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3002 > 89 Drug metabolism and elimination > Flashcards

89 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

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
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3
Q

Where does drug metabolism mainly occur in?

A

Mainly occurs in liver in 2 phases

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4
Q

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

A
  1. Phase I metabolism
    • Generally oxidation, reduction or hydrolysis
    – Introduce/reveal a reactive chemical group
    – “Functionalisation”
    • Products often more reactive
  2. Phase II metabolism
    • Synthetic, conjugative reactions
    • Hydrophilic, inactive compounds generated (usually)

Phase I predominately prepares drugs for Phase II metabolism
– Phase II true ‘detoxification’ pathway

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5
Q

What functional groups does Phase I metabolism introduce or unmask?

A

–OH, -NH2, -SH, -COOH

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6
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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7
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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8
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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9
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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10
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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11
Q

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

A
  1. Glucuronidation
  2. Sulfation
  3. Glycosidation
  4. Methylation
  5. Acetylation
  6. Glutathione conjugation

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

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12
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 conjugation

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13
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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14
Q

What are possible sources of excretion?

A
  • Breath
  • Urine
  • Saliva
  • Perspiration
  • Feces
  • Milk
  • Bile
  • Hair

The kidneys are the most important organs involved in the elimination of drugs and their metabolites

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15
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)
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16
Q

Which product of drug metabolism is found concentrated in bile?

A

Hydrophilic drug conjugates e.g. glucuronides

17
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

18
Q

Name 2 drugs that enter the enterohepatic circulation?

A
  • Oral antibiotics

* Oral synthetic oestrogens

19
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, whilst polar drugs remain in lumen)
20
Q

Weak acids more rapidly excreted if urine is _____

A

Weak acids more rapidly excreted if urine is alkaline

21
Q

Weak bases more rapidly excreted if urine is _____

A

Weak bases more rapidly excreted if urine is acidic

22
Q

What is ion trapping

A

• More ionised drug
• Less able to be
reabsorbed
• Eliminated in urine

23
Q

Zero order kinetics

A 
• Few drugs
• Rate of metabolism is constant
• Does not vary with amount of drug present
• Enzyme saturation
– Alcohol dehydrogenase
24
Q

First order kinetics

A
  • Most drugs
  • A constant fraction metabolised/unit time
  • Increases proportionately to drug
  • More drug, faster metabolism
25
Q

Kinetics of salicylic acid metabolism?

A
  • Non-linear kinetics

* High doses saturate

26
Q

Vd (apparent volume of distribution) of a drug =

A

Total amount of drug in the body/ Blood plasma concentration of drug

Units = L or L/kg

27
Q

CL (clearance) of a drug =

A

Sum of all routes of elimination (e.g. metabolism + excretion)

Units = L/h

28
Q

t1/2=

A

(ln2 x Vd)/ CL

29
Q

Compare the Vd and CL of aspirin to salicylic acid?

A
  1. Aspirin:
  • Volume of distribution (Vd) = 10.5 L
  • Clearance (CL) 39 L/h
  1. Salicylic Acid:
  • Volume of distribution (Vd) = 11.9 L
  • Clearance (CL) 3.6 L/h (dose dep.)
30
Q

Factos that affect metabolism

A
  1. Age
  2. Disease
  3. Genetic variation
  4. Other medications
31
Q

Effect of age on drug metabolism?

A
  • Fetus - maternal protection
  • Children - low level of activity
  • Elderly - starts to decline
32
Q

Effect of disease on drug metabolism?

A
  • Dependent on proper liver function - cirrhosis, hepatitis, cancer
  • Adequate essential amino acid supply - starvation, cancer
  • Other disease conditions - kidney disease, severe burns
33
Q

Effect of genetic variation on drug metabolism?

A
  • Wide range of CYP phenotypes - rapid, slow, unusual metabolisers
  • Race - inherent generalisable variability
34
Q

Effect of other medications of drug metabolism?

A
  • Induction of metabolic enzymes - reduced effectiveness of drugs
  • Inhibition of metabolic enzymes - dietary constituents or drugs

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