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Metabolism > 6 Drug metabolism and adaptations > Flashcards

6 Drug metabolism and adaptations Flashcards

1
Q

4 main stages of drug metabolism?

A

absorption

distribution

metabolism

elimination

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2
Q

phase I metabolism

A

mainly occurs in liver

Oxidation, reduction and hydrolysis

Expose/add a reactive group

cytochrome P450 dependent oxidation
NADPH and NADPH - P450 reductase important factors

diff isoforms (CYP3A4 & CYP2D6)

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3
Q

phase 2 metabolism

A

occurs in liver
conjugation w/ polar molecules makes more water soluble
glutathione, glucuronic acid or sulphate enzymes
specific enzymes required + UDPGA

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4
Q

first pass effect and drug example

A

substance absorbed from ileum lumen extensively metabolised

enter venous blood which drains into HEPATIC PORTAL VEIN moved to liver

eg) 1g paracetamol

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5
Q

how is gout formed from excessive alcohol consumption?

A

reduced NAD+/NADH
increase lactate, kidneys ability to excrete urine decrease, so uric acid levels which increases crystal formation

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6
Q

alcohol metabolism

A

90% metabolised
10% excreted

small amount metabolised in liver alcohol oxidised by CYP2E, the rest by alcohol dehydrogenase

then aldehyde dehydrogenase to acetate

alchol>acetaldehyde>acetate

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7
Q

metabolism of paracetamol

A

therapeutic level 2 tablets 1g, metabolised in phase II

toxic level goes through phase I and II due to saturation

toxic metabolite formed - NAPQI (oxidising agent depletes glutathione)

N-acetyl cysteine - will replenish glutathione

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8
Q

treatment for alcohol dependance

A

disulfram

cause build up acetaldehyde

causes nausea, vomiting - sickness should deter

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9
Q

what causes fatty liver?

A

reduced levels of NAD+

increase acetyl CoA, increase in FA and ketone synthesis

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10
Q

effects of increased acetaldehyde

A

liver enzymes escape into blood (high levels AST/ALT/GGT)

reduced uptake and conjugation of bilirubin causes hyperbilirubinaemia

reduced synthesis of protein

reduced production of urea - hyperammonaemia

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11
Q

what is gestational diabetes?

A

IN SOME WOMEN, the endocrine pancreas is UNABLE to respond to the increased demand of pregnancy AND is unable to respond to the metabolic demands!

fails to release the increased amounts of insulin required

loss of control of metabolism of blood glucose increase -> diabetes

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12
Q

what changes occurred to meet foetal nutrient demand during pregnancy?

A

Reducing the maternal utilisation of glucose by switching tissues to fatty acids

delaying disposal of nutrients after meals

releases FAs form storage - first stage of pregnancy

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13
Q

what is metabolic response to exercise?

A

energy demands of skeletal & cardiac muscle are met by mobilisation of fuel molecules from energy stores

minimal disturbances to homeostasis to keeping the rate of mobilisation equal to the rate of utilisation

glucose supply to brain maintained

end products are removed

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14
Q

Metabolic response to short duration of HIGH intensity exercise (100m
sprint!)

A

muscle ATP and creatine phosphate used ˜5secs

muscle glycogen mobilised to form G6P

G6P metabolised via glycolysis to form ATP from ADP

under anaerobic conditions - forms lactate and H+ causes fatigue

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15
Q

what does drug metabolism convert

A

inactive drugs to active form

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16
Q

How are energy demands of skeletal and cardiac muscle met during metabolic response

A

Mobilise energy stores

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17
Q

How can ketogenic-acidosis occur with alcoholics

A

High acetyl CoA
Low NAD+
ketone body synthesis

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18
Q

How does damage occur to liver due to acetaldehyde

A

Acetaldehyde dehydrogenase has a low km and removes acetylaldehyde as it is formed but with excessive drinking acetylaldehyde can accumulate

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19
Q

How does disulfiram work

A

Aldehyde dehydrogenase inhibitor
If patient drinks alcohol then acetylaldehyde accumulate leading to symptoms of hangover

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20
Q

How does N-acetyl cysteine work

A

replenish glutathione allowing liver to metabolise the NAPQI

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21
Q

How is acetyl CoA formed during alcohol metabolism

A

Acetic acid and CoA join to form Acetyl CoA

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22
Q

How is glucose transported to fetus

A

Active transport GLUT1

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23
Q

How is metformin excreted

A

Not metabolised and excreted as parent drug

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24
Q

How is the concentration of nutrients in maternal circulation kept high(3)

A

Reduce maternal use of glucose, mother uses fatty acids and ketones
Delayed disposal of nutrients after meals
Release fatty acids from stores build during 1st half of pregnancy

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25
Q

How much energy can muscle glycogen provide

A

2 minutes during intensive
60 minutes during low intensity

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26
Q

How much energy does creatine phosphate provide

A

5 seconds worth during sprint

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27
Q

What activates glycogen phosphorylase

A

Adrenaline
glucagon
AMP

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28
Q

What are the 2 divisions of pharmacology

A

Pharmacokinetics
Pharmacodynamics

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29
Q

What are anti-insulin hormones

A

Hormones that oppose insulin action.

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30
Q

What are issues with metformin

A

No hypoglycaemia
Lactic acidosis
Weight loss

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31
Q

What are risk factors for gestational diabetes (3)

A

Maternal age greater than 25
BMI>25
Personal/family history of diabetes

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32
Q

What are some drawbacks of using fatty acids as fuel in exercise

A

Used only in aerobic conditions
Slow release from adipose
Limited carrying capacity in blood
Limited by carnitine shuttle

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33
Q

What are some examples of enzymes deficiencies affecting drug metabolism

A

Plasma cholinesterase enzymes

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34
Q

What are some examples of phase 2 reaction in drug metabolism

A

Glucuronidation
Sulphate conjugation
Glutathione conjugation

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35
Q

What are the 2 functions of drug metabolism

A

Deactivate drug
Elimination of drug

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36
Q

What are the 2 important placental steroid hormones

A

Oestrogen
Progesterone

37
Q

What are the 2 phases of metabolic adaptation during pregnancy

A

Anabolic
Catabolic

38
Q

What are the 3 underlying causes of gestational diabetes

A

Autoantibodies similar to type 1 diabetes
Genetic susceptibility to onset diabetes
Obesity and chronic insulin resistance

39
Q

What are the 4 general processes in pharmacokinetics

A

Absorption
Distribution
Metabolism
Elimination

40
Q

What are the benefits of exercise

A

Decreased adipose and increased muscle
Increased muscle glycogenesis
Blood pressure falls

41
Q

What are the clinical implications of gestation diabetes (4)

A

Increased incidence of miscarriage
Fetal macrosomia (Large body)
Shoulder dystocia
Gestational hypertension and preeclampsia

42
Q

What are the effects of adrenaline and growth hormone rise in marathon

A

Adrenaline stimulate glycogenolysis and lipolysis
Growth hormone mobilise fatty acids

43
Q

What are the energy sources in 100m sprint

A

Creatine phosphate
Anaerobic production of ATP

44
Q

What are the energy sources used in 1500m race(3)

A

Creatine phosphate
Anaerobic glycogen
Aerobic muscle glycogen

45
Q

What can be used to treat alcoholism

A

Disulfiram

46
Q

What can genetic variability cause in P450 activity

A

Increase or decrease activity of the CYP

47
Q

What carrier molecule used to alcohol conversion to acetaldehyde

A

NAD+ converted to NADH+ and H+

48
Q

What component of alcohol metabolism causes liver damage

A

Acetaldehyde

49
Q

What do anti-insulin hormones do

A

Reduce glucose uptake in adipose/muscle

50
Q

What do oestrogen and progesterone do the pancreatic Beta cells in pregnancy

A

Hyperplasia(more cells)
Hypertrophy (bigger cells)

51
Q

What does drug metabolism do the parent drug molecule

A

Convert parent drug to polar, lipid Insoluble water soluble derivative

52
Q

What does increased levels of insulin in mother promote

A

Anabolic state leading to increased nutrient storage

53
Q

What does the absorption of a drug depend on

A

pH of drug
Drug has to non ionised

54
Q

What effect occurs from glucagon levels rising in a marathon

A

Stimulate glycogenolysis
Stimulate glucogenogenesis
Stimulate lipolysis

55
Q

What energy sources are used in a marathon

A

Muscle glycogen
Liver glycogen
Fatty acids

56
Q

What enzyme used to convert acetaldehyde to acetic acid

A

Aldehyde dehydrogenase

57
Q

What enzyme used to convert alcohol to acetaldehyde

A

Alcohol dehydrogenase

58
Q

What factors affect magnitude and nature of metabolic response to exercise(5)

A

Type of exercise
Intensity
Duration
Physical condition
Nutrition state of individual

59
Q

What genetic factors can affect drug metabolism

A

Gene deletions leading to enzyme deficiencies

60
Q

What goes wrong in paracetamol overdose

A

High NAPQI
Glutathione depleted
Glutathione used as anti-oxidant
NAPQI covalent bind to hepatic proteins leading to oxidative stress

61
Q

What hormones changes occur in a marathon (4)

A

Insulin fall
Glucagon rises
Adrenaline and growth hormone rise
Cortisol rise slowly

62
Q

What is cytochrome P450

A

Family of enzymes

63
Q

What is management for gestational diabetes(3)

A

Dietary modification
Insulin injection
Regular ultrasound

64
Q

What is pharmacodynamics

A

What the drug does to the body

65
Q

What is pharmacokinetics

A

What the body does to the drug

66
Q

What is the abnormal function of pseudocholinesterase enzyme

A

Drug metabolised in a few hours

67
Q

What is the co-factor used in glucuronidation

A

UDPGA

68
Q

What is the effect of cortisol rising slowly in a marathon

A

Stimulation of gluconeogenesis and lipolysis

69
Q

What is the effect of induction of P450 enzymes

A

Increase metabolism of other drugs
Decrease plasma concentration

70
Q

What is the effect of inhibition of P450 enzyme

A

Decrease metabolism
Increase plasma concentration

71
Q

What is the main site of action for phase 2 drug metabolism

A

Liver-cystolic enzymes

72
Q

What is the metabolic response to starvation

A

Tissue switch from glucose to fatty acid/ketones
Brain uses ketones

73
Q

What is the most common anti-insulin hormones

A

Corticotropin releasing hormone

74
Q

What is the normal metabolism of paracetamol

A

NAPQI made in phase 1
NAPQI conjugated with glutathione

75
Q

What is the pathway for alcohol metabolism

A

Alcohol to acetaldehyde using alcohol dehydrogenase
Acetaldehyde to acetic acid using aldehyde dehydrogenase

76
Q

What is the polarity of a parent drug

A

Lipid soluble

77
Q

What is treatment of Paracetamol overdose

A

N-acetyl cysteine

78
Q

What occurs in catabolic phase in pregnancy

A

Maternal metabolism adapts to accommodate growing foetus

79
Q

What occurs in anabolic phase in pregnancy

A

Increase maternal fat stores
Small increase insulin sensitivity

80
Q

What occurs in body due to anti-insulin after meal

A

Transient hyperglycaemia

81
Q

What occurs in phase 1 of drug metabolism (3)

A

Convert lipophilic drug to polar molecule
Oxidation, reduction, hydrolysis
Add or expose reactive groups on drugs

82
Q

Where is the main site of action for phase 1 drug metabolism

A

Liver
Microsomes on endoplasmic reticulum of hepatocytes

83
Q

Why cannot most drugs be excreted by kidney

A

Most drugs lipid soluble instead of water soluble

84
Q

Why do lipids accumulate in liver due to liver damage

A

Reduced Protein synthesis
Less lipoprotein synthesis
Lipids produced in liver cannot be transported from the liver hence accumulate

85
Q

Why is NAPQI bad

A

Depletes Glutathione which acts as a anti-oxidant

86
Q

Why may alcoholics have fatty liver

A

High acetyl CoA
Low NAD+
Fatty acid synthesis
Fatty acids converted to Triacylglycerol
Triacylglycerol cannot be transported to liver hence contribute to fatty liver

87
Q

Why may alcoholics have gout

A

NAD+ decreased due to alcohol to acetaldehyde
NAD+ needed for metabolism of lactate to pyruvate
Increased lactate means kidney cannot excrete uric acid hence urate accumulates and forms uric acid crystals

88
Q

Why might alcoholics have hypoglycaemia

A

NAD+ needed for fatty acid oxidation and metabolism of glycerol
Liver cells cannot use lactate and glycerol hence gluconeogenesis not activated

89
Q

Why must ATP be rapidly resythesised in exercise

A

ATP stores are limited in muscle
Only last 2 seconds during sprint

Metabolism (9 decks)

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