Lecture 2 Flashcards
General Concepts 1
Drug-Response Relationship
- straight forward: at a certain drug concentration there will be a certain response
- at a greater drug concentration (larger dose) there will be a greater response
Individual Patient + Drug Response
- Considered a graded response
- Threshold dose - lowest dose for a drug to start doing something. May be below an MEC since the response at this dose may not be a desired therapeutic effect.
- Ceiling effect - max dose where adding more drug doesn’t create a greater response
Therapeutic Window
The range between a threshold dose and the ceiling effect dose.
Population of Patients + Drug Response
- Look for quantization (all or nothing response) rather than a graded response.
- Tend to look for the frequency of effect and values like ED(50) and other measures of level of response
ED(#)
- Effective dose in #% of the population
- (#) is a subscript
Emax
Maximum effective drug concentration (ceiling effect)
MEC
Minimum effective concentration to produce a therapeutic effect. (May be above a threshold dose in certain cases)
Pharmacological Response Assumptions
- [Drug] + [Receptor] <==> [Drug-receptor Complex ==> Response
In other words, if you have enough of the drug and enough working receptors, they should combine and give you the desired drug response - The drug and receptor can combine and/or dissociate
- The formation of the drug-receptor complex is reversible
- The drug only causes a single type of receptor binding (usually not the case, more complex)
Drug-Receptor Interactions
[R] + [D} <==> [R*D]
- follows the law of mass action; therefore, can be expressed in a dissociation constant similar to what we have seen in biochemistry: K(D) = [Reactants]/[Products]
- *If you were looking for an ASSOCIATION constant, you would flip the equation upside down for: K(A) = [Products]/[Reactants]**
Emax Model
- usually a logarithmic graph to get a linear relationship
- the large the Hill coefficient (n), the larger change in response in respect to concentration we can expect
Emax Equation Coefficients (4)
- Emax - Maximum effective drug concentration (ceiling effect)
- C - concentration of drug
- n - Hill coefficient
- EC(50) - (subscript), effective concentration at 50%
Effect Compartment
- Based on PK/PD Models
- PK - pharmacokinetics, amount of drug in the body for unit time
- PD - pharmacodynamics, effect of that drug concentration on the body (usually focus on desired effect). This can be the drug itself or its metabolites
- sometimes causes a non-parallel (or non-direct) response between concentration and effect, especially if you rely on a metabolite
- Hypothetical one-compartment relationship where the drug goes from the blood (plasma compartment) to the effect compartment (target cell)
Effect Compartment Coefficients (3)
- V = volume of drug in compartment
- C = Concentration of drug in that compartment
- k = elimination rate from a compartment (can be plasma or effect compartment)
Hysteresis
- Complex, non-direct relationship between the effect and the concentration of the drug in the plasma
- caused by a time delay of the drug getting into the effect compartment
- Time-dependent
Clockwise Example of Hysteresis
Fentanyl
- measures pain response in brain by spectral edge (Hz) versus the concentration of fentanyl in the blood plasma
- partitioned into fatty tissue since it has a large log(P) value which causes the time delay before the drug can be taken to the receptor
Anticlockwise Example of Hysteresis
Ajmaline
- more and more pharmacological concentration before you start to get the desired effect
- time delay causes by drug binding to plasma protein for extended time before dissociating and entering the effect compartment
Other Factor that Effects Intrinsic Activity
Adding on extra chains of varying length that increases or decreases a drugs activity
Intrinsic Activity Constant
Proportionality constant K(ia) - (subscript)
- Drug A = Full agonist - K(ia) = 1
- Drug B = Partial agonist - K(ia) = 0.4 (40% of the effect (E))
- E(A) = 1[R*D]
- E(B) = 0.4[R*D]
- *If K(ia) = 0, then thats an ANTAGONIST with no effect**
Is Affinity : Potency a constant relationship?
Not necessarily. Two drugs could have equal affinity but one could have worse absorption and therefore show as being less potent even though they have equal affinity for a receptor.
Relative Potency
Utilized when comparing two drugs, like a brand and a test generic, to see how the difference in potency varies between the two
Difference between the doses = d
d = log(dose)A - log(dose)B <==equieffective dose
doses are graphed already logged so you do not need to log the number off the graph
Relative potency = 10^(d)
(In other words, need 10^(d)x the amount of the generic drug to get the same effect as the standard drug)
MTC
Minimum toxic concentration. Not necessarily death, can be vomiting, headaches, etc.
Intensity
Difference of plasma concentration level between the MEC and the peak of absorption.
Duration
Amount of time that passes when the drug concentration in the plasma is at the MEC or higher.
Therapeutic Index
- looks at the risk:benefit profile of one adverse effect of a drug to test its efficacy
- this is PATIENT specific since patients response to drugs vary based on their genetics and immunological state
- Quantitative assessment
- TI = (adverse effect dosage)/(desired effect dosage)
- TI < 10 = dangeous, TI < 100 = should be wary, TI around 1000 is great
Standard Margin of Safety
Good to utilize when death is a concern, compares the dosage given to get an effective response compared to a lethal dose. Population based, not patient specific. Higher the percentage, the safer the drug is to dispense to patient at that given dose.
Standard Margin of Safety Coefficients (2)
- LD(1) = (subscript), lethal dose in 1% of population
2. ED(99) = (subscript), effective dose to get desired response in 99% of population
Multiple Therapeutic Indices
No drug has a singular toxic effect and many drugs have multiple therapeutic effects as well. Therefore, there are multiple therapeutic indices for each drug depending on which therapeutic effect you are doing for and which adverse effect you are trying to avoid.
Potential Rate Limiting Steps in Absorption (4)
- Disintegration of the drug product
- Dissolution of the drug
- Absorption across a cell membrane
- Transport to the target
* *also the order these events occur in**
Drugs Process from Intake to Absorption
Drug Product –> Solid Drug Particles –> Drug in Solution –> Drug in Body –> Drug at Receptor
Dissolution
Drug must dissolve prior to absorption else it passes right through the body and is eliminated. Solution needs to be 3x more dilute than the solubility of a drug
Noyes & Whitney Coefficients
dC/dt = change in concentration over time D = Diffusion coefficient (fixed value) A = surface area h = distance height (reduces with increased stirring rate) C(s) = (subscript), saturated solubility concentration (increases with increased temperature) C = concentration in bulk layer
Apparatuses & Method used for Dissolution Calculations
- Basket (faster RPM)
- Paddle (slower RPM)
- rotate the vessel and insure that the drug is in the exact same place each time in the break to insure consistency
- Use prednisone (rapid) and salicyclic acid (slow) as calibration standards
- as the apparatuses spin, the drug dissolves over time and you get a dissolution curve
Dissolution Profile Comparisons
- Data collected from Dissolution assays is graphed and compared. For example, especially when trying to get bioequivalence between a brand & generic
- Want difference factor to be <20
- Want similarity factor to be between 50-100
- For brand & generics, these profiles need to be essentially the same to receive a biowaiver
