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BFI: ADME > Drug Elimination > Flashcards

Drug Elimination Flashcards

1
Q

Where does drug metabolism occur?

A

In the liver

  • hepatocytes express range of broad-spectrum enzymes
  • hepatic portal vein leads
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2
Q

How many phases of drug metabolism

A

2

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3
Q

Phase 1

A

Reactive centres introduced to drug molecules

  • haem-containing mono-oxygenase enzymes that catalyse many reactions on many substrates
  • multiple isoforms expressed (74 gene families)
  • catalytic mechanism involves cyclic reduction + oxidation of haem iron centre
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4
Q

Phase 2

A

Conjugation of polar/charged groups at reactive centres

  • addition of polar/charge groups to reactive centres
  • commonest conjugation is catalysed by UDP-glucuronyl transferases
  • make drugs less reactive + readily excreted by kidneys
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5
Q

3 stages of drug clearance

A

Glomerular Filtrate
Tubular secretion
Reabsorption

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6
Q

3 mechanisms of drug interaction

A

1) Competition for binding sites
2) Modulation of cytochrome P450
3) Competition for secretion/absorption in kidney tubule

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7
Q

What to use to measure Elimination

A

Half life (t1/2)
Clearance (Cl)
Estimated glomerular filtrate rate (eGFP)

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8
Q

Half life

A

Time taken for plasma level to halve

Good for estimating dosing regimens

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9
Q

Clearance

A

Volume of plasma cleared of drug in a unit of time

Commonest measure of elimination

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10
Q

Half life

A

Time taken for plasma level to halve (fall by 50%)

Good for estimating dosing regimens

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11
Q

What can cause Nephrotoxicity

A

Aminoglycoside antibiotics

  • By killing tubular epithelial cells which impairs renal function
  • impaired renal function means filtration + secretion are reduced + elimination is slowed
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12
Q

2 major transporters

A

Organic ANION transporter

Organic CATION transporter

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13
Q

Organic anion transporter

A

Transports a broad range of monavalent anions
Anion exchange with dicarboxylic acids
Acid drugs secreted

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14
Q

Organic cation transporter

A

Transports a broad range of monovalent cations
Uses membrane potential as driving force
Basic drugs secreted

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15
Q

Drugs + metabolites reabsorbed

A

Passive reabsorption in distal tubule

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16
Q

Grapefruit Juice cause

A

Inhibition of CYP384
increase plasma concentration of oral dose of 40mg Simvastatin after subjects drank 200ml of Grapefruit juice
It reduces impacts of first-pass metabolism

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17
Q

Antibiotic interaction of Erythromycin

A

Inhibits CYP3A subfamily

- reduces impact of first-pass metabolism like grapefruit juice

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18
Q

Antibiotic interaction of Metronidazole

A

Inhibits acetaldehyde dehydrogenase

- interact with alcohol and cause nausea, dizziness

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19
Q

Other consequences of metabolism

A

Active metabolites
Pro-drugs
Side effects

20
Q

Routes of excretion

A

Kidney (water-soluble)
Lung (volatiles)
Bile (large molecular weights)

21
Q

Routes of excretion

A

Kidney (water-soluble)
Lung (volatiles)
Bile (large molecular weights)

22
Q

Biliary excretion

A

Large molecules can be actively transported into bile

Excreted into gut (enterohepatic re-circulation)

23
Q

Role of kidney tubule

A

Clear blood of waste products while retaining essential ions + nutrients
- Electrolyte & water homeostasis maintained

24
Q

Calculate clearance from plasma

A

CLp(plasma) = CLr(renal excretion) + CLh(hepatic metabolism)

25
Q

Calculate half life

A

t1/2 = 0.693Vd / CLp

26
Q

What drugs are reabsorbed?

A

Lipophilic drugs

27
Q

What drugs are retained?

A

Hydrophilic drugs

28
Q

Cytochrome P450

A

Haem-containing mono-oxygenase enzymes that can catalyse many reactions on many substrates
Multiple isoforms expressed (74 gene families)
Catalytic mechanism involves cyclic reduction and oxidation of haem iron centre

29
Q

Antibiotic interaction of Rifampicin

A

Induces CYP3A subfamily

- reduce levels of other medications metabolised

30
Q

Bowmans Capsule

A

Glomerular filtration

31
Q

Proximal tubule

A

Active secretion

32
Q

Distal Convoluted Tubule

A

Reabsorption

33
Q

What drives active secretion

A

Energy via Active transport

34
Q

Impaired renal function

A

Filtration + secretion are reduced + elimination is slowed

35
Q

The more nephrotoxicity…

A

The higher the drug plasma concentration will be

- aminoglycosides + renally-cleared drug at risk of over-dosing

36
Q

What increase half life?

A

Impaired kidney / liver function

37
Q

Consequences of metabolism

A 
Active metabolites 
- products of drug metabolism is active
- active metabolites may have differing pharmacokinetics to parent compound
Prodrugs
- parent drug may be inactive
- depends on metabolism to form species 
Side effects
- metabolite have enhanced toxicity compared to parent drug
38
Q

How can reabsorption be blocked

A

By active elimination e.g. absorbents like charcoal retain in gut

39
Q

Glomerular filtration

A

Hydrostatic + osmotic pressure promotes fluid movement from capillaries to bowman’s capsule

  • small molecules carried by bulk flow but not plasma proteins
  • free conc of drug carried over
40
Q

Active secretion

A

Transporter proteins carry small molecules across apical cells into tubule lumen in proximal tubule

  • Driven by energy (co-transport of ions/ATP hydrolysis)
  • conc of drug can occur
41
Q

Reabsorption

A

Both passive + active reabsorption occurs

  • drugs + metabolites go through passive reabsorption in distal tubule
  • lipophilic drugs reabsorbed, hydrophilic drugs retained
42
Q

Probenecid

A

Competes with other drugs for organic anion transporters in proximal tubule

  • to prolong action of penicillin antibiotics
  • interacts with other drugs
43
Q

Estimated glomerular filtration rate

A

Estimates kidney filtration rate in patient

  • good in identifying renal impairment + tailoring dosing regimens
  • calculated from serum creatinine levels - byproduct of muscle metabolism that is efficiently filtered but not reabsorbed in kidney
44
Q

Calculate clearance

A

CLHepatic + CLRenal = CLPlasma

45
Q

Calculate volume of distribution

A

t1/2=0.693Vd/ CLP

BFI: ADME (5 decks)

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