Medical Pharmacology Topics
Drugs have an effect either by direct chemical interaction (ex. lowering blood pH with bicarbonate) or by interacting with cellular receptors. Receptors are molecular entities with which drugs interact to produce their biological effect.
Most receptors are proteins, but DNA is the receptor for several classes of antineoplastic agents, and RNA forms part of the receptor for some antibiotics. Ligands are ions or molecules that form a complex with the receptor (or other macromolecules).
Properties of Receptors
The key properties of a receptor are its ligands, affinity, specificity and localization.
The strength of interactions between a ligand and a receptor is the ligands' affinity for that receptor. Receptors are discriminating in their binding properties so that different compounds may bind with differing affinities. The specificity of a receptor allows it to discriminate among generally similar molecules and bind only those with specific features.
Localization restricts certain types of receptors to specific cell types. At the cellular level, receptors may be cytosolic or membrane bound.
The ligand must pass through the cell membrane to interact with a cytosolic receptor. Steroid and thyroid hormones activate cytosolic receptors that move to the nucleus and regulate transcription. Since protein synthesis is requird, the effect of drugs that target cytosolic receptors is usually delayed, compared to other receptors.
Enzymes (cytosolic or membrane bound) may be drug receptors. A specific type of enzymatic receptor has tyrosine kinase activity, which in turn regulates intracellular cascades.
In addition to enzymatic receptors, membrane-bound receptors may be ion channels or G-protein linked. An ion channel may be influenced by ligands, including drugs. Other membrane-bound receptors may be linked to intracellular cascades through G-proteins.
Receptor BindingAn agonist is a chemical that, when bound to a receptor, stimulates the receptor to produce its appropiate biological response. The response may be stimulation or inhibition, depending on the type of receptor. A ligand may or may not be an agonist.
k1
R + L 
RL 
response
k-1
The velocities of the forward and reverse reactions are proportional to the concentration of ligand and receptor, and the concentration of ligand-receptor complex, respectively:
vforward = k1 [R] [L] and vreverse = k-1 [RL]
This relationship illustrates the probability that ligand and receptor will form a complex within a set time interval. If we assume that (1) interactions are fully reversible, (2) total receptor (RT) available is a much smaller number than ligand concentration, and (3) the system approximates equilibrium (d[RL]/dt ~ 0), a hyperbolic equation can be derived:
[RL] = [R]T
[L]
Kd + [L]
Kd is the dissociation constant, equal to k-1/k1. The higher the affinity of ligand for a receptor, the lower the Kd.
The hyperbolic curve describing the relationship between [RL] and ligand concentration is known as the Langmuir isotherm. It describes an hyperbolic curve, i.e. there is a saturable increase in ligand-receptor concentration with increases in free or total ligand concentration. The curve approaches an asympotote, or theoretical maximum, equal to the total receptor concentration. The value of Kd equals the ligand concentration producing half maximal binding.
The data from a Langumuir isotherm is often ploted on a semilogarithmic scale, to yield a sigmoidal cuve, commonly called a log-dose response curve. The sigmoidal curve aproaches a value equal to the total receptor concentration, and the inflection point corresponds to Kd. When comparing two ligans' log-dose response curve, the leftmost curve will represent the ligand the th least affinity for the receptor.
Antagonists and Other Agonists
An
antagonist is a chemical that bloock the efect of an agonist on a receptor.
There are four types of antagonists: competitive, noncompetitive and irreversible.
The action of a competitive antagonist (aka surmountable antagnist) can be blocked
by excess agonist.
The actions of a non-competitive antagonist (aka insurmoutable) cannot be blocked by excess agonist. Non-competitive antagonists may be reversible or irreversible.
An irreversible antagonist forms a chemical bond with the receptor thus inactivating it permanently. The action of irreversible antagonists is not diminished by dilution or by washing under conditions that remove reversibly-bound ligands.
Some ligands excert agonistic effects on a receptor but in a way that interfere with regular agonists or basal activity of the receptor. These include the partial agonists and inverse agonists, which in some ways also "antagonize" the action of agonists.
A partial agonist as affinity for the receptor and can excert some agonist action but at a much lower than a "full" agonist. The result is similar to a "week" antagonist.
Inverse agonists bind to receptors and tend to hold them in fully or partial inactive states. If the basal action of the receptor was high enough to bre measurable, then the inverse agonist will lower activity below the basal level.
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[Q1].
Need more practice? Answer the review questions below.
Questions:
1- List 2 ways drugs have their effect.
2- What is a receptor?
3- What are receptors made of?
4- What is a ligand?
5- List 4 key properties of receptors.
6- What is the affinity of a receptor?
7- What is the basic nature of a receptor's affinity regarding different ligands?
8- What is the specificity of a receptor?
9- What is the importance of localization of a receptor?
10- List two possible locations of receptors in the cell
11- List 2 examples of ligands for cytosolic receptors.
12- Explain how do steroid and thyroid hormones work as ligands.
13- Are enzymes receptors?
14- Explain how a tyrosine kinase enzyme can act as a receptor.
15- List 3 types of membrane-bound receptors.
16- What is an agonist?
17- List 2 types of general receptor responses to an agonist?
18- Sketch the reaction scheme representing the interaction between a receptor and an agonist.
19- Define the velocities of forward and reverse reaction for the equation in #18.
20- Explain the velocity relationships in #19 in terms of probability.
21- What equation defines concentration of receptor-ligand complex ([RL]) based of the velocity relationships in #19?
22- List 3 assumptions used to derive the equations in #21.
23- What is Kd?
24- How does affinity relate to Kd?
25- Sketch the graph for the equation defining [RL].
26- working...
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Answers:
1- List 2 ways drugs
have their effect.
direct chemical interaction
interaction with cellular receptors
2- What is a receptor?
Molecular entities with which drugs interact to produce their biological effect.
3- What are receptors
made of?
Most receptors are proteins, but DNA is the receptor for several classes of
antineoplastic agents, and RNA forms part of the receptor for some antibiotics.
4- What is a ligand?
Ions or molecules that form a complex with the receptors (or other macromolecules).
5- List 4 key properties
of receptors.
ligands
affinity
specificity
localization
6- What is the affinity
of a receptor?
The strength of interactions between a ligand and a receptor is the ligands'
affinity for that receptor.
7- What is the basic
nature of a receptor's affinity regarding different ligands?
Receptors are discriminating in their binding properties so that different compounds
may bind with differing affinities.
8- What is the specificity
of a receptor?
Property that allows the receptor to discriminate among generally similar molecules
and bind only those with specific features.
9- What is the importance
of localization of a receptor?
Localization restricts certain types of receptors to specific cell types.
10- List two possible
locations of receptors in the cell
cytosolic
membrane bound
11- List 2 examples
of ligands for cytosolic receptors.
steroid hormones
tyroid hormones
12- Explain how
do steroid and thyroid hormones work as ligands.
The ligand must pass through the cell membrane to interact with a cytosolic
receptor. Steroid and thyroid hormones activate cytosolic receptors that move
to the nucleus and regulate transcription. Since protein synthesis is requird,
the effect of drugs that target cytosolic receptors is usually delayed, compared
to other receptors.
13- Are enzymes
receptors?
Enzymes (cytosolic or membrane bound) may be drug receptors.
14- Explain how
a tyrosine kinase enzyme can act as a receptor.
A specific type of enzymatic receptor has tyrosine kinase activity, which in
turn regulates intracellular cascades.
15- List 3 types
of membrane-bound receptors.
enzymatic
ion channels
G-protein linked
16- What is an agonist?
An agonist is a ligand that, when bound to a receptor, stimulates the receptor
to produce its appropiate biological response.
17- List 2 types
of general receptor responses to an agonist?
stimulation
inhibition
18- Sketch the reaction
scheme representing the interaction between a receptor and an agonist.
k1
R + L
RL
response
k-1
19- Define the velocities
of forward and reverse reaction for the equation in #18.
The velocities of the forward and reverse reactions are proportional to the
concentration of ligand and receptor, and the concentration of ligand-receptor
complex, respectively:
vforward
= k1 [R] [L] and vreverse
= k-1 [RL]
20- Explain the
velocity relationships in #19 in terms of probability.
These relationships illustrate the probability that ligand and receptor will
form a complex within a set time interval.
21- What equation
defines concentration of receptor-ligand complex ([RL]) based of the velocity
relationships in #19?
[RL] = [R]T [L]
Kd + [L]
22- List 3 assumptions
used to derive the equations in #21.
interactions are fully reversible
total receptor (RT) available is much smaller than agonist concentration
the system approximates equilibrium (d[RL]/dt ~ 0)
23- What is Kd?
Dissociation constant, equal to k-1/k1.
Also equals the ligand concentration producing half maximal binding.
24- How does affinity
relate to Kd?
The higher the affinity of ligand for a receptor, the lower the Kd.
25- Sketch the graph
for the equation defining [RL].