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Physiology for Anaesthetists > Metabolism > Flashcards

Metabolism Flashcards

1
Q

Define cellular respiration

A

Series of catabolic processes by which CHO, fats and proteins are broken down to yield ATP through a series of redox reactions using O2 as the oxidising agent.

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2
Q

What are the oxidizing agents used in cellular respiration

A

O2 itself is too reactive to be used directly

Intermediate electron carriers are used :

  1. NAD+
  2. FAD +
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3
Q

What is the eponymous name for glycolysis

A

Embden - Meyerhof pathway

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4
Q

What enzymes convert glucose to glucose 6 phosphate, in which cells do these enzymes act, what hormones/factors influence these enzymes and why is glucose converted into glucose 6 phosphate within the cytoplasm

A

Glucokinase (hepatocytes) –> increase by insulin + decreased in starvation/diabetes

Hexokinase (all other cells) –> not increased by insulin + not decreased by starvation/diabetes

Conversion of glucose to glucose 6 phosphate in the cell maintains a concentration gradient for ongoing entry of glucose into the cell.

Conversion to glucose 6 phosphate also makes the molecule more polar and more difficult for it to diffuse out of the cell

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5
Q

What is the fate of glucose 6 phosphate

A
  1. To proceed to the pentose phosphate pathway (ppp)
  2. To proceed into the glycolysis pathway
  3. Proceed into glycogensis / glycogenolysis
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6
Q

What are the products of glycolysis from 1 molecule of glucose

A

2 x ATP (Net)
2 x pyruvate
2 x NADH

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7
Q

Does glycolysis produce CO2

A

No

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8
Q

Why does lactate accumulate under anaerobic conditions?

A

NAD+ is required for the conversion of Glyceraldyde 3 Phosphate to 1.3 bisphosphoglycerate.

Under aerobic conditions:
1. NADH formed during glycolysis can exchange electrons with NAD+ from within the mitochondrial matrix (as the electron transport chain is active) NAD+ is replenished and glycolysis can continue

Under anaerobic conditions

  1. Pyruvate is converted to lactate which converts NADH to NAD+ allowing glycolysis to continue.
  2. NAD+ is not available to exchange electrons with NADH made by glycolysis as the electron transport chain is not active.

This explains the accumulation of lactate in under local or systemic anaerobic conditions

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9
Q

What are the fates of lactate

A
  1. Pyruvate (If PaO2 restored)
  2. Cori cycle –> to liver –> pyruvate –> glucose (gluconeogenesis)
  3. Fermentation (in organisms without a liver). Lactate is converted to ethanol.
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10
Q

What is the Cori cycle

A

Lactate transported to the liver from tissues.

Converted to pyruvate and then glucose

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11
Q

What intermediate within the process of glycolysis affects the oxyhaemagolbin dissociation curve. How is this curve affected

A

1.3 bisphosphoglycerate isomerizes to 2,3 bisphosphoglycerate (2,3 BPG)

2,3 BPG shifts the P50 of the OHDC to the right reducing affinity of Hb for O2 at tissues starved of O2 (undergoing glycolysis)

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12
Q

How is hyperlactataemia classified

A

Cohen and Woods Classification

Type A

  1. Tissue hypoperfusion
  2. Anaerobic muscular activity
  3. Reduced O2 delivery
Type B
B1 (associated with disease)
- Leukaemia / lymphoma
- Pancreatitis
- Hepatic / Renal failure
- Short bowel
- Thiamine deficiency

B2 (Drugs and toxin)

  • Beta agonist
  • Metformin
  • Alcohols
  • INH
  • Nitroprusside

B3 (Inborn errors metabolism)

  • Pyruvate carboxylase deficiency
  • Oxidative phosphorylation enzym defects
  • G6PD
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13
Q

What is the Citric Acid Cycle? Draw it

A

Complex cycle of metabolic intermediates that occurs within the inner mitochondrial matrix and produces:

  1. Electron donors: NADH and FADH2
  2. CO2
  3. ATP
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14
Q

What is Pasteur’s point?

A

Mitochondrial oxygen tension of 0.4 kPa. Below this level, the electron transport chain ceases to operate and anaerobic generation of ATP ensues.

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15
Q

Where do the substrates for the citric acid cycle come from

A

Acetyl CoA

  1. Pyruvate (from glycolysis)
  2. Beta-oxidation

Keto-acids formed from the deamination of amino acids

Vitamin B5 required for CoA

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16
Q

Draw the citric acid cycle

A

See page 371 chambers

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17
Q

What is the electron transport chain

A

This is the final step of CHO, fate and protein catabolism. There are 5 protein complexes on the inner surface of the inner mitochondrial membrane which use electron donors: NADH and FADH2 to produce ATP.

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18
Q

What is the function of Complex 1, 2, 3, 4 in the electron transport chain. What co-factors are required and what occurs during this process

A

To pump H+ from the inner mitochondrial matrix into the inter-membrane space to establish an H+ concentration gradient.

Cofactors:

  1. Co-enzyme Q –> transfers electrons from complex 1 to complex 3 and from complex 2 to complex 3.
  2. Cytochrome C –> transfers electrons from complex 3 to complex 4
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19
Q

What is another name for complex 4 in the ETC and what is its unique role. Why is this complex of particular importance

A

Cytochrome c oxidase
–> It transfers the collected electrons to Oxygen (O2) forming water (H2O)

This is the part of the ETC that is affected by cyanide poisoning. Cyanide binds to the complex 4 haem group, preventing it from binding O2.

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20
Q

Describe the final complex and process of the ETC

A

Once a H+ gradient has been established by electron transfer between complexes 1 to 4, H+ ions flow down the concentration gradient through complex 5 or ATP synthase. During this process ATP is generated. This is called oxidative phosphorylation

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21
Q

What is meant by uncoupling of oxidative phosphorylation

A

Oxidative phosphorylation is usually coupled, that is, H+ movement across the inner mitochondrial membrane is used to generate ATP.

In brown adipose tissue, pores can be opened that allow H+ to move into the inner mitochondrial matric without passing through ATP synthase (complex 5). This is called uncoupling, where oxidation and phosphorylation ar no longer strictly matched. The energy released during H+ movement generates heat instead of ATP. This is an important mechanism of thermogenesis in neonates

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22
Q

How many molecules of ATP are created by NADH versus FADH2

A

NADH –> 3 ATP

FADH –> 1 ATP

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23
Q

How much ATP is generated from a molecule of glucose during aerobic and anaerobic metabolism?

A

1 molecule of glucose makes:

Anaerobic = 2 ATP

Aerobic = 36 ATP

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24
Q

What is meant by “fats have a high energy value”

A

They produce more than twice the amount of ATP than equivalent masses of CHO or protein.

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25
Q

Summarise the events that take place during beta-oxidation

A

Takes place in the inner mitochondrial matrix.
Catabolism of fatty acids that involves removing successive two-carbon units from the fatty acid, each event producing one molecule of acetyl CoA which enters the citric acid cycle.

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26
Q

How are free fatty acids stored. Describe the structure of this molecule

A

Triglyceride. Three fatty acids esterified with glycerol. When needed triglycerides are hydrolysed by lipases to regenerate free fatty acids and glycerol

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27
Q

The fatty acids undergo beta oxidation, what happens to the glycerol molecule

A

Hepatocytes transform glycerol into glucose during gluconeogenesis

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28
Q

How do short, medium and long chain fatty acids enter the inner matrix of the mitochondria for beta oxidation to take place

A

Short and medium fatty acids –> small enough to enter on their own

Long chain fatty acids require the carnitine shuffle. –> i.e. are bound to a carrier in order to cross the mitochondrial membrane.

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29
Q

Name the three common ketone bodies and how and when are these formed

A

When carbohydrates are scarce (e.g. starvation) or are unable to enter the cell (diabetic ketoacidosis), beta oxidation becomes the main source of energy.

This results in high mitochondrial Acetyl CoA concentration and the following ketone bodies are formed by condensation of two molecules of acetyl CoA.

  1. Acetone
  2. Acetoacetic acid
  3. Beta-hydroxybutyric acid
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30
Q

In times of starvation how do the liver, heart and brain respond to high ketone bodies

A

Liver –> converts them back into Acetyl CoA and then back into Kreb’s cycle

Heart –> Favours fatty acids as its energy source but can use ketone bodies in times of starvation

Brain –> does not normally metabolize fatty acids. Usually entirely dependent on glucose for ATP. But the brain can adapt to using ketone bodies during times of starvation. (70% of metabolic demands max)

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31
Q

Can RBC’s use ketone bodies as an energy source? why

A

No. RBCs do not have mitochondria and rely 100% on glycolysis for ATP.

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32
Q

Describe the products of the beta oxidation of a 12 Carbon fatty acid

A

6 x Acetyl CoA –> Citric acid cycle
7 x NADH ———–> ETC
7 x FADH2 ———–> ETC

All converted into approximately 100 ATPs

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33
Q

When are proteins catabolized?

A

When amino acids are plentiful

During starvation

34
Q

How energy efficient is protein catabolism versus glucose catabolism

A

Inefficient: 1.75 g protein equivalent ATP to 1 g glucose.

35
Q

Why is protein catabolism an energy inefficient process.

A

Oxidative deamination produces a keto acid and NH3 (ammonia). NH3 is toxic and must be removed. NH3 enters the urea (ornithine) cycle which is an energy consuming process and requires 3 ATP per urea molecule formed.

36
Q

what must first be done to amino acids so that they can be used in biochemical processes and metabolism. How is this achieved?

A

The amino group needs to be removed to form keto acids. Keto acids have the following fates:

  1. Enter Citric Acid Cycle
  2. Transformed into glucose (gluconeogenesis)
  3. Synthesis of other amino acid or fatty acid

Processes used to remove amino group

  1. Oxidative deamination
    - -> forms NH3 toxic –> must be removed by urea cycle (3 ATPs required per one urea formed)
  2. Transamination –> aminotransferases remove the amino group and transfer to a keto acid or another amino acid to form a new amino acid
37
Q

List the nine essential amino acids (that can’t by synthesized by the liver)

A

HLLP ! TV TIM (too much TV, hopefully essential amino acids can help)

Histidine
Lysine
Leucine
Phenylalanine

Threonine
Valine

Tryptophan
Isoleucine
Methionine

38
Q

How much glycogen is stored in the liver and how long can this maintain plasma glucose for? What mechanism takes over thereafter to maintain blood glucose levels

A

100 g
24 hours

Gluconeogenesis

39
Q

How much glycogen is stored within the muscles and can this be released as glucose into circulation

A

200 g

Cannot be released. Ca only be used for metabolic processes within the muscle

40
Q

Describe glycogenesis

A

Follwoing CHO based meal, insulin stimulates glycogen synthase to link multiple Glucose-6-Phosphate molecules together to make glycogen.

41
Q

What is glycogenolysis

A

When blood glucose falls, glucagon and adrenalin stimulate glycogen phosphorylase to reform glucose from glycogen

42
Q

What causes glycogenolysis in liver versus muscle

A

Liver: glucagon and adrenalin

Muscle: Growth Hormone

43
Q

Why can glucose released from glycogen stored in the muscles not be released into the systemic circulation?

A

Muscle cells do not contain Glucose - 6 - phosphosphatase, the enzyme required to convert Glucose 6 phosphate into glucose. the liver cells contain this enzyme

44
Q

What is a chylomicron

A

These are ultra-low density lipoproteins that containL triglycerides, cholesterol, proteins and phospholipids. They transport dietary (EXOGENOUS) lipids from the intestines to other tissues in the body.

45
Q

What is lipogenesis. What initiates lipogenesis

A

Hepatocytes synthesize triglyceride in an anabolic process called lipogenesis.

Meal –> high insulin levels –> Once liver glycogen stores are full –> any excess CHO or amino acids are converted to fatty acids and glycerol which are esterified to give triglyceride.

46
Q

What is the fate of triglycerides once synthesized in the liver by lipogenesis.

A

Packaged as VLDL and released into circulation

47
Q

What is the difference between a chylomicron and VLDL

A

Chylomicron = ultra-low density lipoprotein which transports exogenous lipids from the intestine to other tissues in the body

VLDL = Very Low Density Lipoprotein which transports endogenous (synthesized via lipogenesis in the liver) lipids to other tissues in the body.

48
Q

Where is the metabolic store of protein for use in times of starvation

A

The muscle mass

49
Q

What is gluconeogenesis

A

Energy consuming anabolic process in which glucose is synthesized from non-carbohydrate precursors

50
Q

Where does gluconeogenesis occur

A

Mainly in the liver

Small contribution by the kidney

51
Q

Which tissues depend on glucose for energy

A

Brain - predominantly (can use ketone bodies in starvation for 70% of metabolic processes)

RBCs - rely 100% on glucose for ATP

52
Q

List the molecules used as substrates for gluconeogenesis

A
  1. Lactate
  2. Pyruvate
  3. Glycerol
  4. Amino acids
  5. All the intermediates of the citric acid cycle
    (Citrate, Isocitrate, alpha-ketoglutarate, succinyl CoA, succinate, Fumurate, Malate, Oxaloacetate)
53
Q

Is gluconeogenesis the reverse of glycolysis

A

No. It is a separate biochemical pathway

54
Q

How does metformin work

A

Metformin

  1. Inhibits gluconeogenesis
  2. Reduces glucose uptake from GIT
  3. Improves insulin sensitivity
55
Q

What is the pentose phosphate pathway

A

Also called the hexose monophosphate shunt.

Anabolic carbohydrate pathway with 2 functions:

  1. Produce pentose sugars for NUCLEIC ACID SYNTHESIS
  2. Produce NADPH for intracellular REDUCTION REACTIONS (i.e. reverse of oxidation)
56
Q

Describe the pentose phosphate shunt

A
  1. Glucose - 6 - phosphate
    Acted on by glucose - 6 - phosphate dehydrogenase (G6PD) to make:
  2. NADPH

If NADP+ levels are high –> G6PD is activated to make more NADPH.

NADPH is used to reduce glutathione which is an antioxidant used to prevent oxidative damage by ROS.

57
Q

What is the function of NADPH

A
  1. Used to reduce glutathione which is then used as antioxidant to prevent cellular damage from ROS.
  2. Used in RBCs to maintain the Fe2+ (Ferrous) state.
58
Q

What happens in G6PD deficiency

A

Pentose Phosphate Pathway cannot be utilized. Decreased reducing power. –> damage from ROS and Methaemaglobinaemia (Fe3+) formation

59
Q

What is insulin and where is it produced

A

Peptide hormone. Produced in the beta cells of the islets of Langerhans in the pancreas

60
Q

Summarise the key aspects of insulin synthesis within the beta cell of the islets of Langerhans

A

Precursor = Proinsulin
Proinsulin is an A and B chain joined together by two disulfide bridges and a C-Peptide.

Proinsulin is cleaved by endopeptidases and insulin and free C-peptide are packed together in vesicles.

61
Q

What is the primary trigger for insulin vesicles to undergo exocytosis. Describe the cellular mechanism for insulin release

A

Increase in plasma glucose concentration –> facilitated diffusion (GLUT 2) of glucose into beta cells –>Increase metabolic activity of cell –> increased ATP –> ATP gated K channels are closed by high ATP –> reduced potassium flux –> membrane depolarization –> opening of voltage gated Ca channels –> Ca influx –> exocytosis of vesicles

62
Q

Discuss the distinct phases of insulin release from beta cells

A
  1. Initial phase –> stored insulin is released

2. Thereafter, pre-formed insulin is depleted and insulin is released as it is synthesized

63
Q

Describe the effects of the sympathetic nervous system on the Beta-islet cells and insulin release

A

SNS –> direct neural input: inhibits insulin release via alpha 2 adrenoreceptor

Adrenalin (released from adrenal medulla) –> stimulates beta 2 adrenoreceptors –> increase insulin secretion (muscles require insulin for glucose uptake through GLUT-4 glucose transporter.

64
Q

Where are the GLUT-1, GLUT-2 and GLUT-4 glucose transporters found and which of these are sensitive to insulin

A

GLUT-1: Brain
GLUT-2: Liver
GLUT-3: Neurons
GLUT-4: Adipose, Skeletal Muscle, Heart

GLUT-4 is insulin dependent

GLUT-1, GLUT-2, GLUT 3 are not insulin dependent
–> Neurons, brain and Liver can take in glucose without insulin

65
Q

How does insulin affect storage of metabolic substances?

A
  1. LIVER: Increased glycogenesis
  2. LIVER: Increased fatty acid synthesis
  3. ADIPOSE: Increased esterification of fatty acids and glycerol
66
Q

How does insulin inhibit endogenous glucose production?

A

Inhibition of:

  1. Gluconeogenesis
  2. Lipolysis
  3. Glycogenolysis
67
Q

Summarise the function of insulin

A
  1. Facilitate glucose uptake
    - GLUT-4
  2. Storage of metabolic substrates
    - LIVER: Glycogenesis and free fatty acid synthesis
    - ADIPOSE: Triglycerides
  3. Inhibit endogenous glucose production
    - Inhibit glycogenolysis
    - Inhibit lipolysis
    - Inhibit gluconeogenesis
  4. Promote cellular uptake
    - amino acids
    - Potassium
68
Q

What is the difference between lipolysis and beta-oxidation

A

Lipolysis: Triglycerides are broken down into glycerol and free fatty acids

Beta oxidation: occurs in the inner matrix of the mitochondria - sequential removal of two carbon portions of the fatty acid chain to form Acetyl-CoA which enters the citric acid cycle.

69
Q

Why does insulin promote the cellular uptake of potassium?

A

Increased K uptake is a feedforward response to prevent hyperkalaemia.

Following a meal, the presence of increased glucose suggests feeding and the likelihood of increased potassium.

70
Q

Which cells produce glucagon

A

alpha cells of the islets of Langerhans

71
Q

How is glucagon secretion stimulated?

A
  1. Hypoglycaemia induced ANS activity.

2. Increased circulating adrenalin stimulates glucagon secretion

72
Q

Which of the islet of Langerhans are sensitive to glucose levels

A

Beta cells only –> high glucose –> high ATP –> ATP gated K channels close –> reduced K flux –> Depolarisation of cell –> voltage gated Ca chennels open –> Increased intracellular calcium –> exocytosis insulin and C-peptide.

alpha cells are not sensitive to glucose levels and glucagon is released subsequent to increased ANS signals and adrenalin levels during hypoglycaemia

73
Q

How is glucagon release inhibited?

A
  1. Insulin
  2. Somatostatin
  3. Increased ffa and ketone body concentrations
74
Q

By what mechanisms does glucagon increase plasma glucose

A
  1. Increase gluconeogenesis
  2. Increase glycogenolysis
  3. Inhibit glycolysis –> intermediates of glycolysis are shifted to gluconeogenesis
75
Q

Define basal metabolic rate
What is BMR corrected for
What is normal BMR for an adult

A

This is the amount of energy a patient consumes per unit time in a state of mental and physical rest in a comfortable environment, 12 hour after a meal.

BMR is corrected for age and surface area

Normal BMR adult = 200 kJ/(m^2h) or 40 kcal/(m^2h)

76
Q

What factors increase and decrease BMR

A

Increase BMR

  1. Exercise
  2. Raised catecholamines
  3. Hyperthyroidism
  4. Pregnancy and lactation
    - Placental and fetal metabolism + growth uterus and breasts. Milk production
  5. High and low environmental temperature
  6. Recent meal (oxidative deamination amino acids) within 6 hours following large meal
  7. Children - metabolic needs of growth and thermoregulation

Reduced BMR

  1. Hypothyroidism
  2. Starvation
  3. Advancing age (2% per decade)
77
Q

What is the BMR of neonates compared to adults and why

A

Double. Thermoregulation and growth

78
Q 
What is:
1 MET
3 METS
4 METS
8 METS
> 10 METS
A

1 MET = equals in a state of rest, awake, fasted > 12 hours –> BMR

3 METS = walking at moderate pace

4 METS = climbing two flights of stairs without stopping

8 METS = Jogging

> 10 METS = strenuous exercise

79
Q

Which tissues have a propensity for anaerobic metabolism –> mnemonic…

A

Think Lactate When you Can’t Make Respirations

Testes
Lens
WBCs
Cornea
Medulla (kidney)
RBCs

These are the tissues with a propensity for glycolysis / anaerobic metabolism

80
Q

Discuss the possible fate of pyruvate under aerobic and anaerobic conditions

A

Anaerobic (cytosol)
1. CORI cycle:
Enzyme: Lactate dehydrogenase
Lactate –> blood stream –> liver –> pyruvate –> gluconeogenesis –> glucose –> blood stream –> muscle –> glycolysis –> repeat

  1. CAHILL cycle: Alanine (as above
    Enzyme: Alanine Transferase

Aerobic (mitochondria)
Oxaloacetate (Pyruvate carboxylase) –> enter TCA cycle (need Biotin = B7)

Acetyl CoA (Pyruvate dehydrogenase) –> enter TCA (need B1, B2, B3, B5, Lipoic acid

81
Q

Which amino acids are:

  1. Ketogenic
  2. Ketogenic and Glucogenic
  3. Glucogenic
A

KETOGENIC
Leucine
Lysine

KETOGENIC and GLUCOGENIC
Isoleucine
Tyrosine
Tryptophan
Phenylalanine
GLUCOGENIC (AAAGG)
Alanine
Aspartate
Asparagine
Glutamine
Glycine

Threonine (TV)
Valine

Cysteine (CHAMPS)
Histidine
Arginine
Methionine
Proline
Serine
82
Q

List the essential amino acids

A

HLLP TV TIM (Help TV Tim with essential amino acids)

Histidine
Lysine
Leucine
Phenylalanine

Threonine
Valine

Tryptophan
Isoleucine
Methionine

Physiology for Anaesthetists (61 decks)

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