Lecture 2- Basic Pharmacological Principles Flashcards
Pharmacodynamics
What the drug does to your body
Alterations in the function or process of a tissue by the drug
How is pharmacodynamics expressed?
In relative terms; relative to the physiological condition that exists at the time of drug administration
Ie: lessening of pain; increase in euphoria; reduction in depression
Site of Action
Part of the body (organ, tissue, cell, receptor/transporter protein) where a drug acts to initiate a chain of events leading to an effect
Where a drug acts to produce an effect
Mechanism of action
Means by which the presence of the drug produces an alteration in function at the site of action to produce a drug effect
How a drug acts to produce an effect
Receptors
Tissue element (usually a protein) with which drugs act to produce a characteristic biological effect
Ehrlich’s Receptor Theory of Drug Action
A drug must interact by combining or binding with the macro molecular tissue element (receptor) at the site of action in order to initiate a series of events that produce its biological effect
Forces to attract drug to receptor
Drugs can only produce their effects when they fit the receptor as a special key fits a well designed lock
What do drugs binding to receptors show?
Remarkable selectivity (most drugs bind strongly to one particular receptor)
What do receptors show?
Specificity (most receptors only allow certain drugs to bind)
Are drug receptor binding complexes stable? What does this enable?
Relatively stable
Enabling the initiation of the action effect sequence
Not so stable that it cannot be reversed
What are selectivity, specificity and reversibility due to in regards to a receptor?
Due to the synchronous operation of a number of chemical bonds- not a single bond
Chemical bonds
Forces that hold drugs to its receptor
Ionic bonds
Electrostatic attraction Transfer of electrons (+ molecule binds to a - molecule and vice versa) Rapid and relatively strong bond Can occur across distances Hold a drug to its receptor
What holds a drug to its receptor?
Ionic bonds
Covalent bonds
Sharing a pair of electrons
Very strong bond (20x stronger than ionic bonds)
Accounts for the stability of most organic molecules
What accounts for the stability of most organic molecules?
Covalent bonds
Hydrogen bond
Type of ionic bond with hydrogen (+ charged)
Weak bond, but if multiple hydrogen bonds are formed can lead to high stability
Van Der Waals Forces
Weak attractive force between 2 neutral atoms
Operate In close range
“Final notches In key that opens the door”
Basic pharmacological principle
The degree of a drug effect produced by a drug is a function of the quantity of drug taken
Dose
Amount of drug needed at a given time to produce a particular biological response
Amount of drug needed to achieve a particular concentration of a drug at the site of action
Factors of absorption, distribution, bio transformation and excretion
What two things does the concentration of a drug at its site of action depend on?
The dose administered
Time (to get to and from the site of action)
Drug effect is a consequence of what?
A reversible chemical or physiochemical reaction between a drug and a receptor leading to a biological change
Occupancy of receptors by a drug is proportional to what?
The concentration of the drug and the concentration of free, unoccupied receptors
Magnitude of the pharmacological effect elicited by a drug should be directly proportional to what?
The number of receptors occupied by the drug
What are AJ Clark’s 4 quantification of dose-effect relationships assumptions?
- Law of mass action is applicable to reversible reactions between a drug molecule and one receptor
- All receptors are identical and equally accessible to the drug
- Intensity of the response to a drug is directly proportional to the number of receptors occupied by the drug and is a direct consequence of he drug-receptor interaction
- Amount of drug that interacts with receptor is negligible compared to the amount of drug to which the receptors are exposed; effective drug concentration does not change during drug-receptor interactions
C
Concentration of drug (equal to that of unbound drug)
Y
% of total number of receptors occupied by a drug
(100-Y)
% of unoccupied, free receptors
K1
Constant specific for he given reaction of the drug/receptor combination
K2
Constant specific for he reverse reaction of the given drug/receptor combination
Rate of drug-receptor combination=
K1C(100-Y)
Rae of dissociation of he drug receptor combination=
K2Y
C=
K2Y/k1(100-Y) or if ratios of 2 constants is constant =Kd*Y/100-Y
What is radioligand binding assay used to estimate?
How much receptor might be in a given tissue and the affinity of the receptor for the drug
What are the steps of radioligand binding assay?
- Homogenize (grind up) tissue of interest that contains your receptor (this liberates the cellular compartment that contains your receptor)
- Incubate your tissue with increasing concentrations of a radioactive drug that is known to bind to your receptor or (if you are testing a new drug) that you suspect binds to your receptor
- In control tissue, add your radioactive drug + a high concentration of a non radioactive drug that is known to also bind to the receptor (nonspecific binding control)
- Wash off excess drug(s)
- Measure radioactivity in samples from both conditions to get 2 curves
- Subtract the area under the curve for your non-specific binding from that of your total binding—> specific binding curve
Bmax
Maximal binding= 100% receptors are occupied ~total number of receptors at target site
What is the kd calculated as?
The concentration of radioligand that results in 50% of maximal binding (Bmax)
In scatchard plot, when one binding site is involved, what does the data follow? What is the kd and what is the Bmax?
Straight line
Slope=kd
X intercept=Bmax
In Scatchard plot, with two binding sites, what does the data follow? How do you get Kd and Bmax?
Convex curve
Slope of each line=kd
X intercept=Bmax
Kd
Measure of affinity of a drug for a particular receptor; effectiveness of drug-receptor interaction
Higher affinity —>
Better propensity to bind to a receptor; the Lower the kd
The lower the value of kd=
The lower the concentration of drug needed to produce the same intensity of response as a drug with a higher kd
What portion of he curves indicates relative affinities?
X axis (higher affinities lie closer to the Y axis)
What can a dose response curve provide a measure of?
Potency
Potency
The dose needed to produce a particular effect of a given intensity
Potency varies with what?
Inversely with the magnitude of dose
Affinity=
Kd
What two things does potency depend on?
- Depends on inherent ability of the drug to bind to a receptor
- Depends on factors regulating how much drug reaches the site of action
Potency is what type of expression of what?
Comparative expression of drug activity at a particular site (relative to a standard of reference)
Drug effect is a consequence of what?
A reversible chemical or physiochemical reaction between a drug and a receptor leading to a biological change
Occupancy of receptors by a drug is proportional to what?
The concentration of the drug and the concentration of free, unoccupied receptors
Magnitude of the pharmacological effect elicited by a drug should be directly proportional to what?
The number of receptors occupied by the drug
What are AJ Clark’s 4 quantification of dose-effect relationships assumptions?
- Law of mass action is applicable to reversible reactions between a drug molecule and one receptor
- All receptors are identical and equally accessible to the drug
- Intensity of the response to a drug is directly proportional to the number of receptors occupied by the drug and is a direct consequence of he drug-receptor interaction
- Amount of drug that interacts with receptor is negligible compared to the amount of drug to which the receptors are exposed; effective drug concentration does not change during drug-receptor interactions
C
Concentration of drug (equal to that of unbound drug)
Y
% of total number of receptors occupied by a drug
(100-Y)
% of unoccupied, free receptors
K1
Constant specific for he given reaction of the drug/receptor combination
K2
Constant specific for he reverse reaction of the given drug/receptor combination
Rate of drug-receptor combination=
K1C(100-Y)
Rae of dissociation of he drug receptor combination=
K2Y
C=
K2Y/k1(100-Y) or if ratios of 2 constants is constant =Kd*Y/100-Y
What is radioligand binding assay used to estimate?
How much receptor might be in a given tissue and the affinity of the receptor for the drug
What are the steps of radioligand binding assay?
- Homogenize (grind up) tissue of interest that contains your receptor (this liberates the cellular compartment that contains your receptor)
- Incubate your tissue with increasing concentrations of a radioactive drug that is known to bind to your receptor or (if you are testing a new drug) that you suspect binds to your receptor
- In control tissue, add your radioactive drug + a high concentration of a non radioactive drug that is known to also bind to the receptor (nonspecific binding control)
- Wash off excess drug(s)
- Measure radioactivity in samples from both conditions to get 2 curves
- Subtract the area under the curve for your non-specific binding from that of your total binding—> specific binding curve
Bmax
Maximal binding= 100% receptors are occupied ~total number of receptors at target site
What is the kd calculated as?
The concentration of radioligand that results in 50% of maximal binding (Bmax)
In scatchard plot, when one binding site is involved, what does the data follow? What is the kd and what is the Bmax?
Straight line
Slope=kd
X intercept=Bmax
In Scatchard plot, with two binding sites, what does the data follow? How do you get Kd and Bmax?
Convex curve
Slope of each line=kd
X intercept=Bmax
Kd
Measure of affinity of a drug for a particular receptor; effectiveness of drug-receptor interaction
Higher affinity —>
Better propensity to bind to a receptor; the Lower the kd
The lower the value of kd=
The lower the concentration of drug needed to produce the same intensity of response as a drug with a higher kd
What portion of he curves indicates relative affinities?
X axis (higher affinities lie closer to the Y axis)
What can a dose response curve provide a measure of?
Potency
Potency
The dose needed to produce a particular effect of a given intensity
Potency varies with what?
Inversely with the magnitude of dose
Affinity=
Kd
What two things does potency depend on?
- Depends on inherent ability of the drug to bind to a receptor
- Depends on factors regulating how much drug reaches the site of action
Potency is what type of expression of what?
Comparative expression of drug activity at a particular site (relative to a standard of reference)
