Sesame Street pharmacology
Caffeine as a gateway drug, part four
This is part four in the Caffeine as a Gateway Drug series where we explore how drugs work by looking at caffeine.
In previous instalments we talked about how drugs get into the body and either act locally or make their way to the bloodstream for system wide effects.
We’re now going to look at how drugs work at a molecular level, known as pharmacology. You can’t really talk about pharmacology without getting a little bit technical. But the mission of this newsletter is to try help people understand how drugs work while walking the line between over the top technical, and too basic and condescending, so let’s give it a go…
There are a few things from Sesame Street that I have carried into adulthood.
One is the ABC song which I believe, as an Australian, is the one time it’s ok to pronounce the letter ‘z’ zee rather than zed despite what my kids teachers may say.
The other is the song that floats through my head whenever I count to 12.
One-two-three-four-five-six-seven-eight-nine-ten-eleven twe-e-e-e-e-e-elve
This song was part of the classic pinball countdown animation series. You can watch the full series and experience the nostalgia via the YouTube link below.
For those who aren’t familiar with it, it’s a series of 12 animations, each representing a number from 1 to 12.
Each animation starts with the same sequence. Someone launches a ball in a pinball machine while the catchy ‘1, 2, 3, 4, 5…’ song chimes as you follow the ball to its final destination. As it nestles into the receptacle you wait with anticipation to see which number it’ll be today…
The number sets a unique set of events in motion. Number 2 launches off on some rollercoaster carnival type thing with a creepy looking clown. Number 4 initiates a micro game of mini golf, 9 a micro game of baseball.
We’re going to use the Sesame Street pinball machine to understand how drugs elicit their effects in the body. It’s by no means a perfect analogy, but it’ll help convey the key concepts without getting too bogged down by technical terms, so I think it’s worth a try. You will need some imagination though…it’s Sesame Street after all!
Now you have to understand this pinball machine isn’t your standard variety. It’s capable of having multiple balls in play at any given time that travel around on a shared journey as the ‘eleven twe-e-e-e-e-elve’ reaches the finale and the ball arrives at its receptacle.
Unlike regular ball bearing style pinballs, these ones don’t have a perfectly smooth surface. Instead they’ve got some texture. Each pinball has a unique arrangement of bumps and grooves on its surface.
What you don’t see in the animation (because we’re imagining it) is how the surface of the pinball determines how it interacts with the receptacle. If the grooves and bumps of the ball are a match it’ll nestle nicely into the receptacle, bring up the number and trigger the pre-determined sequence of events. If not, it’ll just bounce out and keep on moving around until it finds its match somewhere else.
When the particular receptacle finds a match it brings up the same number every time. And the sequence of events that follows is the same every time. For instance, number 2 will always lead to this…
Some balls are very specific- they exclusively match with one receptacle so they will always brings up the same number sequence.
Others are non-specific- they’ve got lots of bumps and grooves on their surface so they can match with several receptacles, resulting in a range of possible number sequences.
So now we’re immersed in the world of the pinball machine, let’s think of it as a part of the body zoomed into the micro level where you can see things at a molecular level.
The pinball itself represents a signalling molecule called a ligand. These are substances that occur naturally in the body- things like hormones, peptides and neurotransmitters.
As explained in bodily logistics, substances like ligands are moved around the body by the one way transportation network of blood vessels that is the general circulation (queue the one-two-three-four-five music) until they arrive at a destination cell. Just like the pinball arriving at the receptacle.
In the case of a ligand, the receptacle at the destination cell is called a receptor.
A receptor is a protein that’s either accessible on the surface of the cell, or housed within the cell. Receptors that are inside the cell are harder to access by signalling molecules that reach the cell through the blood stream than those located on the surface.
Just as the bumps and grooves of the pinball determine which receptacles it matches with, so too structure of the ligand determine how it binds to the receptor.
When a ligand binds to a receptor it triggers a pre-determined sequence of events, although nothing as exciting as the pinball machine. The sequences they trigger inside a cell are things like the opening of a transport channel that lets something into or out of the cell, or a sequence that results in the production of a specific protein. We call this the intrinsic activity.
Ligands bind to a matched receptor and trigger a predetermined sequence of events in any tissue where the receptor is present. The way this shows up in the body will depends on how that intrinsic activity impacts the tissues the cells are situated in.
So far we’ve been talking about the signalling molecules (ligands) that occur naturally in the body. The technical term for this is endogenous substances- originating from within.
As we talked about in caffeine as a gateway drug part two, drugs come into the body from the outside. This is called an exogenous substance.
To think about the main two ways drugs work on receptors let’s return to the pinball machine.
Think of the drug molecule as an imposter pinball. Remember those surface bumps and grooves that determine whether or not the pinball nestles into the specific receptacle? The imposter pinballs have enough similar features to do the same.
But when the imposter pinball nestles into that receptacle one of two things will happen. Either it’ll bring up the number and the predetermined sequence of events.
Or…nothing.
It’ll just sit there blocking any other pinball from coming along and bringing up the number sequence.
When a drug matches with a receptor and sets off the sequence of events like the endogenous ligand it’s called an agonist. A drug that block the endogenous ligand’s sequence of events is called an antagonist.
The way this action of the drug on the cell (intrinsic activity) shows up in the body is referred to as the pharmacological effect. How many pharmacological effects you experience when you take a drug depends on the features of the drug, and how your specific body is made up.
To understand this better, let’s go back to our drug of choice, caffeine.
The pharmacology of caffeine
Caffeine has a few different actions in the body, but at the doses most people use it’s the interactions with adenosine receptors that are most important.
Adenosine is one of those endogenous ligands we talked about earlier. The physiological effects that result from adenosine activating its receptors are pretty broad but you can loosely think of it as being related to sleep and slowing things down.
Because adenosine is part of the metabolic pathway (how the body uses energy to do the things it needs to do) its receptors are found all over the body. When adenosine acts on these receptors as part of the body’s natural signalling processes, blood vessels dilate, nerve activity slows down, filtration by the kidney reduces, heart rate decreases and airways constrict, and more. This is part of the body’s way of keeping itself balanced.
Caffeine works by blocking the adenosine receptor (an antagonist). As we talked about in part three, it can travel everywhere in the body — including past the blood brain barrier and into the central nervous system. This means caffeine is capable of reaching the adenosine receptors throughout the body.
If you’ve got caffeine blocking the adenosine receptors it means the usual effects of adenosine throughout the body are blocked. The blood vessels aren’t dilated. The nerves aren’t slowed down. The filtration by the kidney isn’t reduced. The heart rate isn’t decreased. The airways aren’t constricted.
The way this can show up in your body is that you might have a slightly higher blood pressure, feel more alert and react quicker, urinate more, feel like your heart’s beating faster and breathe a bit more easily.
When these effects are considered acceptable to us, we call them desired or therapeutic effects. When the effect isn’t what we want, we call them side effects or adverse effects.
Obviously you and I may have a different idea about what’s considered desirable. There’s always a subjective component when it comes to the drug experience. Context is really important here. Another thing that’s important is dose. A bigger dose means more caffeine will reach the adenosine receptors across the body, resulting in more effects, many of which will be considered universally as undesirable.
There’s also a physiological reason why we each respond differently to drugs. In the case of caffeine, we each have a different ‘map’ of adenosine receptors in our bodies. There’ll be differences in the number of receptors overall, where they’re located and how densely they’re found in particular tissues. We call this the expression of receptors in the body.
Expression of adenosine receptors (and many other receptors) isn’t fixed, it changes over time. We can make more receptors (up-regulation) or have less (down-regulation) depending on certain factors.
When it comes to adenosine receptors, repeated exposure to caffeine (like drinking several cups of coffee each day) can result in more adenosine receptors being expressed in certain parts of the body. As a result you may find that a dose of caffeine no longer affects you in the same way after a period of time. This is known as tolerance (for those South Australians reading, this is probably why Peter Malinauskas can still go to sleep at night after drinking his 7 cups of instant coffee per day).
A final thing to note about the pharmacology of caffeine, and a good way to bring this lengthy newsletter to a close, is that the caffeine molecule doesn’t stay blocking the adenosine receptor forever. After a time the caffeine molecules come away from the receptor, leaving it free to accept the adenosine once more. By this time, there’s probably a lot of adenosine hanging around waiting for something to do, so it moves in quickly, bringing its sleep inducing, cognition blunting fatigue like effects – colloquially known as the caffeine related energy crash.
That was a lot to get through, but if you’ve come this far you’ve got yourself a pretty decent understanding of the mechanism of how many drugs work in the body. Noting that not all drugs work through receptor interactions, or by mimicking the effects of endogenous ligands. Maybe we’ll get to some of those in future writings after I’ve seen through my current obsession with caffeine.
Next week we’ll explore how we clear caffeine from the body, and start thinking about drug interactions - like the way smoking cigarettes impacts your body’s ability to get rid of caffeine.
Thanks so much for reading!
Until next time,
Lauren
That is so fascinating Lauren, I’m sharing it with my sister !