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Gastrointestinal Biology > GB 17. Liver - Detoxification and Excretion > Flashcards

GB 17. Liver - Detoxification and Excretion Flashcards

1
Q

What is Pharmacokinetics?

A

it is the movement of drugs into, around and out of the body

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2
Q

What are the 4 aspects of pharmacokinetics?

A

[1] Absorption
[2] Distribution
[3] Metabolism
[4] Excretion

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3
Q

What is drug metabolism?

A

metabolism is the process whereby drugs in the body undergo transformations catalysed by enzymes
- the products of these transformations are called metabolites

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4
Q

What are metabolites?

A

they are products of metabolism transformations (that are catalysed by enzymes)

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5
Q

Why is drug metabolism important in to help with renal excretion?

A

generally in drug metabolism:

lipophilic drugs (hydrophobic cannot be excreted) 
are converted to 
hydrophilic metabolites (lipophobic and are excretable)
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6
Q

What are some of the outcomes of drug metabolism?

A

[1] drug can be converted to a form which is excretable

[2] drug action can be terminated

[3] drug can be converted to a metabolite which has pharmacological activity of its own

[4] an inactive compound called PRO-DRUG can be converted to an active metabolite

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7
Q

Where does drug metabolism occur?

A
  • liver is the principal organ of drug metabolism

- liver cells contain efficient enzymes for metabolism of foreign materials

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8
Q

In most cases, the liver produces a material that is…

A
  • water soluble

- easier to excrete

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9
Q

What is the First Pass Effect?

A
  • there is a problem when orally administered drugs are rendered inactive the first time they pass through the liver
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10
Q

What are the steps involved in the First Pass Effect?

A

[1] drug is taken orally

[2] drug enters the GI tract

[3] active drug is absorbed from stomach and small intestines

[4] high blood concentration of drug is in hepatic portal vein

[5] low blood plasma levels of drug after passing through the liver due to metabolism
- drug is over metabolized in liver (?)

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11
Q

What are Phase 1 reactions? (general overview)

A
  • transformation of drug into a more Polar Metabolite by introducing a functional group
    (e. g. via oxidation, reduction or hydrolysis)
  • main function of phase I metabolism is to prepare drugs for phase II metabolism
  • oxidation reactions are often catalyzed by a member of the cytochrome P450 family
  • these enzymes are mostly located in the ER of the hepatocytes
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12
Q

What are Phase 2 reactions? (general overview)

A
  • gets rid of the drug
    • a hydrophilic groups is conjugated with a functional group giving a water soluble product (excreted in bile or urine)
  • involves the combination of glucoronic acid, sulfate, acetic acid or amino acid with a functional group (which may or may not result from phase I) to form a polar conjugate that can be readily excreted
  • enzymes catalyzing these reactions are mostly located in the cytosol of the hepatocytes
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13
Q

What are the phase I reactions? [4]

A

[1] oxidation
[2] dealkylation
[3] reduction
[4] hydrolysis

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14
Q

What are some of the functional groups that are added to the drug? [3]

A

[1] Hydroxyl (OH)
[2] Amino (NH2)
[3] Carboxylic Acid (COOH)

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15
Q

Many of the oxidation reactions in phase 1 metabolism are catalyzed by?

A

they are catalyzed by:

  • Mixed Function Oxidase (MFO) system
  • — Cytochrome P450
  • — NADPH
  • — molecular O2
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16
Q

What is the main goal of the phase I Oxidation/Hydroxylation reaction?

A

adding an OH group

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17
Q

What are the 3 types of phase I oxidation reactions?

A 
[1] Hydroxylation
- adding of OH
[2] Dehydrogenation 
- removal of hydrogen (normally 2 hydrogens)
[3] Dealkylation 
- removing an alkyl group
18
Q

What is an example of a phase I oxidation/hydroxylation reaction?

A
  • oxidation of Lidocaine/Lignocaine
  • it is originally lipophilic/very hydrophobic [as it is a benzene ring with methyl groups]
  • an OH group is added
  • the reaction is catalyzed by MFO system (with P450, NADPH and O2)
19
Q

What is lidocaine/lignocaine?

A
  • it is a local anesthetic

- the metabolism of which involves hydroxylation as a first step

20
Q

What is an example of a phase I oxidation/dehydrogenation reaction?

A
  • metabolism of ethanol (mainly occurs in liver)
  • it is a 2-stage reaction

[1] ethanol converted to ethanal (acetaldehyde) by alcohol dehydrogenase (ADH) in ENDOPLASMIC RETICULUM

[2] ethanal converted to acetate by aldehyde dehydrogenase (ALDH) in the MITOCHONDRIA

  • NADH is used in both reactions
21
Q

What is a treatment for alcohol abuse? How does it normally work?

A

Disulpharim
- highly lipid soluble (accumulates in adipose tissue) and has 80% bioavailability after an oral dose

  • usually alcohol is metabolized in the liver to acetaldehyde by alcohol dehydrogenase (ADH) which is then oxidized to acetate by aldehyde dehydrogenase (ALDH)
  • disulphiram irreversibly inhibits the oxidation of acetaldehyde by competing with cofactor NAD for binding sites on ALDH
  • disulphiram causes a 5 to 10x increase in the concentration of acetaldehye which produces unpleasant (hang-over like) side effects
22
Q

What is an example of a phase I oxidation/dealkylation reaction?

A
  • dealkylation of codeine converting it to morphine + methanal
  • the reaction is an oxidative dealkylation because the alkyl group of codeine is oxidized to an aldehyde
23
Q

What are the main Phase I reactions?

A

[1] Oxidation

(a) hydroxylation
(b) dehydrogenation
(c) dealkylation

[2] Reduction
- involves the addition of 2 hydrogens to the molecule

[3] Hydrolysis
- involves the addition of water (H2O) to the molecule resulting in breaking it into 2 parts

24
Q

What is an example of a phase I reduction reaction?

A

Cholaramphenicol is reduced

  • 2 hydrogens are added to it
  • changes from NO2 to NH2
  • the enzymes are nitroreductases
25
Q

What is an example of a phase I hydrolysis reaction?

A
  • usually esters undergo hydrolysis reactions via esterase enzymes
  • the OR group on the esters get switched out to something else
26
Q

What is the most common phase I reaction?

A

hydrolysis reactions

27
Q

What are the main conjugation reactions in phase II metabolism?

A

[1] Glucoronic Acid Conjugation (on -OH, -COOH, -NH2, -SH groups)

[2] Sulfate Conjugation (on -NH2, -OH groups)

[3] Glycine Conjugation (on -COOH groups)

[4] Glutathione Conjugation (onto epoxides, organic halides or electrophilic compounds)

28
Q

What is the most common phase II metabolism conjugation reaction?

A

Glucoronic Acid Conjugation (on -OH, -COOH, -NH2, -SH groups)

29
Q

What are the steps involved in a phase II reaction of conjugation with glucoronic acid?

A
  • conjugation with glucoronic acid (glucoronidation)
  • it gives a glucoronide

common for drugs with:
- OH, - COOH and -NH2 groups

  • glucoronic acid is transferred to the drug from Uridine Diphosphate Glucoronic Acid (UDP-GA) in the presence of Glucoronyl Transferase
30
Q

What are the steps involved in a phase II reaction of conjugation with Sulfate (sulfation)?

A
  • is common for phenols (aromatic alcohol)
  • sulfate is transferred to the drug from the reactive intermediate 3-Phosphoadenosine-5’-Phosphosulfate (PAPS) in the presence of Sulfotransferase
31
Q

What is the substrate that both glucoronide formation and sulfation often compete for?

A

paracetamol

32
Q

What are the steps involved in a phase II reaction of conjugation with glycine?

A
  • the reaction is catalyzed by the glycine transferase enzyme
33
Q

Explain the metabolism of aspirin. Explain the steps involved and so on.

A

[1] aspirin undergoes a phase I hydrolysis reaction and is converted into salicylate + acetate

[2] there are then 3 different metabolic pathways (phase II reactions) that it may undergo depending on levels

[3] at LOW DOSES:
- there is a phase II metabolism, glycine conjugation reaction
(glucoronic conjugation)

[4] at HIGHER DOSES:

  • it is a phase II metabolism, it becomes saturated and glucoronide conjugation occurs
  • this converts salicylate to glucoronide conjugates
  • glucoronide conjguates is excreted

[5] at TOP DOSES:
- the salicylate undergoes direct urinary excretion after saturation of conjugation pathways

34
Q

Explain the structure of paracetamol and its general traits.

A
  • it is a phenol (phenolic drugs usually undergo glucorodination or sulfation)
  • paracetamol has analgesic and anti-pyretic effects but WEAK anti-inflammatory activity
  • there are several possible mechanisms of action
35
Q

Explain the metabolism of paracetamol. Explain the steps involved and so on.

A
  • it has no phase I metabolism stages

there are 2 possible phase II metabolic pathways…

[1] Sulfation

  • paracetamol is converted to another structure via the sulfotransferase (PAPS) enzyme
  • this structure is then excreted

[2] Glucorodination

  • paracetamol is converted to another structure via the UDP-Glucoronyl Transferase enzyme (UDP-GA)
  • this structure is then excreted
36
Q

What is the other minor phase I metabolic pathway of paracetamol?

A

[1] paracetamol converted to N-Acetyl-p-benzoquinone imine, NAPQI (electrophilic species) through the P450 system (oxidation)
- this is a phase I metabolism

(NAPQI is toxic to the liver but at low doses this is not a problem as it conjugates with glutathione (GSH) and is excreted.

There is then 2 possible pathways:
LOW DOSES:
[a] NAPQI is converted to a structure through the glutathione transferase enzyme (GSH)
- this is a phase II reaction

HIGH DOSES:
[b] NAPQI is converted in the liver as the protein adducts

[3] this structure is then excreted

37
Q

What is the paracetamol toxicity antidote?

A

N-Acetylcysteine

- is an antidote to paracetamol poisoning

38
Q

What is a pro-drug?

A

it is a pharmacologically inert precursor to an active drug

IUPAC definition:

  • a prodrug is any compound that undergoes bio-transformation before exhibiting its pharmacological effects
  • prodrugs can thus be viewed as drugs containing specialized protective groups used in a transient manner to alter or to eliminate undersirale properties in the parent molecule

prodrug –> active drug
- through enzymatic conversion

39
Q

Explain how the pro-drug, sulfasalazine works to help Ulcerative Colitis

A
  • the active component is 5-aminosalicylic acid (5-ASA)
  • but 5-ASA cannnot be administered directly because they cannot reach the colon due to absorption before reaching the colon
  • the 5-ASA is linked with sulfapyridine by an azo linkage
  • the azo linkage is broken down by the azoreductases in the colon
40
Q

Explain how the pro-drug diamorphine is used to deliver morphine across the BBB

A
  • diamorphine delivers morphine across the BBB
  • -OH groups of morphine are acetylated in diamorphine (they are more lipophilic than morphine and cross the BBB more easily)
  • the acetyl groups are removed from diamorphine (it is an ester hydrolysis reaction by esterase)
    • this forms morphine
41
Q

Explain what the prodrug, Enalapril does.

A
  • enalapril is a prodrug for enalaprilat
  • enalapril is poorly absorbed because of its polarity
  • you put it through a reaction with esterases to convert it to enalaprilat
  • enalaprilat is an ethyl ester and is less polar + better absorbed
  • – ACE inhibitor (angiotensin-converting enzyme inhibitor)
  • – used for treatment of hypertension
42
Q

Explain what the pro-drug, Haloperidol Decanoate does

A
  • haloperidol decanoate is an ester pro-drug
  • haloperidol decanoate is converted to haloperidol through esterase enzymes
  • it is injected intramuscularly
  • it has a slow conversion
  • it results in antipsychotic activity (mainly treats schizophrenia and tourette’s disorder)
  • haloperidol is a potent orally active CNS depressant, sedative + tranquilizer

Gastrointestinal Biology (15 decks)

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