Pharmacokinetics: Metabolism and Excretion Flashcards
Where does drug metabolism happen at tissue level?
- Liver for foreign bodies and particles
- Kidneys acting as a filter
- Lungs for the volatile anaesthetics
Where does drug metabolism happen at intracellular level?
- Mitochondria- cell organelle involved in producing ATP
2. Smooth Endoplasmic reticulum
What properties can change when the parent compound metabolises into the metabolite?
- Increase in water solubility
- Decrease in biological activity
- Increase in biological activity- need to consider the concentration
- Change in the nature of the biological activity
What is the phase 1 reaction of metabolism?
- Preparing the molecule that expose function groups
2. Different conjugative entities that are added to the drug
What is the 3 main chemical reactions that the drug structure must go under to prepare it for the conjugative step itself?
- Oxidation
- Reduction
- Hydrolysis
What are cytochrome P450, where are they located and what is its role?
- 20 Isoenzymes that are located in the smooth ER
2. which are very diverse to metabolise different compounds (any foreign bodies)
Explain the how a molecule interacts with cytochrome P450?
- Molecule interacts with cytochrome P450 to get oxidised
2. 1 to 4 family groups of cytochrome P450 are involved in drug metabolism
How does the phase 2 reaction of metabolism work?
- Involves the formation of a covalent bond
- Results in a H2O soluble conjugate (excretion)
- Products are predominantly INACTIVE (to remain excreted), but in some cases the activity remains
How does codeine work when metabolised?
- Codeine is metabolised to morphine and then to Morphine-6-glucuronide
- Leads to increase of analgesic effect through opioid receptor agonist profile
What is 1st pass metabolism? And give examples of where it happens?
- When the metabolism begins before the drug reaches general circulation
2. Examples of where it happens: Liver Lung Intestinal lumen Intestinal wall
What are the two factor that affect metabolism and give two examples of them?
- Genetic influences
- Example: different races turn a different percentage of codeine into morphine
- Some are poor, intermediate, ultra rapid, and extensive - External factors
Example: grape fruit inhibits the enzymes CYP3A4 and CYP1A2 and this reduces the first pass effect of drugs
- Drugs are metabolised by enzymes in the guy wall
- Increases concentration in the plasma
- Doesn’t affect IV drugs
What are the various routes of excretions in fluids, solids and gases?
Fluids: Important for low MW compounds
- urine
- bile
- sweat
- tears
- breast milk
Solids: Important for high MW compounds
- Faeces
- Hair
Gases (expired air): important for volatile compounds
Where are compounds excreted in the renal system?
- Glomerular
- Reabsorption
- Tubular Excretion- distal tubular end
What is glomerular filtration?
- Blood flow through the glomerulus filtering the compound through the blood stream itself
- Allow passage if 20kDa molecules or below
- Occurs under hydrostatic pressure
- Contains about 20% of the plasma volume delivered
How does tubular secretion work?
- Renal tubule has secretory transporters on both basolateral and apical membranes
- They can transport acidic (organic anion transporters) or basic compounds (organic cation transporters)
- Lead to a rate of rapid decrease in plasma concentration of unbound drug which causes a rapid dissociation of any drugs bound to proteins in the plasma