“Corpora non agunt nisi fixata [drugs will not act unless they are bound]” – Paul Ehrlich
It was the renowned German scientist, Paul Ehrlich (1854-1915), who devised the concept of the ‘magic bullet’, that is to say, a drug with direct specificity to treat a given disease. Since then discovering such a ‘magic bullet’ has proved increasingly difficult. The nearest modern approximation one might point to would be monoclonal antibodies, drugs with a very high degree of specificity.
The quote from Ehrlich is particularly relevant in this regard. At that time, Ehrlich postulated that drugs do not act unless they are bound, but what exactly do drugs bind to and what are the mechanisms that underpin this process?
Let’s take a look at some common drug interactions:
Drug interactions due to their acidic or basic properties
1. Antacids have the effect of neutralising acidity in the stomach by increasing pH. Examples of antacids include magnesium hydroxide, calcium carbonate and aluminium hydroxide.
2. The anticoagulant effects of heparin can be reversed by protamine sulfate; a cationic peptide that forms a stable ionic complex with heparin, inhibiting its effects.
Interaction of a drug as a membrane surfactant
3. The antifungal (and in some cases antiprotozoal) drug amphotericin B acts in this way. It binds to ergosterol in the cell membranes of fungi. This is highly specific because ordinary cells use cholesterol rather than ergosterol. Amphotericin B binds with ergosterol, creating a polar pore by which ions, such as potassium, can leak out and cause cell death.
The use of astringents
4. Astringents are agents that act to constrict body tissue – they invariably achieve this through denaturing proteins. By shrinking the mucous membranes, they assist in the treatment of sore throats and oozing blisters. Examples of common astringents include calamine, zinc oxide, acacia and cold water.
What are Receptors & What are the Major Subtypes?
Even though many drugs act through mechanisms, such as those described above, the most common mechanism is through interactions with receptors or receptor sites. So what are the distinguishing features of receptors?
Receptors bind drugs (also referred to as ligands) with a relatively high degree of specificity.
Receptors, after binding of the ligand, initiate a cascade of reactions known as the signal, in order to exert its biological effect.
Drugs may bind to receptors but they may also bind to other proteins, such as albumin or glycoproteins, but this binding does not produce a signal and, as a result, these proteins cannot be considered receptors.
For the purposes of this introduction, we will analyse three major subtypes of receptors:
Enzymes are proteins that assist in metabolic reactions that help to maintain the integrity of a living organism. Thus, if you disrupt these metabolic processes then you disrupt the integrity of the living organism and it’s with this principle that drugs can target metabolic processes to achieve its therapeutic effect.
An example of this is the drug used in the treatment of hyperuricemia and gout. Xanthine Oxidase is an enzyme that contributes to the production of uric acid – the substance involved in the precipitation of gout. Therefore, if you can inhibit the production of uric acid you go in some way to helping either to prevent or treat gout itself. Allopurinol is a drug that acts as a xanthine oxidase inhibitor and therefore reduces the production of this uric acid. However, it’s important to note that Allopurinol does not treat an acute attack of gout but rather acts as a prophylactic against future attacks of gout.
Ion channels control the flow of ions across the cell membrane of cells and this is important for functions such as maintaining the resting membrane potential and regulation of cell volume. Drugs can act on these ion channels and initiate therapeutic effects.
An example of this can be seen in the antiarrhythmic drug Verapamil which acts on L-Type Calcium Channels. By blocking the calcium channels (a type of ion channel), they can decrease the conduction of impulses through the atrioventricular node of the heart and thereby prevent arrhythmias occurring in the ventricles. Calcium channels are also found on blood vessels and so when Verapamil blocks these channels it has a consequent effect of helping to dilate these blood vessels, thus helping in the treatment of hypertension.
A second example concerns a drug that acts on ion channels at the neuromuscular junction. This junction that, as the name suggests, connects the nervous system with the musculoskeletal system, acts to initiate muscular movement through the action of neurotransmitters that came from motor nerves. Thus, by blocking the action of neurotransmitters at this neuromuscular junction we can initiate a therapeutic effect.
An example of this is the action of d-Tubocurarine on ion channels at the neuromuscular junction. This drug was originally used by South American natives as an arrow poison in hunting. Even though the animal was contaminated with d-Tubocurarine, the natives were still able to consume the meat because this drug does not easily cross mucous membranes. The name itself, d-Tubocurarine, takes its name from the arrow poison, called ourare, and the fact the plant from which it’s derived was shipped to Europe in tubes. The plant from which this alkaloid drug is derived is the climbing vine, Chondrodendron tomentosum.
Despite this interesting history, d-Tubocurarine has the effect of blocking the nicotinic acetylcholine receptor (called nicotinic as the receptor is also activated by nicotine as well as acetylcholine), which is a type of well-studied ion channel, and thereby causes the relaxation of voluntary muscles. However, we must not lose sight of the fact that the central point to be gained from the examples of Verapamil and d-Tubocurarine is that they both act on different types of ion channels and it’s these ion channels that are a subtype of receptors and its receptors that initiate therapeutic effects for many drugs.
Membrane receptors, when activated, usually result in activation of secondary enzymes or ion channels through the medium of what are known as G proteins. In other words, once the membrane receptor is activated, it sends a signal to the intracellular side of the cell membrane which ultimately affects these G proteins. These G proteins, in turn, activate enzymes or ion channels which can cause a therapeutic effect. Check out the illustration on the right for a diagrammatic representation of this process.
An example of this type of receptor activation behaviour would be the drug Atropine. This drug is a naturally occurring alkaloid that is extracted from the deadly nightshade plant, Atropa belladonna. The name atropine comes from the name of Atropos who was one of the three Fates of Greek mythology (along with Clotho and Lachesis) who controlled the direction, or fate, of every mortal being. Atropine, being a blocker at the muscarinic acetylcholine receptor, has the effects of dilating the pupils, raising the heart rate and reducing secretions and salivation.
Thus, we have so far come across two types of acetylcholine receptor: [popup url=”http://pharmafactz.com/wp/wp-content/uploads/2014/12/nicotinic-ach-receptor.jpg” width=”555″ height=”323″ scrollbars=”no” alt=”Nicotinic ACh Receptor”]nicotinic[/popup] and [popup url=”http://pharmafactz.com/wp/wp-content/uploads/2014/12/muscarinic-ach-receptor.jpg” width=”555″ height=”617″ scrollbars=”no” alt=”Muscarinic ACh Receptor”]muscarinic[/popup]. If you remember back, it was d-Tubocurarine which blocked the nicotinic acetylcholine receptor, which was a receptor associated with ion channels. The muscarinic acetylcholine receptor, by contrast, is associated with G proteins. We saw that the former were named nicotinic receptors because of their affinity for nicotine (as well as acetylcholine of course) – muscarinic acetylcholine receptors have an affinity for muscarine. Muscarine is a product of certain mushrooms and was first extracted from the Amanita muscarina variety.
Chemical Interactions between Drug & Receptor
So far, we’ve looked at the way how drugs work in terms of both non-receptor and receptor activity. Now we’re going to move on and take a look at the various chemical interactions that can take place between the drug and the receptor is aims to interact with. There is a wide variety of chemical interactions with which drugs can interact with their receptors, some of the most notable include:
Electrostatic Interactions: These interactions include [popup url=”http://pharmafactz.com/wp/wp-content/uploads/2014/12/hydrogen-bonding.jpg” width=”340″ height=”258″ scrollbars=”no” alt=”Hydrogen Bonding”]hydrogen bonds[/popup] and [popup url=”http://pharmafactz.com/wp/wp-content/uploads/2014/12/van-der-waals-forces.jpg” width=”500″ height=”490″ scrollbars=”no” alt=”Van der Waals Forces”]Van der Waals[/popup] forces. These are the most common types of interaction between drug and receptor.
Covalent Bonds: These are the least common type of interaction between drug and receptor. An example of this type of reaction would be [popup url=”http://pharmafactz.com/wp/wp-content/uploads/2014/12/phenoxybenzamine.jpg” width=”488″ height=”675″ scrollbars=”no” alt=”Phenoxybenzamine”]Phenoxybenzamine[/popup] binding to alpha-adrenergic receptors.
Hydrophobic Interactions: This type of [popup url=”http://pharmafactz.com/wp/wp-content/uploads/2014/12/hydrophobic-interactions.jpg” width=”555″ height=”389″ scrollbars=”no” alt=”Hydrophobic Interactions”]drug-receptor interaction[/popup] is important for lipid soluble drugs.
Stereospecific Interactions: Greater than fifty percent of drugs exist as stereoisomers. This stereospecificity is crucial in the drug interacting appropriately with the receptor to induce the correct response. As an example, S (-) Carvedilol binds to both α and β adrenoceptors whereas the R (+) Carvedilol binds selectively to a adrenergic receptors. Carvedilol acts as a drug in the treatment of hypertension and congestive heart failure. In addition, see [popup url=”http://pharmafactz.com/wp/wp-content/uploads/2014/12/optical-isomers.jpg” width=”555″ height=”295″ scrollbars=”no” alt=”Name”]Optical Isomers[/popup] for an illustration of the difference between the R and S enantiomers of the drug Thalidomide and how this difference can have markedly different effects.
The Dose-Response Relationship
There are only a given number of receptors and therefore the amount of these receptors that are filled acts as the degree of concentration for that drug. Evidently, the more receptors that are occupied then the greater the concentration of the drug. The concentration can increase to a point where all available receptors have been occupied. The graph below illustrates this occupancy of receptors by the drug. These graphs thus illustrate the dose-response relationships. Dose-response relationships are an important tool that one can use to greatly facilitate not only how drugs work but also the means by which they are potent and efficacious.
You’ll note that the graph on the left is in a linear scale. The shape of the graph can be described as hyperbolic and can be explained by a Langmuir binding isotherm. We can see that as the concentration of drug increases it reaches a saturation point where no further receptors can be occupied by the available drug. However, when this graph is plotted on semi-log scale (log of drug conc. versus effect), we can see that it turns to a sigmoidal shape. This method of scaling dose-response relationships is the most preferred method because it allows you to accurately figure out what the EC50 value is. The EC50 can be defined as the concentration that produces 50% of the maximum response for that receptor.
What are Agonists & Antagonists?
We have been discussing for quite a long time in this article what we mean by receptors and detailing the different types of receptor and how they interact with the drug. This final section takes a look at what we call the drugs depending on the action that they have. The traditional distinction is between that of the Agonist and the Antagonist – so what exactly are agonists and antagonists.
An agonist can be defined as a drug that bind to receptors and activate them.
An antagonist can be defined as a drug that binds to a receptor without activating them and consequently prevents the agonist from binding to the receptor.
A commonly used illustration to help understand the agonist and the antagonist is to think of a lock and key. The key (agonist), as long as it’s the correct shape and size, will have the correct properties to enable it to enter the lock (receptor). However, if you have a key that is slightly different in properties then it will stop you from opening the lock properly; this is akin to the antagonist.
At this point it would be fruitful to understand the various properties of what it means to be an agonist. Two central properties are Affinity and Efficacy.
Affinity can be defined as the ability with which the drug is capable of binding to its receptor. A drug with a high affinity will have a greater probability of binding to an available receptor should they become available. A drug with a higher affinity is said to have a greater potency – in other words, imagine you have Drug A and Drug B. Drug A, at a lower concentration than Drug B, can exert its biological effect, therefore we can say that Drug A is more potent than Drug B, as you require more of Drug B to achieve that of Drug A.
Efficacy can be defined as the ability with which the drug is capable of exerting its biological effect in the correct way.
To illustrate this, take a look at the following graph.
In order to distinguish between potency and efficacy, we need to look at the graph in two ways. First, we need to note that all four drugs (A, B, C and D) all have the same efficacy, that is to say, that all achieve 100% biological response at some point in time. However, you’ll notice that some drugs achieve this biological response with lower concentrations, this is because Drug A has a greater degree of potency than Drug B etc. In other words, you require less of Drug A to achieve the same biological response as you do for Drug D, which requires more, as the graph illustrates.
We can also see from this graph that the EC50 values are shown. Therefore, we can confidently say that the most potent drug will also have the lowest EC50 value. If we recall the definition of the EC50 as that value which is required to produce 50% of the maximum response for that receptor, then this would make perfect sense.
However, just to complicate things only slightly, agonists can differ in terms of their relative efficacy. In this sense, we can define relative efficacy as the relative maximum response from the drug. Drugs that produce less than the maximum activation of a given receptor are referred to as Partial Agonists. We can understand this concept more clearly by taking a look at the graph below.
We can learn quite a few new things from this graph and neatly follows on from what we’ve been discussing previously. First of all, we need to see that all four drugs are equipotent, that is to say, they have the same potency. This can be seen by due fact that they all harbour equal EC50 values. However, while these drugs have the same potency, they differ in terms of their efficacy, we can see this by looking at the % biological response from each drug. Drug A can be considered a classic agonist in that it produces maximal response and we can also see that it is exactly twice as efficacious as Drug C. We can see that Drug B is also an example of a partial agonist. Drug D would be an excellent candidate to act as an antagonist and has approximately 100 times less efficacy than Drug A.
This completes our basic exploration into how drugs work in the body.
We went through acidic/basic drugs, astringents and membrane surfactants to highlight the way drugs can act. We then went through the most common methods by which drugs act; and that is through the use of receptors. We looked at the various types of receptors (enzymes; ion channels; and membrane receptors) and then concluded by looking at the relationship between drug and receptor. This meant assessing chemical interactions, dose-response relationships, and finally concluding with a brief discussion of agonists, antagonists, partial agonists and each of their relative properties.