Drug Metabolism And Elimination Flashcards
What is drug metabolism?
Removal of lipid soluble drug molecules to prevent reabsorption by kidneys
How is drug metabolism achieved?
Converting drugs into water soluble molecules
Where does drug metabolism take place?
Mostly in liver, but also in plasma, long and intestinal epithelium
What is excretion?
Removal of drugs/ metabolites from the body
Where are drugs excreted (8)?
Mostly in urine, but also bile, faeces, sweat, tears, saliva, exhaled air and milk (more lipid soluble drugs)
What is drug clearance?
The volume of plasma cleared of drug per unit time
What is the formula of clearance for a drug that is removed by liver metabolism and kidney excretion?
Plasma clearance = hepatic clearance + renal clearance
What does it mean if a drug has a high plasma clearance?
The body’s more capable of removing it (and usually has a smaller half life too)
What determines the amount of drug available at the site of action?
Metabolism and plasma clearance
What affects the time between doses?
Time taken for a drug to reach steady state levels
What safety issues are there with drugs?
Metabolism produces new chemical entities that may have their own effects
Components of racemic molecules handled differently
What is a prodrug?
Drugs that are activated by metabolism
Give an example of a prodrug, with the product and the facilitating enzyme
Enalapril -> enalaprilat by esterases
When does drug removal begin?
Immediately
What do most drugs undergo to increase excretion?
Metabolism
What happens if theres a loss of or reduced biological activity when a drug is metabolised?
Increase polarity/ less receptor binding
Give an example of a drug that is eliminated without being metabolised
Digoxin
Why would you use prodrugs(4)?
better pharmacokinetic profile
orally available
More Readily absorbed
Better bioavailability
What are the two phases of drug metabolism?
Phase 1 and 2
What does phase 1 of drug metabolism include?
Introduces chemically reactive groups
What does phase 2 of drug metabolism include?
Increases water solubility of drug for excretion
What processes happen in phase 1 of drug metabolism?
- oxidation in the liver
- addition of oxygen molecules to carbon, nitrogen, sulfur molecules in drug structure
What is phase 1 of drug metabolism carried out by?
Cytochrome P450 enzymes
What do cytochrome P450 enzymes do?
Binds molecular oxygen to the drug
The other oxygen is reduced to water
What happens in phase 2 of drug metabolism?
Adds the phase 1 product to an endogenous substance through the production of stable covalent bonds
Give an example of the phase 2 in drug metabolism
Glucuronidatoin
What is glucuronidation?
Phase 2 reaction with glucose
What is the exception to the phase 1/2 scheme?
Paracetamol
Through which phase is paracetamol more readily metabolised?
Phase 2
What are the two phase 2 reactions that paracetamol could undergo?
Glucuronidation
Sulfate conjunction
What is glucuronidation?
The addition of a glucose molecule
When do phase 2 reactions not happen on paracetamol?
When you run out of glucose, sulfate and enzymes
What happens if the phase 2 enzymes in paracetamol metabolism are saturated?
A phase 1 reaction happens - cytochrome p450
What does paracetamol and cytochrome p450 make?
Quinone
What can make quinone safe and water soluble?
Glutathione
What does the amount excreted through the glomerulus depend on?
The levels of drug bound to plasma proteins
What sized molecules does glomerulus filtration filter?
<20kDa
How does reabsorption happen in the kidneys?
- molecules pass through tubules, becoming more concentrated.
- this creates a large conc grad for reabsorption
Why do drugs need to be water soluble?
To allow them to be reabsorbed
How does tubular secretion work?
- Acid/base molecule carries transposing molecules into tubular fluids
- lower levels of unbound drug in plasma, pushing reaction for plasma proteins to release more free drug for secretion by carriers
Give the formula for excretion that includes filtration, secretion and reabsorption
Excretion= filtration - reabsorption + secretion
What is renal clearance?
The volume of plasma cleared of drug per unit time in one pass through the kidney
Where does the drug go once it is cleared from the blood?
Urine
What does decreased renal elimination lead to?
Increased plasma half life
What are the four factors that affect drug metabolism and excretion?
Age, genetics, drug metabolising enzymes and disease
How does age affect drug metabolism and excretion?
- Cytochrome P450 activity and GFR reduced in neonates/ the elderly
- increased to fat content in elderly
How does genetics affect drug metabolism and excretion?
45% in Europe and USA as a pose to 80-90% in Asians fast acetylators
1/3000 slow metabolism by pseudocholinesterase
How do drug metabolising enzymes affect drug metabolism and excretion?
Can be induced or inhibited by other drugs or lifestyle factors
Eg taken with a specific food/ at a certain time of day
How does disease affect drug metabolism and excretion?
Liver disease impairs drug metabolism- drug toxicity
Renal disease may alter pharmacokinetics
Why would you need to monitor drug concentrations (7)?
- drugs that have a narrow therapeutic index
- drugs that relate well to either theraputic effect or toxic effect, or both
- to individualise therapy
- to confirm adherence of therapy
- to diagnose toxicity
- to determine the presence of other drugs before starting therapy
- as part of post marketing surveillance to drug-drug interaction
