Wk 4 - Receptor and ADME Flashcards
What is pharmacokinetics?
The action that the body has on the drug
Pharmacodynamics?
The action that the drug has on the body
ADME
Absorption:
- Passage of drug from administration site to blood
Distribution:
- Passage of drug from blood to tissues
Metabolism/biotransformation:
- Chemical modification of drug to make more water soluble/excreted
Excretion:
- Passage of drug from blood to outside of body through urine
Passive diffusion
- Driven by concentration gradient
- Doesn’t require energy
- Doesn’t saturate
G-protein coupled receptors
- Most common drug receptor group
- Generate 2º messenger to change cell function
2º messengers: cAMP, Ca++, etc… - Drug binds to receptor coupled to G protein which does the effector function
What’s an orphan receptor?
When you don’t know what ligand the receptor binds to
Ligand-gated ion channels
Mechanism:
- Ligand binds
- Channel opens
- ions flow through and down gradient
- Depolarization of membrane
- Generation of action potential
Receptor direct binding/∆ gene transcription
- Often associated with chaperone protein
Filtration transport
- Doesn’t require ATP
- Bulk flow of fluids through channel
- Driving force = osmotic pressure difference
- Move down gradient
Endocytosis transport
- Requires ATP
- Active bulk flow through membrane
- Move in both directions
Facilitated diffusion
- Carrier mediated
- Doesn’t required ATP
- Saturable
- Selective
- Moves down gradient
Active transport
- Requires ATP
- Carrier mediated
- Saturable
- Selective
- Moves AGAINST gradient
What does Fick’s law describe?
FLUX!
FLUX = rate of transport = (permeability constant)(Cout-Cin)
What is bioavailability?
How much of a drug that’s administered to a patient is ABLE to move into circulating plasma
- Fraction of total amount that could EVER get into circulation
- 100% bioavailable? IV administration
- Expressed from 0 –> 1
What should you take away from Lipinski’s rule of 5?
- A compound with good bioavailability will be relatively small and MODERATELY lipophilic
Tissue perfusion rates (distribution)
It’s easy to diffuse into tissues that are highly perfused with blood
Plasma binding proteins (distribution)
High affinity??
More plasma binding protein and LESS DISTRIBUTION
Partitioning between plasma and tissues (distribution)
[ ] of drug between plasma and tissues not equal
Done via ion trapping, lipid solubilty, tissue binding protein
Volume of distribution
Fluid volume that would be required to contain the amount of drug present in the body at the same concentration as observed in the plasma
Vd = total amount of drug given/concentration of drug in plasma
The HIGHER the concentration in the plasma the LOWER the volume of distribution
Tells us about the relative distribution of the drug in the body
… Use body weight to normalize the Vd
Variation of Vd (lipophilic/hydrophilic drugs)
Vd will be lower in fat people if it’s a lipid soluble drug
Termination: Storage/redistribution
- Drug can be trapped via redistribution and stuck in places where it shouldn’t be
Ex: anesthesia example
Works with 1st and 2nd pass distribution
Termination: excretion/elimination
Kidney is major player
1º function: remove excess water soluble molecules from blood and return water
Filtration (through glomerular capillaries –> pre-urine)
Reabsorption (concentration gradient in collecting tubule and diffuses back out)
Secretion (selectively pull impounds from plasma and dump them in urine)
EXCRETION = FILTRATION - REABSORPTION + SECRETION
Renal clearance (Clr)
Volume of plasma that’s cleared of drug by the kidney per hour
Clr = (CuVu)/Cp
GFR = glomerular filtration rate
Renal clearance different types
No reabsorption/secretion? (filtered only)
GFR = Clr = 125mL/min
Filtered and reabsorbed
Clr < GFR (less getting out)
Filtered and secreted
Clr > GFR
