Day 2 (Ligand binding + Dose response 1 + Quantal Dose )

which of the following lines are Kon vs which are Koff ?

1. L + R <—- LR —> response

2. L+R —> LR —> response

1. Koff

2. Kon

what is Kd?

what is its general formula?

equilibrium dissaciation constant

Kd = Koff/ Kon

= [L] [R] / [LR]

what is the formula for [LR[

[LR] = [L] [R] / Kd

higher Kd = less ligand-receptor complex

how can we increase drug response?

[LR] = [L] [R] / Kd

increase drug response by increasing the concentration of the drug and receptor

when would you increase the concentration of the receptor instead of the ligand to increase drug response ?

if the patient has a disease or repeated ligand drug exposures then you would prefer to increase recepter concentration (dont want too much of the drug)

what does Ro represent?

total concentration of the receptors (bound AND unbound)

[LR] + [R]

which equation can you use to find which fraction of the receptors are bound to drug?

[RD] / [R0] = [D] / [D] +[Kd]

In ligand-receptor binding which falls on the x axis and which falls on the y axis?

• Fractional Occupancy of Receptors

• Equilibrium Disassociation Constant

X = equilibrium disassociation constant (concentrations of free ligand)

Y= fractional occupancy of receptors [LR] / [R0]

when does [L] = Kd ?

when 50% of the receptors are bound to a ligand

drug A has a lower Kd than drug B

does drug A have a higher or lower affinity for the target receptor?

HIGHER

50% of receptors are bound with less of the drug

Drug B needs a higher concentration of the drug for 50% of the receptors to be bound to the drug

what is true about [LR] / [R0] when Kd = [L]

[LR]/ [Ro] = 1/2

would a high affinity drug with greater tendency to bind to teceptor have a low or high Kd?

what does kd stand for?

LOW

equilibrium disassociation constant

Example Exam Question

Terasozin used to treat high blood pressure and benign prostatic hypertrophy is an ANTAGONIST for a-1 adrenergic and has Kd of 1nM

If the concentration of Terasozin is 0.5 nM what is the percentage of receptors occupied?

[DR]/ [R0] = [D] / [D] + Kd

= [0.5] / [0.5] + 1

= 33%

Calculate the percentage of receptors occupied for a patient administered 1nM of Terazosin with a kd of nM

when kd = [D] then 50% of receptors are occupied

because [DR] / [R0] = [Kd] / [Kd] + [Kd] = 0.5

the response of a drug is directly proportional to the concentration of _____________________

receptors bound by the drug

______ molecule of chemical reacts per receptor

one

do we assume that the drug far exceeds the total number of receptors?

YES

Can you produce maximal effects with less than 100% receptor occupancy?

YES

you may have spare receptors that don’t have to to be bound for the drug to reach max effect

if a drug achieves 50% of its response when 50% of the drug is bound does it have spare receptors?

NO a drug with spare receptor is able to reach 50% effectiveness without having 50% of the receptors bound

when is the biological effect proportional to [DR] at all drug concentrations?

when there are NO spare receptors

roughly about what percentage of receptors are bound to the drug to achieve 50% effectiveness when there are spare receptors involved?

10% [DR] for 50% effect

is the [DR] ever proportionate to the effectiveness of a drug when there are spare receptors involved?

yes but only at smaller concentrations will having more drug = more effect since they are starting to bind to receptors

however once its max effect it won’t matter how many more receptors are bound

drug effects are nonlinear between ligand and binding and the effect is because of _______ __________and ________ _____________

spare receptors

signal amplification

what is the fractional effect?

what is the equation for fractional effect?

the response of the drug versus how high it has the potential to go

response (E) / max response (Emax)

Receptor- Mediated Effects / Responses are affected by…

1. properties of the ________ and its interaction with the _________

2. the number of _______ (extra or spare)

3. efficacy of coupling to __________ ______ or _______ __________

1. ligand receptor

2. receptors

3. signal transduction or intrinsic activity

the amount of drug administered

dose

the effects produced by a chemical on a biological system or organization

response

dose-response relationship:

• response is due to __________

• ___________ of the reaction is related to the dose

  • there is a molecular ______ ____ for chemical action

  • initiation and extent of response is related to the _____ of the chemical at the _______ ________

• there is a __________ method of measuring and a precise means of reporting the response

• chemical administered

• magnitude

  • target site

  • concentration target site

• quantifiable

what is the difference between graded and quantal dose-response curves?

graded = effect of various doses on ONE individual

quantal = effect of various dose on SEVERAL individuals

what are two ways to plot graded dose responses?

1. arithmetically (dose = x , response % = y)

2. semi log (log dose = x , response % = y)

3. recipricol values (1/dose = x , 1/response =y)

can visualize dosage which leads to 50% effect

what is the advantage of plotting reciprocal values of dose and response for a graded dose-response graph?

linear plot and able to extrapolate

what is the difference between potency and efficacy?

which axis should you evaluate for both?

potency:

which drug is able to achieve 50% of ITS max effect with lower concentration (x- axis)

efficacy:

which drug is able to have a higher effect overall (y axis)

are potency and efficacy intrinsically related?

NO

a drug can be potent and reach 50% of its max effect with less of the drug, but not reach as high of an effect as the other drug

can a single mediator/ drug can have multiple receptors ?

YES

does a drug’s potency remain constant throughout different receptors?

provide an example

NO

Norepinephrine is MOST potent in smooth muscle contraction but LEAST potent for cardiac contraction

Isoproterenol is LEAST potent in smooth

MOST potent in cardiac

what can you infer about the receptor if the EC50 of a drug is less than Kd?

there are spare receptors

doesn’t have to reach 50% [D] to get 50% effect

the receptor remaining activated beyond the drug departing allowing for the activation of other receptors

as well as signal activation by G-protein coupled receptors and cyclic AMP

allows for ____ to be less than _____

Ec less than Kd

Ec already at 50% before 50% receptors are bound

how are signals amplified allowing for max response to achieved without all receptors being bound

G-protein coupled receptors + Cyclic AMP

average effect of a drug, as a function of its dose in a population of individuals

QUANTAL dose-response

does quantal or graded dose response observe for the presence of absence of a response

QUANTAL

the _____________curve graphs the percentage of individuals that respond to each dose of the drug

quantal dose- response

how can quantal-dose response graphs predict the effects and toxicity of drugs on a population?

most sensitive patients will be on the left of the curve

the dose that was most effective amongst individuals will be in the middle

individuals with high tolerance will be on the right since it takes a higher dose to achieve an effect

which quantal- dose curve includes

• bars in a frequency histogram representing the % of individuals with the effect MINUS the % of individuals that respond at a lower dose

Gaussian Distribution

standard deviation — bell curved

which quantal- dose curve

• adds together the number of individuals that respond to each consecutive dose (CUMULATIVE REPONSE)

sigmoidal dose- response

what is the difference between Gaussian and Sigmoidal Distribution?

sigmoidal is CUMMULATIVE and will show how many people responded to each dose (if a person responded to 5 mg they will also appear under 10 mg as well

Guasian will show how many people responded the first time NOT CUMULATIVE

if a person responds at both 5mg and 10mg they will only show up once under 5mg

____________ ___________ of doses of a drug required to produce specified effects

• shaded boxes and bell-shaped curved

• the percentage of animals that require a particular dose to exhibit the dose

frequency distribution

_______ _____________ distribution

• open boxes and sigmoidal curves

• log-normally distributed

what is the difference between ED50 and EC50

EC50 = dose needed for an INDIVIDUAL to get 50% effect out of a drug

ED50 = dose needed for 50% of individuals to achieve a therapeutic response

what is TD50 ?

the dosage that causes 50% of individual to experience toxic effects

what is LD50

the dosage that causes 50% of the population to die (lethal doses)

is TD50 the dosage it takes for 50% of individuals to experience a THERAPEUTIC effect

NO

TOXIC effect

Therapeutic = ED50 (lethal)

what is meant by population sensitivity ?

how much of the drug it takes to achieve therapeutic effect

high sensitivity = peak of bell curve closer to the left side of graph (x = dose)

low sensitivity = peak of bell curve is farther down the right (higher dose needed to acheive therapeutic effect)

drug A and C have the same sensitivity and are more sensitive than drug B

what would you expect this to look like on a graph?

the peak of the bell curve for A and C are located at the same dosage on the x axis

the peak of the bell curve of B is further down the x-axis as it requires a greater dose for the majority to achieve an effect

what does it mean for a population response to be more homogenous than another?

homogenous (all responses are around the same dosage so the standard deviations are smaller — more narrow curve)

if two drugs have the same homogeneity what do you expect their curves to look like compared to one another?

the same width of their bell curve since standard deviation is how far away individuals are from the average dose

if homogenous = standard deviation low NARROW bell

if heterogenous = high standard deviation WIDE bell

what is the equation used to calculate therapeutic window?

TI (therapeutic index) = TD50 / ED50

range of doses of a drug that elicits a therapeutic response without unacceptable adverse effects (or toxicity) in a population of patients

therapeutic window

does aspirin or heparin have a more narrow therapeutic response?

is it better or worse to have a wider therapeutic index?

heparin

WORSE because it can take a little extra dose to cause you to have toxic effects

this is why Heparin is NOT sold over the counter because if you take it incorrectly and give yourself the wrong dose it can have toxic effects

does penicillin have a wide or narrow therapeutic index compared to warfarin?

large

dose-dependent relationship between desired biological effect and toxicity

Therapeutic index

calculate TI

TI = TD50/ED50

= 1000/100 = 10

in what instance is using the therapeutic index not useful?

if the two curves are not parallel

when would you use margin of safety instead of therapeutic index to evaluate safety?

if the curves of toxicity and efficacy are not parallel to one another

how to calculate margin of safety

TD1% / ED99%

what dose does 1% experience toxicity

what dose does 99% of individuals experience therapeutic effect

the ratio of doses that cause toxicity in 1% of the population to that cause the desired effect in 99% of the population

margin of safety