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202 > Pharmacolgy > Flashcards

Pharmacolgy Flashcards

1
Q

What are xenobiotics?

A

A substance that is foreign to the body. Including drugs, poisons, chemicals and pollutants

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2
Q

Drugs elimination can be through?

A

Excretion
Biotransformation

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3
Q

What is biotransformation?

A

Drug metabolised is transformed to a less toxic/benign molecule

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4
Q

What is excretion?

A

Removal of the drug or its metabolites from the body

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5
Q

How can excretion occur?

A

Via kidneys
Hepatobiliary system
Via lungs
Via milk and sweat

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6
Q

Most common type of excretion?

A

Via kidneys

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7
Q

Excretion in the hepatobiliary system?

A

Active secretion of drugs molecules or their metabolites from hepatocytes into the bile, they may be reabsorbed in the intestines and the cycle repeats

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8
Q

What is enterohepatic cycling?

A

Where drugs that have been excreted into the bile are reabsorbed into the intestines

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9
Q

Examples of a drug that undergoes enterohepatic cycling?

A

Morphine

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10
Q

Drugs that are likely to be excreted by the hepatobiliary system?

A

High protein bound (lipophilic)
>500kDa

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11
Q

Example of a drug that is excreted via the lungs?

A

Volatile gaseous anaesthetics

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12
Q

Are lipophilic or hydrophilic drugs excreted via the kidneys?

A

Hydrophilic (water soluble)

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13
Q

Where does biotransformation occur?

A

Mainly liver and intestines but can occur in the plasma of any body cell

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14
Q

Why does biotransformation mainly occur in the liver/small intestine?

A

They have the highest concentrations of xenobiotic transforming enzymes

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15
Q

Four potential biotransformations?

A

Active drug to inactive metabolite
Active drug to active metabolite
Prodrug to active drug
Active drug to toxic metabolite

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16
Q

Phase 1 biotransformation reactions mainly increase…..

A

Reactivity

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17
Q

Phase 2 biotransformation reactions mainly increase…..

A

Solubility

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18
Q

What happens in phase 1 biotransformation reactions?

A

Addition of low molecular weight function groups (polar) to increase reactivity. Usually producing a nucleophile

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19
Q

What happens in phase 2 biotransformation reactions?

A

Conjugation with a higher molecular weight water soluble group, to increase solubility

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20
Q

What is functionalisation?

A

Introducing a polar function group during phase 1 biotransformation

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21
Q

Common function groups added during functionalisation?

A

Hydroxyl OH
Amino NH2
Sulfhydryl SH
Carboxyl COOH

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22
Q

Common types of reactions involved in type 1 biotransformation?

A

Oxidation
Hydrolysis
Reduction

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23
Q

Are phase 2 transformation reactions always necessary?

A

No- if the drug is sufficiently polar after phase 1 then it may be excreted

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24
Q

Phase 2 reactions generally results in?

A

An inactive product

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25
Q

Example of a drug that is activated rather than inactivated after phase 2 biotransformation?

A

Minoxidil

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26
Q

Do all drugs undergo biotransformation?

A

No

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27
Q

Examples of drugs that are excreted unchanged (not biotransformed)?

A

Benzylpenicillin
Aminoglycosides
Meanwhile formin
Tubocurarine
Amantadine

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28
Q

Examples of drugs that are only partially bio transformed (some excreted unchanged and some as metabolites)?

A

Paracetamol
Salicylates
Phenobarbital

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29
Q

Examples of drugs that are fully biotransformed (excreted as metabolites)?

A

TCAs
Phenothiazines
Chloramphenicol

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30
Q

What is oxidation?

A

Gain of oxygen/ loss of electrons/ loss of hydrogen

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31
Q

What is reduction?

A

Loss of oxygen/ gain of electrons/ gain of hydrogen

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32
Q

What is hydrolysis?

A

Where water is used to break chemical bonds in the other reactant

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33
Q

What are microsomes?

A

fragments of endoplasmic reticulum and attached ribosomes that are isolated together when homogenized cells are centrifuged

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34
Q

Types of enzymes that carry out phase 1 oxidation reactions?

A

Microsomal
Non-microsomal

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35
Q

Examples of microsomal enzymes?

A

Cytochrome P-450 (CYP)
Microsomal flavine-containing monooxygenase (FMO)

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36
Q

Examples of non-microsomal enzymes?

A

Monoamine-oxidases
Molybdenum-containing oxidases (xanthine oxidase and aldehyde oxidase)
Alcohol and aldehyde dehydrogenases

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37
Q

Main type of enzyme responsible for drug biotransformation?

A

Cytochrome P450 (CYP)

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38
Q

Most common CYPs?

A

CYP2D6
CYP3A4
CYP2C9

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39
Q

Function of CYPS other than xenobiotic transformation?

A

Biosynthesis or catabolism of endogenous molecules such as steroid hormones, bile acids, fat-soluble vitamins, fatty acids and eicosanoids

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40
Q

Where are most CYPs found?

A

In microsomes in the liver and gut

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41
Q

What an enzyme do CYPs work with?

A

NADPH-cytochrome P450 oxidoreductase (NADPH-CYP)

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42
Q

What does NADPH-CYP do?

A

Transfers electrons to CYPs

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43
Q

CYPs contain which molecule that functions to bind and activate 02 radicals?

A

Iron-Protoporphyrin IX

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44
Q

CYPs carry out which oxidative reactions?

A

1) hydroxylation of an aliphatic or aromatic carbon
2) epoxidation of a double bond
3) heteroatom (S, I, N) oxygenation and N-hydroxylation
4) heteroatom (O, N, Si, S) de-alkylation
5) oxidative group transfer
6) cleavage of esters
7) dehydrogenation

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45
Q

How many families of CYPs?

A

74

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46
Q

How many isoemzymes of CYPs?

A

Over 400

47
Q

Examples of drugs metabolism by CYP3A4?

A

Midazolam
Amitriptyline
Carbamazepine
Citalopram
Quetiapine
Amiodarone
Simvastatin
Verapamil
Clarithromycin
Codeine
Paracetamol

48
Q

Examples of drugs metabolism by CYP2E1?

A

Clozapine
Venlafaxine
Ethanol
Isoflurane
Ritonavir

49
Q

CYP nomenclature?

A

Based on shared homology of amino acid sequence
CYP3A4*1 example:
CYP= cytochrome P450
3= family name (>40% amino acid homology with other members)
A= subfamily (>55% amino acid homology with other members)
4= isoform
1= allele

50
Q

Examples of drugs metabolised by CYP2C9?

A

Warfarin
Tolbutamide
Fluoxetine
Losartan
Some NSAIDs

51
Q

Examples of drugs metabolised by CYP2D6?

A

TCAs
Beta blockers
Sertraline
Paroxetine
Tamoxifen

52
Q

Where is alcohol dehydrogenase found?

A

In the cytosol of mainly the liver but also kidneys, lungs and gastric mucosa

53
Q

What does alcohol dehydrogenase do?

A

Oxidises ethanol to acetaldehyde

54
Q

What is alcohol flush syndrome?

A

Increased acetaldehyde due to deficiency of ALDH-2 (aldehyde-dehydrogenase) which induces catecholamine release

55
Q

Alcohol flush syndrome is most prevalent in what population?

A

Asian

56
Q

Is methanol toxic?

A

No, but its metabolites are

57
Q

What is methanol metabolised to?

A

Formaldehyde
Formate

58
Q

How to treat methanol/ethylene glycol poisoning?

A

A competitive alcohol dehydrogenase inhibitor such as:
Ethanol
Fomepizole

59
Q

How is levonorgestrel metabolised?

A

Undergoes reductive biotransformation by NADPH-cytochrome P450 reductase to its inactive form

60
Q

Drugs containing which functional groups can undergo hydrolysis?

A

Ester
Amide

61
Q

Types of enzymes that carry out hydrolysis?

A

Peptidases
Esterases
Alkaline phosphates

62
Q

Enzymes that cause hydrolysis reactions are often found in?

A

The plasma

63
Q

How does aspirin become active?

A

It is hydrolysed to salicylic acid by an esterase in the plasma

64
Q

What substitute groups are involved in conjugation?

A

Glucuronic acid
Sulfate group
Acetyl group
Methyl group
Amino acids (glycine and glutamic acid)
Glutathione

65
Q

Conjugation is carried out by what type of enzymes?

A

Transferase enzymes

66
Q

Common enzymes involved in phase 2 metabolism?

A

UDP glucuronosyl-S-transferase
ST sulfotransferase
GST glutathione-S-transferase

67
Q

Majority of drugs which undergo phase 2 metabolism undergo which types of reactions?

A

Glucuronidation
Sulfation
Glutathione conjugation

68
Q

What is glucuronide derived from?

A

Glucose

69
Q

During glucuronidation what is transferred to the substrate?

A

Glucuronic acid

70
Q

Glucuronidation is catalysed by?

A

UDP-glucuronosyl transferase

71
Q

Examples of drugs that are substrates for glucuronide?

A

Paracetamol
Aspirin
Morphine

72
Q

Examples of endogenous substances that are substrates for glucuronide?

A

Bilirubin
Adrenal corticosteroids

73
Q

What does UDP stand for in UDP-glucuronic acid?

A

Uridine diphosphate

74
Q

Where do glucuronide conjugation reactions take place?

A

In the lumen of the endoplasmic reticulum

75
Q

Glucuronide conjugates commonly undergo what kind of excretion?

A

Biliary

76
Q

Opioid metabolism?

A
77
Q

Opioids act on which receptor?

A

Mu-opioid receptor

78
Q

What is the active drug in opioids?

A

Morphine

79
Q

Where are opioids mainly metabolised?

A

In the liver

80
Q

Why is morphine more effective when administered IV?

A

No first pass metabolism

81
Q

Which enzyme is responsible for the glucuronide conjugation reaction with morphine?

A

UDP-glucuronosyl transferase 2B7

82
Q

Metabolites of morphine?

A

90% morphine-3-glucuronide
10% morphine-6 glucuronide

83
Q

Which metabolite of morphine is active?

A

Morphine-6-glucuronide

84
Q

Which metabolite of morphine is inactive?

A

Morphine-3-glucuronide

85
Q

Does morphine undergo enterohepatic circulation?

A

Yes

86
Q

How long does morphine undergo enterohepatic circulation?

A

~24 hours

87
Q

The majority of metabolites of morphine are excreted in what timeframe?

A

~72 hours

88
Q

Morphine undergoes what kind of conjugation reaction?

A

Glucuronidation

89
Q

Paracetamol undergoes what type of conjugation reactions?

A

Glucuronidation
Sulfation
Glutathione

90
Q

What percentage of paracetamol undergoes glucuronidation?

A

55%

91
Q

What percentage of paracetamol undergoes sulfation?

A

35%

92
Q

How are the products of paracetamol glucuronidation and sulfation excreted?

A

In the urine

93
Q

What enzyme is responsible for sulfation in paracetamol?

A

Sulfotransferases SULTs

94
Q

What is the most common sulfo group donor in sulfotransferases?

A

3’-phosphoadenosine-5’-phosphosulfate (PAPS)

95
Q

When an alcohol is the acceptor of a sulfo group what is the product?

A

A sulfate

96
Q

When an amine is the acceptor of a sulfo group what is the product?

A

A sulfamate

97
Q

What happens during glutathione conjugation?

A

The reduced form of glutathione (GSH) is transferred to the substrate

98
Q

Glutathione mainly conjugates to what kind of substrates and why?

A

Electrophilic substrates because glutathione has a strong nucleophilic character

99
Q

Why does glutathione have a strong nucleophilic character?

A

The presence of a thiol (-SH) group

100
Q

Glutathione make up what percentage of total proteins in the liver?

A

10%

101
Q

How are glutathione conjugates excreted and why?

A

Via the bile due to its size, it can be further metabolised and excreted via the urine

102
Q

Glutathione is made up of which amino acids?

A

Glutamic acid
Cysteine
Glycine

103
Q

How is glutathione conjugation involved in paracetamol metabolism?

A

It conjugates NAPQI which is a toxic metabolite of paracetamol

104
Q

Which paracetamol metabolite is toxic?

A

NAPQI

105
Q

What does NAPQI stand for?

A

N-acetyl-p-benzoquinone imine

106
Q

What percentage of paracetamol is metabolised to NAPQI?

A

5%

107
Q

What type of conjugation reaction does NAPQI undergo?

A

Glutathione conjugation

108
Q

Which CYPs are responsible for converting paracetamol to NAPQI?

A

CYP2E1
CYP3A4

109
Q

What causes liver damage in paracetamol overdose?

A

Sulfate and glucuronide pathways become saturated to CYPs convert more paracetamol to NAPQI which depleted the livers glutathione and directly damages liver cells

110
Q

How does NAPQI cause liver necrosis?

A

Binds covalently to thiol groups in proteins, inactivating them

111
Q

Why are alcoholics hypersensitive to paracetamol-induced liver damage?

A

1) have increased levels of CYP2E1 leading to increased NAPQI
2) have reduced levels of glutathione

112
Q

What is the treatment for paracetamol overdose?

A

N-acetylcysteine

113
Q

N-acetylcysteine mechanism of action in paracetamol?

A

Processes to L-cystine which is used in the synthesis of glutathione

114
Q

Example of a drug that is activated by sulfation?

A

Minoxidil

202 (6 decks)

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