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Pharmacology > PK: Drug Metabolism > Flashcards

PK: Drug Metabolism Flashcards

1
Q

Main routes of loss of drug from the body

Processes by which there is loss of drugs from the body

A

Kidneys

Hepatobiliary system

Lungs

// Metabolism and excretion

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2
Q

What are xenobiotics

What are these compounds susceptible to

A

Foreign chemicals - most drugs are xenobiotics

Susceptible to transformation by mechanisms evolved to modify these compounds

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3
Q

Drug metabolism/biotransformation

A

Collective term for these enzymatic alterations

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4
Q

What happens to lipophilic drugs in the body

A

Not excreted

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5
Q

What happens to hydrophilic metabolites in the body

A

They are excretable

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6
Q

What does water solubility result in @ the kidneys

A

Increased renal excretion

Decreased tubular absorption

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7
Q

Name the 4 important ways metabolism alters a drug

A
  1. Convert an active drug into an inactive drug
  2. Convert an inactive prodrug to an active drug
  3. Convert an active drug to an active or toxic metabolite
  4. Convert an unexcretable drug to an excretable metabolite
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8
Q

Overview of the main routes of drug administration and elimination

A
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9
Q

Name the principal organ of drug metabolism

Hence what effect is it responsible for

A

Liver

First Pass Effect

(Skin, lungs, GIT and kidneys also contribute to drug metabolism)

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10
Q

What enters and exits the liver

What important organelle is found in the liver

What enzymes are found in the liver

A
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11
Q

Phase I metabolism

A

Main function is to prepare drugs for phase II metabolism

Functional groups e.g. -OH, -NH2, -COOH introduced into drug molecule

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12
Q

Phase II metabolism

A

Groups in a drug molecule (which may or may not result from phase I) are CONJUGATED with HYDROPHILIC groups

This increases water solubility and ease of excretion

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13
Q

What do phase I reactions include

A

FUNCTIONALISATION RXNS

  • Oxidation - metabolism of approx 75% of all drugs - catalysed by the mixed function oxidase (MFO) system - cytochrome P450 // NADPH // molecular O2
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14
Q

Most common Oxidation/reduction system of phase I drug metabolism

A

P450 enzyme system of the liver is the most common

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15
Q

CYP1 family

A

Primarily metabolise carcinogens, some drugs as well

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16
Q

CYP2 family

A

Metabolise many important drugs

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17
Q

CYP3 family

A

Most abundant family in human liver (60% of drugs)

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18
Q

Describe the substrate specificity of oxidases

How are these enzymes named

A

Most oxidases exhibit broad substrate specificity many of the P450 enzymes have overlapping specificities

P450 followed by number of P450 enzyme family, captial letter of the subfamily and an additional number to identify the specific enzyme e.g. P450 3A4

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19
Q

Define hydroxylation

What sort of metabolism is it

Give an example of a drug metabolised in this way

A

Addition of an -OH grp

A type of phase I oxidation rxn

LIDOCAINE (a local anaesthetic) - hydroxylation is the first step in its metabolism

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20
Q

Give an example of dehydrogenation (phase I rxn)

A
21
Q

Where is the majority of ethanol metabolised

Where is a minority metabolised

What is the next step in ethanol’s metabolism

A
  • Most ethanol is metabolised by the liver
  • The kidneys and bone marrow oxidise ethanol to a small extent
  • The next step is to further oxidise the acetaldehyde to acetate (CH3COO-)
22
Q

What happens in the metabolism of acetaldehyde (met. of alcohol)

A

Oxidation of the acetaldehyde occurs enxymatically in the mitochondria

Relies on the enzyme Aldehyde Dehydrogenase (ALDH)

Acetate is then released to the blood for subsequent oxidation to CO2 by other tissues

23
Q

What is disulfiram used for

Where does it accumulate

What is its bioavailability

A

Used in the management of alcoholism, it helps to maintain abstinence

Highly lipid soluble - accumulates in adipose tissue

80% bioavailability after an oral dose

24
Q

Pathophysiology of disulfiram

A

Alcohol mainly metabolised in the liver to acetaldehyde by ADH which is then oxidised to acetate by aldehyde dehydrogenase (ALDH)

25
Q

MOA of disulfiram

A

Irreversibly inhibits the oxidation of acetaldehyde by competing with the cofactor nicotinamide adenine dinucleotide (NAD) for binding sites on ALDH

Disulfiram causes a 5-10x increase in the conc of acetaldehyde which produces unpleasant side effects

26
Q

Overview of phase I rxns

A
27
Q

Phase 2 rxns include…

A

Conjugations with glucuronide, sulphate

Hydrolysis often included here

28
Q

What happens in phase II metabolism

What is needed for these rxns to take place

Name the main rxns

A
  • A hydrophilic group is conjugated with a grp already in the molecule (may or may not result from phase I metabolism) giving a water-soluble product which is excreted in bile or urine
  • These conjugation rxns are catalysed by transferase enzymes and various coenzymes are also needed
  • MAIN RXNS:
    • Glutathione conj.
    • Glucuronic acid conj.
    • Sulfate conj.
    • Glycine conj.
29
Q

What sort of rxns are phase II rxns

What are the substrates for these rxns

What is formed

What typically happens to drugs

A
  • biosynthetic
  • Substrates include both metabolites of phase I rxns and compounds that already contain chemical grps appropriate for conjugation e.g. hydroxyl, amine or carboxyl moieties
  • Formation of covalent link between functional grp and endogenously derived conjugating molecule
  • Typically drugs are made more polar and pharmalogically inactive EXCEPT morphine glucuronide
30
Q

In phase II rxns, drugs are made more polar and pharmacologically inactive, TYPICALLY. What is the exception

A

Morphine glucuronide

31
Q

Define glucuronidation

Give examples of drugs metabolised in this way

A
  • UDP-glucuronyl transferase catalyses the transfer of glucuronic acid from UDPGA to a substrate resulting in a glucuronidated substrate and leaving uridine 5’-diphosphate
  • Acetaminophen (paracetamol)
  • Morphine
  • Oxazepam
32
Q

Define prodrugs

A

Inactive compounds that are metabolised into their active, therapeutic forms

33
Q

Metabolite of tamoxifen

How does it differ from its parent

A

4-hydroxytamoxifen

30-100 x more active than its parent

34
Q

Metabolite of codeine (3-methoxymorphine)

What enzyme carries out this rxn

What happens if this enzyme is not present

What is codeine often combined with

A
  • Morphine
  • CYP2D6 - demethylation - 20% analgesic potency of morphine
  • About 10% of population is resistant to the analgesic effect of codeine because they lact the demethylating enzyme that converts it to morphine
  • Often combined with paracetamol or NSAIDs in proprietary analgesic preparations
    • synergistic effect but potential for safety concerns
35
Q

Metabolite of enalapril

A

Enalprilat

36
Q

Metabolite of prednisone

A

Prednisolone

37
Q

With what drugs does site specific action occur

A

Sulfasalazine and 5-ASA

38
Q

Synonym for paracetamol

A

Acetaminophen

39
Q

Main metabolic pathway for paracetamol

how much of its metabolism does this pathway account for

A

45-50%

40
Q

Minor metabolic pathway for paracetamol

How much does it account for

A

4-5%

41
Q

Name the product of the paracetamol metabolic pathway that is toxic

A

NAPQI is toxic to the liver but at low doses (1-2 g) this is not a problem as it conjugates with glutathione (GSH) and is excreted

42
Q

How is paracetamol fatal at high doses

A

Dose of 10-15g

The glutathione pathway becomes saturated and NAPQI attacks the liver and this can be fatal

43
Q

Name the P450 forms induced by ethanol

A

CYP1A2

CYP2E1

CYP3A4

Alcohol abusers have 4x levels of these enzymes in their livers over non-drinkers

44
Q

What happens when CYP2E1 and CYP3A4 are induced by alcohol

A

A greater amount of paracetamol is converted to NAPQI

45
Q

What substance helps in conjugation of NAPQI with glutathione

A

NAC

46
Q

Treatment of paracetamol overdose

A

Paracetamol nomogram

Give acetylcysteine

47
Q

MCQ

A
48
Q

MCQ

A

Pharmacology (23 decks)

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