P4: Drug Metabolism and Excretion Flashcards
Define drug clearance
The removal of a drug from the body by all metabolic and excretory processes
What are the two major mechanisms of drug clearance?
- Renal clearance
- Hepatic clearance
What is renal clearance?
Elimination of the drug through the urine
What is hepatic clearance?
Metabolism of the drug in the liver
Name two drugs that are fully cleared by the kidney
- Atenolol
- Gabapentin
For most drugs what clearance mechanism do they follow?
Combination of renal and hepatic clearances
How are volatile drugs such as inhalation anaesthetics or ethanol cleared?
Combination of renal, hepatic and lung clearance
Roughly how much plasma is filtered through the kidneys per day?
180L
What is the role of efflux transporters that are located on the wall of a PCT?
Removal of a wide range of molecules
Why is renal clearance of lipophilic drugs harder than other drugs?
- Lipophilic molecules tend to bind to protein
- As water is reabsorbed in the nephron the conc of the filtrate increases, filtrate to tissue fluid gradient is established, lipophilic drugs move down this and re-enter the plasma.
What is phase I metabolism?
Functionalisation – add or reveal reactive groups
What is phase II metabolism?
Conjugation – add groups that improve water solubility
List some phase I metabolism reactions
- Oxidation
- Reduction
- Hydrolysis
- Hydration
- Dehalogenation
List some phase II metabolism reactions
- Sulfation
- Glucuronidation
- Glutathione conjugation
- Acetylation
- Amino acid conjugation
- Methylation
What are the 3 main enzyme families that are involved in Phase I metabolism reactions?
- CYP1
- CYP2
- CYP3
Give an example of a drug that skips Phase I reactions
Temazepam
Diazepam undergoes Phase I to become Temazepam
What is the difference between metabolism and detoxification?
- Drug metabolism can produce toxic metabolites
- Detoxification does not produce these toxic metabolites
Name some hepatic metabolism inhibitors
- Grapefruit juice
- Fluoxetine
- Disulfiram
Name some hepatic metabolism inducers
- Barbiturates
- St John’s wort
- Tobacco
Name some minor excretion routes
- Bile - temoporfin (anti-cancer)
- Lungs
- Stomach and Intestine - nicotine excreted into gastric juices, water soluble drugs excreted into intestines
- Saliva
- Breast milk
- Sweat
- Semen
Explain enterohepatic recirculation
- Drug absorbed and carried to liver
- Then converted to glucuronide conjugate, then secreted into bile
- Bile containing conjugate is secreted when food is eaten
- Conjugate is hydrolysed by beta - glucuronidase by GI flora
- Then it is reabsorbed
Besides renal and hepatic clearance how else can clearance happen
- Lungs - ethanol
- Faeces - carried in bile
Quick note
Rate or clearance is proportional to drug conc and rate of clearance is important when choosing drugs, especially if patient has kidney of liver problems
What is the equation for drug clearance
rate = k x C^n k = rate constant n = order
Describe a first order decay curve on a Conc/Time graph
Rate declines
Half life is constant
Where are drugs reabsorbed in the nephron
- PCT - active reuptake of drugs
- DCT - reabsorption of liphophilic drugs
How does penicillin’s low pKa (2.7) affect its excretion
Actively secreted into tubular fluid
- lower pKa = lower degree of penicillin ionisation
- non-ionic penicillin is passively reabsorbed from urine
- Increases penicillin half life
What enzyme’s family members account for 75% of drug metabolising enzymes
Cytochrome P450
What is the main reaction catalysed by drug metabolising enzymes
mono oxygenation
Name some other major enzymes involved in drug metabolism
- Flavin-containing monooxygenases (FMO)
- Monoamine oxidases (MAO)
- Alcohol Dehydrogenase
- microsomal reductases
- circulating esterases
Give examples of phase 1 reactions
Alcohol oxidation -
Ethanol (+ alcohol dehydrogenase) –> Acetaldehyde (+ aldehyde dehydrogenase) –> Acetic Acid
S-oxidation -
Thioridazine (+ Cytochrome P450) –> Thioridazine 2-sulfoxide
Why is it easy to maintain long half life drugs in a therapeutic window
Small fluctuations between doses
use loading dose to avoid lag time of onset
Why is it hard to maintain short half life drugs in a therapeutic window
Large fluctuations between doses (rapid attainment of steady state)
E.g. morphine - respiratory depression at peaks and pain at troughs