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In this step, Dr Harriet Scott, Specialty Registrar in Anaesthesia and Pain Medicine at Barts Health, and Dr Lesley Bromley, retired Consultant and Senior Lecturer in Anaesthesia and Pain Medicine at University College London, explain some pharmacokinetic principles to help you better understand how opioids exert their effects.
The other important aspect of the interaction between drug and patient is what the body does to the drug. This is called pharmacokinetics.
Why is this important? Because how the drug gets into the body (absorption), is moved around the body (distribution), how it is handled (metabolism) and then removed (elimination) varies from drug to drug. This can influence the drug we choose to give, as well as how we choose to give it.
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Opioids and Surgery
If we give morphine intravenously, for example, it enters the circulation straight away and can be measured in blood samples immediately. Despite this, there is a lag time of up to 15 minutes before a clinical effect is felt by the patient. This is because the site of action (the effect site) is in the central nervous system, and molecules have to pass through the tissues and across cell membranes to reach the opioid receptors. How this happens depends on the specific physical and chemical characteristics of morphine which affect its ability to cross cell membranes.
The amount of morphine in the blood then falls away as it is removed from the circulation: some of it is metabolised (detoxified by the liver) and excreted straight away; some passes into the tissues and interacts with the receptors, before diffusing back into the bloodstream to be metabolised and excreted.
Understanding what happens at a molecular level helps us to predict the clinical effect the dose of morphine we are giving our patient will have.
Pharmacokinetics is subdivided into four distinct processes:
|How the drug gets into the blood
|How the drug travels between compartments to an effector site
|How the drug is broken down into metabolites
|How the drug is removed from the body
Absorption and Distribution
Because cell membranes are largely composed of lipids, drugs need to be fat-soluble in order to cross them. Most drugs are chemically weak acids or bases. This means that at the pH of the body a proportion of the molecules will be ionised (carrying a charge) and the rest will be unionised (and therefore uncharged). It is these unionised molecules that are more lipid soluble, and which can more easily leave the circulation and move to the receptors.
Molecules that are fat soluble are going to get to the effect site more quickly. We can see this in action if we compare morphine, which is partly ionised at the body’s pH of 7.4, with alfentanil and fentanyl which are less ionised (and therefore more lipid-solube) at this pH, leading to the more rapid onset of the latter two drugs.
Let us conduct an experiment. A drug company has developed a new opioid analgesic. They think it is going to be more rapid in onset and last longer than morphine. They need to know how it is handled in the body.
Using six ampoules of this drug, six human volunteers and an accurate assay of the drug in plasma, how can we find out the characteristics of the drug?
With proper precautions and consent we insert two intravenous cannulae in each volunteer, one in each antecubital fossa. We will inject the drug into one of these cannulae and then sample from the other cannula at time intervals after the injection. If we analyse the samples and plot the concentration in the plasma against time on normal graph paper, we will produce a curve like this:
This is called an exponential decline curve. From it we can derive some useful information about what has happened. The main characteristic of this type of curve is that the more drug is in the plasma, the faster the rate at which it declines (the steeper the downward slant). There are some common characteristics to this sort of curve that are measured or derived. First of all, we can measure the time taken for the concentration to fall by half its value. This is called the half-life (T1/2). If we choose a value on the concentration axis and call it ‘A’ and draw a line to the curve and drop down from that point to read the time, then repeat the process at the value of half of ‘A’ we get a second time. The difference between the two times is the half-life.
This is another important concept that needs to be taken into consideration when deciding how much of a drug is being prescribed.
Bioavailability describes the ratio of the drug which reaches the bloodstream when it is given by a particular route compared with the same dose given intravenously (when all of the drug reaches the plasma – the bioavailability of all drugs via the intravenous route is 100% by definition).
For example, if we give the drug orally it has to be absorbed from the gut, pass through the liver and then enter the systemic circulation. Not all of the drug will be absorbed and some will be metabolised as it passes through the liver (first-pass metabolism) such that only a proportion of the dose will appear in the plasma. If only half the dose is found to reach the systemic circulation, the bioavailability is said to be 50%. For a drug with this bioavailability, the oral dose would need to be twice the intravenous dose to achieve the same plasma concentration (and hence the same clinical effect).
The higher bioavailability via the intravenous route is shown in the graph below:
Bioavailability varies according to the pharmacokinetic characteristics of a specific drug and the route of administration. For example, opioids given rectally or buccally (absorbed directly from the mucosal membranes of the mouth) are absorbed without passing through the liver so have a much better bioavailability than those given orally (which are swallowed and absorbed from the gut).
Some opioids are very lipophilic (lipid-soluble) and so can be passively absorbed through the skin from transdermal patches which facilitate continuous analgesia: fentanyl given via this route has a bioavailability of up to 90%. Absorption is slower than intravenous injection, however: a steady-state plasma concentration is usually attained 24-48 hours after application of such a patch, providing a controlled drug delivery rate independent of first-pass metabolism.
Why do we need the half-life?
This value helps us to decide how much time to leave between separate opioid doses, and also how to administer them as infusions. Drugs with a long half-life need to be given less frequently than those with shorter half-lives.
Methadone, for example, has a very long half-life of up to 27 hours and can therefore be given be given as a once-daily dose. Immediate-release morphine, on the other hand, has a serum half-life of 1.9 hours, and has to be given more frequently. The situation with morphine is slightly more complicated, however, because it is metabolised to active compounds which have their own half-lives, prolonging its effect.
The half-life is also important to consider when we give drugs by continuous infusion, as it determines the steady-state rate (the rate required to maintain the blood levels the same after the infusion has been going for some time), and the loading dose required to reach that state. The shorter the half-life, the more suitable a drug is to be given by infusion. Thus, drugs such as alfentanil and remifentanil, which have shorter half-lives than other opioids, are excellent for use as infusions.
Metabolism and elimination
Finally, pharmacokinetics also looks at how the drug is removed from the body.
Clearance is one of the theoretical concepts used to look at this. It is defined as ‘the volume of plasma that is completely cleared of the drug per unit time’. Of course, this does not reflect the way the body actually removes the drug from the body. Plasma concentration falls gradually over time, as we saw in our experiment, but this idea of clearance is a useful concept when comparing drugs.
Total clearance is the sum of the clearance of a drug by different organs, so we talk about hepatic, renal or pulmonary clearance which all contribute to total clearance. Mathematically, clearance can be calculated from the plasma-concentration curve, which we saw earlier. It is also used in the calculation of steady-state rates for infusions.
Drug metabolism is the process by which the body breaks down and transforms a drug into different compounds (metabolites), often to make it easier for the body to eliminate. This metabolic process, primarily carried out by enzymes in the liver, plays a key role in determining a drug’s effectiveness, duration of action, and potential side effects.
While metabolism usually reduces the activity of a drug, it can sometimes increase its activity. When most of the therapeutic activity of a compound is caused by its metabolites, we call it a prodrug. Prodrugs have no therapeutic activity of their own before they undergo metabolism and are converted by the body into an active compound.
Examples of opioid prodrugs include codeine, oxycodone, hydrocodone, diamorphine and tramadol, all of which have limited analgesic effect on their own when ingested.
In general, metabolism produces a more water-soluble molecule that can be excreted in bile or urine.
There are 2 phases of metabolism: Phases I and II.
Phase I reactions (particularly oxidation) are particularly important in opioid metabolism and are catalysed by enzymes in the endoplasmic reticulum of the liver. As you may already know, these enzymes form the cytochrome P450 system. Interestingly, the cytochrome P450 system is not unique to the liver – these enzymes are also found in the gut mucosa, lung, brain and kidney. Many drugs require more than one enzyme to break them down.
Renal clearance is the principal method of elimination of opioids and their metabolites, as a result opioid dosing needs close attention in patients with reduced kidney function. As opioids are made water-soluble by their metabolism in the liver, liver impairment will also require dose adjustment for most opioids.
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Opioids and Surgery
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