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Y2 - PHARM > Drug Metabolism > Flashcards

Drug Metabolism Flashcards

1
Q

What is the basis of drug metabolism - what does it do? (2 things)

A
  1. Reduces or eliminates pharmacological / toxicological activity
  2. Converts lipophilic chemicals to polar derivatives (readily excreted by kidneys)
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2
Q

What is hepatic first pass metabolism?

A

Metabolic conversion of the drug before the drug enters the systemic circulation via the portal or enterohepatic circulation. Drug first passes through the liver before entering systemic circulation

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3
Q

What is the route of blood circulation and thus drug circulation?

A

Enters the liver from the intestines through the portal circulation and then the blood is passed to the systemic circulation via the hepatic vein

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4
Q

Why does first pass metabolism pose a problem for drugs and how can you overcome this problem?

A
  • If a drug undergoes extensive first pass metabolism, only a small amount of active drug will be released into systemic circulation - leading to low biovailability
  • To overcome this, you can administer the drug intravenously
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5
Q

4 stages of drug pharmacokinetics?

A
  1. Administration
  2. Distribution
  3. Metabolism
  4. Excretion
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6
Q

1) What type of reactions occur in phase 1 metabolism reactions?
2) What is the main purpose of phase 1 metabolism reactions?
3) How do phase 1 reactions affect the activity of drugs?

A

1)

  • Oxidation / reduction creates new functional groups
  • Hydrolysis unmasks functional groups

2)

  • The functional groups added or unmasked act as points of attachment for phase 2 metabolism reactions

3)

  • Inactivate drugs
  • Activate drugs (by converting the prodrug into the active drug)
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7
Q

Which enzyme system is very important in phase 1 metabolism reactions?

A

Cytochrome P450 system (CYP450)

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8
Q

Where are CYP450 enzymes predominantly found?

A

In the endoplasmic reticulums of the liver

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9
Q

How many CYP450 isozymes are involved in human drug metabolism?

A

57

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10
Q

What is the overall reaction for CYP450 mediated oxidation in phase 1 metabolism reactions?

A

RH + NADPH + O2 + H+ (+CYP450)⇒ ROH + NADP+ + H2O

CYP450 catalyst

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11
Q

1) What is the structure of CYP450 enzyme sites?
2) Outline the stepwise process of CYP450 mediated oxidation of a drug (RH)

A

1)

  • Porphyrin ring
  • Oxidised ‘ferric’ iron (Fe3+ )

2)

  1. CYP450 binds the drug substrate
  2. NADPH reduces the Fe3+ in CYP450 to the ferrous ion Fe2+
  3. O2 binds and oxidises the Fe2+ to Fe3+, O2 is obviously reduced in this process to O2-
  4. NADPH reduces Fe3+ again to Fe2+
  5. Fe2+ reduces O2- again to form O22- and Fe3+
  6. One of the O atoms is cleaved from O2 is then donated to the drug RH on the CYP450 complex to from ROH
  7. The remaining O2- ion is mopped up by 2H+ ions to form H2O
  8. The ROH is released from this drug-CYP450 complex. So the oxidation of RH to ROH is complete
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12
Q

List 5 types of oxidation reactions

A
  1. Aliphatic / aromatic hydroxylation
  2. N-demethylation
  3. O-demethylation
  4. N-oxidation
  5. Alcohol oxidation
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13
Q

Give an example of aliphatic hydroxylation, what catalyses it and what type of reaction is it?

A
  • Pentobarbitone hydroxylation - inactivates it
  • CYP450 enzyme catalyses the reaction
  • Oxidation - hydroxylation really though
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14
Q

Give an example of aromatic hydroxylation, what catalyses it and what type of reaction is it?

A
  • Acetamilide is hydroxylated to form paracetamol (prodrug → drug conversion)
  • Oxidation - hydroxylation really though
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15
Q

1) What is an N-demethylation reaction and what type of reaction is it?
2) What enzyme catalyses it?
3) Give an example of an N-demethylation reaction?

A

1)

  • Form of oxidation reaction
  • Oxidation of a methyl group on a nitrogen atom to remove the methyl group - often leaving as a formaldehye group

2)

  • CYP450

3)

  • Imipramine (+CYP450) ⇒ Desmipramine + HCHO (formaldehyde)
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16
Q

1) What is an O-demethylation reaction and what type of reaction is it?
2) What enzyme catalyses it?
3) Give an example of an O-demethylation reaction

A

1)

  • Oxidation reaction
  • Oxidation of a methyl group on an O atom to remove the methyl group - often leaving as a formaldehyde group

2)

  • CYP450

3)

  • Codeine (+CYP450) ⇒ Morphine + HCHO (formaldehyde)
17
Q

1) What happens in an N-oxidation reaction and what type of reaction is it?
2) What enzyme catalyses it?
3) Give an example of an N-oxidation reaction

A

1)

  • Form of oxidation reaction
  • The lone pair on an N atom forms a dative bond with an O atom that is donated

2)

  • Flavin-containing monooxygenase

3)

  • Trimethylamine (+Flavin containing monooxygenase) ⇒ Trimethylamine-N-oxide
18
Q

1) What is the presentation of fish odour syndrome?
2) What is the pathophysiology behind fish odour syndrome?

A

1)

  • Sweat and breath stinks of fish

2)

  • Flavin-containing monooxygenase deficiency
  • So no conversion of trimethylamine to trimethylamine-N-oxide by N-oxidation
  • Trimethylamine-N-oxide is odourless whereas trimetylamine has the fish odour and so is sweated and breathed out
19
Q

1) Give an example of an alcohol oxidation reaction and outline the steps. What type of reaction is this?
2) What enzyme catalyses this reaction?
3) What order kinetics does the reaction follow?

A

1)

  • CH3CH2OH (ethanol) (+ADH) ⇔ CH3CHO (acetaldehyde) ⇔ acetic acid
  • Oxidation reaction

2)

  • ADH (alcohol dehydrogenase)

3)

  • 0 order kinetics
20
Q

Where are the following enzymes found cellularly?

1) CYP450
2) Flavin-containing monooxygenase
3) ADH (alcohol dehydrogenase)

A

1)

  • Smooth endoplasmic reticulum

2)

  • Smooth endoplasmic reticulum

3)

  • Soluble so cytoplasmic
21
Q

1) Give an example of a phase 1 reduction reaction
2) What type of enzyme carries out this reduction reaction?
3) Give 2 reasons why reduction mainly occurs in the GI

A

1)

  • Prontosil ⇒ sulphanilamide + another amine

2)

  • Reductases

3)

  1. Low O2 environment
  2. Presence of bacterial reductases
22
Q

1) Give an example of a hydrolytic reaction and then talk through it
2) Give 2 types of enzymes that are involved in hydrolytic reaction

A

1)

  • Procainamide (+an amidase) ⇒ S-aminobenzoic acid + another amine
  • Procainamide is a local anaesthetic and is metabolised around the amine functional group to generate a COOH acid (S-aminobenzoic acid), and an amine

2)

  • Esterases - hydrolysis of an ester
  • Amidases - hydrolysis of an amide
23
Q

Phase 1 reactions introduce functional groups to drugs, list some functional groups that they’d introduce

A

-OH, -NH2, -SH, or -COOH

24
Q

What is one problem with phase 1 metabolism reactions

A

Sometimes produce toxic metabolites

25
Q

What are the general principles behind phase 2 metabolism reactions?

A
  • Conjugates are mostly pharmacologically inactive
  • Less lipid soluble
  • Easier to excrete
26
Q

List the different types of phase 2 metabolism reactions and the conjugating agents for these reactions and the functional groups that they target

A
  1. Glucoronidation - UDPGA - OH, COOH, NH2, SH
  2. Acetylation - Acetyl CoA - OH, NH2, COOH
  3. Amino acid conjugation - Glycine, Glutamine, Taurine - COOH
  4. Methylation - S-adenosyl-methionine - OH, NH2
  5. Sulphation - 3’-phosphoadenosine-5’-phosphosulphate - OH, NH2
  6. Glutathione conjugation - glutathione - electrophiles
27
Q

1) What is a glucoronidation reaction including what type of reaction it is and a general equation (using OH as the targed functional group)?
2) What is the conjugating agent?
3) What is the enzyme?
4) Where is the product of the reaction often found?
5) Give an example reaction

A

1)

  • Phase 2 metabolism reaction
  • ROH + UDPGA ⇒ RO-D-glucoronide

2) UDPGA
3) Glucuronyl transferase
4) Often found in the bile as large molecular weight molecules are excreted in the bile and products of glucuronidation conjugation are often large molecular weight molecules
5) Ibuprofen + UDPGA (+glucuronyl transferase) ⇒ ibuprofen glucuronide conjugate

28
Q

1) What is an acetylation reaction including what type of reaction it is and a general equation (using NH2 as the targed functional group)
2) What is the conjugating agent?
3) What is the enzyme?
4) What often happens with the products of the reaction?
5) Give an example reaction

A

1)

  • Phase 2 conjugation reaction
  • Acetyl group (CH3CO) transferred to an electron rich atom (N, O or S)
  • RNH2 + CH3COSCoA (Acetyl CoA) ⇒ RNHCOCH3 + CoASH

2)

  • Acetyl CoA

3)

  • Acetyl transferase

4)

  • The acetylated derivative of the drug then goes into intermediate metabolism

5)

  • Acetylation of sulphanilamide
29
Q

1) What is a methylation reaction including what type of reaction it is and a general equation using RZH as the drug, Z representing the part of the possible functional groups, and list the atoms that Z could represent?
2) What is the conjugating agent?
3) What is the enzyme?
4) Give an example reaction

A

1)

  • A phase 2 conjugation reaction
  • RZH + S-adenosylmethionine (+methyltransferase )⇒ RZ-CH3 + S-adenosylhomocysteine
  • Z could be N, O, S

2)

  • S-adenosylmethionine

3)

  • Methyltransferase

4)

  • Noradrenaline + S-adenosylmethionine (+methyltransferase) ⇒ Adrenaline + S-adenosylhomocysteine
30
Q

1) What is an sulphation reaction including what type of reaction it is and a general equation using ROH as the drug (assuming OH functional group)?
2) What is the conjugating agent?
3) What is the enzyme?
4) Give an example reaction

A

1)

  • Phase 2 conjugation reaction

2)

  • PAPS

3)

  • Sulfotransferases

4)

  • Paracetamol + PAPs (+sulfotransferase) ⇒ something + PAP
31
Q

5 importances of drug metabolism?

A
  1. Decreases biological half lives of drugs
  2. Decreases duration of exposure
  3. Prevents bioaccumulation
  4. Potency / duration of biological activity of the chemical can be altered
  5. The pharmacology / toxicology of the drug can be governed by its metabolism

Y2 - PHARM (27 decks)

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