The Lego® Model of Pharmacology

In understanding drugs and how they work, it can be helpful to think of the body and its atoms as a giant set of Lego® bricks[1]. A child can use Lego® bricks to make buildings, space ships, cars, etc; and the body can use its atoms to build muscles, bones, signaling molecules, etc. Moreover, just as the child can disassemble her building and then use the bricks to make a car, the body can disassemble its muscle and build bone. Of course, the car requires special bricks (e.g. wheels) which aren’t needed to make a building, and bone needs special atoms (e.g. calcium) which aren’t needed to make a muscle: the number of cars the child can make is limited by the number of wheels she has, and the amount of bone the body can make is limited by the amount of calcium available.

This last point is important. It means that if we want to regulate the number of cars that the child makes, we only need to regulate the number of wheels we allow her to use. We might do this because we have too many cars, and don’t want any more, or we might do so because we don’t have enough buildings (or space ships, or bridges) and want to conserve our bricks to make those instead of cars.

In the body, if we want to regulate the amount of bone we make, we can regulate the amount of calcium there is to make it with. We might do this because we have too much bone, and don’t want any more, or we might do so because we don’t have enough of something else, and want to conserve building materials to make, say, muscle.

Pharmacology (the science of drugs) manipulates the body by interfering with the way it uses its atoms. Continuing with the Lego analogy, drugs are the equivalent of another person adding or removing bricks to the buildings, cars, space ships, etc as they’re being built or after they’re finished; or adding or removing bricks from the box of unused bricks.

[1] Lego® is a registered trademark of the LEGO® Group of companies, which does not sponsor, authorise, or endorse this site

Immune system animations

The immune system is a vast collection of tissues and cells that work together to keep the body free of infection. In doing so, the system has to balance between hypoactivity, which allows infection to reign, and hyperactivity, which causes allergies and autoimmune conditions. A complex system of local and long-distance signals allow for the system to respond appropriately. Long distance signals place the body and the immune system on alert. Local signals tell arriving immune cells that they are entering the war zone, and to draw their weapons (keeping the weapons holstered until they arrive at the battle field reduces friendly-fire incidents)

There is also the problem of recognition - immune cells are worthless if they don't know what to attack, since they ignore pathogens (bacteria, etc) and attack host cells (self). The system by which immune cells are schooled requires specialized environments and signaling processes.

This site shows animations that explain many of the intricacies of the immune process. It's much more than you need for the MCAT, but very useful for those of you already into med school.

The Action Potential

Action Potential is the term describing the sending of a signal from one end of an axon (the axon hillock) to the other end of the axon (by the synapse). What follows is the basics of this phenomenon.

Remember that in almost every cell, including neurons, the Na/K pump is continuously running in the background. This pump, of course, pumps three Na+ out for every two K+ it pumps into the cell. In doing so, it creates several gradients:*

1. a Na+ gradient, where Na+ is greater on the outside of the cell than on the inside
2. a K+ gradient, where K+ is greater on the inside of the cell than on the outside
3. an electrical gradient, where the outside of the cell has more positive charges (is more positive than) the inside of the cell. Thus, the inside of the cell is negative in comparison to the outside of the cell, and a polarity exists across the cell membrane. This electrical gradient is known as the membrane potential, and it’s normal value (inside perhaps -70 mV with respect to the outside) is referred to as the resting (membrane) voltage, or resting potential.

Because of these gradients, if we were to open a Na+ channel, Na+ would be drawn into the cell for two reasons:

1. there is more Na+ outside of the cell than inside of it
2. the inside of the cell is negative with respect to the outside of the cell, attracting the positively charged Na+ ions

If we were to open a K+ channel, K+ would be torn between two impulses:

1. the K+ gradient, which would push K+ out of the cell
2. the electrical gradient, which would pull the positively charged K+ ions into the relatively negative interior of the cell

An action potential involves channels for both Na+ and K+. Both channels are voltage-gated (which means that they are triggered to open by changes in membrane potential). Na+ channels open quickly, but after being open for a brief time they lock closed. K+ channels don’t open as fast as the Na+ channels do. K+ channels do not lock closed. Threshold potenital is the membrane potential at which the channels are triggered.

If we focus on the cell body of the neuron, and on its dendrites, we find several ion channels in it. These channels open and close in response to incoming signals, and let positive and negative ions enter and leave the cell. If enough positive ions enter the cell, then the voltage across the membrane (the membrane potential) reaches the threshold potential and triggers those Na+ and K+ channels on the axon hillock. These channels then open.

DEPOLARIZATION:
The Na+ channels open first. Na+ pours into the cell, bringing its positive charge with it. This positive charge continues to grow, and eventually spreads as far as the next voltage-gated Na+ channel. When the positive charge at this next Na+ channel grows to a large enough size, it triggers that Na+ channel (remember, the Na+ channels are triggered to open by the membrane potential). Sodium flows in through this Na+ channel, and the positive charge spreads down to a third Na+ channel, triggering it to open. This process continues, opening the Na+ channels one at a time, with each Na+ channel allowing in the Na+ ions that trigger the next Na+ channel to open. This advancing wave of positive charge is the signal that is passed down from one end of the cell to the other. We call this phenomenon depolarization because the initial polarity across the cell membrane is lost as the positively charged Na+ ions enter the cell. (In fact, we actually end up with the cell interior being slightly positive.)

REPOLARIZATION:
If all we had was Na+ channels, we could send a signal, as described above, but then positive charge would have filled the axon, and there would be no way to send a second signal. So, we have to have a way to reset this membrane potential. This resetting is the job of the K+ channels. Recall that the same membrane voltage changes that trigger the Na+ channels also trigger the K+ channels, but that the K+ channels are slower to react. Eventually, however, the K+ channels do react, and do open, and K+ rushes out of the cell. K+’s exit moves positive charge out of the cell, returning the cell membrane voltage to its normal value of slightly negative inside the cell, and frankly overshooting a bit, so we end up a bit too negative. The Na/K pump helps return the cell from this overshoot (hyperpolarization) to normal membrane potential. We have regained our normal, resting membrane voltage, so we call this repolarization.

DEPALARIZATION + REPOLARIZATION = ACTION POTENTIAL:
The wave of depolarization, followed by its wave of repolarization, is known as the action potential.

REFRACTORY PERIODS:
Above, I noted that the Na+ channels, after being open for a brief moment of time, lock closed. Obviously, as long as they are locked closed, they cannot open, and so cannot participate in an action potential. This period during which the Na+ channels are locked closed is known as the absolute refractory period, since no amount of stimulation can cause another action potential to pass down the neuron.

Following the absolute refractory period is the relative refractory period. Remember how the K+ channels cause us to overshoot our target membrane voltage? Until the Na/K pump has returned the membrane to its proper resting voltage, the cell membrane is too negative, and a larger than normal force is required to change the cell membrane voltage enough to trigger an action potential.

* The pump also creates an osmotic gradient, where the number of particles outside the cell is greater than those inside the cell. The osmotic gradient is not used in the action potential, and is further complicated by the fact that running the pump splits ATP (a single osmotic particle) into ADP and Pi (two osmotic particles), which would tend to cancel the osmotic effect of pumping three ions out of the cell for each two ions pumped in. However, the ADP and Pi are generally swiftly recycled back into ATP, etc, etc, and at this point we're getting to be more complicated than we need to be. Focus on the three gradients already mentioned, and you should be fine.