Pharmacology is the study of how drugs affect the body and is divided into two fundamental components:
Pharmacokinetics are the set of principles that govern what the human body will do to a drug. What the drug does to the body is governed by the principles of pharmacodynamics (Loftsson, 2015), which will be covered in a subsequent article.
This article gives an overview of the principles of pharmacokinetics, which are broken down into four separate processes:
These principles—ADME—apply to a drug from the moment of ingestion to the excretion of its last remnants and will now be explored individually.
Absorption
Absorption is the process a drug undergoes to enter the circulation. The most common route is the oral route, where drugs are ingested orally, and then absorbed from the gastrointestinal tract into the blood. This however means that the drugs are affected by the first pass metabolism in the liver. Other routes of administration include: sublingual; topical; transdermal; rectal; vaginal; inhaled and parenteral, which includes intravenous (IV), spinal, intramuscular and subcutaneous routes. In the case of the oral route, the drug is ingested, passes through the stomach, and is absorbed across the membranes of the intestine. This may be via diffusion of small drug molecules through the mucosa; molecules too large to diffuse are moved by active transport, and finally some lipid-soluble molecules are able to move freely through the lipid bilayer and into the circulation. Several factors will affect absorption via the oral route. A drug must be able to survive in the acid environment of the stomach first of all, but can be affected by excessive levels of gastric acids. If transit into the small intestine is impaired, this will affect the drug's ability to reach the intestinal mucosa. Equally, if intestinal blood flow is reduced, less drug will be moved from the gut through the hepatic portal vein to the liver and hence the rest of the body.
The amount of drug that makes it into the circulation is referred to as its bioavailability. Due to the nature of oral administration, there will never be 100% bioavailability of an oral medication; other routes are more effective if a high bioavailability is required. The most effective and fastest means of getting a drug into the circulation is intravenously, as all the mechanisms that reduce the uptake of a drug are circumvented by placing it directly into a blood vessel, resulting in a bioavailability of 100%.
Distribution
Once a drug has been absorbed, it needs to be transported around the body in order to reach the target organ. It is noted however that a drug generally does not target only the desired organ and will be distributed throughout the body. When in the bloodstream, the amount of drug available will depend on how much drug remains in its unaltered form in the circulation. Some drugs will become bound to protein molecules in the blood plasma, rendering them unable to be metabolised or take effect until released from these proteins. The amount of drug that will become protein-bound depends on the concentration of the drug in the circulation, the affinity of the drug for proteins and the concentration of protein in the blood.
Distribution is, in addition to plasma proteins, affected by the blood supply; a shocked patient will distribute a drug less effectively than a haemodynamically competent one. A well-perfused organ will also receive more of a drug than an organ with poor perfusion. Those patients with a comorbid condition that can affect circulation may also suffer impaired distribution—diabetes and heart failure being examples. Finally, distribution may be impaired by the brain and placental barriers, stopping the drug from moving into those respective areas. The next process a drug will undergo—although not all the drug in the circulation—is metabolism.
Metabolism
Metabolism takes place mainly in the liver, although it does also occur elsewhere in some cases. The enzymes in the liver, commonly the cytochrome family, will act upon the free drug found in the circulation and break it down into metabolites; these may be themselves capable of causing an effect on the body or may be inactive. In the case of oral medication—because all the blood flow from the intestine passes through the hepatic portal vein into the liver before entering the rest of the circulation—this is referred to as first-pass metabolism and means that any drug taken orally will be acted upon by the liver before it has any chance to take effect on the body. If the drug is extensively metabolised by the liver, this may render the oral route unsuitable. In the case of glyceryl trinitrate (GTN), this drug is nearly 100% metabolised into an inactive form, hence being given sublingually rather than orally (Hashimoto and Kobayashi, 2003).
The extent to which a drug is metabolised will be affected by the efficacy of those liver enzymes; this in itself can be affected by other drugs or substances. Some substances are enzyme inhibitors, thus stopping the enzymes from metabolising as efficiently as normal. This results in more free drug in the circulation and will hence usually enhance the effect of the drug. Alternately, some substances are enzyme inducers, and they enhance the enzyme's effect, thus leading to more metabolism and less unmetabolised drug in the circulation with less available to take therapeutic effect. The presence and efficacy of liver enzymes is further affected by blood flow to the liver, alcohol and smoking, diet and medication, genetic variation, liver disease and extremes of age. Hence the more in depth metabolism is examined, the more complex it becomes. The final process is excretion whereby the drug is removed from the body.
Excretion
Once a drug is used, it will be excreted from the body, most commonly via the kidneys and urine but can also be through faeces, bile, glands and breast milk. Excretion is affected by the blood flow to the kidneys. In a shocked state, reduced blood flow will reduce ability to renally excrete drugs; the same is said for reduced renal function—a normal part of ageing but also a potential function of acute illness and dehydration. If a drug cannot be excreted, it can accumulate in the body and exceed safe levels, resulting in increased risk of side effects.
Half-life and therapeutic index
In addition to the ADME processes, it is important to consider the concepts of half-life and the therapeutic index when dosing a drug.
Half-life refers to the time taken for the plasma concentration of a drug in the body to halve; this is a constant and varies from drug to drug. The shorter the half-life, the longer the interval will be when giving repeat doses.
This links into the concept of the therapeutic window of a drug. In short, the therapeutic window is the range between the minimum effective and maximum tolerated concentration. These terms represent a minimal dose needed to ensure a therapeutic effect is achieved and the maximum dose above which undesirable or toxic effects are seen.
In practice, these concepts will help define how much medication needs to be given, as well as how often it is dosed in order to keep the concentration of active ingredient in the body in the therapeutic window and hence delivering clinical effects without undesired effects. It should be noted that while these processes are explained in a chronological order, they do in reality occur simultaneously from the point of ingestion until there is no drug left in the body.
Example: morphine
Conclusion
This article gives an overview of the ADME processes that make up the pharmacokinetics of a drug. While pharmacokinetics may seem somewhat abstract as it cannot be easily observed, an understanding of it is important as it underpins why we give medicines via the routes we give them, and why we give the doses we do. Pharmacokinetics is what tells us to give GTN sublingually as otherwise it will not work. Pharmacokinetics tells us to increase the dose of morphine when giving it orally, as otherwise its efficacy is reduced. Pharmacokinetics tells us how to give a drug in order that it can go on to take its effect on the body—something which is explained next month as the principles of pharmacodynamics.