Drug Elimination

Question 1

Where does drug metabolism occur?

Answer 1

In the liver

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

Question 2

How many phases of drug metabolism

Answer 2

2

Question 3

Phase 1

Answer 3

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

Question 4

Phase 2

Answer 4

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

Question 5

3 stages of drug clearance

Answer 5

Glomerular Filtrate
Tubular secretion
Reabsorption

Question 6

3 mechanisms of drug interaction

Answer 6

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

Question 7

What to use to measure Elimination

Answer 7

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

Question 8

Half life

Answer 8

Time taken for plasma level to halve

Good for estimating dosing regimens

Question 9

Clearance

Answer 9

Volume of plasma cleared of drug in a unit of time

Commonest measure of elimination

Question 10

Half life

Answer 10

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

Good for estimating dosing regimens

Question 11

What can cause Nephrotoxicity

Answer 11

Aminoglycoside antibiotics

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

Question 12

2 major transporters

Answer 12

Organic ANION transporter

Organic CATION transporter

Question 13

Organic anion transporter

Answer 13

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

Question 14

Organic cation transporter

Answer 14

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

Question 15

Drugs + metabolites reabsorbed

Answer 15

Passive reabsorption in distal tubule

Question 16

Grapefruit Juice cause

Answer 16

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

Question 17

Antibiotic interaction of Erythromycin

Answer 17

Inhibits CYP3A subfamily

- reduces impact of first-pass metabolism like grapefruit juice

Question 18

Antibiotic interaction of Metronidazole

Answer 18

Inhibits acetaldehyde dehydrogenase

- interact with alcohol and cause nausea, dizziness

Question 19

Other consequences of metabolism

Answer 19

Active metabolites
Pro-drugs
Side effects

Question 20

Routes of excretion

Answer 20

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

Question 21

Routes of excretion

Answer 21

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

Question 22

Biliary excretion

Answer 22

Large molecules can be actively transported into bile

Excreted into gut (enterohepatic re-circulation)

Question 23

Role of kidney tubule

Answer 23

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

Question 24

Calculate clearance from plasma

Answer 24

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

Question 25

Calculate half life

Answer 25

t1/2 = 0.693Vd / CLp

Question 26

What drugs are reabsorbed?

Answer 26

Lipophilic drugs

Question 27

What drugs are retained?

Answer 27

Hydrophilic drugs

Question 28

Cytochrome P450

Answer 28

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

Question 29

Antibiotic interaction of Rifampicin

Answer 29

Induces CYP3A subfamily | - reduce levels of other medications metabolised

Question 30

Bowmans Capsule

Answer 30

Glomerular filtration

Question 31

Proximal tubule

Answer 31

Active secretion

Question 32

Distal Convoluted Tubule

Answer 32

Reabsorption

Question 33

What drives active secretion

Answer 33

Energy via Active transport

Question 34

Impaired renal function

Answer 34

Filtration + secretion are reduced + elimination is slowed

Question 35

The more nephrotoxicity...

Answer 35

The higher the drug plasma concentration will be | - aminoglycosides + renally-cleared drug at risk of over-dosing

Question 36

What increase half life?

Answer 36

Impaired kidney / liver function

Question 37

Consequences of metabolism

Answer 37

``` 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 ```

Question 38

How can reabsorption be blocked

Answer 38

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

Question 39

Glomerular filtration

Answer 39

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

Question 40

Active secretion

Answer 40

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

Question 41

Reabsorption

Answer 41

Both passive + active reabsorption occurs - drugs + metabolites go through passive reabsorption in distal tubule - lipophilic drugs reabsorbed, hydrophilic drugs retained

Question 42

Probenecid

Answer 42

Competes with other drugs for organic anion transporters in proximal tubule - to prolong action of penicillin antibiotics - interacts with other drugs

Question 43

Estimated glomerular filtration rate

Answer 43

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

Question 44

Calculate clearance

Answer 44

CLHepatic + CLRenal = CLPlasma

Question 45

Calculate volume of distribution

Answer 45

t1/2=0.693Vd/ CLP