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Introduction to Pharmacodynamics

Pharmacodynamics = what a drug does to the body


drug is any exogenous chemical which affects the workings of body.


To understand pharmacodynamics we must understand the drugs, receptors and signaling involved.  These different mechanisms of action will lead to different physiological responses.


Most drugs “act” on receptors (there are some that don’t – these are discussed briefly at the end of this article). Receptors are molecules (usually proteins) to which specific substances can bind and cause effect. If a drug works by binding with a receptor, it can also be called a ligand.  A drug is an exogenous ligand, i.e. it comes from outside the body.  However, many molecules in the body work by binding to receptors too; these are therefore called endogenous ligands, i.e. they come from inside the body.


Ligands bind to a discreet area of the receptor (often referred to as the active or binding site) that is complementary in size and shape to the ligand.  It is easy to think of this using a lock-and-key metaphor.  The key (ligand) inserts into the lock (receptor) and causes a response.  Only some keys will fit the lock, and only some of those keys will be able to cause a response.


When we think about how they cause their effect, drugs can be referred to as agonists or antagonists.


Agonists v. antagonists


Agonists can be subdivided further to full, partial, and inverse agonists.

  • A full agonist will produce a full response, i.e. 100% of the response seen by endogenous ligands.  Using our analogy, the lock is fully opened.
  • Partial agonists stimulate the receptor to a limited extent, but in doing so prevent any further stimulation from endogenous substances.  This means you can still get a response from the drug, but it may not be as much as that from endogenous ligands.  Unfortunately this situation stretches our analogy a little – the best fit would be the key opens the lock a little bit, and in doing so prevents the full agonist from opening it fully.
  • An inverse agonist is one which reverses constitutive activity of a receptor.  Using our analogy, this is when in its natural state the lock is already open, producing a baseline response.  The inverse agonist therefore closes the lock, and so reduces the response.  You may think that surely this means this type of drug is an antagonist, not an agonist.  However, remember an antagonist merely prevents the agonist from exerting an effect – it doesn’t actually cause an effect itself.  An inverse agonist does exert an effect itself, and so is an agonist.


Antagonists can also be subdivided into competitive or non-competitive, reversible or irreversible.

  • A competitive antagonist competes with the substrate to bind to the receptor.  This means it takes a higher concentration of agonist to overcome the competition from the antagonist, ie. the antagonism is surmountable/reversible.  Using our analogy, the key goes into the lock but can’t open it, and it’s presence in the lock prevents the right key going in.
  • A non-competitive antagonist inhibits the response by binding to an area separate to the active site of the receptor.  Again the analogy needs to be stretched – let’s say it’s a bit like when you slide that button down on a Yale lock so even if someone on the outside has the correct key, they can’t turn the latch.
  • Reversible and irreversible inhibition is pretty easy to explain.  Either it can be reversed…or it cannot.  Aspirin is a good example – it binds irreversibly to its receptor COX-1, and this blockade cannot be overcome until the body manufactures more COX-1 and breaks down the old inactivated COX-1.



The actions of agonists and antagonists can be plotted on graphs, with dose on the x axis and response on the y axis.  These are known as dose-response curves, and are used in the development and marketing of drugs.  You will therefore need to have a basic understanding of them when drugs reps are trying to market their new drugs.


For example, a dose-response curve for a full agonist will look like this:


Dose-response curve of an agonist

As you can see it reaches a plateau level where all the receptor binding sites are occupied by the agonist, and so increasing the dose even further will not make any difference.


If you add in a competitive antagonist, the curve is shifted to the right, like so:


Dose-response curve of a competitive antagonist

This shows that a full response can still be achieved despite the presence of an antagonist; it just requires a higher dose.  Therefore, the antagonist must be competitive.


By comparison, adding in a non-competitive or irreversible antagonist shifts the dose-response curve downwards:



Dose-response curve of a non-competitive antagonist

This is because the blockade cannot be overcome by increasing the dose of agonist.




Secondary Messengers

Binding to the receptor is not the whole story in the how drugs lead to their correct effect in the body. In many cases drug-receptor binding activates (or inhibits in the case of antagonists) either an enzyme or a series of secondary messengers. These are chemical substances that relay signals from an activated receptor to a target molecule in the cell, and so altering the physiology of the cell.


When a receptor is activated, its 3D shape changes.  This can then activate secondary messengers in different ways:

  • Sometimes this has the effect of turning the receptor into an active enzyme, and it can then alter the structure or function of a secondary messenger by catalysing a reaction. 
  • Sometimes activation means the receptor can bind to another protein, which when bound changes shape itself and then becomes an active enzyme.
  • Lastly, sometimes activation means the receptor becomes an open ion channel, and ions can flow from one side of a membrane to the other.  These ions can then act as secondary messengers by binding to target cells or other messenger molecules.


An example of a secondary messaging system is G-proteins.  These are proteins within the cytoplasmic side of the cell membrane which, when activated by binding a chemical called GTP, splits into two pieces.  One of these pieces increases levels of an enzyme called adenylate cyclase, which in turn increases cellular production of cAMP (cyclic adenosine monophosphate).   cAMP is a common intracellular secondary messenger used in many different cellular processes throughout the body.


This may seem like a complicated way to send a signal from receptor to target.  However, the use of secondary messengers is nature’s clever way of amplifying a signal.  It’s a bit like one of those emails that say ‘distribute it to 10 people and you will win a million pounds’.  One person receives the email and sends it to 10 people.  Those 10 people then send it to 10 people each, who then send it to 10 people.  Within four stages you have increased the number of emails to 1000, five stages 10,000 etc.  In the same way, one ligand molecule binding to one receptor can result in hundreds of secondary messengers in the cytoplasm within nanoseconds.  These hundreds of secondary messengers can bind to thousands of target molecules and your signal is greatly amplified.  This process is called signal transduction.


G-proteins aren’t the only type of transducers.  Box 1 gives an overview of the different types of receptors and their signaling.


Receptors and their transduction systems

Efficacy and safety of drugs


Many different types of experiments are used to determine drug action.  In most instances you cannot just plot a dose-response curve, work out the dose needed to cause a maximum cellular response, and give that to a patient.  The efficacy and safety of drugs are multifactorial – our bodies are very complex, with thousands of chemical reactions going on at any one time.


All drugs have a therapeutic index.  This is a comparison between the dose which is effective and the dose that is toxic to the patient.  It is given as a ratio between two figures: the ED50 and the TD50.

  • ED50 is the dose that produces a therapeutic effect in 50% of the population (ED = effective dose)
  • TD50 is the dose that produces a toxic effect in 50% of the population (TD = toxic dose)

You may also come across the term LD50 (LD = lethal dose).  This is used in animal studies, and describes the dose required to kill 50% of the animal sample.  For obvious reasons, we do not use this in human studies!


These figures can be easily seen on dose-response curves:


Therapeutic Index


Therapeutic indexes can be quite narrow, such as with some antibiotics such as gentamicin or vancomycin.  These drugs therefore have more potential to do harm if prescribed incorrectly, or blood levels not monitored and doses adjusted accordingly.


Narrow Therapeutic Index

Pharmacodynamic complications


Over  time the body’s response to a drug may change.  A well known example of this is in the long-term use of opioid drugs, e.g. in heroin users.


Opioid users, whether therapeutic or recreational, can develop drug tolerance.  The fancy pharmacology word for this is tachyphylaxis.  The continued use of opiates results in downregulation of opioid receptor synthesis, i.e. less production of the receptors.  Fewer receptors logically results in less of a response to the same dose of opiate.  This is why over time heroin users have to increase the amount of drug they take, in order to get the same effect.


There are many other causes of changes in sensitivities to drugs, but these are largely beyond the scope of medical students!



Drugs that do not work via receptors


Some drugs work by binding to other things in the body, or not binding to anything at all.  Examples are antacids (neutralise the acid in the stomach), chelating agents (bind to heavy metal toxins and neutralise their effect), and osmotic laxatives (which draw water into the bowels just by their presence).




  1. Neal MJ.  (2009) Medical Pharmacology at a Glance, London: Wiley-Blackwell.
  2. McKay GA, Reid JL, Walters MR.  (2010) Clinical Pharmacology and Therapeutics Lecture Notes, London: Wiley-Blackwell.
  3. Harvey R.  (2008) Lippincott's Illustrated Review: Pharmacology, International Edition, London: Lippincott Williams & Wilkins.

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