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→Full and Partial Agonists
|linkpage =WikiDrugs
|linkpage =WikiDrugs
|linktext =WikiDrugs
|linktext =WikiDrugs
|sublink = Basic Concepts of Pharmacology
|sublink1 = Basic Concepts of Pharmacology
|sublink = Basic Concepts of Pharmacology
|subtext1 = Basic Concepts of Pharmacology
|pagetype = Drugs
|pagetype = Drugs
}}
}}
'''Pharmacodynamics is the actions of drugs on the body.'''
'''Pharmacodynamics is the actions of drugs on the body.'''
For drugs to act upon the body the must be able to exert some chemical influence upon a cell to result in a physiological response. They are capable of doing this by binding to a target molecule (usually proteins).
For drugs to act upon the body they must be able to exert some chemical influence upon a cell to result in a physiological response. They are capable of doing this by binding to a target molecule (usually proteins).
There are four main kinds of targets for the drugs to bind to:
There are four main targets which drugs to bind to:
* '''Receptors''' - these are protein molecules that are capable of responding to endogenous chemical signals. They are usually found on the cell membrane, in the cytoplasm or on the nucleus and other organelles.
* '''Receptors''' - these are protein molecules that are capable of responding to endogenous chemical signals. They are usually found on the cell membrane, in the cytoplasm or on the nucleus and other organelles.
An agonist can be defined as '''a drug that binds to a target molecule and results in activation of the receptor and thus a tissue response'''.
An agonist can be defined as '''a drug that binds to a target molecule and results in activation of the receptor and thus a tissue response'''.
* An agonist forms a complex with the receptor. This complex is '''dynamic''' as the agonist will continously dissociate and associate with the receptor. The agonist will continue to do this and thus producing a response, until the concentration of the agonist is reduced to a level at which no tissue response occurs.
* An agonist forms a complex with the receptor. This complex is '''dynamic''' as the agonist will continously associate and dissociate with the receptor. The agonist will continue to do this and thus produce a response, until the concentration of the agonist is reduced to a level at which binding no longer occurs.
* The rate of complex fromation is dependent on two factors: '''agonist concentration''' and the '''number of free receptors'''.
* The rate of complex formation is dependent on two factors: '''agonist concentration''' and the '''number of free receptors'''.
* The '''affinty''' of a drug to a receptor varies and can be compared using the '''equilinbrum constant or K<sub>A</sub>'''.
* The '''affinity''' of a drug to a receptor varies and can be compared using the '''equilibrium constant or K<sub>A</sub>'''.
This can be defined as the concentration of a drug which results in 50% of receptors being bound in equilibrium or when '''K<sub>1</sub>=K<sub>-1</sub>'''.
This can be defined as the concentration of a drug which results in 50% of receptors being bound in equilibrium or when '''K<sub>1</sub>=K<sub>-1</sub>'''.
<big>'''Drug + Number of Free Receptors = Drug-Receptor Complexes'''</big>
<big>'''Drug + Number of Free Receptors = Drug-Receptor Complexes'''</big>
Where '''K<sub>1</sub>''' is the rate constant in a forward direction
Where '''K<sub>1</sub>''' is the rate constant in a forward direction (association rate constant)
and '''K<sub>-1</sub>''' is the rate constant in a backward direction
and '''K<sub>-1</sub>''' is the rate constant in a backward direction (dissociation rate constant)
Therefore a drug that has a higher affinity to a receptor has a lower '''K<sub>A</sub>''' value.
Therefore a drug that has a higher affinity to a receptor has a lower '''K<sub>A</sub>''' value.
* The biological response of resulting from an agonist is proportional to the number of receptors occupied. The size of a response can be measured and plotted against the dose/concentration of the agonist. As the size of a response normally increasee in a non-linear manner (until the maximum is reached) the response is normally plotted against the log of the concentration.
* The biological response resulting from an agonist binding is proportional to the number of receptors occupied. The size of a response can be measured and plotted against the dose/concentration of the agonist. As the size of a response normally increases in a non-linear manner (until the maximum is reached) the response is normally plotted against the log of the concentration.
'''Please Insert Appropriate Graphs'''
'''Please Insert Appropriate Graphs'''
[[File:Dose-Response Curve.png|thumb|dose-response curve used to calculate EC50]]
From these graphs two figures can be achieved, the '''ED50''' or '''EC50'''. The ED50 is the effective dose at which 50% of a maximal response occurs or 50% of individuals respond. The EC50 is the same but is the effective concentration. Agonists with higher affinities will have a lower concentration and so EC50 than an agonist with a lower affinity. The first drug is therfore said to be more '''potent'''.
From these graphs two figures can be achieved, the '''ED50''' or '''EC50'''. The ED50 is the effective dose at which 50% of a maximal response occurs or 50% of individuals respond. The EC50 is the same but is the effective concentration. Agonists with higher affinities will have a lower concentration and so EC50 than an agonist with a lower affinity. The first drug is therfore said to be more '''potent'''.
The difference between the full and partial agonist is it's '''efficacy'''. This is defined as the strength of the tissue response that results from the formation of a agonist-receptor complex. The efficacy of the partial agonist is lower than that of the full agonist.
The difference between the full and partial agonist is its '''efficacy'''. This is defined as the strength of the tissue response that results from the formation of a agonist-receptor complex. The efficacy of the partial agonist is lower than that of the full agonist.
It is still unclear why molecules that are chemically very similar have differing efficacies. Only now are the mechanisms behind it being gradually understand. This however doesn't mean that we ignore efficacy. It is of great practical importance as some drugs of equal affinity for a specific receptor may have widely differing efficacy.
It is still unclear why molecules that are chemically very similar have differing efficacies. Only now are the mechanisms behind it being gradually understand. This however doesn't mean that we ignore efficacy. It is of great practical importance as some drugs of equal affinity for a specific receptor may have widely differing efficacy.
===Inverse Agonists===
===Inverse Agonists===
These are agonists that bind to receptors that are continuely activated (even if no ligand is present) and result in the reduction of the level of activation. They therfore have a negative efficacy.
These are agonists that bind to receptors that are continuely activated (even if no ligand is present) and result in the reduction of the level of activation. They therefore have a negative efficacy.
===Effector Linkage Mechanisms===
===Effector Linkage Mechanisms===
* By an intracellular second messenger system
* By an intracellular second messenger system
* By DNA transcription
* By DNA transcription
==Antagonists==
==Antagonists==
===Self-antagonism===
===Self-antagonism===
If some drugs are repeadtedly given its effect can decrease. This is called '''tachyphylaxis''' or '''desensitisation'''. If a gradual decrease in response to a drug occurs this is called '''tolerance''' and if the drug looses total therapeutic efficacy it is deemed '''refractory'''. Many types of mechanisms occur to cause this phenomenon, the most important include:
If some drugs are repeatedly given its effect can decrease. This is called '''tachyphylaxis''' or '''desensitisation'''. If a gradual decrease in response to a drug occurs this is called '''tolerance''' and if the drug loses total therapeutic efficacy it is deemed '''refractory'''. Many types of mechanisms occur to cause this phenomenon, the most important include:
* chnage in receptor type
* change in receptor type
* loss of receptors
* loss of receptors
* exhaustion of cell mediators
* exhaustion of cell mediators
* physiological adaptation
* physiological adaptation
* active extrusion of the drug from cells
* active extrusion of the drug from cells
===Chemical Antagonism===
===Chemical Antagonism===