What are bases? How do the work - pharmacological action

[Lightning-Nl]

I've been confused on this for quite some time. I'm confused about medications and their "salts" but if I list everything I don't know, we could be here all day - so let me start off with the things I do know.

Paroxetine Hydrochloride is the most prescribed, most sold prescription drug in the world. Studies showed it to be effective in treating depression - but only when bound to Hydrochloric acid. The reason for this is due to the fact that Paroxetine in freebase (all by itself, in it's natrual form) can't be effectively distributed into the plasma by the gut, so it's unable to enter the blood in quantities that are even measurable.

Why is this? Because Paroxetine freebase has an electrical charge that is too great. The studies on Paroxetine aren't specific, but I believe this means that Paroxetine has an electrical charge that is positive and too evenly distributed (this is kind of my question so I'm probably wrong, but lemme get into that), this means, the body can't do anything with it, because it can't cross the lining of the stomach or small intestine.

So how do we solve this? By reacting it to a chemical that DOES NOT have a positive electrical charge. What kinds of chemicals have negative charges? Acids.

The world wants to be homeogenious. Everything wants to be at a balance - so in order to be balanced, opposites will be attracted to each other in order to reach an equilibrium. Positive charges, will be attracted to negative charges. These are chemical reactions in chemistry.

Anyways. That's my understanding of why they use bases in order to make biologically active medications. I believe this is correct, but I want to make sure - the hydrochloric acid they react Paroxetine freebase with to make Paroxetine Hydrochloride, doesn't actually share electrons with the Paroxetine, but it does want to be near them because opposites attract - correct? This means that bonds aren't the same as complexes, but are similar in function to attraction seen between your hair and a balloon caused by static electricity.

Or is it - they are sharing electrons, which is why they're attracted in the first place, but the electrons are distributed evenly across both substances so because of that, it never forms a complex?

In either case, how does this allow anything to be absorbed by the gut? Is the gut tissue literally a solvent? And they distribute across the barrier of the gut because their equal makes the compound non-competative?

Thanks guys.

Oh hey - side question. If you're trying to neutralize an incredibly volatile acid like hydrofluoric acid, using sodium bicarbonate to neutralize it would be deadly because it would fracture the fluorine off of the molecule and make incredibly toxic fluorine gas. Would using a stronger alkalizer prevent this gass from being formed? So would using Sodium Hydroxide be a safer idea?

 

[sekio]

You need to take a chemistry class, Swampfox, you're way off base.

Paroxetine Hydrochloride is the most prescribed, most sold prescription drug in the world. Studies showed it to be effective in treating depression - but only when bound to Hydrochloric acid. The reason for this is due to the fact that Paroxetine in freebase (all by itself, in it's natrual form) can't be effectively distributed into the plasma by the gut, so it's unable to enter the blood in quantities that are even measurable.

Reference for this? The stomach is about 0.1 molar hydrochloric acid, is it not?

Anyways. That's my understanding of why they use bases in order to make biologically active medications. I believe this is correct,

Far from it...

The formation of salts (& freebase) is a pH dependent equilibrium. In acidic environments, the basic nitrogen atom picks up a positive charge and becomes paired with the anion of whatever protonated it, as a salt (c.f. cocaine base plus hydrochloric acid equals cocaine hydrochloride). In basic environments the "strong base liberates the weak base from the acid" - cocaine hydrochloride plus sodium carbonate or bicarbonate equals cocaine base and sodium chloride (and water and carbon dioxide).

The salt <-> freebase conversion is actually an equilibrium - unless there is an excess of acid or base, or some driving force (precipitation of solid base out of solution), the reaction can reverse.

In the stomach this isn't really much different, you can conusme most freebases and they will dissolve in the acid environment of the stomach to form hydrochlorides.

Most unprotonated free base drugs are actually quite lipophilic. (c.f. crack cocaine is waxy and insoluble in water) Sometimes this makes them difficult to handle, for instance amphetamine base is a caustic liquid at room temperature. Salts, being a compound formed from some positive ion and some negative ion, are charged compounds, and hence don't really pass the blood brain barrier at all. But wait, I hear you thinking, this makes no fucking sense. People eat hydrochlorides of drugs (paroxetine etc) and yet they somehow end up in the brain? And people inject them, too!

Here's why. The stomach is not the only pH controlled environment in the body. In fact, only the first bit of the gastric tract is acidic. The hydrochloric acid from the stomach would normally wreak havoc on the intestines, hence it is neutralised with bicarbonate in the duodenum. Here drugs are converted to their freebase and diffuse through the fatty tissues into the blood - the gastric pH in the small intestine can get as high as 10 if I recall right.

The blood is buffered by bicarbonate too, to be at a steady pH of 7.4. This explains how most drugs can pass the blood brain barrier - many aren't protonated, or only partially protonated (some fraction of them are 'free base') - so they can diffuse as non-charged compounds across the BBB without needing active transport.

Compounds that remain charged at physiological pH don't cross BBB very well. You can look at some of the third generation antihistamines for good examples - the carboxylate groups are deprotonated at pH 7, so they stick around mostly in the peripheral circulation and don't make it to the brain to cause sedation.

Oh hey - side question. If you're trying to neutralize an incredibly volatile acid like hydrofluoric acid, using sodium bicarbonate to neutralize it would be deadly because it would fracture the fluorine off of the molecule and make incredibly toxic fluorine gas.

Would it really? I thought it would just make sodium fluoride. Bicarbonate is not an oxidising agent; you need a pretty rough oxidiser to turn HF to F2.

 

[Lightning-Nl]

Maybe I just suck at explaining my thoughts, but what you wrote was my exact interpretation of chemical bonds, and the relationship that pH plays. Either way, thanks for answer.

 

[Lightning-Nl]

I had taken a fuck ton of stimulants when I wrote this. Wasn't thinking clearly obviously. Anyways, lemme explain this thread to some legibility.

I'm confused why acids are used to increase the bioavailability of certain drugs. I don't know I didn't just say this first, but anyways, let me know if this is correct.

Amphetamine has a high solubility in solvents because of it's nitrogen bond. The electrons on the nitrogen aren't occupied (so nitrogen is being held there by....magnetism?) Because amphetamine has "free" electrons, they can easily be "shared" with other atoms. This, I believe, makes amphetamine very polar (correct?) and while amphetamine is pretty damn polar, it's still very slightly negatively charged - or alkaline. (Again, correct?)

Well, the lining of the stomach is one big lipid - it's not polar. Oils don't like solvents (as a genral rule of thumb) so amphetamine, by itself, it's unable to cross the linkg of the stomach because of its slight base. So the acid is reacted with amphetamine to from amphetamine hydrochloride or what have you, because this makes amphetamine more lipid soluble which allows it to easily cross the lining of the stomach, to through the liver, and enter the blood. From there, the blood carries the amphetamine from the liver all over the body - but mos importantly into the brain, blah, blah, blah. That's not my question.

My question is, do they react certain drugs with an acid to form one of its salts in order to make it non-polar enough to cross the lining of the stomach? I don't care about BBB in this question. Strictly asking about oral bioavailability.

 

[nAON]

Got it the wrong way round I think - bases usually don't dissolve in water but salts do.

 

[atara]

Physics first:

So the reason many drugs are called bases is that they are just that: bases. That is, they are molecules with a region of negative charge which can form a bound state ("bond") with a nearby proton (Brønsted bases) or complementary molecule with a region of positive charge (Lewis bases). However, in general they are neutral bases, and in fact they behave as asymmetric electric dipoles: in the case of a typical "freebase", the negative charge is concentrated at a single region, and the positive charge is diffused across the rest of the molecule. The result is that the negative charge of the molecular dipole is more "visible" to potential interactions and can bond to a proton, or in rare cases a Lewis acid. When this bond is formed, the base becomes a positively charged molecule, which is an ion or specifically a cation, and when the cation is present in solution thermodynamics dictates that many negative ions, called anions, must also be present in solution; this is caused by a "statistical force".

Often the anions are negatively charged in a very diffuse way, in contrast to the concentrated charge on the molecular dipole, and so pairs of ions exist in solution rather than neutral molecules. When the solvent is removed, the ions do not revert to being molecules, but form a crystal lattice with ionic bonds; this is a "salt", and a pair of ions in solution is also referred to as a "salt".

Now chemistry:

So a molecule with concentrated negative charges is usually considered a base when it is not protonated, and a salt when it is protonated. This is a convenient explanation because everything in the body is treated as being "in solution", usually water. But how do the concentrated negative charges get there?

Nitrogen is important in biological systems for precisely this reason. The geometry of a nitrogen atom is dictated by quantum mechanics: as with all row-2 elements, there are four "bonding directions" which arrange themselves in a tetrahedron, or triangular pyramid, or 3-simplex, with the nucleus of the atom at its center. Each orbital is filled with two of the available outer electrons, and nitrogen has five outer electrons, which means that one of its orbitals is natively filled and the other three will share an electron with a neighboring atom, which is called a "bond". The natively filled orbital is called a "lone pair".

Since the bonds are between the nuclei of two atoms, they may be considered to have zero charge, as the pair of nuclei balances, geometrically, the effect of the electrons in the bonding orbital. The lone pair, however, is not between two atoms, but is only next to the nitrogen nucleus in one direction, and so it appears to have a negative charge "pointed" in the other direction, which acts a dipole with a concentrated region of negative charge. If we imagine the nitrogen atom as a triangular pyramid (tetrahedron), we can think of positive charge as being distributed among three corners of one face, with negative charge concentrated on the final point. This negative "spike" of the lone pair makes the nitrogen atom a "sticky point" on the molecule. The molecules are forced into various shapes by the atoms which constitute them, and so a nitrogen-containing molecule may be more or less basic depending on its preferred shape, or conformation.

Now biology:

The effect of incorporating nitrogen into a molecule in this way is that it affects the way the molecule will bend into different shapes, become protonated, or stick to other molecules, sometimes even itself. There are other reasons nitrogen is important in governing the behavior of molecules in living systems, such as hydrogen bonding, but we'll ignore that for now.

Each living thing on Earth is a device of greater intricacy than a human being can possibly imagine. The arrangements of positive and negative charges on molecules in living systems guide their behavior in arbitrarily complex ways: the conformational state of orotidylate decarboxylase, an enzyme composed of many thousands of atoms, causes it to stick to the molecule orotidylate in many different positions and gently "pull" off a carboxylate moiety. Enzymatic reactions are magical by the standards of modern organic chemistry.

A drug molecule often contains nitrogen to work in a similar way: its ultimate shape is created by an arrangement of charges, and this allows it to stick to various molecules naturally occurring in the body. Nitrogen is important in forming complex shapes, and it is particularly useful because nitrogen-containing compounds tend to be nontoxic and to form shapes similar to those naturally occurring in the body, which allows it to modify the molecular dynamics occurring in parts of an organism.

The basic drug molecules containing nitrogen may be combined with an acid, forming a salt, and because of the behavior of water, the molecules often enter solution more readily when they are protonated. This is because water itself is a dipole, and it exhibits some attraction to the charge distribution of a protonated base, which is more "visible" and exhibits a larger dipole moment than the "freebase": we might say a salt is drawn into water by a statistical force, and since this is absent with the freebase, it may be less likely to dissolve in water, and thus to participate in reactions in biological systems.

In fact once a molecule is in the body it quickly attains equilibrium with the concentration of free protons -- the pH -- of bodily fluids, usually about thirty protons per billion molecules of water. But in order to put it in the body and to maintain stability outside of the body we need to put it into various forms: for example, a cocaine salt will dissolve more easily in the nasal mucosa, facilitating its entry into the bloodstream, but the salt, as a strong dipole, has a high "energy barrier" associated to crystallization which makes it resistant to vaporization. In order to smoke cocaine, the crystal energy barrier must be broken, and usually this is done by adding a stronger base such as sodium bicarbonate to form the "freebase", which causes the proton to be released from the bond with nitrogen, as the bicarbonate has a stronger region of negative charge (insert sex joke here). This allows the cocaine to be inhaled into the lung, and the decomposition of bicarbonate in the process produces a pleasant popping sound.

Please don't smoke crack. It's very bad for you.

 

[sekio]

My question is, do they react certain drugs with an acid to form one of its salts in order to make it non-polar enough to cross the lining of the stomach? I don't care about BBB in this question. Strictly asking about oral bioavailability.

Most often, drugs are sold as salts because the salts are more resistant to degradation, are easier to handle (higher melt points, closer to neutral pH, lower volatility) and the formation of a salt from a freebase is basically an extra step of purification.

In the case of amphetamine, the bioavailibility of the freebase and the BA of the salt should essentially be the same. But amphetamine freebase is a fairly strong alkali and it's a liquid, which actually has an appreciable vapour pressure & will evaporate. The HCl salt is a non volatile crystalline powder which is slightly acidic. It's just much more convenient. (In the stomach, due to the presence of hydrochloric acid, the freebase will be rapidly converted to the HCl salt anyway.)

Some drugs like methaqualone used to be sold as freebases.

The important thing to grasp is - amphetamine isn't absorbed in the stomach (because it gets protonated and becomes a polar salt there, and polar compounds don't like fats), it is absorbed as a freebase in the small intestine, after the gastric mucosa excrete bicarbonate to neutralise the stomach acid.

 

[Lightning-Nl]

[...]

Very nice explaination atara. Cleared up a lot of my confusion

Most often, drugs are sold as salts because the salts are more resistant to degradation, are easier to handle (higher melt points, closer to neutral pH, lower volatility) and the formation of a salt from a freebase is basically an extra step of purification.

In the case of amphetamine, the bioavailibility of the freebase and the BA of the salt should essentially be the same. But amphetamine freebase is a fairly strong alkali and it's a liquid, which actually has an appreciable vapour pressure & will evaporate. The HCl salt is a non volatile crystalline powder which is slightly acidic. It's just much more convenient. (In the stomach, due to the presence of hydrochloric acid, the freebase will be rapidly converted to the HCl salt anyway.)

Some drugs like methaqualone used to be sold as freebases.

The important thing to grasp is - amphetamine isn't absorbed in the stomach (because it gets protonated and becomes a polar salt there, and polar compounds don't like fats), it is absorbed as a freebase in the small intestine, after the gastric mucosa excrete bicarbonate to neutralise the stomach acid.

I also heard tha Amphetamine is not readily able to cross the lining of the tissue in the gastrointestinal tract without first being equalized with an acid. But okay.

Also, Methaqualone isn't the only drug that was sold as freebase. Many still are - benzo's are a good example. Every notice how a generic bottle of Oxycodone always says "Oxycodone Hydrochloride" ? While all benzo's just say "diazepam" or "lorazepam" those are in freebase form as well.

But at least those make sense, there very lipid soluble.