PHARMACODYNAMICS

Pharmacodynamics is the study of the biochemical effects and mechanism of action of a drug or substance.

This field concerns itself with how the drug causes its effects on your brain and body once it is absorbed.

This will be a quick introduction to the major components of pharmacodynamics and will introduce common jargon that will be referenced in future entries.

So, How Do Drugs Work and What the Hell is an Agonist or Antagonist?

When discussing psychopharmacology, we are looking at a category of a drugs that has an impact on the central nervous system. These types of drugs predominantly impact their effects by "binding" to specific enzymes called "receptors" that are covered over all of our neurons.

A Synapse

A neuron is a nerve cell and is characterized with have numerous long stretchy arms called dendrites, and one long stretchy arm called an axon. The dendrites are essentially the "inputs" to the neuron, and the axon is the "output". Each axon is connected to one (technically an axon can connect with numerous synapses, but for the sake of simplicity let's just look at the case of a 1:1 connection) dendrite from another neuron, forming a connection. The axon of the previous neuron and the dendrite of the next neuron do not physically touch, and the small gap is called a "synapse".

Neurons use charged ions to propagate a signal from the synapse down the dendrite to the soma (cell body). Once enough charge has accumulated, the cell undergoes a series of changes known as an action potential, which is colloquially referred to as the neuron "firing". Depending on what previous neurons this neuron has received signals from, the strength of those signals (which can increase over time as a natural part of learning), and a variety of other factors, neurons may or may not fire an action potential as it continuously receives signal from previous neurons.

When a neuron decides to fire, ions travel down the axon to the synapse, where the magic happens.

A neuron that has fired will trigger the release of one or more neurotransmitters (chemicals that act as signalling agents in the nervous system) to be released from the axon of the firing neuron to the axon of the receiving neuron. The types and amount of neurotransmitters released depends on the nature of the neuron itself (various neurons in your brain are configured to release different neurotransmitters). On the axon of the receiving neuron, there are located numerous enzymes that are called receptors. These are specific structures that have very complex shapes that only certain chemical compounds can interact with. Once a compound of the right structure and chemical property comes in contact with the receptor, it can bind itself to the receptor, causing various effects to occur on the cell.

Think of this like a lock and key. Only a specific key of a specific shape can open a specific lock, any other key will either jam up or won't fit into the key socket.

This leads us to the first important aspect of a drug's pharmacodynamics, it's binding affinity.

Binding Affinity

Now, the previous explanation made it seem like each receptor has a specific shape and only one compound that happens to fit it perfect can fit it. However in reality, this lock and key analogy actually breaks down. Most receptors are not that selective, and often times many compounds can bind to many different receptors.

That's right, it goes into the square hole!

Instead of a strictly binary, yes or no, receptors actually can probablistically receive different compounds (a compound that binds to a receptor is also known as a ligand), with compounds having a more fitting shape and chemical property being more likely to bind to a specific receptor. Furthermore, a drug is distributed in the bloodstream mostly pretty randomly, and there's no way to tell a molecule to go to a specific neuron and try to bind itself to a specific receptor. It will get there when it gets there. However, when talking about millions of molecules as an aggregate total, we can start using the law of large numbers to come up with some useful averages.

This is exactly where binding affinity comes in. The binding affinity of a compound for a specific receptor is its likelihood to bind to that receptor. The binding affinity is usually given as an inhibition constant (Ki value), which measures the average concentration of a specific compound that is required to occupy 50% of the given receptor. The Ki value has an inverse relationship with potency, meaning the lower the value, the less of the drug you need to feel the same intensity of effect.

LET'S LOOK AT A CASE EXAMPLE:

LSD and DMT are two well known psychedelic compounds. They exert most of their activity via biased agonism of the 5ht2a receptor (a subset of the serotonin receptor). However, LSD is far more potent than DMT, with a common dose being in the 100-200 micrograms range. DMT is generally dosed in the 20-40 milligrams range, requiring about a 200 times larger dose.

We can see a hint to cause of this behavior by looking at their comparative binding affinities at the 5ht2a receptor.

LSD

Binding Affinity at 5ht2a: 2.9nM [source]

This means 2.9 nano-moles of LSD molecules are needed to saturate half of your serotonin subtype 2a receptors.

DMT

Binding Affinity at 5ht2a: 0.237mcm (if my inconsistent sig figs bother you, there's a drug for that). [sauce]

This means that 0.237 micro-moles i.e. 237 nano-moles of DMT molecules are needed to achieve the same level of saturation.

This represents an 81.72x higher concentration needed.

Of course this doesn't map directly to the 200 number above, this is because of a combination of: potentially different intrinsic activity (what the drug does after it binds), inaccurate data about "common dosages", the significant effects that activity at other receptors might add, and the sheer fact that psychopharmacology is complicated.

Intrinsic Activity (Agonism. Antagonism)

Intrinsic Activity is the ability for a drug, once binded to a receptor, to achieve its maximum results. Just because a drug binds to a receptor, doesn't mean it will cause the receptor to do the same thing as if a different compound binded it!

Before we dive too deep, let's look at a relatively oversimplified picture of things. In today's discussion we will skip the concept of GPCRs (g-protein coupled receptors) and biased agonism / functional selectivity and only focus on a simplified model of agonism /antagonism. We will fill in these oversimplifications in future articles.

ENDOGENOUS LIGAND

Every receptor is assumed to have an endogenous (naturally produced in your body) neurotransmitter or compound that is "meant to" bind to it and cause a certain amount of activity. This neurotransmitter is generally referred to as the "endogenous ligand" for a given receptor, with the receptor and the ligand generally sharing a name. For example, Serotonin is the endogenous ligand for the family of Serotonin Receptors (such as the 5ht2a one we discussed earlier).

AGONIST / FULL AGONIST

We first have to look at the endogenous ligand for a receptor, and see what impact it has. We define this amount and type of response as "full agonism". Here, agonism essentially just means "causing the same effect that the endogenous ligand would". A drug that can cause 100% of the same effects that the natural chemical would is considered a "full agonist", and it is said to achieve full-agonism at the receptor.

PARTIAL AGONIST

Now what if we had a compound that can only achieve 50% the effects of the natural chemical, no matter how much you take, even if every single receptor is saturated? This is something that is considered a "partial agonist". A partial agonist essentially is any compound that achieves less than the full effects of the endogenous ligand even at max or infinite dosage.

ANTAGONIST / SILENT AGONIST / SILENT ANTAGONIST

Now there are even compounds that bind to a receptor and then does absolutely nothing. It causes 0% of the effects of the endogenous ligand. This is now called a silent agonist, or more commonly an "antagonist". Once this compound binds to the receptor and sits there pointlessly, it is now also competing for that spot against your own endogenous ligand. If you had a bunch of antagonists that binded to your dopamine receptors, for example, your own dopamine will need to play musical chairs with this drug, lowering its ability to bind to the receptor. Because of this, antagonists are seen as an antidote of the receptor's primary function by competing for position in the receptor. (There are also noncompetitive antagonist and allosteric modulators, which we will get to in a future article).

INVERSE AGONIST

There's also a class of drugs that seem to have an inverse effect compared to the endogenous ligand. Not only does it compete for position, it also intrinsically reverses the effects that the ligand-receptor pair normally would have

SUPER AGONIST

There's no reason to assume our own body's natural chemicals are the most perfect fit for our receptors. In fact this is often not the case! We have discovered drugs that can have an even stronger on the receptor than its own endogenous ligand! These are known as super agonists.

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Now what are these intrinsic behaviors and what do different receptor/ligand compounds do? That's a very complex question that we'll discuss more in the future!

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Pharmacodynamics Basics. What the hell is an agonist or antagonist?