Pharmacodynamics

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).

There are four main kinds of targets for the 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.
• Enzymes - both intracellular and extracellular ones.
• Ion Channels
• Transport proteins

Agonists

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.

• The rate of complex fromation 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_A.

This can be defined as the concentration of a drug which results in 50% of receptors being bound in equilibrium or when K₁=K_-1.

Drug + Number of Free Receptors = Drug-Receptor Complexes
 
 Where K1 is the rate constant in a forward direction
 and K-1 is the rate constant in a backward direction

Therefore a drug that has a higher affinity to a receptor has a lower K_A 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.

Please Insert Appropriate Graphs

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 potency of a drug is very important clinically as it will determine the dose needed to have the desired clinical effect. Often if a drug is more potent it is usally more selective to which target molecules it binds to.

Full and Partial Agonists

• A full agonist is defined as an agonist that is capable of producing the maximal response of a tissue. To achieve this the number of receptors occupied varies and in some cases very few receptors need occupying. This is called the spare receptor hypothesis and is very relevant when thinking about multiple drugs working at the same receptor site simultaneously.

• A partial agonist is unable to produce the maximum tissue response however great the dose or concentration of the drug. It must be remembered that a partial agonistmay have a greater, lesser or equal affinity to a receptor site compared to a full agonist.

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.

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

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.

Effector Linkage Mechanisms

Once the agonist binds to the receptor the cell response can be formed in three different ways:

• By the opening of a ligand gated ion channel
• By an intracellular second messenger system
• By DNA transcription