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MD3002 Week 1 0 > 1. Drug metabolism and elimination > Flashcards

1. Drug metabolism and elimination Flashcards

1
Q

Name the different sites of drug metabolism?

A 
– Gut lumen 
– Gut wall
– Plasma
– Lungs
– Kidneys 
– Nerves 
– Liver
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2
Q

What are the two phases of drug metabolism in the liver?

A

Phase 1 metabolism:

  • Generally OXIDATION, reduction or hydrolysis. Introduce/reveal a reactive chemical group
  • Products often more reactive
  • “functionalisation”

Phase 2 metabolism:

  • Synthetic, conjugative reactions
  • Hydrophilic, inactive compounds generated
  • True “detoxification” pathway
  • Leads to product that favours excretion
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3
Q

What are the different oxidations that occur during phase 1 drug metabolism in the liver?

A

Mixed-function oxidase system (cytochrome P450)
Alcohol dehydrogenase
Xanthine oxidase

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4
Q

What are the different reduction reactions that occur in phase 1 drug metabolism in the liver?

A

Ketone reduction

Anaerobic cytochrome p450 metabolism

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5
Q

What are the different hydrolysis reactions that occur in phase 1 drug metabolism in the liver?

A 
Ester hydrolysis (e.g. cholinesterases)
Amide hydrolysis
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6
Q

Mixed-function oxidase system (CYP450s):
Microsomal (ER) enzymes in…
Consists of?
Requires?

A 
Microsomal (ER) enzymes in the liver, kidney, lung, intestine etc
Consists of:
-Cytochrome P450
-NAPDH-CYP450 reductase
-Lipid (held together in lipid plane)

Requires:

  • Molecular oxygen (to allow aerobic reaction)
  • NADPH
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7
Q

Characteristics of the products of phase 2 metabolism in the liver?

A

Detoxified, water-soluble, easily secreted.
Hence suitable for excretion in bile or urine
(Done by various methods of conjugative reactions that overlap in the groups they conjugative)

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8
Q

Name the 6 conjugative reactions that occur in phase 2 drug metabolism?

A 
Glucuronidation
Sulfation
Glycosidation
Methylation
Acetylation
Glutathione conjugation

Conjugates groups via transferases to make them non-toxic, hydrophilic and easily excreted

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9
Q

What is the process of aspirin metabolism?

A

Drug –> Derivative –> Conjugate.
In aspirin (drug) –> Salicylic acid (derivative)
–> Glucuronide (Conjugate)

Phase 1= Drug–> Derivative
Via oxidation, hydroxylation, dealkylation, deamination, hydrolysis. Reaction due to environment not enzyme.

Phase 2= Derivative –> Conjugate
Via cojugation

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10
Q

Drugs are eliminated either unchanged or as _______.

In general, hydrophilic drugs eliminated more readily than _____ drugs

A

Drugs are eliminated either unchanged or as metabolites

In general, hydrophilic drugs eliminated more readily than lipophilic drugs

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11
Q

Name 3 compounds which are involved in the transfer of drugs from plasma to bile?

A

Organic cation transporters (OCTs)
Organic anion transporters (OATs)
P-glycoproteins (P-GP): Non-specific

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12
Q

Which product of drug metabolism is found concentrated in bile?

A

Hydrophilic drug conjugates e.g. glucuronides

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13
Q

What is the process of reabsorption of drugs from bile?

A

Hydrolysis of the conjugate can occur

Reabsorption of the liberated drug by entry to the enterohepatic circulation

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14
Q

Name 2 drugs that enter the enterohepatic circulation?

A

Oral antibiotics

Oral synthetic oestrogens

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15
Q

What is the process of renal excretion of drugs?

  1. Glomerular filtration
  2. Tubular secretion
  3. Diffusion across renal tubule
A
  1. Glomerular filtration
    - Filters drugs below 20kDa in molecular weight
    - Not filtered if drug is bound to plasma albumin
  2. Tubular secretion
    - Via OATs and OCTs
    - OATs transport against electrochemical gradient
    - Cleared even if bound to plasma albumin
  3. Diffusion across renal tubule
    - If tubule freely permeable, 99% of drug reabsorbed.
    - (i.e. lipophilic drugs are excreted poorly as they are easily reabsorbed, whilstpolar drugs remain in lumen)
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16
Q

Weak acids more rapidly excreted if urine is _____

A

Weak acids more rapidly excreted if urine is alkaline

17
Q

Weak bases more rapidly excreted if urine is _____

A

Weak bases more rapidly excreted if urine is acidic

18
Q

What is ion trapping

A

When a more ionised drug is less able to be reabsorbed so is elimination in urine

19
Q

Zero order kinetics

A

Contant amount of drug being removed per unit of time

e.g. Alcohol 1-1.5units/hour

20
Q

First order kinetics

A

Constant rate/proportion of drugs removed per unit of time

e.g. most drugs

21
Q

Difference between zero and first order kinetics?

A 
Zero order:
-Few drugs
-Rate of metabolism is constant
-Does not vary with amount of drug present
- Enzyme saturation
• Alcohol dehydrogenase

First order:

  • Most drugs
  • A constant fraction metabolised/unit time
  • Increases proportionately to drug
  • More drug means faster metabolism
22
Q

Kinetics of salicylic acid metabolism?

A

Non-linear kinetics

High doses saturate

23
Q

Vd (apparent volume of distribution)=

A

Total amount of drug in the body
/
Blood plasma conc of drug
Units: L or L/Kg

24
Q

CL (clearance)=

A

The sum of all routes of elimination (e.g. metabolism + excretion)
Units: L/hr

25
Q

t1/2=

A

ln2 x Vd
/
CL

26
Q

Compare the Vd and CL of aspirin to salicylic acid?

A

Aspirin:
Volume of distribution (Vd) 10.5 L
Clearance (CL) 39 L/h

Salicylic acid:
Volume of distribution (Vd) 11.9 L
Clearance (CL) 3.6 L/h (dose dep.)
HIGHER HALF L IFE as clearance is lower. So will take longer for inital value to reduce to 1/2

27
Q

Factos that affect metabolism/

A

Age
disease
other meds
genetic variation

28
Q

Effect of age on drug metabolism?

A

Foetus: Maternal protection
Children: Low level of activity
Elderly: Starts to decline

29
Q

Effect of genetic variation on drug metabolism?

A

Wide range of CYP phenotypes: Rapid,s low, unusual metabolisers
Race: Inherent generalisable variability

30
Q

Effect of disease on drug metabolism?

A

Dependent on proper liver function: E.g. cirrhosis, hepatitis, cancer
Adequate essential amino acid supply: e.g. starvation, cancer
Other: Kidney disease, burns

31
Q

Effect of other medications of drug metabolism?

A

Induction of metabolic enzymes: Reduced effectiveness of drugs
Inhibition of metabolic enzymes: Dietary constituents or durgs

32
Q

Result of metabolism

A 
Pharmacological deactivation
Pharmacological activation
Type of pharmacological response
No change in pharmacological activity
Change in drug uptake
Change in drug distribution
33
Q

Metabolism aim?

A

Hydrophilic, inactive compounds for excretion in faeces/urine

MD3002 Week 1 0 (11 decks)

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