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Pharmocokinetics > Liver disease and drug handling > Flashcards

Liver disease and drug handling Flashcards

1
Q

metabolic reactions are either what phases?

A

Phase 1/ 2

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2
Q

Example of phase 1 reactions

A

Oxidation
Hydroxylation
Dealkylation
Deamination
Hydrolysis

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3
Q

Is phase 1 reactions anabolic/ catabolic?

A

catabolic —> breaking down of drug

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4
Q

Is phase 2 reactions anabolic/ catabolic?

A

anabolic : (conjugation)

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5
Q

Aspirin metabolic reactions : phase 1/phase 2

A

Phase 1 creates salicylic acid and Phase 2 creates a water-soluble molecule for excretion

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6
Q

what phase (1/2) drug reactions are affected more by increase in age?

A

Phase 1 drug reactions affected more than Phase 2

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7
Q

renal function can lead to reduced excretion of drugs. how? some factors

A

renal blood flow, filtration, renal mass decrease with age
Co-morbidities contribute to this decline

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8
Q

prothrombin time define:

A

how long it takes for clot to form

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9
Q

rifampicin induces what enzyme?

A

CYP2C9

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10
Q

Omeprazole inhibits what enzyme?

A

CYPC219

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11
Q

Omeprazole by inhibiting CYP2C19 this has what effect on clopidogrel?

A

prevents the production of active metabolite of clopidogrel

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12
Q

Rifampicin induces and enzyme. This has what effect on warfarin?

A

reduces anti-coagulant effect of warfarin

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13
Q

Liver metabolises?

A

carbohydrates (glycogen)
protein
lipids

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14
Q

Example of causes of liver disease?

A

alcohol, obesity, viral hepatitis

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15
Q

Stages of liver damage

A

healthy liver –> liver steatosis –> fibrosis liver —> cirrhosis liver –> liver cancer

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16
Q

wilsons disease is?

A

inherited disorder- accumulation of copper

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17
Q

Hemochromatosis disease is?

A

inherited disorder- Accumulation of iron

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18
Q

Examples of unusual cases that cause liver disease

A

tropical infections
TB
syphilis
lymphoma

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19
Q

example of drug-induced liver injury : DILI

A

Paracetamol
NSAID
Antidepressants

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20
Q

steps of drug-induced liver injury : DILI (detail)

A
  1. Inhibition of mitochondrial function–> preventing fatty acid metabolism, & accumulation of lactate & reactive oxygen species
  2. Disruption of bile canalicular transport mechanisms
  3. Disruption of intracellular homeostasis
  4. Formation of non-functioning adducts which may then lead to
    …presentation on the surface of hepatocytes as new immunogens (attacked by T-cells)
  5. Induction of apoptosis
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21
Q

steps of drug-induced liver injury : DILI ( simplified)

A
  1. Mitochondrial impairment
  2. Inhibition of biliary efflux
  3. Lysosome impairment
  4. Reactive metabolites
  5. Endoplasmic reiticulum stress
  6. Immune system
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22
Q

Drug- induced liver injury can either be:

A

intrahepatic
extrahepatic

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23
Q

intrahepatic define:

A

involving hepatocytes

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24
Q

extrahepatic define:

A

outside hepatocytes

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25
Q

signs of intrahepatic DILI

A

often an immune-mediated response to a drug
May be asymptomatic and may be associated with features of drug hypersensitivity e.g: skin,rash,fever

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26
Q

symptoms of intrahepatic DILI

A

Nausea, vomiting, anorexia, jaundice, right upper quadrant pain

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27
Q

signs of extrahepatic DILI

A

Jaundice, itching (due to accumulation of bile salts)

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28
Q

Extrahepatic DILI also called? What is it?

A

Also called cholestasis
Reflects the inability of liver to remove bile from body due to blocked biliary ducts

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29
Q

Symptoms of extrahepatic DILI

A

May be asymptomatic

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30
Q

Intrahepatic vs extrahepatic

A

Intrahepatic = often an immune-mediated response to a drug
Extrahepatic = reflects the inability of liver to remove bile from body due to blocked biliary ducts

31
Q

Why might a patient experience disorientation/ confusion from DILI?

A

Liver is unable to get rid of toxic metabolites which can cause them to be confused

32
Q

Liver function test: for hepatocellular damage

33
Q

Liver function test: choleostasis, impair conjugation or biliary obstruction

A

Bilirubin
ALP

34
Q

Liver function test: synthetic function

35
Q

Liver function test: choleostasis or biliary obstruction

A

GGT
Bile acids
5- nucleotides

36
Q

AST ? Present also where?

A

Aspartate aminotransferase

Present in the heart, muscle, kidney, brain

37
Q

ALP? Present also where?

A

Alkaline phosphatase

Present in placenta, bone

38
Q

ALT? Present also where?

A

Alanine aminotransferase

More specific to the liver

39
Q

GGT? Present also where?

A

Gamma-glutamyltransferase
Present in kidney, pancreas, heart, brain

  • chronic ethanol consumption
40
Q

Raised ALP but normal GGT/ and or bilirubin, indicates?

A

Increased bone turnover/ vitamin D deficiency / bone fractures

41
Q

Amino transferases are?

A

Enzymes contained in hepatocytes that leak into blood when cells are damaged

42
Q

Raised ALT/ ATP indicates?

43
Q

Raised ALT/ AST indicates?

A

Viral hepatitis
- specific for liver injury + good marker for acute liver injury

44
Q

Raised AST/ ALT indicates?

A

Alcohol liver disease/ NAFLD / cirrhosis
- but also raised in myocardial infarction/ burns / trauma

45
Q

Raised ALP / GGT and /or bilirubin

A

Cholestatic
(Gall stones blocking the bile duct / induced medication)

46
Q

Low albumin levels indicates?

A

Reduced synthetic function of the liver

47
Q

Raised PT/ INR indicates?

A

prolonged clotting and reduced synthetic function in context of liver disease

48
Q

Albumin levels can be low by other causes, examples?

A

Malnutrition, sepsis

49
Q

What should be excused as the cause of a prolonged PT?

A

Vitamin K deficiency

50
Q

Prothrombin time indicator of?

A

Acute and chronic liver disease

51
Q

What treats coagulation factors?

A

Prothrombin

52
Q

% Of cardiac output that passes through the liver?

53
Q

Liver metabolism can produce what? (Negative)

A

Toxic metabolites

54
Q

Paracetamol metabolism

A

Phase 1 metabolism: by CYP450 isoforms to form NAPQI
- NAPQI detoxifies through conjugation with glutathione

Phase 2: metabolism = conjugation with glucoronide, sulphate
- since non-toxic metabolites = elimination via kidneys

55
Q

Phase 2: metabolism = conjugation with glucoronide, sulphate of paracetamol is eliminated via the kidneys. Why?

A

Non-toxic metabolite

56
Q

If paracetamol taken in overdose, what happens in metabolism?

A

Paracetamol into phase 2 metabolism becomes saturated = more goes into phase I metabolism

= more NAPQI formation = more hepatotoxic and nephrotoxic ( can’t be eliminated via kidneys)

57
Q

Dose - related toxicity is what type of ADR/ adverse drug reaction?

A

Type A ( augmented)

58
Q

How can NAPQI cause renal failure?

A

Bind renal cells

59
Q

NAPQI is highly reactive. This can have what effect?

A

Oxidises key enzymes causing cell death

60
Q

What is given for paracetamol overdose? And mechanism.

A

N acetyl cysteine (NAC)
Replenishes glutathione to get rid of excess NAPQI

So it can carry on to phase 2 to be eliminated in the kidneys

61
Q

Unpredictable, ‘idiosyncratic’ is what type of ADR?

A

Type B (bizarre)

62
Q

Excessive drinking of alcohol leads to metabolic tolerance and increased levels of acetaldenyde. How?

A

Acetyladehyde dehydrogenase becomes fully saturated with alcohol leading to buildup of acetyladehyde

63
Q

Chronic exposure to drug is what type of ADR?

64
Q

Why avoid opioids in liver failure?

A

Central depressant action in patients with hepatic encephalopathy

65
Q

Why avoid diuretics in liver failure?

A

Dehydration= Increased risk of hepatic encephalopathy

66
Q

Why avoid warfarin in liver failure?

A

Enhances effects

67
Q

Why avoid NSAIDs in liver failure?

A

Increased risk of bleeding

68
Q

Why avoid oral hypoglycaemics in liver failure?

A

Loss of glucose homeostasis
Increased risk of lactic acidosis

69
Q

Why avoid ACE inhibitors in liver failure?

A

Hepatorenal failure

70
Q

Drugs to avoid in liver failure : examples

A

Warfarin
opioids
Oral hypoglycaemics
Ace inhibitors
Diuretics
NSAIDs

71
Q

Ammonia toxin accumulating in blood =

A

Hepatic encephalopathy

72
Q

DILI: Methotrexate can cause what type of liver damage?

73
Q

DILI: paracetamol can cause what type of liver damage?

A

Acute hepatic necrosis

Pharmocokinetics (22 decks)

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