PHARMACOKINETICS
Pharmacokinetics is often differentiated from the rest of pharmacology, as it is the study of what the body does to drugs as opposed to what drugs do to the body. For the aid of pharmacology students, it is usually broken down into four stages, mirroring the drugs passage through the human body: absorption, distribution, metabolism and excretion.
Absorption
The classical route of drug administration is orally. There are many factors altering the absorption of orally administered drugs: gastric contents, intestinal pH and most importantly, the physiochemistry of the drug. Drugs which are most rapidly absorbed are drugs which can easily pass through the membrane of cells which make up the drug wall. This means the drug needs to be partially lipophillic, that is, soluble in fats, to be rapidly absorbed. Drugs also can pass between cells, as opposed to through them, so lipophobic chemcails can also be absorbed though this is a limited pathway. Conversely, the drug also needs to be partially hydrophilic, because it needs to be able to dissolve in the watery (aqueous) environment of both the gut and the blood. That means drugs like ethanol are very rapidly absorbed from the gut (it rapidly passes through cell membranes, being both lipophillic, hydrophilic and physically small) while hydrophobic benzodiazpines often take hours to reach the maximum plasma concentration after a single dose (though the water soluble benzodiazepine midazolam is absorbed over twice as fast as it’s more hydrophobic cousins, such as diazepam and alprazolam).
The lipophillicity of drugs can also be effected by the pH of the gastric contents. Chemicals which are either basic (like amphetamines) or acidic (like barbiturates) become more fat soluble (and hence more easily absorbed) in acidic or basic solutions. So theoretically, once could eat something acidic or basic and enhance the absorption of drugs from the gut (though in practice this has an equal an opposite reaction in regards to excretion). Also, most absorption happens in the small intestine, where pH is kept below 7 (~pH 5) by bile secretions, and hence any attempts to manipulate gastric pH are probably pointless.
As any drinker knows, one can also alter the absorption of drugs by filling the stomach with food, which slows the movement of drugs form the stomach, to the small intestine. However, one can find reports of fatty foods increasing the absorption of drugs, specifically highly lipophillic compounds or compounds where are extended release formulations (XR). This is because these drugs do not dissolve in aqueous environments, and essentially stay in a big clump, slowing their transit out of the gut and into the blood, and increasing the fat content of the gastric canal allows them to dissolve. There is evidence that some benzodiazepines may be fat soluble enough for this effect to come into play.
Distribution
Once drugs are absorbed, either through oral, intravenous or any other way, they are distributed throughout the body via the blood. Orally administered drugs are absorbed through the intestinal wall, where they dissolve into the blood in the hepatic-portal vein which travels directly to the liver. From there the blood travels to the heart and is pumped around the body. What is of most interest to the users of recreational drugs is getting the drug distributed into the brain. The brain is unlike any other organ in the body, and it uniquely protected by the “blood-brain-barrier” (BBB) which is a conceptual term for the nature of the blood vessels which permeate the brain. The cells which make up these blood vessels are tightly bound together, so that drugs can not move in between cells as they can in other tissue types, and must pass through the cells. They are also bristling with so-called “multi-drug transporters” (like P-glycoprotein), molecular pumps which actively extrude drugs back into the blood. While these transporters can not pump all drugs out of the brain, they can certainly effect the brain permeation of a lot of chemicals.
Because drugs MUST be lipophillic to pass through the BBB some drugs are excluded from the brain. The classical example of BBB impermeable drugs are the new generate of “non-sedating antihistamines”. Old antihistamines were fat soluble, and could enter the brain, blocking histamine receptors, and causing sleeplyness. 2nd generation antihistamines were generally made by adding lipophobic groups such carboxycylic acids and alcohols to the structure of first generation antihistamines, making the whole molecule fat insoluble and preventing their passage into the brain; stopping them causing sedation. Another example which frustrates some recreational drug users is the potent opioid loperamide, which although fat-soluble, is a high affinity substrate for P-glycoprotein transporter, and is essentially excluded from the brain (indeed, P-glycoprotein transporters in the gut wall prevent it from getting much further than the intestines). Cannabinoids are also distributed in an interesting way. They are in generally, extremely fat soluble and water insoluble, which lends them to dissolving in fat tissue in the body. Because of this cannabinoids can take weeks to clear from the body after a single dose, while most, more water soluble drugs, are nearly completely cleared from the body after 3-5 days,
Metabolism
Drugs which are taken orally are taken directly to the liver via the hepatic portal vein. The liver is a densely infused with blood vessels, and metabolic enzymes for various classes. Because nearly all chemicals absorbed from the gut needs to pass through the liver, the metabolism that takes place there, before the chemical enters the rest of the body is called “first pass metabolism”. Metabolism in the liver can be broadly split into two catagories, phase I and phase II metabolism. Phase I metabolism envolves breaking down chemicals. The classical phase I enzymes are the super family of enzymes know as the cytochrome P450 enzymes (CYP), which has about 50 subtypes, in 17 families, each with several subfamilies. Each enzyme has a name like CYP2D6, which means it’s the 6th subtype in the D subfamily in the 2 family. Most drugs are metabolised by drugs in the 1,2 and 3 family, specifically, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5. Furthermore, drugs can be metabolized by a whole range of hepatic enzymes, like monoamine oxidase, alcohol dehydrogenase, flavin-containing monooxygenases and many others. It is worth noting that the majority of these enzymes are expressed in the gut wall, and begin to metabolize drugs well before they get into the blood stream.
Phase II enzymes add things to the drugs, usually to make them highly water soluble, so they are excreted by the kidneys into the urine. Phase II enzymes conjugate large molecules like glutathione and glucuronide or small sulphate molecules to drugs. Phase II reactions are generally subsequent to phase I reactions, though not exclusively.
The activity and quantity of phase I enzymes are plastic, that is to say, the amount of enzymes and the speed at which the break down drugs can be increased by chemicals known as “inducers” and decreased by drugs called “inhibitors”. This means that coadministration of drugs with enzyme inhibitors leads to an increased amount of drug which make it into the systemic blood supply and ultimately to the brain. Conversely, coadministration of inducers with a drug means that less of the drug gets into the brain. Enzyme inhibitors and inducers usually only effect a small number of enzymes. Enzyme inhibitors can work via a number of mechanisms. Suicide inhibitors work by being a substrate for the enzyme, but undergo an irreversible reaction once in contact with enzyme, covalently binding to the active site of the enzyme, rendering it useless. Other inhibitors bind to allosteric sites on the enzyme, slowing it’s activity. One needs to be careful about mixing drugs and chemicals which inhibit their metabolic enzymes. More than one death is attributed to mixing MDMA and the anti-HIV drug ritonavir which potently inhibits CYP2D6, the primary enzyme responsible for MDMA metabolism. The danger appears because it adds two more levels of variablitity. Drugs are absorbed variabley from person to person, and enzyme inhibitors act to varying amounts from people to people. Hence a dose of inhibitor which might reduce the activity of an enzyme by 20% in one person, might reduce it by 80% in another, making a normally safe dose of drug lethal. One can also essentially inhibit an enzyme by taking two drugs at the same time which are metabolized by the same enzyme. Here you get “enzyme competition”. For enzyme competition to work, one needs to nearly saturate the metabolic capacity of an enzyme, and this can usually only be achieved when there is only a limited amount of the enzyme. For instance administering two drugs which are metabolized by CYP3A4 are unlikely to compete, because CYP3A enzymes make up 40-60% of the total amount of CYP450 in the liver, however two drugs which are metabolized by CYP2D6 are likely to compete as they make up only 2% of liver CYP450s. Hence it can be dangerous to mix drugs which use the same metabolic enzymes.
Administering drug via routes other than oral skips first pass metabolism, though of course, the drug will pass through the liver eventually, where metabolism will begin. The differences in metabolism and distribution between intravenous and oral administration produces some interesting effects. If a drug is administer intravenously (IV) one measures the plasma concentration of the drug over time, you get will a graph as shown in figure 1. If one administers the same dose of the drug orally and measures the same properties, you will get a similar curve, though shifted to the right and far more squat. This should be obvious to anyone who has used intravenous drugs. The peak of the drug effect, which corresponds (roughly) to the plasma peak happens essentially instantaneously with IV administration, though when the same amount of drug is administered orally, the maximum effect (and plasma peak) happens much later and is much less. If one measures the area under the curve (AUC) of the plasma concentration x time graph one can judge the amount of metabolism a drug undergoes in the body. For example, if a drug is in no way metabolized during oral administration, then the AUC is equal to the AUC during intravenous use. However, if the drug is metabolized, the AUC decreases below than of the IV graph. If one takes the AUC of the oral dose and divide it by the AUC of the intravenous dose, you get a value known as the “bioavailability” which is essentially the percentage of the drug which escapes first pass metabolism, e.g. a non metabolized drug has a bioavailability of 100% while an extremely metabolized drug would have a bioavailability of 1%. Not only do different drugs have different bioavailabilties but so do different routes of administration, e.g. smoking has 100% bioavailability but intramuscular or subcutaneous administration usually have bioavailabilties below 100% as there are metabolic enzymes in the skin and muscle.
Figure 1. Blood concentration vs time of a hypothetical drug given IV (red) or orally. If the drug is not subject to first pass metabolism it will have an area under the curve (AUC) equal to the IV graph (dark blue). If the drug is subject to first pass metabolism it will have an AUC less than the IV curve (light blue)
Metabolism doesn’t always reduce the effectiveness of drugs. Many drugs need to be metabolized to work, these drugs are called “pro-drugs”. A classical pro-drug is codeine, it is metabolized by CYP2D6 into morphine. Codeine itself it virtually inactive at any of the opioid receptors, how morphine is a potent mu-opioid receptor agonist (it is worth noting that the phase II metabolite of morphine, morphine-6-glucuronide, is far more potent than morphine, and there has been considerable debate as to whether morphine is a morphine-6-glucoronide prodrug). Because codeine needs hepatic enzymes to be active, it is most potent via oral administration, as it the case with all prodrugs dependent on hepatic enzymes. The CYP2D6 mediated conversion of codeine to morphine can be saturated by codeine doses of 200-400mg, and hence doses higher than this have no effect.
Excretion
The final pathway for nearly all drugs is excretion via the kidneys. The kidneys work by essentially filtering all components of the blood out apart from very large very large molecules and blood cells, and then transporting all the useful components back into the blood, like salts, water, glucose, amino acids etc. As the kidney is designed to remove noxious chemicals, this is a cleaver system; as the body can’t know what poisons it could face, a system designed to actively remove toxins wouldn’t work, so the system instead removes everything, then keeps only that what it needs.
Unfortunately for the kidney, this system is not fool proof, as the kidney has difficulty excreting lipophilic chemicals, as they can permeate back through the walls of the kidney (you now see why phase II enzymes are important, by making noxious chemicals water soluble chemicals from escaping the kidney). As already mentioned certain chemicals can change their fat solubility depending on the pH of the solution they are dissolved in. Basic chemicals like amphetamines become fat soluble in basic environments and water soluble in acidic environments. Indeed, it has been shown that in subjects who have had treatments to make their urine more basic, they excrete amphetamine at a rate 10x slower than subjects who were treated to produce hyper-acidic urine.
Figure 2. The main metabolic enzymes or clearance mechanisms for common recreational drugs