Pharmacology Block 01 – Lecture 03 – Receptors and Dose-Response Relationships

Threshold point
At what dose does a drug have to pass to have a therapeutic or toxic effect?

Maximum Response
Dose at which maximum therapeutic or toxic effect will always be produced

Sigmoid or “S” curve
What type of curve does a log scale for dosages produce?

1.Quantal dose-response curve
2.Graded response curve
What are the two types of dose-response curves?

Quantal dose-response curve
What type of curve is known as the “all-or-none” response?

-Ten cages of humans with ten humans in each cage are set up.
-In the first cage, each human is given a dosage of the drug.
-In each subsequent cage, the humans in that cage will receive a higher and higher dosage.
-After waiting amount of time for drug to work, % of humans affected is plotted as a fxn of the administered dose.
-Dose-response curve for THERAPEUTTIC EFFECT is generated.
Explain the basis of Quantal dose-response

NO. They are also used to determine toxicity. (Can really be used for any binary question – kl)
Do Quantal dose-response curves only test for effectiveness of a drug?

-Re-orienting yourself when you realize you are not in the upright position (when you begin to fall asleep and you nod awake.)
-When you LOSE this, you are asleep.
What is the “righting reflex?”

Median ED50 – “Median effective dose 50%”
What is the dose which produces an effect in 50% of subjects tested?

-Measures the therapeutic effects of drugs
What does ED50 describe?

Median TD50 – “Median toxic dose 50%”
What is the dose which produces a toxic effect in 50% of subjects tested?

-Basically a measure of safety.
TI=TD50/ED50
-(TITE)
-Basically a measure of safety.
TI=TD50/ED50
-(TITE)
What does TI measure

-The LARGER TI = the safer the drug
-Means that the TD50 is much higher than the ED50, so you can take extra and it shouldn’t matter.

Desired = 10X

Which drug is safer, one with a very large TI or one with a very small TI?

-Biological variability – even if animals were same sex, same size, given same dosage, all bodies react differently.
Why would every subject’s curve have different values than anyone else even though same dosage were given?

Graded dose-response curve
Which type of curve deals with multiple doses administered to a single subject?

-One subject tests a drug at a certain concentration.
-Once the drug effects have subsided, the subject is then tested with a higher dose, etc.
-Mean ED50, TD50 generated
Describe Graded dose-response curve

Quantal
Which curve (Quantal or Graded) measures MEDIAN ED50 or TD50?

Graded
Which curve (Quantal or Graded) measures MEAN ED50 or TD50

-In vitro, EC50 is used because we can hold the concentration constant
What is one type of situation where ED50 is not applied?

-The one shifted far left would have a higher potency
-If drug A had an ED50 with a log dose of 1, and drug B had an ED50 with a log dose of 100, drug A is 100x more potent as drug B
-The one shifted far left would have a higher potency
-If drug A had an ED50 with a log dose of 1, and drug B had an ED50 with a log dose of 100, drug A is 100x more potent as drug B
Which drug has a higher potency?

NO
Does high potency always mean better drug?

Relative potency
What compares ED50 values of drugs that produce similar effects, mostly comparing them at same binding site?

-Method used to classify receptors
-The RPS is the
-Method used to classify receptors
-The RPS is the “fingerprint” for the RECEPTOR and its SUBTYPES
-A way for pharmaceutical companies to determine which drugs target specific receptor subtypes
What is a relative potency series used to classify?

Efficacy and Intrinsic activity
What are two terms used for comparing maximum responses to drugs?

-A has a higher intrinsic activity and efficacy
-Ex. A is morphine and B is aspirin
-A has a higher intrinsic activity and efficacy
-Ex. A is morphine and B is aspirin
Which has a higher intrinsic activity, or efficacy

Potentiation
-Adding an agent can increase maximum response (shift up), lower ED50 (shift left) or BOTH
Potentiation
-Adding an agent can increase maximum response (shift up), lower ED50 (shift left) or BOTH
What is the term used to describe an increase in responsiveness to a drug?

Synergism
Synergism
The effect of two drugs given together is greater than the additive effect of each drug given alone is called…

Tachyphylaxis
Tachyphylaxis
A RAPIDLY-occurring decrease in response to a drug after repetitive administration

-Intermediate required for the response is “used up”
-Receptors internalized
-Signal transduction becomes uncoupled
Three ways tachyphylaxis can occur

Tolerance: opiates
Tolerance: opiates
A SLOWLY-occurring decrease in the response to a drug after repeated administrations. Ex?

Adaptive changes occur in underlying physiology of organ systems, organs, or cells
Way tolerance occurs

Receptor
A high affinity cellular binding site for endogenous substances and drugs which, when bound by a ligand, alters cellular function

1. Binding to receptor alters activity of enzyme or ion channel
-Cardiac glycosides with Na/K-ATPase
2. Binding to receptor initiates biological response (receptor is transducer, once activated – cellular transduction occurs)
Two general types of receptor interactions:

Agonist
a SPECIFIC agent, usually resembling an endogenous substance, which binds to a receptor and initiates a response

Affinity
Level (strength) at which agonist binds to receptor

Antagonist
Specific agent usually resembling endogenous substance, which binds to a receptor but does NOT initiate a response

Agonists DO
Antagonists DO NOT
Do agonists or antagonists have efficacy/intrinsic activity?

The effect a drug has on a cell is determined by its STRUCTURE
BASIS OF PHARMACOLOGY

1. Ka – dissociation constant (affinity of drug for receptor)
2. Intrinsic activity (how big of a response is generated by receptor once drug binds)
What two things are ED50 dependent on?

-All three drugs have same dissociation constant, but DIFFERENT INTRINSIC ACTIVITIES
-All three drugs have same dissociation constant, but DIFFERENT INTRINSIC ACTIVITIES
Full agonist, partial agonist, antagonist: What are their intrinsic values?

A - highest efficacy
B - middle
C - Lowest efficacy
A – highest efficacy
B – middle
C – Lowest efficacy
A term applied when maximum response is obtained and all receptors are NOT OCCUPIED; there are SPARE RECEPTORS which are not occupied when maximum response is produced

Agonists
Have intrinsic activity >0 and ≤1 and efficacy >1

-A - has spare receptors that haven't been used; therefore, highest efficacy
-B - reaches maximum response, but uses all receptors; therefore, efficacy lower than A
-C - reaches lower response than A and B; lowest efficacy
-A – has spare receptors that haven’t been used; therefore, highest efficacy
-B – reaches maximum response, but uses all receptors; therefore, efficacy lower than A
-C – reaches lower response than A and B; lowest efficacy
Table and figure from last slide

NO
Does potentcy depend on a drugs mechanism of action?

nitroglycerine, tyramine
Examples of drugs that exhibit Tachyphylaxis

opioids, antibiotics
Examples of drugs that exhibit tolerance?

Concentration of agonist, and the dissociation constancy
What is the fraction of bound receptors determined by?

alpha times fraction of bound receptors
Spare receptor effect = maximal dose achieved without all receptors being bound
What is the effect on a given dose of an agonist relative to its maximal dose determined by?
Exception?

Intrinsic activity of a drug
Define Alpha

EC50 the drug concentration giving 50% maximal effect (not binding affinity – the magnitude of a drug effect is not proportional to the proportion of receptors occupied by that drug) a drug with a lower EC50 is more potent (half …

systemic dose relationship has two components: Dose – Plasma concentration relationship -Determined by pharmacokinetics parameters of drug (half life, clearance, volume of distribution) Plasma Concentration – Response relationship -Can be studied using in vitro studies How to Determine a Dose- …

Non-catalytic Receptors Ligand or drug reversibly binds the receptor and elicits an effect; the ligand remains unaltered by the non-catalytic receptor Catalytic Receptors Ligans or drug reversibly binds the receptor and elicits an effect; the ligand is altered by the …

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1. A drug, given as a 100-mg single dose, results in a peak plasma concentration of 20 μg/mL. The apparent volume of distribution is (assume a rapid distribution and negligible elimination prior to measuring the peak plasma level): A. 0.5 …

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