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Metabolism > Session 6 > Flashcards

Session 6 Flashcards

0
Q

What happens to drugs as soon as they enter the body?

A
  • Deactivated and eliminated by metabolism

- As drugs are foreign to the body and may have toxic effects

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1
Q

What is pharmacology made up of?

A
  • Pharmodynamics: how drugs work
  • Pharmokinetics: Absorption
    Distribution
    Metabolism
    Elimination of a drug (ADME)
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2
Q

Why is it unusual for a drug to be secreted in an unchanged form?

A
  • Drugs are lipid-soluble, therefore would be reabsorbed into the blood in the renal tubes if they were to be excreted in aqueous urine via the kidneys
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3
Q

How are drugs changed during metabolism?

A
  • Made water-soluble so that they can be excreted in urine
  • Drug is usually deactivated as the metabolites are usually pharmacologically inactive (not always eg given prodrugs which are metabolised to active form)
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4
Q

What stages occur in drug metabolism?

A
  • Phase I

- Phase II

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5
Q

What happens during phase 1 metabolism?

A
  • Reactive group is exposed or added to the parent stable and unreactive drug molecule
  • Reactive intermediate is formed which is conjugated in phase II with a water-soluble molecule to form a water-soluble complex
  • Common reactions if phase I: oxidation; reduction; hydrolysis
  • Requires enzyme system cytochrome P450 (CYP) system and NADPH as a cofactor
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6
Q

Why can some drugs bypass phase I drug metabolism?

A
  • Already contain a reactive group in their molecule

- Eg morphine

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7
Q

What happens in phase II metabolism?

A
  • Reactive intermediate from phase I is conjugated with a polar molecule
  • Forms a water-soluble complex in conjugation
  • Glucuronic acid is the most common conjugate (freely available as a by product of cell metabolism)
  • Sulphate ions and glutathione are also common conjugated
  • Requires specific enzymes and uridine diphosphate glucuronic acid (UDPGA) high-energy cofactor
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8
Q

Where does drug metabolism occur?

A
  • Liver
  • Hepatocytes contain all necessary enzymes
  • Also: liver; kidneys; gastrointestinal tract; plasma
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9
Q

What are some reasons for the variation in drug metabolism in the population?

A
  • Genetic factors
  • Environmental influences
  • First pass effect
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10
Q

How do genetic factors cause variation in drug metabolism in the population?

A
  • Everyone differs in the level of expression of each enzyme -> each drug is metabolised at different rates in every individual -> drug effects will vary from person to person
  • 50 different Haem containing enzymes in cytochrome P450 system which each differ eg CPY3 A4 is very important
  • Some people lack gene that codes for a crucial enzyme eg enzyme that causes acetylation in phase I -> are slow acetylators
  • Some people have lower levels of pseudocholinesterase enzymes in plasma -> affects ability to metabolise drugs containing ester bond eg suxamethonium a muscle relaxant used during anaesthesia
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11
Q

How do environmental influences cause variation in drug metabolism?

A
  • Enzyme levels in the body are not fixed and can be influenced by external factors
  • Enzyme inhibition or induction may occur if two drugs are given together -> metabolism of one may affect the other
  • Eg some pesticides cause enzyme induction in the liver
  • Ethanol, nicotine and barbiturates are enzyme inducers
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12
Q

What is the first-pass effect and how does it affect dosages?

A
  • Swallowed drugs absorbed in the ileum enter the venous blood, which drains into the hepatic portal vein and is transported directly to the liver
  • Are metabolised during the first pass through the liver before they can have any effect on other tissues
  • Eg most of paracetamol is metabolised during the first pass through the liver so a larger dosage is needed to have an effect
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13
Q

What happens to alcohol in the body?

A
  • 90% is metabolised

- 10% is excreted passively in the urine and on the breath

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14
Q

Where is alcohol mainly metabolised?

A
  • Liver
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15
Q

How is alcohol metabolised?

A
  • Alcohol is oxidised to acetaldehyde by alcohol dehydrogenase (low-specificity enzyme)
    CH3CH2OH + NAD+ -> CH3CHO + NADH + H+
    Enzyme: alcohol dehydrogenase
  • Acetaldehyde is oxidised to acetate by aldehyde dehydrogenase
    CH3CHO + NAD+ + H2O -> CH3COO- + NADH + 2H+
    Enzyme: aldehyde dehydrogenase
  • Acetate is converted to acetyl CoA
    CH3COO- + ATP + CoA -> CH3CO~CoA + AMP + 2Pi
  • Alcohol can also be oxidised by cytochrome P450 2E1 enzyme (which is inducible)
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16
Q

What happens to acetaldehyde from alcohol metabolism?

A
  • Is extremely toxic to cells
  • Aldehyde dehydrogenase has a very low Km for acetaldehyde and removes acetaldehyde as soon as it is formed to minimise toxicity
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17
Q

What happens when alcohol consumption is prolonged and excessive?

A
  • Sufficient acetaldehyde can accumulate to cause liver damage
  • NAD+/NADH ratio decrease and increased availability of acetyl CoA have significant effects on liver metabolism
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18
Q

What are the effects of a decrease of the NAD+/NADH ratio on liver cell metabolism?

A
  • Increased levels of NADH in the liver is caused by alcohol oxidation
  • NAD+ levels are inadequate for fatty acid oxidation, conversion of lactate to pyruvate and metabolism of glycerol
  • Lactic acidosis can occur as decreased lactate utilisation by liver cells causes lactate to accumulate in the blood
  • Increased lactate reduces kidneys ability to excrete uric acid
  • Uric acid levels increase and cause accumulation of urate crystals in tissues causing gout
  • Low NAD+ and inability of liver cells to use lactate and glycerol prevents gluconeogenesis from being activated causing fasting hypoglycaemia
  • Poor dietary habits can also contribute to hypoglycaemia as liver glycogen tends to be low
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19
Q

What are the effects of increased availability of acetyl CoA in alcohol metabolism?

A
  • Increased Acetyl CoA which cannot be oxidised by liver cells because of the low NAD+/NADH ratio
  • Increased synthesis of fatty acids and ketone bodies
  • Fatty acids are converted to triacyglycerols which cannot be transported from liver cells as there is a lack of lipoprotein synthesis so contributes to fatty liver
  • Ketone body production can be sufficient to cause ketoacidosis
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20
Q

What do damaged liver cells have as a result of toxic acetaldehyde?

A
  • Leaky plasma membranes
  • Enzymes eg transaminases and gamma glutamyl transpeptidase are lost from the cell
  • Appearance of enzymes are used diagnostically in liver function tests to indicate liver cell damage
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21
Q

How are the functions of damaged liver cells affected?

A
  • Produces a variety of signs and symptoms
  • Reduction in capability to take up and conjugate bilirubin leads to hyperbilirubinaemia, that can lead to jaundice
  • Reduction in capability to produce urea can lead to hyperammonaemia and increased levels of glutamine
  • Reduced protein synthesis leads to reduced albumin, clotting factors and lipoprotein synthesis; low serum albumin leads to oedema; low clotting factors leads to increase in blood clotting time; low lipoproteins leads to fatty liver as lipids synthesised in the liver cannot be transported out
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22
Q

What are the indirect effects of alcohol consumption?

A
  • Cost of alcoholic beverages and effects on CNS causes poor dietary habits to be associated with excessive consumption
  • Vitamin and mineral deficiencies
  • Inadequate protein and carbohydrate intake
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23
Q

What are the direct effects of alcohol on the gastrointestinal tract?

A
  • High concentrations of alcohol damage cells lining GI tract -> variety of GI tract disturbances -> compound effects of a poor diet
  • Loss of appetite, diarrhoea and impaired absorption of nutrients eg vitamin K, folic acid, pyridoxine and thiamine
  • Signs and symptoms of a specific vitamin deficiency is often seen in alcoholics
  • Thiamine and pyridoxine deficiencies -> Neurological symptoms
  • Folic acid deficiency -> haematological (eg anaemia) problems
  • Thiamine deficiency -> Wernicke-Korsakoff syndrome with mental confusion and unsteady gait
24
Q

How is the disulfiram drug used to help treat chronic alcohol dependence?

A
  • Inhibits aldehyde dehydrogenase enzyme
  • Acetaldehyde is not converted to acetic acid (acetate)
  • Acetaldehyde accumulates in the blood when patient drunks causing ‘hangover’ symptoms eg nausea
  • Effective with additional support
25
Q

How is paracetamol normally metabolised?

A
  • Is an antipyretic drug which is safe with a normal dosage

- Normally metabolised by phase II conjugation with glucuronide or sulphate

26
Q

What happens to paracetamol metabolism if a toxic levels is digested?

A
  • Normal phase II pathways are quickly saturated
  • Paracetamol undergoes phase I metabolism producing a toxic metabolite N-acetyl-p-benzo-quinone imine (NAPQI)
  • Metabolite is toxic to hepatocytes
  • NAPQI also undergoes phase II conjugation with glutathione
  • Depletes cells of glutathione, an important antioxidant
  • Causes destruction of liver cells and liver failure occurs over a period of several days
27
Q

How should an overdose of paracetamol be treated?

A
  • Rapid treatment with N-acetylcysteine (an antioxidant)

- Death from liver failure may be inevitable is treatment is delayed

28
Q

What determines the availability of fuel molecules in the blood?

A
  • Hormones
29
Q

What are the effects of insulin (overall)?

A
  • Lowers concentration of fuel molecules in the blood?
30
Q

What are glucagon, growth hormone, cortisol and adrenaline collectively known as and what do they do (overall)?

A
  • Anti-insulin hormones

- Raises concentrations of fuel molecules in the blood

31
Q

Which out of the glycogen in the liver and muscle can be broken into ️glucose that can be used in tissues such as the CNS?

A
  • Liver

- Link! Skeletal muscle lacks an enzyme?

32
Q

What tissues can not use fatty acids as fuel?

A
  • Erythrocytes

- Central nervous system

33
Q

Where do fatty acids come from?

A
  • Triacylglycerols in adipose tissue
34
Q

Where do ketone bodies come from and when are they produced?

A
  • Fatty acids are converted to ketone bodies in the liver

- Produced when glucose is in critically short supply eg starvation to be used as a fuel by tissues including the CNS

35
Q

When is protein broken down in proteolysis?

A
  • In shortage of other fuel molecules
  • Produces amino acids to be used as fuel by conversion to glucose or ketone bodies, or by direct oxidation
  • Fuel reserve for 2 weeks of normal metabolism
36
Q

When does hypoglycaemia occur?

A
  • When blood glucose drops to 3.0 mmol/L or lower
37
Q

What are the signs and symptoms of hypoglycaemia?

A
  • Trembling
  • Weakness
  • Tiredness
  • Headache
  • Sweating
  • Sickness
  • Tingling around the lips
  • Palpitations
  • Changes in mood (angry/bad temper)
  • Slurred speech
  • Staggering walk
  • Unconsciousness
  • Death
38
Q

What can hypoglycaemia be confused with?

A
  • Intoxication
39
Q

When does hyperglycaemia occur?

A
  • When fasting blood glucose levels are elevated to above 7.0 mmol/L
40
Q

What systems of the body are affected by hyperglycaemia?

A
  • Cardiovascular
  • Renal
  • Nervous
41
Q

Why does polyuria occur in hyperglycaemia?

A
  • Glucose is over renal threshold so is not all absorbed back into the blood from the kidney tubules
  • Glucose has an osmotic effect so causes more water to stay in the kidney tubules and causes more to diffuse from the blood
  • Causes polydipsia
42
Q

What is hyperglycaemia associated with?

A
  • Abnormal metabolism of glucose to products that may be harmful to cells
  • Increased glycosylation of plasma proteins eg lipoproteins that leads to disturbances in function
43
Q

What is the feeding/fasting cycle?

A
  • Individuals that eat regular meals experience a regular cycle of metabolic changes
44
Q

What are the effects of feeding?

A
  • Absorption of glucose, amino acids and lipids from the gut
  • Blood concentration raises
  • Increase stimulates endocrine pancreas to release insulin
45
Q

What actions does insulin have?

A
  • Increase glucose uptake and utilisation by muscle and adipose tissue
  • Promotes stored of glucose as glycogen in liver and muscle
  • Promotes amino acid uptake and protein synthesis in liver and muscle
  • Promotes lipogenesis and storage of fatty acids as triacylglycerols in adipose tissue
46
Q

What are the effects of fasting?

A
  • Blood glucose concentration falls
  • Insulin secretion is depressed
  • Reduces uptake of glucose by adipose tissue and muscle
  • Also stimulates glucagon secretion from the endocrine pancreas (insulin/anti-insulin ratio decreases)
47
Q

What are the actions of glucagon?

A
  • Glycogenolysis in the liver to maintain blood glucose for the brain and other glucose dependent tissues
  • Lipolysis in adipose tissue to provide fatty acids for use by tissues
  • Gluconeogenesis to maintain supplies of glucose for the brain
48
Q

How long does fasting last for to become starvation?

A
  • More than 10 hours
49
Q

What is the initial response to starvation?

A
  • A prolonged version of normal fasting response
  • Blood glucose falls but is maintained at 3.5 mmol/L by actions of glucagon which stimulates breakdown of hepatic glycogen
50
Q

What happens when stores of glycogen are depleted?

What are the effects of various hormones on metabolism?

A
  • Continuing reduction in blood glucose stimulates pituitary gland to release ACTH, consequently raising blood cortisol
  • Cortisol maintains blood glucose by: stimulating gluconeogenesis and stimulating breakdown of protein and fat to produce substrates of gluconeogenesis (mainly alanine and glycerol)
  • Glucagon also stimulates gluconeogenesis
  • Both hormones together increase amounts and activities of gluconeogenic enzymes in liver cells as well as increasing availability of gluconeogenic substrates
51
Q

What happens to lipolysis and lipids during starvation?

A
  • Occurs at a high rate
  • Due to fall in insulin and rise in lipolytic hormones glucagon, cortisol and growth hormone
  • Free blood fatty acids rise to 2 mmol/L from normal 0.3 mmol/L
  • Cortisol simulates fat breakdown
  • Reduction of insulin and effects of cortisol prevent most cells using glucose so they prefer to use fatty acids
  • Glycerol then provides an important substrate for gluconeogenesis to reduce the need for protein breakdown
52
Q

Describe production of ketone bodies in starvation

A
  • Fatty acids are oxidised in the liver to produce ketone bodies
  • Due to decreased insulin/anti-insulin ratio
  • Ketone bodies replace glucose as a fuel for the brain
  • Further reduces need for gluconeogenesis in the liver and spares body protein
53
Q

What are the concentrations of ketones in the fed state, after 3 days of starvation and 1-2 weeks of starvation?

A
  • Fed state: 0.01 mmol/L
  • 3 days of starvation: 2-3 mmol/L
  • 1-2 weeks of starvation: 6-7 mmol/L - physiological ketoacidosis
54
Q

What 2 factors become important during adaptation to starvation?

A
  • Brain becomes able to use ketones as a fuel, reducing its glucose requirements from 140g/day to 40g/day
  • Kidneys begin to contribute to gluconeogenesis
55
Q

What does the brain’s use of ketones reduce?

A
  • Reduces the need to breakdown protein for gluconeogenesis
  • By 4-5 weeks of starvation gluconeogenesis reduces to around 30% of that seen in early starvation
  • Urinary nitrogen excretion falls from 12g/day (mostly urea) to 4g/day (equal urea and NH4+)
56
Q

What does the reduction of urea synthesis during starvation lead to?

A
  • Decrease in the amount and activity of enzymes involved in urea synthesis in liver cells
  • Must not give large amounts of protein and/or amino acids in the early stages and should be increased gradually to prevent re-feeding syndrome
57
Q

What happens when all the body’s fat stores are depleted?

A
  • System reverts to using protein as a major fuel
  • Protein is rapidly used up
  • Death follows shortly from a number of causes related to loss of muscle mass eg serious respiratory infections due to loss of respiratory muscle

Metabolism (11 decks)

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