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Pharmacokinetics

Pharmacokinetics is the study of how the body works on or affects a drug once it has been administered. This is different to pharmacodynamics which is the study of how a drug affects the body. Pharmacokinetics refers to the body's affect on the drug.

Depending on which literature you read, there are at least four main phases of pharmacokinetics.

  • Absorption
  • Distribution
  • Metabolism
  • Excretion

Routes or Modes of administration

Before we delve into the phases of pharmacokinetics, we need to look at the different modes or routes of administration.

The main modes of administration that we are familiar with as paramedics are intramuscular, intravenous, intranasal and oral. Oral can be sublingual, buccal or swallowed into the GI tract. There are other modes of administration such as transcutaneous (skin patches), subcutaneous (under the skin but not intra-muscular) and parenteral (rectal) but they are not as common in paramedicine. As we will see, the mode of administration can affect the bioavailability of a drug.

Bioavailability is simply the amount of drug that reaches its target site in the body after it has been administered.

Absorption

The absorption of a drug refers to how the molecules of that drug make their way to the blood stream after being administered.

The route or mode of administration can alter the absorption process, sometimes reducing the overall amount of drug that is available or the time that the drug takes to reach therapeutic levels.

Intramuscular

Intramuscular (IM) administration will allow for therapeutic levels within a few minutes and will generally allow for the entire volume of the drug to take effect. The drug is first absorbed into the muscle tissue and then makes its way into the blood stream through diffusion from muscle cells into the capillaries. IM avoids the hepatic first pass, meaning that the drug circulates though the blood stream before it is metabolised by the liver, allowing for the entire drug to take effect.

Intravenous

Intravenous (IV) administration is a common and familiar route of administration for Paramedics. We wont cover intravenous cannulation in this session, but vascular access is obviously and important intervention to have performed prior to administering a drug intravenously! IV administration allows a drug to take effect very quickly, in some cases within seconds. This is the most direct form of administration for most dugs and requires that a drug has been appropriately prepared for IV administration. Not all drugs are suitable for IV administration and you should never attempt to use any drugs that are not prepared for IV use. IV administration also bypasses the hepatic first pass.

Intranasal

Intranasal refers to the administration of a drug, generally in liquid form, into the nasal passages where it diffuses rapidly through the nasal mucosa and into the blood stream. Commonly, the liquid form will be atomised into a fine mist, which will encourage the drug to cling to the nasal mucosa and absorb. It is not common practice in paramedicine to administer drugs intranasally in a powdered form as we see in the movies! IN administration also avoids the hepatic first pass.

Oral (Sublingual and Buccal)

Sublingual, meaning “below the tongue”, refers to a drug that dissolves in saliva under the tongue. Generally, these drugs are manufactures in such a way that they dissolve quickly and can be in tablet/wafer form, drops or liquid and a spray. SL drugs absorb quickly into the oral mucosa and make their way directly to the blood stream, also avoiding the hepatic first pass.

Saliva is 99.9% water and contains enzymes such as Amylase and Lipase which help to begin digestion of carbohydrates/starches and lipids. The pH of saliva is relatively neutral at 6.3.

Oral (GI Tract (Enteral))

The GI tract is different to most other modes of administration in that it involves the hepatic first pass and due to its function, generally results in a prolonged absorption time. This can make it unsuitable for immediate or critical care, especially cardiac drugs and analgesia. For many oral drugs administered via the GI tract,, the onset of action can be up to 20-30 minutes with peak serum levels and therapeutic effect ranging between 30 minutes to over an hour. For example, Paracetamol is usually effective within 45 minutes of oral administration via the GI tract.

Some drugs begin to absorb in the stomach, but most drugs will absorb in the intestinal system. For example, alcohol is absorbed in the stomach, which is why it seems to affect people very quickly in large amounts. Some medications are designed to digest slowly and will have an enteric coating that means the drug and its excipients disperse through the intestinal system over a longer period. These drugs will not break down in the stomach and will be resistant to the low pH of the upper GI tract.

Since the hepatic first pass is involved, this means that some of the drug is processed by the liver immediately after entering the blood stream which can result in a varied bioavailability of that drug when compared to an IV administration. For example, 100mg of a drug ingested, might only yield 60mg of that drug being bioavailable.

Distribution

Distribution refers to how the molecules of the drug are transported through fluids and tissues of the body to their target site. There are four main compartments that the drug can be distributed to as well as some minor compartments.

  • Blood
  • Intracellular Fluid
  • Extracellular Fluid
  • Fat

Some definitions:

  • Hydrophilic: Easily attaches to, or dissolves in water molecules
  • Hydrophobic: Does not attach to, or dissolve in water molecules
  • Lipophilic: Easily attaches to, ot dissolves in lipids (fats)
  • Lipophobic: Does not attach to, or dissolve in lipids

Plasma Protein Binding

Tissue Distribution

The Blood Brain Barrier (BBB)

Metabolism

Specifically, xenobiotic metabolism, is the process of transforming the drug molecule from a lipid soluble form, into water soluble form through enzymatic reactions. This results in smaller compounds known as metabolites. One common xenobiotic enzyme is cytochrome P450 which is used to metabolise nearly every drug or poison that enters the body. Xenobiotic metabolism is one of many metabolic pathways in the body, but unlike most other pathways, it acts on foreign molecules that do not participate in catabolic or anabolic processes.

The product of xenobiotic metabolism is metabolites and a reduction of circulating drug. Imagine a racetrack with lots of cars racing around it. Every now and then a car gets pulled off the track and split into parts. It now can’t participate in the race so there are less cars on the track. Metabolism acts in a similar fashion. The liver can only deal with so many molecules at one time, so not every molecule gets processed each time it passes through. The administration, absorption, distribution and volume of drug, among other factors, will affect the time and nature of how each drug is metabolised.

Drug metabolism works in two phases.

Phase 1: A chemical process that generally involves cytochrome P450. Usually an enzyme driven, oxidative process that produces pharmacologically inactive metabolites

Phase 2: The process of combining metabolites with a substrate that produces a water soluble, inactive conjugate that can be easily excreted from the body.

Excretion

The removal of the metabolites from the body, generally by the kidneys. Because the metabolites are converted into a water soluble form, they are easily removed in the urine. Some drugs can be excreted in faecal matter or through the lungs as expired air.


Page contributors:

chrisgray

Chris Gray, AP20186
Ambulance Paramedic, Metropolitan Ambulance Service

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