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
Biotransformation
In liver
Purpose: make compounds more polar so they can be more water soluble and excreted in the urine
- Might be required to activate a drug from prodrug to drug
Phase I and II reactions often coupled but not required
Biotransformation phase I reactions
- Add/expose functional groups
- Oxidation to make metabolites more polar/water soluble
- Metabolites often become less active
- MAJOR PLAYER = CYP450 - DO METABOLISM OF 75% OF DRUGS IN SER
Biotransformation phase II reactions
- Conjugation/synthesis reaction
- Most common: glucuronidation
- Usually results in inactivation
- Can + large anionic groups to detoxify reactive electrophiles
- SER
Inhibitors of biotransformation
- Inhibit CYP450 through competitive inhibition
- Non-microcosmal drug reaction like disulfiram reaction
Drug occupancy theory and the 2 assumptions
Relationship between drug dose and effect (using law of mass action)
Assumptions:
- Effect is proportional to the receptor occupancy
- Interaction between drug and receptor is monovalent
Agonist
Drug capable of inducing maximum response
Full efficacy
Alpha = 1
Partial agonist
Drug is faction of the maximum that can be elicited overall
Partial efficiacy
1 > alpha > 0
Antagonist
Drug can’t bind receptor and induces no response
Zero efficacy
Alpha = 0
Affinity
Ability of drug to form complex with receptor
1/Kd
Greater affinity of drug for receptor the lower the [ ] of drug necessary to occupy receptor
Efficacy
Capacity of drug/receptor complex to produce a response
EC50
[ ] of a drug that produces 50% of maximal response
Potency
COMPARATIVE TERM!
- Doesn’t refer to maximal response
- Will always be a ratio
Competitive antagonism
- Reversible
- SLOPE STAYS THE SAME! (max response is same)
- EC50 DECREASES
- Graph shifts to the right
Noncompetitive antagonism
- Irreversible
- Max response decreased
- Affinity of agonist for receptor doesn’t ∆
- Apparent # of receptors decreased
Physiological antagonism
- Can antagonize multiple pathways
Ex: insulin/glucocorticoids
Inverse agonist
- 2 state model theory
- Does opposite of what normal agonist does
- Binds inactive form to shift equilibrium to inactive form
- Doesn’t follow occupancy theory because not necessarily monovalent
Spare receptors
- Small % of receptors to elicit max response
- EC50 and Kd values different — violation of occupancy theory
Describe 2 state theory
- Can be activated by agonists
- Can be stopped by antagonist
- Can be made inactive by inverse agonist
Quantal log dose-response curve
- All or nothing
- Frequency distribution curve of response of population to a drug
- Uses medan effective dose (ED50) = dose required to produce response in 50% of population
- Helps judge drug potency
Therapeutic index
- Measure relative safety of a drug
- Want it to be high
- Ratio of LD50 – kill 50% of population:effective for 50% of population
Certain safety factor
- Ratio of death of 1% of population to therapeutic dose of 99% of population
