Basics of Pharmacology I – Characteristics of Drugs Any substance or drug can act either as an 

agonist or an antagonist. An agonist is a
substance that acts as an activator, or promotes activity of a specific regulatory
Pharmacology, oh pharmacology. Truly, quite a challenging field to master. Do I really have to
system or body process. An antagonist is a substance that acts as an inhibitor, having
know ALL these drug names?
But not to worry, mastering pharmacology comes with mastering the basics of this field. the opposite effect to the agonist.
For those of you who don’t know, pharmacology is a very broad term that refers to the study of But wait, what do these drugs act on? Drugs act on a regulator molecule, known as
substances that interact with living systems through chemical processes. These chemical a receptor, which literally receives the agonist or antagonist molecule, and sends the
processes can be triggered especially due to two major mechanisms: signal to the body system it regulates, changing it to the liking of the agonist (activate)
or antagonist (inhibit).
1. Activating or inhibiting normal body processes.
2. Binding to regulatory molecules.
Furthermore, these substances that induce these chemical reactions can either have:

1. Therapeutic Effects, by disrupting some negative process occuring in the patient.

2. Toxic effects, as used by parasites on their host.
That’s right, pharmacology isn’t all the drugs we all assume it to be – it literally includes any
substance that can act on the body, therapeutic or toxic.
Thus, it is important to specify what we mean exactly, by pharmacology.
The study of the therapeutic portion of pharmacology is referred to as medical
pharmacology, which is the science of substances used to prevent, diagnose and treat a
particular illness.

A drug must have certain characteristics that make it appropriate for interacting with a
In contrast, the study of the toxic or undesirable effects of substances on individual cells or
entire ecosystems is toxicology. receptor, and each receptor is very specific, only responding to a very specific drug.
Furthermore, in pharmacology, a drug must also be easily delivered to a patient.
However, remember that although toxicology probably makes you think about poisons and Thus, drugs that are artificially delivered to patients must have the following
parasites, any substance, even those intended to be therapeutic drugs, can be toxic in high characteristics in order to be an effective pharmacological drug:
amounts.
Just as an additional point of note, different drugs can actually have marginally (or majorly)
1. The drug must have a very specific size, shape, atomic configuration and
different effects on the body based on each individual’s genetics. The study of the relationships
electrical charge to be able to interact with the receptor.
of drugs in pharmacology to the genetic makeup of an individual is known
2. A drug must have the necessary properties to travel to its site of action or
as pharmacogenomics.
receptor from its site of administration.
Now that we’ve covered some general terms, let’s talk about the real meat of pharmacology.
3. It must be easily inactivated or excreted from the body once it has been
Nature of Drugs
used for its purpose.
We can define a drug as any chemical that brings about a change in biologic function
These drugs can either be synthesized within the body, in which case they are
through its chemical actions. Compare this to the definition of pharmacology! The
called hormones, or chemically synthesized outside the body.
“substances” referred to in the definition of pharmacology are in fact, drugs, be it
therapeutic or toxic.
 Of these drugs, poisons are drugs with harmful effects, HOWEVER, any drug or
hormone in extremely high amounts can have harmful effects and thus, function as a
poison. Of these poisons, toxins are poisons that are biologically synthesized.

So if we think about a drug from here on out, we would have to think about two things:

1. The effect of the drug on the body: This is known as pharmacodynamics.

2. The effect of the body on the drug (eg. what does the body do with the drug?
This includes factors like how the body breaks down the drug, and how the body
transports and removes the drug). This is known as pharmacokinetics.

(Diagram courtesy Basic and Clinical Pharmacology).

Before we can talk about either of these though, we must consider the characteristics of a drug.

Characteristics of Drugs:
 The molecular size of a drug varies from the very small, (eg. lithium ion, MW of 7) to
very large (eg. alteplase, of MW 59,050).
Physical and Chemical Nature of Drugs
Ideally however, a drug has a molecular weight between 100 and 1000.
Any drug given to the body can either be a solid (eg. aspirin), liquid (eg. ethanol) or
Let us think about what sizes like this would mean for a drug.
gas (nitrous oxide).
Remember first of all, that a drug has to be sufficiently unique in order to have effects
What is the importance of this physical nature?
at receptors, which are very specific for size, charge, shape and atomic configuration.
The physical nature of the drug determines how the drug is administered to the body.
It is found that a drug must be of a certain size to have sufficiently unique
Furthermore, drugs administered can all be carbohydrates, lipids or proteins, and this
characteristics that allow it to bind to a receptor. This size is approximately 100MW.
also affects their route of administration. The route of administration is a matter of
Thus, the  lower limit of drug size, 100MW, is determined by the need for the drug to
pharmacokinetics, and will be discussed in detail in a later post, “Basics of
be sufficiently unique and interact with the receptor.
Pharmacology III – Pharmacokinetics.”
This means the drug can be anything above 100MW right? Not particularly.
One must also take note of the chemical nature of drugs. The addition of simple
chemical groups have a large difference on the overall nature of the drug and its
interactions with receptors and enzymes. As an example, a drug, acetylcholine, is
usually hydrolyzed by acetylcholinesterase. When a methyl or a CH3 group is added
however, the resultant methacholine is much more resistant to the effect of
acetylcholineesterase. Furthermore, if an amine group is substituted for a methyl
Look at this dog trying to fit through the cat door – it just can’t fit!
group, then the resultant carbachol is completely resistant to the effects of
If we think about the drug as the dog, and the cat door as the space allowed for
acetylcholineesterase.
transport of a drug, then we see the problem. All drugs must be able to carry
out diffusion to move to the compartments in which they are needed. If the drug size
is too large, then there is no way for the drug to diffuse into compartments, and the
ability to diffuse decreases. Small drugs are able to fit through the small pores and
into compartments where they can be used. Larger drugs just can’t fit.
It is found that the upper limit of drug size then, is determined by the need for the
drug to be able to be transported or moved within the body. Thus, drugs larger than
1000MW do not diffuse readily, and thus most drugs are below 1000MW.
Note that however, drugs larger than 1000MW can still be used, but must be directly
injected into the compartment where they act, so as to minimize the distance the drug
must move, or be transported. As an example, alteplase, MW 59,050 is a clot
dissolving drug that is injected directly to the vascular compartment by an intravenous
or intra-arterial administration.
To summarize, the drug size must high enough to be unique to a receptor (this
determines the lower limit of drug size, 100 MW – a drug ideally should not be lower
than this), but must be low enough to still be able to move properly to the target cells
Drug Size
 (this determines the upper limit of drug size, 1000MW – a drug ideally should not be  Usually found in the interactions between highly lipid-soluble drugs
higher than this, as the transport of the drug will be negatively impacted. and lipids in the cell membranes.
What is important is not the actual nature of the chemical bond, but the strength of the
Drug Reactivity and Drug Bonds
bond, and it’s significance to the drug-receptor interaction.
Drug-receptor bonds are of 3 major types:
Suppose we want a drug that is highly specific, and only interacts with very few and
very specific target cells, then would it make sense to use an extremely reactive drug,
 Covalent
that would easily react with a number of substances along its way to the target cell, or
 Covalent bonds, as you know, are very strong bonds, that are not
would not be able to differentiate between two resembling, but different receptors?
readily broken. An example of a drug that uses a covalent mechanism of action
The answer is no. Therefore, the strength of the drug-receptor bond determines the
is aspirin, which forms a covalent bond with its target enzyme, cyclooxygenase.
specificity of the drug. Drugs that bond via weak interactions usually are more
 Aspirin works in two ways:
specific, simply because only one particular type of receptor can be able to bind it and
 An anti-inflammatory drug for pain relief and anti-
thus induce its effect. Another side effect of using a weakly reactive drug is that the
inflammation, by preventing production of the cyclooxygenase
drug cannot remain bound for very long, and thus has only short acting effects.
produced substance, prostaglandins.
Thus ,to summarize, if we wish to have a specific, short-acting effect, a drug with low
 An anti-clotting agent, or blood “thinner,” by
reactivity is ideal. If we wish to have a broad acting, powerful and long-lasting
preventing the production of thromboxane A2, another
effect  (think aspirin, as discussed above), we use drugs with higher reactivity.
cyclooxygenase produced substance.
 Wouldn’t you ideally want a blood thinning, pain relief drug
to be long lasting? There lies the logic behind covalently bound drugs –
their duration of action. The only way to reverse the effects of aspirin
would be to synthesize new enzymes in new platelets, a process that
would take several days to complete.
 Electrostatic
 This is a much more common type of bond in drug-receptor
interactions, and is weaker than the covalent bonds.
 They can either be:
 Relatively strong ionic linkages between permanently
charged molecules (eg. electrostatic interaction between Na+ and Cl-).
 Weaker hydrogen bonds that occur in highly polar
molecules.
 Very weak induced dipole interactions such as Van Der
Waals forces.
 Hydrophobic
Drug Shape
 These bonds are quite weak. Look at the picture below:
 However, remember that the more active enantiomer at one receptor does not
necessarily have to be the more active enantiomer at another receptor. For example,
in a drug called carvedilol, one enantiomer, the (S)(-) enantiomer, is a potent Beta-
receptor blocker, while the (R)(+) enantiomer is 100 times weaker. However, both
enantiomers are equally effective with Alpha receptors. When a drug is given that
Conceptually, think of a receptor as a lock, and the enzyme as the key that “activates”
contains both chiral forms of the drug, it is referred to as a racemic mixture.
the lock. For this to happen, the drug has to be a perfect shape to “fit” into the
receptor.
Chemically, a drug has to have a certain configuration that allows it to be chemically
active and thus, react with a drug.
Hence, the drug must be of a specific  shape that allows it to interact with the
receptor.
Now look at this image below:

It’s easy to see why a right hand would fit into a right sided glove, than the left hand
right? Similarly, remember that many molecules demonstrate chirality, and
form enantiomers. To elaborate, I mean that some molecules and drugs have the
same chemical and structural formulae, but they are arranged differently in space. As Similarly, one should remember that enzymes and drug transporters are also
an example: sensitive to different enantiomers, and thus act more strongly against one enantiomer
to another, affecting ease of transport and length of action of the drug. This is another
way in which chirality affects the action of a drug.

Both of these molecules are exactly the same in all ways except that one is like a
mirror reflection of the other. This is just like looking at our hands isn’t it? Our hands
are basically a reflection of each other, but have very similar anatomies.
Now imagine the receptor being specifically, a left sided glove. It is easy now to see
why chirality is important. Only the one that is correctly placed in space or oriented,
will fit into the receptor, and this is why both drug chemical makeup and chirality are
important for the drug-receptor interaction.