going to discuss the important topic of how drugs do enter the nervous system. We'll begin with our four drugs from the previous session, and we'll talk about nicotine. nicotine, as you know can enter the body by being smoked in tobacco cigarettes, pipes, cigars. It can also enter through the mucous membranes of the mouth by being chewed as tobacco leaves or by being chewed as gum for smoking cessation. It can also be placed into skin patches, and with a suitable solvent, it can then pass through the skin and enter the bloodstream for smoking cessation purposes. So, there are various routes for nicotine to enter the body. Lidocaine, the local anesthetic, is mostly used as an injected form, although it can also be placed in creams, where it enters the body for local relief, for instance in sunburn creams. Morphine can enter the body by being smoked. Opium leaves, by being injected for analgesic or for anesthesia, or for sedation. And morphine can also be placed in suppositories where it's quite effective. And finally, Botulinum toxin, our protein drug, for drug purposes cosmetic purposes, is usually injected locally. when it is a poison having been, having grown in food it is usually eaten. So these are a few routes into the body for our drugs. But let's look in detail about the events that occur once a drug gets into the body. We'll talk about it, typical alkaloid, for instance, and in this case, the alkaloid has a general other group, and it in addition, it has an amine in this example. It has a primary amine. Now, perhaps the most important concept in drug ent, entry into the brain is the fact that neutral molecules often pass through membranes, lipids, fats, by diffusion. They are quite soluble in these fatty and oily compartments. And so they go right through. However, the neutral molecule is usually not the pharmacologically active form.
The active form, the form that acts on
the receptor, is usually the protonated charged form. And there's an equilibrium between the neutral and the charged form. This equilibrium occurs in the brain, and it also occurs in other compartments of the body. So the concept that a drug acts in a charged form, but permeates in a neutral form, is quite important for most of, drugs and the brain. now, in some cases, we can move the equilibrium toward the charged form, toward the permeate form with higher PH. And I'll show you an example of that, in our next slide. Moving to the specific case of nicotine's path from the lungs to the blood and the brain. When a person takes a puff on the cigarette, which happens about 150 billion times a day in the world, vaporized nicotine enters the lungs. we then watch nicotine passing through six cell membranes made up of three cells. One of those cells is the endothelium of the alveolar epithelium. And two other cells, as we'll see in a few slides, are in the capillary in the brain. So nicotine passes through those six cell membranes and then enters the brain. This doesn't take long, as any smoker knows it take just a few seconds for nicotine to get to the brain. In the brain again, nicotine can be protonated, can gain a proton, can gain a positive charge. And it is this positively charged form of nicotine that interacts with the receptors. The pKa, the pH at which roughly half the nicotine is protonated and half deprotonated, is around eight. The pH of extracellular fluid is around 7.4 so that means that most of the nicotine in the brain is in the charged form. But again, this inter-conversion takes just a millisecond or so. Now, this inter-conversion can also occur in the lungs. Most cigarette, and cigarette manufacturers know this. And so, most cigarettes also contain ammonium hydroxide, to maintain neutral pH, or a bit basic.
As a result, in the lungs, or in the the
mouth, the nicotine is forced into more of the uncharged permeate form, and can permeate a, a bit more easily. So this is the example of Nicotine, obviously a crucial one for drugs and the brain. as a result, the concentration of Nicotine reaches a spike within just a few seconds. It's probably faster than indicated in these data from 10 or 15 years years ago. And then, Nicotine is metabolized by enzymes, mostly in the liver over the next 20 minutes to a couple of hours. And the result is that the Nicotine concentration in the blood falls to a steady state level between cigarettes. So here we have an example of the pharmacokinetics of Nicotine. Another example of drug permeation comes to us from therapy for Parkinson's Disease. In Parkinson's Disease, al, as we'll learn later on, most of the neurons that make Dopamine in the brain die. And so the challenge is to replace the Dopamine in the brain. However, Dopamine itself does not cross the blood brain barrier, does not go from the blood into the brain, it's charged, and therefore we need another tactic. The tactic is to use L-dopa, or Levodopa, which is a derivative of Dopamine that does permeate through the blood brain barrier. The way it permeates is not by being non polar. It is indeed neutral, but it's still fairly polar. It is zwitterionic because it has both the charged amine group and the charged carboxyl group. Instead the way Dopamine enters the brain, is by being transported by a specific protein that lives in cell membranes. Once it gets into the brain, an enzyme which is a catalytic protein, decarboxylates L-dopa. Turns it into Dopamine which can then be taken up into dopaminergic neurons, and released by dopaminergic neurons. So, this is an example, if you like, of a pro-drug. a drug that turns into another drug because
it is modified in the body.
What about this blood brain barrier? We've talked about it. Let's look at it in a bit more detail. Outside the brain, a capillary is, has connective tissue around it, but it also has a layer of cells called endothelial cells, outside the brain. There are gaps between the endothelial cells, allowing various types of molecules to diffuse across the connective tissue into the fluid outside the capillary. Proteins can diffuse. Non-polar moleucles can diffuse. Polar molecules such as glucose can also diffuse out of the capillary. In the brain however there are no spaces between the endothelial cells In the capillaries. There are capillaries of course, there are endothelial cells, but they have this structure called the tight junction connecting them. As a result proteins can't diffuse out of the capillary, polar molecules cannot diffuse out of the capillary. Non polar molecules can diffuse the way nicotine does through the endothelial cell membrane and, and into the brain. So the brain has a specialized barrier that prevents drugs from entering. Another view of the blood brain barrier emphasizes a group of cells called the glial, or glue cells. Glial cells are not neurons. There are, a large number of them in the brain. They send processes out that surround the capillaries. These are the glial feet. It used to be thought that the feet come closely together and provide the blood brain barrier. But now we know that, in fact, it's the tight junctions, between the endothelial cells that cause the blood brain barrier. Protects many drugs from diffusing out of the capillary into the brain. Again we have the tight junctions between the endothelial cells. Well what is this tight junction? It is the structural basis of the blood brain barrier. And you could think of the tight junction as a waterproof zipper.
These are individual protein molecules
that interact with each other and hold the cell membranes of 2 adjacent cells together in the capillaries of the brain. So if we have the extra cellular space for instance, in the blood here at the top, the extracellular space in the brain here at the bottom. The tight junctions provide a continuity, a seal, between cells, so that most small molecules cannot diffuse through them. So that's the structural basis of the blood brain barrier. Well, we've discussed drugs in the body and in neurons at the organ system level. We've talked about acid base equilibrium and permeability, uptake from the stomach, uptake from smoke. We've spent a little time on a more reductionist level talking about pro-drugs. in later lectures, we'll talk about the storage of drugs, more about the enzymatic breakdown of drugs, and about other ways of breaking down drugs and finally, elimination. So, this topic would be called pharmacokinetics. We've talked about the blood in more reductionist detail. We've talked about the blood-brain barrier. Its molecular basis. obviously the blood brain barrier is an opportunity for making specific drugs that don't enter the brain. But it's also a real problem if one wants to make drugs that do enter the brain. more reductionist still, we have mentioned crossing the cell membrane. And there are drugs that actually help other drugs, or prevent other drugs from calling cell membranes. We'll talk about neurotransmitter transport inhibitors in a later lecture. And finally, a topic that's not usually discussed in a neuropharmacology course, I call subcellular pharmacokinetics. we'll discuss drugs that short-circuit synaptic vesicles, allowing transmitters to leave those vesicles. And we'll also talk about pharmacological chaperoning,
that takes place in the endoplasmic
reticulum. That topic that I call inside-out pharmacology. So these are topics that we're going to emphasize in later sessions. But for now, let's get to the topic of proteins and drug receptors in our next session.