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MPharm2 SL22105 > Liver > Flashcards

Liver Flashcards

1
Q

What are the 5 functions of a healthy liver?

A
  • Synthesis and secretion of bile
  • Plasma proteins - (albumin and clotting factors)
  • Metabolism
  • Storage
  • Endocrine function – production of IGF-1 (insulin-like growth factor)
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2
Q

What are the 5 consequences of liver impairment?

A
  • Loss of glucose homeostasis
  • Loss of protein synthesis
  • Failure of bilirubin metabolism
  • Loss of immune cells
  • Altered drug metabolism
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3
Q

What are the 3 main causes of liver impairment?

A
  • Alcohol consumption
  • Obesity
  • Viral Infection
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4
Q

What are the 4 stages of liver disease?

A
  • hepatitis
  • fibrosis
  • cirrhosis
  • failure
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5
Q

What are the 5 main symptoms of late stage liver disease?

A
  • Pruritis
  • Jaundice
  • Cognitive effects
  • Increased sensitivity to alcohol and medications
  • Staggering gait
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6
Q

What are the 9 LFTs?

A
  • Alanine aminotransferase (ALT)
  • Aspartate aminotransferase (AST)
  • Alkaline phosphatase (ALP)
  • Albumin and total protein
  • Bilirubin
  • Gamma-glutamyltransferase (GGT)
  • L-lactate dehydrogenase (LD)
  • Prothrombin time (PT)
  • INR
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7
Q

What are the 5 treatments to manage pruritis?

A
  • Treat obstruction (endoscopy)
  • Antihistamines
  • Topical therapies
  • Rifampicin
  • Opioid antagonists
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8
Q

What is Wernicke’s encephalopathy, what are thet three main symptoms and how is it treated?

A

Lack of vitamin B1 (thiamine)
An acute neurological condition
- ophthalmoplegia
- ataxia
- confusion

Treatment - vitamin supplement

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9
Q

What is hepatic encephalopathy and what are the main two treatments?

A

Build up of ammonia bypassing the liver
Ammonia increases the permeability of the blood-brain barrier

Treatment
Lactulose
Rifaximin

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10
Q

What are the three ways you can
manage ascites?

A

Surgery - Paracentesis with albumin cover
Salt restriction
Diuretics:
Spironolactone
+/- Furosemide

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11
Q

How can you manage oesophageal varices?

A
  • Endoscopic band ligation (elastic bands)
  • Terlipressin (for portal hypertension) + antibiotics
  • Non-selective Beta blocker:
    • Propranolol
    • Carvedilol
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12
Q

How can you manage acute alcohol withdrawal syndrome?

A
  • Assess for signs and symptoms of withdrawal using CIWA scale
  • Consider symptom-triggered treatment with benzodiazepine
  • Admit to hospital if at risk of withdrawal seizures or delirium tremens, treated with IV benzodiazapine
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13
Q

What are the 6 key considerations for drugs in liver impairment?

A
  • Reduced hepatic function -> reduced ability to metabolise drugs
  • Reduced plasma proteins -> increased free drug levels of protein bound drugs
  • Reduced first-pass metabolism in cirrhosis, increased bioavailability
  • Avoid hepatotoxic drugs
  • Avoid sedative drugs
  • Be alert for drug side effects – dose reductions may be necessary
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14
Q

What are the 6 phase 1 reactions?

A

Oxidations
Hydrolysis
Hydration
Dethioacetylation
Isomerisation
Reduction

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15
Q

What are CYP450 enzymes?

A

Play important roles in the detoxification of drugs, cellular metabolism, and homeostasis.

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16
Q

What is the mechanism of CYP450 enzymes?

A
  • Enzymes possess a haem group
  • Reaction requires dioxygen, NADPH, and a reductase
  • Enzymes catalyse their reactions by negative catalysis
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17
Q

What are enzymes super families?

A

A super-family is ‘The whole group of enzymes that catalyse the same or a similar type of reaction using a similar mechanism and are related by primary sequence homology or identity’;

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18
Q

What are the 9 types of CYP450 enzyme reactions?

A

Aromatic hydroxylation.
Aliphatic hydroxylation.
Aliphatic dealkylation after hydroxylation.
Oxidative deamination.
Alcohol oxidation.
Epoxidation.
Heteroatom oxidation.
Dehalogenation.
Reduction

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19
Q

What is aromatic hydroxylation?

A

Addition of an OH group to aromatic ring dependent on specific enzyme and drug

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20
Q

What is aliphatic hydroxylation?

A

Addition of an OH group, usually stereospecific when a new chiral centre is formed

Position and chirality of hydroxyl group depends on specific CYP and drug.

21
Q

What is aliphatic dealkylation after hydroxylation?

A

Removal of an alkyl group from an amine
Unstable hydroxylated intermediate (e.g., hemiacetal) formed.
Carbonyl compound eliminated

22
Q

What is oxidative deamination?

A

Amino groups are removed from amino acids, resulting in the formation of corresponding keto acids and ammonia

23
Q

What is alcohol hydroxylation?

A

This is elimination of water from a hydrated aldehyde
This is a major route of ethanol metabolism during chronic use.

24
Q

What is epoxidation?

A

Epoxides are electrophiles that can be hydrolysed to diol by epoxide hydrolase.
Epoxide metabolites are often highly reactive and cause toxicities.

25
Q

What are the 3 intrinsic factors affecting drug metabolism by CYPs?

A
  • Age (neonates/elderly – different expression of CYP enzymes).
  • Hormonal & gender differences.
  • Genetic variability of CYP enzymes (can lead to differences in metabolic rates of up to a factor of 100 and increase or decrease risk of getting particular diseases)
26
Q

How and why do you model CYP enzymes?

A

X-ray crystal structures provide atomic level detail of binding.

Structures can explain functional effects of enzyme polymorphisms, can design drugs to avoid metabolism by specific CYP enzymes.
Later stage drug development usually requires determination of which CYP enzymes metabolise the drug.

27
Q

What are the 5 external factors affecting drug metabolism?

A
  • Diet & nutritional status.
  • Alcohol & smoking
  • Co-administration of drugs
  • Exposure to drugs, solvents, xenobiotics, pollutants
  • Diseases (especially of liver e.g., alcoholism).

Factors divided into short, nedium and long term

28
Q

What are the 7 types of phase 2 metabolism?

A

Glucuronidation (nucleophiles)
Glutathione conjugation (electrophiles)
Sulfation and phosphorylation
Methylation
Amino acid conjugation
Acetylation and acylation
Acyl-CoA formation

29
Q

What is glucoronidation?

A

Glucuronidation is the addition of glucuronic acid (an electrophile) to nucleophiles..

30
Q

What is UDP-GT?

A

Catalyse the addition of glucuronic acid to a wide range of lipophilic chemicals.
UDPGTs found in membrane of ER
UDPGTs are found in many tissues

Low enzyme activity in babies and neonates = extended times to eliminate drugs
Decreased first pass metabolism of drugs in elderly

31
Q

What is entereohepatic circulation?

A

The circulation of biliary acids, bilirubin, drugs or other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transport back to the liver

32
Q

What is gilberts syndrome?

A

UDP-GT deficiency
Liver’s inibility to process bilirubin (excess bilirubin causes jaundice)
Extremely common (4-8% of population) recessive condition

33
Q

What are the consequences of gilberts syndrome?

A

Rises tend to be cyclical – can be promoted by stress, heavy exercise, dehydration etc.
Symptoms are generally mild but can get periodic jaundice. Many patients get mild symptoms so often diagnosed when having liver function tests for other conditions.
Affects metabolism of a few drugs including paracetamol

34
Q

What are the 4 ways that drugs interact with UDP-GT?

A
  • Being metabolised by the same enzyme.
  • Reduced metabolism from depletion of UDP-glucuronic acid by drug
  • Increased metabolism due to enzyme induction
  • More than one glucuronidation site
35
Q

What is the structure of Glutathione?

A

Glutathione is a substance made from the amino acids glycine, cysteine, and glutamic acid.
Glutathione is involved in tissue building and repair, making chemicals and proteins needed in the body, and in immune system function.
It’s capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, peroxides and heavy metals

36
Q

What are glutathione-s-transferases?

A

GST is a multifunctional enzyme, involved in detoxification processes. This role is achieved by catalytic conjugation of glutathione with a large number of electrophilic toxins and carcinogens.
Glutathione is used to detoxify electrophiles

37
Q

How are GST enzymes induced?

A

Found mainly in the cytosol
Encoded by three separate families of genes (designated cytosolic, microsomal and mitochondrial transferases)

38
Q

How do the polymorphisms of GST aid chemo?

A

Cancer chemotherapy often uses cytotoxic drugs as therapeutic agents.
These are often highly electrophilic
Cancer drugs often react with DNA but are also reactive with other nucleophiles.
Metabolism of these drugs is via the GST enzymes.

39
Q

What are Ester Hydrolases?

A

Carboxylic ester hydrolases catalyze the hydrolysis of ester bonds into alcohols and carboxylic acids
Can also be important in phase 1 metabolism to eliminate drug

40
Q

What are sulfotransferases?

A

Sulfation reactions are carried out by sulfotransferases
Performs sulfation of endogenous substrates

SULT 1-4 families

41
Q

What is a sulfation reaction?

A

Occurs in the liver
Sulfotransferases are found in the cytosol.
Requires PAPS as cosubstrate.

The product is a sulfate ester which is negatively charged.

42
Q

Why do sulfation and glucoronidation compete?

A

Most drugs with nucleophilic groups can be glucuronidated and sulfated. These pathways can compete.
Sulfation usually predominates at low drug concentrations and glucuronidation at high drug concentrations.
This is because the amount of PAPS is limiting (UDP-glucuronic acid is plentiful).
Sulfation product from a carboxylate group is likely to be unstable and rapidly hydrolyse (because it is an acid anhydride).
Therefore, glucuronidation will predominate for carboxylate groups.

43
Q

What is phosphorylation?

A

Phosphorylation is uncommon compared to sulfation.
Requires a nucleophilic group to react with (typically an aliphatic alcohol).
Cosubstrate is ATP

Drugs can be monophosphorylated or multiple phosphate groups can be added, e.g., 3-azido-2-deoxythymidine (AZT, anti-HIV drug) is triphosphorylated.
Separate enzymes required to add each phosphate group.

44
Q

What is O-methylation?

A

Oxygen
Reactions catalysed by O-, N- or S-Me transferase enzyme.

O-Methylation of drugs mostly carried out in the cytosol.
Opposite reaction to demethylation by cytochrome P450 enzymes.

45
Q

What is N-methylation?

A

Catalysed by histamine N-methyl transferase and nicotinamide N-methyl transferase
NNMT metabolises most drugs due to lower substrate selectivity. Can produce positively charged quaternary amines, which have increased renal clearance.

46
Q

What is S-methylation?

A

Sulfur

47
Q

What is amino acid conjugation?

A

Converts carboxylate drug to carboxylate
Drug activated with ATP to give AMP mixed anhydride.
Most common amino acid conjugated is glycine.

Conjugate has higher molecular weight and therefore may be excreted in the bile.

48
Q

How is Co-A formed?

A

Derived from glucose, fatty acid, and amino acid catabolism

CoA-SH used to form the acyl-CoA ester.
Acyl-CoA esters are good electrophiles and react with nucleophiles such as alcohols (to form esters)

49
Q

What is acetylation and acylation?

A

Acetylation adds an acetyl to an amino, alcohol or sulfhydral group to make an amide, ester or thioester.
Product will be heavier (potential for increased biliary excretion) and less polar.
Reaction uses an N-acetyl transferase
An endogenous N-acetyl transferase is used to produce mercapturates
Important source of chloramphenicol resistance (used to treat eye infections).

MPharm2 SL22105 (8 decks)

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