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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
Example of a drug that is activated rather than inactivated after phase 2 biotransformation?
Minoxidil
26
Do all drugs undergo biotransformation?
No
27
Examples of drugs that are excreted unchanged (not biotransformed)?
Benzylpenicillin Aminoglycosides Meanwhile formin Tubocurarine Amantadine
28
Examples of drugs that are only partially bio transformed (some excreted unchanged and some as metabolites)?
Paracetamol Salicylates Phenobarbital
29
Examples of drugs that are fully biotransformed (excreted as metabolites)?
TCAs Phenothiazines Chloramphenicol
30
What is oxidation?
Gain of oxygen/ loss of electrons/ loss of hydrogen
31
What is reduction?
Loss of oxygen/ gain of electrons/ gain of hydrogen
32
What is hydrolysis?
Where water is used to break chemical bonds in the other reactant
33
What are microsomes?
fragments of endoplasmic reticulum and attached ribosomes that are isolated together when homogenized cells are centrifuged
34
Types of enzymes that carry out phase 1 oxidation reactions?
Microsomal Non-microsomal
35
Examples of microsomal enzymes?
Cytochrome P-450 (CYP) Microsomal flavine-containing monooxygenase (FMO)
36
Examples of non-microsomal enzymes?
Monoamine-oxidases Molybdenum-containing oxidases (xanthine oxidase and aldehyde oxidase) Alcohol and aldehyde dehydrogenases
37
Main type of enzyme responsible for drug biotransformation?
Cytochrome P450 (CYP)
38
Most common CYPs?
CYP2D6 CYP3A4 CYP2C9
39
Function of CYPS other than xenobiotic transformation?
Biosynthesis or catabolism of endogenous molecules such as steroid hormones, bile acids, fat-soluble vitamins, fatty acids and eicosanoids
40
Where are most CYPs found?
In microsomes in the liver and gut
41
What an enzyme do CYPs work with?
NADPH-cytochrome P450 oxidoreductase (NADPH-CYP)
42
What does NADPH-CYP do?
Transfers electrons to CYPs
43
CYPs contain which molecule that functions to bind and activate 02 radicals?
Iron-Protoporphyrin IX
44
CYPs carry out which oxidative reactions?
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
45
How many families of CYPs?
74
46
How many isoemzymes of CYPs?
Over 400
47
Examples of drugs metabolism by CYP3A4?
Midazolam Amitriptyline Carbamazepine Citalopram Quetiapine Amiodarone Simvastatin Verapamil Clarithromycin Codeine Paracetamol
48
Examples of drugs metabolism by CYP2E1?
Clozapine Venlafaxine Ethanol Isoflurane Ritonavir
49
CYP nomenclature?
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
Examples of drugs metabolised by CYP2C9?
Warfarin Tolbutamide Fluoxetine Losartan Some NSAIDs
51
Examples of drugs metabolised by CYP2D6?
TCAs Beta blockers Sertraline Paroxetine Tamoxifen
52
Where is alcohol dehydrogenase found?
In the cytosol of mainly the liver but also kidneys, lungs and gastric mucosa
53
What does alcohol dehydrogenase do?
Oxidises ethanol to acetaldehyde
54
What is alcohol flush syndrome?
Increased acetaldehyde due to deficiency of ALDH-2 (aldehyde-dehydrogenase) which induces catecholamine release
55
Alcohol flush syndrome is most prevalent in what population?
Asian
56
Is methanol toxic?
No, but its metabolites are
57
What is methanol metabolised to?
Formaldehyde Formate
58
How to treat methanol/ethylene glycol poisoning?
A competitive alcohol dehydrogenase inhibitor such as: Ethanol Fomepizole
59
How is levonorgestrel metabolised?
Undergoes reductive biotransformation by NADPH-cytochrome P450 reductase to its inactive form
60
Drugs containing which functional groups can undergo hydrolysis?
Ester Amide
61
Types of enzymes that carry out hydrolysis?
Peptidases Esterases Alkaline phosphates
62
Enzymes that cause hydrolysis reactions are often found in?
The plasma
63
How does aspirin become active?
It is hydrolysed to salicylic acid by an esterase in the plasma
64
What substitute groups are involved in conjugation?
Glucuronic acid Sulfate group Acetyl group Methyl group Amino acids (glycine and glutamic acid) Glutathione
65
Conjugation is carried out by what type of enzymes?
Transferase enzymes
66
Common enzymes involved in phase 2 metabolism?
UDP glucuronosyl-S-transferase ST sulfotransferase GST glutathione-S-transferase
67
Majority of drugs which undergo phase 2 metabolism undergo which types of reactions?
Glucuronidation Sulfation Glutathione conjugation
68
What is glucuronide derived from?
Glucose
69
During glucuronidation what is transferred to the substrate?
Glucuronic acid
70
Glucuronidation is catalysed by?
UDP-glucuronosyl transferase
71
Examples of drugs that are substrates for glucuronide?
Paracetamol Aspirin Morphine
72
Examples of endogenous substances that are substrates for glucuronide?
Bilirubin Adrenal corticosteroids
73
What does UDP stand for in UDP-glucuronic acid?
Uridine diphosphate
74
Where do glucuronide conjugation reactions take place?
In the lumen of the endoplasmic reticulum
75
Glucuronide conjugates commonly undergo what kind of excretion?
Biliary
76
Opioid metabolism?
77
Opioids act on which receptor?
Mu-opioid receptor
78
What is the active drug in opioids?
Morphine
79
Where are opioids mainly metabolised?
In the liver
80
Why is morphine more effective when administered IV?
No first pass metabolism
81
Which enzyme is responsible for the glucuronide conjugation reaction with morphine?
UDP-glucuronosyl transferase 2B7
82
Metabolites of morphine?
90% morphine-3-glucuronide 10% morphine-6 glucuronide
83
Which metabolite of morphine is active?
Morphine-6-glucuronide
84
Which metabolite of morphine is inactive?
Morphine-3-glucuronide
85
Does morphine undergo enterohepatic circulation?
Yes
86
How long does morphine undergo enterohepatic circulation?
~24 hours
87
The majority of metabolites of morphine are excreted in what timeframe?
~72 hours
88
Morphine undergoes what kind of conjugation reaction?
Glucuronidation
89
Paracetamol undergoes what type of conjugation reactions?
Glucuronidation Sulfation Glutathione
90
What percentage of paracetamol undergoes glucuronidation?
55%
91
What percentage of paracetamol undergoes sulfation?
35%
92
How are the products of paracetamol glucuronidation and sulfation excreted?
In the urine
93
What enzyme is responsible for sulfation in paracetamol?
Sulfotransferases SULTs
94
What is the most common sulfo group donor in sulfotransferases?
3’-phosphoadenosine-5’-phosphosulfate (PAPS)
95
When an alcohol is the acceptor of a sulfo group what is the product?
A sulfate
96
When an amine is the acceptor of a sulfo group what is the product?
A sulfamate
97
What happens during glutathione conjugation?
The reduced form of glutathione (GSH) is transferred to the substrate
98
Glutathione mainly conjugates to what kind of substrates and why?
Electrophilic substrates because glutathione has a strong nucleophilic character
99
Why does glutathione have a strong nucleophilic character?
The presence of a thiol (-SH) group
100
Glutathione make up what percentage of total proteins in the liver?
10%
101
How are glutathione conjugates excreted and why?
Via the bile due to its size, it can be further metabolised and excreted via the urine
102
Glutathione is made up of which amino acids?
Glutamic acid Cysteine Glycine
103
How is glutathione conjugation involved in paracetamol metabolism?
It conjugates NAPQI which is a toxic metabolite of paracetamol
104
Which paracetamol metabolite is toxic?
NAPQI
105
What does NAPQI stand for?
N-acetyl-p-benzoquinone imine
106
What percentage of paracetamol is metabolised to NAPQI?
5%
107
What type of conjugation reaction does NAPQI undergo?
Glutathione conjugation
108
Which CYPs are responsible for converting paracetamol to NAPQI?
CYP2E1 CYP3A4
109
What causes liver damage in paracetamol overdose?
Sulfate and glucuronide pathways become saturated to CYPs convert more paracetamol to NAPQI which depleted the livers glutathione and directly damages liver cells
110
How does NAPQI cause liver necrosis?
Binds covalently to thiol groups in proteins, inactivating them
111
Why are alcoholics hypersensitive to paracetamol-induced liver damage?
1) have increased levels of CYP2E1 leading to increased NAPQI 2) have reduced levels of glutathione
112
What is the treatment for paracetamol overdose?
N-acetylcysteine
113
N-acetylcysteine mechanism of action in paracetamol?
Processes to L-cystine which is used in the synthesis of glutathione
114
Example of a drug that is activated by sulfation?
Minoxidil

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