glucokinase: high Vm level
After meals
In presence of Fructose-6-phosphate translocates glucokinase to nucleus, inactivating it.
Glucokinase regulatory protein or GKRP
Often exacerbated by pregnancy
Glucokinase deficiency
The rate limiting step for glycolysis.
Catalized by Phosphofructokinase-1, conversion of Fructose-6-phosphate to Fructose-1,6-biphosphate
Key inducers of glycolysis
AMP, Fructuose-2,6-bisphosphate (insulin and glucagon)
Is the rate limiting enzyme for gluconeogenesis.
Fructose-1,6-bisphosphate 1
Likes to drive PKK2/FBPASE2 phosphorylated to favor glycolisis
Glucagon
Fructose-1,6-phosphate to 2 GAP, reversible for gluconeogenesis.
Splitting stage of glycolisis
Total ATP per glycolisis
4 (2 ATP per GAP)
2 ATP net
Inhibitors of piruvate kinase
ATP, alanine
Plasma elevations are common in hemolysis, myocardial infarction and some tumors
Lactate deshidrogenase (LDH)
Sepsis, bowel ischemia, seizures. Elevated anion gap acidosis. - HCO3, -pH.
Lactic acidosis
Too much exercise = too much NAD consumption (exceed capacity to TCA cycle/electron transport). Elevated ratio NADH/NAD. Favors piruvate to lactate (pH = falls in muscle)
Muscle cramps
Autosomal recessive disorder, RBCs (most affected, lack mitochondria, membrane failure = phagocytosis in spleen.) New born with extravascular hemolysis and splenomegaly
Piruvate kinase deficiency
Synthesized as an offshot of glycolisis. Alters hemoglobin binding and helps the red cell deliver oxygen to tissues in certain setings.
2, 3 - Bisphosphoglycerate
Malate aspartate shuttle is used for oxidate phosphorylation (liver, heart)
32 ATP
Glycerol 3-phosphate shuttle (muscle)
30 ATP
No oxygen, no mitochondria
2 ATP + 2 lactate + 2 H2O
Insulin is standard therapy for ?. Insulin drives potassium into cells, lowering the serum potassium level.
Hyperkalemia.
Insulin is always given together with glucose when treating hyperkalemia. If given alone, insulin can cause
Hypoglycemia, seizures, or death.
Fructose 1,6 Bisphosphatase1 is the rate-limiting enzyme in gluconeogenesis. In the fed state, when insulin levels rise, this enzyme will become
Less active
Sources of glucose
Pyruvate, lactate, amino acids, propionate (odd chains fats), glycerol (fats)
Inactive without Acetyl-CoA (allosteric activator of gluconeogenesis)
Piruvate Carboxylase
Enzimes used in step 1 of gluconeogenesis (piruvate to phospoenolpiruvate (PEP))
Piruvate carboxylase (ATP, CO2 donate COOH, Biotin: in mitochondria)
PEP carboxykinase (GTP donate a phosphate)
Used by the mitochondria in the gluconeogenesis to get out to the cytosol the oxalacetate (OAA)
Malate shuttle
Deficiency of biotin
Massive consumption of raw egg whites (avidin); dermatitis, glossitis, loss of appetite, nausea
Pyruvate carboxylase deficiency
Presents in infancy with failure to thrive, high levels of pyruvate and lactate, and a lactic acidosis.
Rate limiting step of gluconeogenesis
Fructose-1,6-bisphosphate to fructose-6-phosphate (catalyzed by Fructose 1, 6 bisphosphate 1 tend to be activated by high levels of ATP, inhibited by AMP)
ON/OFF switch glycolysis.
High: favors glycolisis
Low: favor gluconeogenesis.
Manipulates enzimes PFK1 and Fructose-1,6-bisphosphate 1.
Fructose-2,6-bisphosphate
Levels rise with high insuline (fed state)
Levels fall with high glucagon (fasting state)
Fructose-2,6-bisphosphate
Converts glucose-6-phosphatase to glucose. Occurs mainly in the kidneys and liver. Endoplasmic reticulum.
Glucose-6-phosphatase
Can become glucosa
Odd chain fatty acids
The body stores fatty acids as
Triacylglycerol
Raises blood glucose. Gluconeogenesis and glycogen breakdown.
Epinephrine
Increases gluconeogenesis enzymes, hyperglycemia common side effect steroid drugs.
Cortisol
Increases gluconeogenesis
Thyroid hormone
Enzime only present in the liver that can mantain glucose levels during fasting
Glucose-6-phosphatase
Creates glucose-1-phosphate
Stops when glycogen branches decreased to 2-4 linked glucose molecules (limit dextrins).
Stabilized by vitamin B6.
Phosphorylase
Cleaves limits dextrins
Debranching enzime
Elevated in fasting or fight or flight, they favor the breakdown of glycogen into glucose
Glucagon, epinephrine
When its phosphorilazed it’s activity falls
Glycogen synthase
When its phosphorilazed it increases it activity, breaks down more glycogen into glucose
Glycogen phosphorilase
Desphosphorylazation of glycogen synthase and glycogen phosphorilase
Insulin
Has a tyrosine kinase bound to it. This tyrosine kinase will phosphorylate an enzyme called protein phosphatase 1. The phosphorylated protein phosphatase 1 can remove the phosphate group from GP kinase A (= DECREASE IN GLYCOGEN BREAKDOWN)
Insulin receptor
Can directly activate GP kinase A which will phosphorylate glycogen phosphorylase and lead to glycogen breakdown.
Calcium/calmodulin
When AMP levels are high, this means that the cell is breaking down lots of ATP and it needs more energy. So this will activate the
Breakdown of glycogen into glucose
A deficiency of the enzyme glucose-6-phosphatase (type Ia)
Glucose transporter deficiency (type Ib)
Von Gierke’s Disease (Glycogen storage disease type 1)
Results in deficient breakdown of glycogen in lysosomes leading to glycogen accumulation. This disorder can be classified as a lysosomal storage disease and a glycogen storage disease. In the classic infantile form of Pompe disease, glycogen accumulates in lysosomes in the heart and muscles. It causes primarily muscle dysfunction with no direct effects on the liver. A baby with cardiomegaly and hypotonia should bring this disorder immediately to mind. Often presents in the first few months of life. An enlarged tongue is a classic finding. On blood work, creatine kinase is usually elevated indicating muscle damage. In contrast to other glycogen storage diseases, hypoglycemia is not present.
Acid alpha-glucosidase (also called acid maltase) deficiency, also known as Pompe disease.
Because glycogen is stored in the liver, many glycogen storage diseases result in hepatomegaly from glycogen accumulation. That is not usually the case in ?, however. In ?, heart failure results from cardiac glycogen buildup. This leads to pulmonary edema and congestion of the liver.
Pompe disease
Glycogen debranching is impaired in ? which is associated with hypoglycemia.
Cori’s disease (glycogen storage disease type III)
Thrombosis of the hepatic vein causes the ?. This can lead to liver enlargement and ascites. This is seen in hypercoagulable states and in patients with hepatocellular carcinoma.
Budd Chiari syndrome
Is caused by a debranching enzyme deficiency. The debranching enzyme cleaves limit dextins as part of glycogen breakdown. In absence of this enzyme, limit dextrins accumulate in the liver causing hepatomegaly.
GSDIII (Cori disease)
Liver enlargement also occurs in GSDI due to
Accumulation of glycogen (not just limit dextrins).
Often presents at an older age (early childhood) than GSDI (newborn) as the liver is capable of some degree of glycogen breakdown.
GSDIII
Muscle weakness in GSDIII occurs because muscle glycogen stores are ineffective at generating energy for myocytes. In contrast, muscle weakness is not typical in ? because this disorder disrupts glycogen metabolism in the liver but not in muscle.
GSDI
Growth restriction, hepatomegaly, and elevated AST/ALT from liver damage occur in both disorders.
GSDI I and III
Post-prandial hyperglycemia is seen in ? (sometimes called glycogen storage disease type 0).
Glycogen synthase deficiency
GSDI can be managed with dietary modifications.
Cornstarch
The alanine cycle converts the amino acid alanine into glucose in the liver. This is disrupted in GSDI and, therefore,
Elevated serum alanine levels occur.
Occurs in urea cycle disorders and organic acidemias.
Hyperammonemia
Occur in the fatty acid disorder, medium chain acyl-CoA dehydrogenase (MCAD) deficiency.
Urinary dicarboxylic acids
In this disorder, myocytes cannot break down glycogen which leads to exercise intolerance, myalgias, and weakness. Muscle damage with exercise (rhabdomyolysis) may occur leading to myoglobinuria, dark urine, and an elevated creatine kinase level.
Myophosphorylase deficiency (McArdle disease).
Creatine kinase is a muscle enzyme that converts creatine to phosphocreatine. Its presence in the serum is used as
A marker of muscle damage
The HMP shunt serves two major purposes in cellular metabolism. It generates ribose 5-phosphate used in the synthesis of nucleic acids. It also produces NADPH, a substance used in a number of synthetic pathways. NADPH protects red cells against oxidative damage. It is also used as part of the respiratory burst in phagocytes. In addition, the enzyme fatty acid synthase requires NADPH.
Fatty acid synthesis will be impaired in the absence of normal NADPH production by the HMP shunt
Ribose-5-phosphate
Nucleic acids/DNA/RNA
NADPH
Red cell oxidative protection
Respiratory burst in phagocytes
Fatty acid synthesis
Red blood cell membranes are vulnerable to oxidative damage in patients with ?. Synthesis of membrane proteins, however, is not directly impaired by inhibition of the HMP shunt.
Glucose-6-phosphate dehydrogenase deficiency
Do not require NADPH or other metabolites produced by the HMP shunt.
The TCA cycle and oxidative phosphorylation
Among chronic alcohol users with thiamine deficiency, only 13% develop the Wernicke-Korsakoff syndrome. This subset of patients has been found to have an altered form of the enzyme ?. It is an enzyme of the HMP shunt.
Transketolase in fibroblasts
Is an irreversible encephalopathy associated with chronic alcohol use and thiamine (vitamin B1) deficiency.
The Wernicke-Korsakoff (WK) syndrome
May be seen among alcohol users with and without WK syndrome.
Hypomagnesemia, folate deficiency, alcohol withdrawal, and increased serum AST
Is the most common red cell enzyme disorder. An inherited condition, it is caused by a defect in the enzyme ? which generates NADPH as part of the HMP shunt.
G6PD deficiency
In the absence of normal G6PD function, red cells are vulnerable to oxidative damage. Many foods (fava beans) and drugs (antibiotics used for urinary infections like sulfa drugs or nitrofurantoin) generate hydrogen peroxide in red cells. NADPH is required to metabolize hydrogen peroxide into ?. In absence of sufficient NADPH, patients with G6PD deficiency develop hemolysis due to oxidative membrane damage from hydrogen peroxide.
Water
G6PD deficiency: Glutathione is metabolized to glutathione disulfide by the enzyme glutathione peroxidase in red cells. In absence of NADPH, glutathione becomes trapped as glutathione disulfide, and cannot be regenerated into glutathione. This results in
Increased levels of glutathione disulfide in red cells.
Deficiency of the glycolysis enzyme pyruvate kinase may lead to hemolysis. This presents in
The newborn period
Patients with CGD are deficient in the enzyme ? used as part of the respiratory burst by phagocytes (neutrophils and macrophages). In the absence of this enzyme, superoxide (O2-), hydrogen peroxide, and hypochlorous acid cannot be generated for bacterial and fungal killing. This leaves patients vulnerable to infection by catalase-positive organisms.
NADPH oxidase
Diagnosis is made through neutrophil function testing (dihydrorhodamine 123 fluorescence; Nitroblue tetrazolium test).
CGD
Are found in large amounts in cells of the liver, adipose tissue, the adrenal cortex, the testes, and mammary glands. The common theme among these tissues is the need to synthesize fatty acids or steroids in large quantities. High levels of ? are also found in neutrophils and macrophages which use NADPH for the respiratory burst.
HMP shunt enzymes
The rate-limiting enzyme of the HMP shunt. The HMP shunt generates NADPH for steroid and fatty acid synthesis.
Glucose-6-phosphate dehydrogenase (G6PD)
The HMP shunt occurs in the ? like glycolysis.
Cytoplasm
Pyruvate is shunted into lactate and alanine. This causes a severe lactic acidosis and hyperalaninemia. Hyperventilating in response to acidosis. Secondary hyperammonemia has occurred due to liver dysfunction. Note that serum glucose is normal. Fasting does not worsen the condition.
Pyruvate dehydrogenase (PDH) deficiency
Babies with PDH deficiency develop worsening symptoms after eating ? like glucose or starch. These are metabolized into pyruvate which is shunted to lactic acid leading to vomiting, hyperventilation, and other symptoms.
Carbohydrates like glucose or starch. These are metabolized into pyruvate which is shunted to lactic acid leading to vomiting, hyperventilation, and other symptoms.
Prolonged fasting should be avoided in ? where fasting metabolism is abnormal. In PDH deficiency, fasting does not worsen the condition.
Glycogen storage diseases and fatty acid disorders
Are recommended in PDH deficiency since beta-oxidation can generate acetyl-CoA without need for PDH.
High-fat diets
Cofactors for the PDH complex
Vitamins B1, B2, B3, and B5
Mutations in genes coding for the E1 subunit of pyruvate dehydrogenase (PDH) lead to PDH deficiency. In this disorder, pyruvate cannot be metabolized into acetyl-CoA for entry into the TCA cycle. When carbohydrates are ingested, pyruvate is shunted to lactic acid causing a severe lactic acidosis. This results in an increased anion gap metabolic acidosis with
Low serum bicarbonate.
¿Why Hypoglycemia is not a prominent feature of PDH deficiency?
Gluconeogenesis and glycogenolysis are intact.
Occur in disorders of beta-oxidation such as medium-chain acyl-CoA dehydrogenase (MCAD) deficiency
Urinary dicarboxylic acids and hypoketosis
In the fasting state, beta-oxidation of fatty acids leads to increased levels of acetyl-CoA in liver cells. High acetyl-CoA levels inhibit ? by activating kinase enzymes that phosphorylate PDH to render it less active.
Pyruvate dehydrogenase (PDH) activity
High levels of acetyl-CoA also activate ? which diverts pyruvate towards gluconeogenesis. Pyruvate is converted into oxaloacetate, the first step towards liver synthesis of glucose.
Pyruvate carboxylase (PC)
Arsenic has several toxic effects on cellular metabolism. One of them is binding to ?, a co-factor for the pyruvate dehydrogenase complex and the alpha-ketoglutarate complex (TCA cycle). Cells exposed to arsenic cannot generate ATP leading to cell death.
Lipoic acid
In exercising muscle, calcium release from the sarcoplasmic reticulum activates several enzymes of the TCA cycle including isocitrate dehydrogenase. Isocitrate dehydrogenase catalyzes ?. Its activity is increased by calcium and ADP, and inhibited by ATP and NADH. Increased TCA cycle activity leads to more ATP generation for exercising muscle.
The rate limiting step of the TCA cycle
Fats and amino acids can be used as substrates for gluconeogenesis in the liver through conversion into ?. A number of non-carbohydrate substances can be converted to glucose in the liver via ?. These include odd chain fatty acids and some amino acids. Once converted to ?, they can be metabolized into succinate which can enter the TCA cycle. Through the TCA cycle, succinate is metabolized to oxaloacetate which can enter gluconeogenesis.
Succinyl-CoA
This woman is twenty-four hours into the fasting state. At this point in time, glycogen stores will be depleted. Fatty acids will be metabolized via beta oxidation in the liver raising the level of acetyl-CoA. The rise in acetyl-CoA will have several effects to direct the metabolism of the fasting state.
First, pyruvate dehydrogenase is inhibited to prevent pyruvate metabolism into acetyl-CoA. Also, pyruvate carboxylase is activated directing pyruvate metabolism into oxaloacetate and, therefore, into gluconeogenesis. A final effect of increased acetyl-CoA is the synthesis of ketones by the liver, a normal finding in the fasting state.
Glycolysis converts glucose into
2 pyruvate
2 ATPs
2 NADH
Acetyl CoA can then enter the TCA cycle and be converted to:
1 GTP
3 NADH
1 FADH2
The first step is conversion of oxaloacetate into malate, in doing this NADH is converted to NAD plus and what this essentially means is that NADH transfers its electrons to oxaloacetate, and that creates a molecule of malate.
Malate shuttle
The major pathologic effect of CO is
Binding to iron in the Fe2+ state in hemoglobin. This creates a functional anemia by rendering many of the oxygen-binding sites unavailable for oxygen. A secondary pathologic effect of carbon monoxide occurs in the mitochondria where CO inhibits electron transport. CO binds to Fe2+ iron found in cytochromes of the electron transport complexes. This renders them unable to transport electrons to generate protons in the intermembrane space. As a result, the electrochemical gradient for ATP production falls.
Uncouplers
Allow protons to move out of the intermembrane space without generating ATP. They do not disrupt the transfer of electrons between the complexes of the electron transport chain.
Occurs in glycolysis when ATP is synthesized from ADP via enzymes.
Substrate level phosphorylation
CO binds to iron in the Fe2+ state, not
The Fe3+ state
Is a highly-lethal, mitochondrial poison that binds to Fe3+ iron in complex IV of the electron transport chain.
Cyanide
The most common mechanism of exposure is from fires where cyanide is liberated from rubber and other substances. Presenting signs are often non-specific including
Headache, agitation, or confusion. The smell of almonds on the breath is a classic finding (the “funny smell” this man detects). Because mitochondria are poisoned by cyanide, oxygen is not consumed by tissues and remains in the blood. As a result, venous blood is highly oxygenated and develops a bright red color. This gives the skin a characteristic pink discoloration.
Mitochondrial poisoning by cyanide will interrupt the electron transport chain. This will stall the TCA cycle and, thus, metabolism will be shunted towards
The production of lactate.
Venous oxyhemoglobin levels are increased in cyanide toxicity. As a result, the difference between arterial and venous blood is
Decreased
Salicylates directly stimulate the respiratory center in the medulla. This leads to hyperventilation and a respiratory alkalosis. The second effect is the uncoupling of oxidative phosphorylation. As a result, protons in the mitochondrial intermembrane space are transported abnormally across the inner membrane such that they do not generate ATP. This creates heat and causes a fever. Mitochondrial dysfunction also shifts cells to anaerobic metabolism. This leads to an anion gap metabolic acidosis due to an accumulation of lactic acid in addition to the respiratory alkalosis.
Aspirin
Is an uncoupler of electron transport that disrupts ATP production by allowing protons to leave the intermembrane space without generating ATP. Oxygen consumption via the electron transport chain will proceed normally as it is undisturbed by ?
2,4 dinitrophenol
Will halt both ATP production and oxygen consumption.
An inhibitor of electron transport (e.g., cyanide)
Inhibitors shut down ATP production by shutting down electron transport (and, therefore consumption of oxygen).
Uncouplers allow electron transport (i.e., oxygen consumption) to proceed normally but ATP production is inhibited through proton escape from the intermembrane space.
Is a rapid-active vasodilator with effects on arterioles and veins. It is used in the treatment of hypertensive emergency. A potentially life-threatening adverse effect is cyanide toxicity which may occur since nitroprusside contains cyanide moieties.
Nitroprusside
Cyanide is an inhibitor of electron transport. When the electron transport chain shuts down in the setting of cyanide toxicity, glucose metabolism is directed toward the formation of lactate. As a result, lactic acidosis develops. The hallmarks of cyanide toxicity from nitroprusside are delirium and lactic acidosis. An unexplained fall in the bicarbonate level indicating acidosis is a concerning finding in a patient on nitroprusside. Risk factors for cyanide toxicity include
Prolonged treatment (>24 hours), renal failure, and excessive dosages.
Treatment of cyanide toxicity includes withdrawal of the offending drug and administration of an antidote. ? is the first line and acts by directly binding cyanide molecules.
Hydroxocobalamin
Is an adjunctive agent that is used with hydroxocobalamin. This compound provides sulfur groups to enzymes that can detoxify cyanide. If these agents are not available, nitrites can be used to induce methemoglobinemia, which has a high affinity for cyanide.
Sodium thiosulfate
Is used in the treatment of methemoglobinemia
Methylene blue
Is a chelating agent used in a variety of heavy metal toxicities, including lead and iron.
Dimercaprol
Is used in the treatment of acetaminophen toxicity.
N-acetylcysteine
Elevated liver enzymes, hyperammonemia, hypoglycemia, and hypoketosis. These findings are consistent with a
Beta-oxidation disorder
Is required to shuttle fatty acids into the mitochondria. ? is esterified with fatty acids to form acylcarnitines (i.e., “carnitine esters”) as part of lipid metabolism.
Carnitine
Lead to poor beta-oxidation of lipids.
Deficient carnitine levels
In a carnitine deficiency, serum carnitine is low (absence of carnitine) and acylcarnitine levels are also low. In a beta-oxidation enzymatic defect,
acylcarnitines accumulate
Primary carnitine deficiency
impaired membrane transport prevents carnitine uptake by cells. Carnitine is also lost in the urine leading to low serum carnitine levels. Babies with this condition develop hypoketotic hypoglycemia, liver failure, and hyperammonemia (secondary to liver failure). Symptoms worsen during fasting when fatty acid metabolism is required for fuel.
