Abstract
Drugs may be given by a variety of routes; the route chosen depends on the desired site of action and the type of drug preparations available. Routes used commonly by the anaesthetist include inhalation, intravenous, oral, intramuscular, rectal, epidural and intrathecal. Other routes, such as transdermal, subcutaneous and sublingual, also can be used. The rate and extent of absorption after a particular route of administration depends on both drug and patient factors.
Absorption
Drugs may be given by a variety of routes; the route chosen depends on the desired site of action and the type of drug preparations available. Routes used commonly by the anaesthetist include inhalation, intravenous, oral, intramuscular, rectal, epidural and intrathecal. Other routes, such as transdermal, subcutaneous and sublingual, can also be used. The rate and extent of absorption after a particular route of administration depends on both drug and patient factors.
Not all drugs need to reach the systemic circulation to exert their effects, for example, oral vancomycin used to treat pseudomembranous colitis; antacids also act locally in the stomach. In such cases, systemic absorption may result in unwanted side effects.
Intravenous administration provides a direct, and therefore more reliable, route of systemic drug delivery. No absorption is required, so plasma levels are independent of such factors as gastrointestinal (GI) absorption and adequate skin or muscle perfusion. However, there are disadvantages in using this route. Pharmacological preparations for intravenous therapy are generally more expensive than the corresponding oral medications, and the initially high plasma level achieved with some drugs may cause undesirable side effects. In addition, if central venous access is used, this carries its own risks. Nevertheless, most drugs used in intensive care are given by intravenous infusion.
Oral
After oral administration, absorption must take place through the gut mucosa. For drugs without specific transport mechanisms, only the unionised fraction passes readily through the lipid membranes of the gut. Because the pH of the GI tract varies along its length, the physicochemical properties of the drug will determine from which part of the GI tract the drug is absorbed.
Acidic drugs (e.g. aspirin) are unionised in the highly acidic medium of the stomach and therefore are absorbed more rapidly than basic drugs. Although weak bases (e.g. propranolol) are ionised in the stomach, they are relatively unionised in the duodenum, so are absorbed from this site. The salts of permanently charged drugs (e.g. vecuronium, glycopyrrolate) remain ionised at all times and are therefore not absorbed from the GI tract.
In practice, even acidic drugs are predominantly absorbed from the small bowel, as the surface area for absorption is so much greater due to the presence of mucosal villi.
However, acidic drugs, such as aspirin, have some advantages over basic drugs in that absorption is initially rapid, giving a shorter time of onset from ingestion, and will continue even in the presence of GI tract stasis.
Bioavailability
Bioavailability is generally defined as the fraction of a drug dose reaching the systemic circulation, compared with the same dose given intravenously. In general, the oral route has the lowest bioavailability of any route of administration. Bioavailability can be determined from the ratio of the areas under the concentration–time curves for an identical bolus dose given both orally and intravenously (Figure 2.1).
Factors Influencing Bioavailability
Pharmaceutical preparation – the way in which a drug is formulated affects its rate of absorption. If a drug is presented with a small particle size or as a liquid, dispersion is rapid. If the particle size is large, or binding agents prevent drug dissolution in the stomach (e.g. enteric-coated preparations), absorption may be delayed.
Physicochemical interactions – other drugs or food may interact and inactivate or bind the drug in question (e.g. the absorption of tetracyclines is reduced by the concurrent administration of Ca2+ such as in milk).
Patient factors – various patient factors affect absorption of a drug. The presence of congenital or acquired malabsorption syndromes, such as coeliac disease or tropical sprue, will affect absorption, and gastric stasis, whether as a result of trauma or drugs, slows the transit time through the gut.
Pharmacokinetic interactions and first-pass metabolism – drugs absorbed from the gut (with the exception of the buccal and rectal mucosa) pass via the portal vein to the liver where they may be subject to first-pass metabolism. Metabolism at either the gut wall (e.g. glyceryl trinitrate (GTN)) or liver will reduce the amount reaching the circulation.
Therefore, an adequate plasma level may not be achieved orally using a dose similar to that needed intravenously. So, for an orally administered drug, the bioavailable fraction (FB) is given by:
Here FA is the fraction absorbed, FG the fraction remaining after metabolism in the gut mucosa and FH the fraction remaining after hepatic metabolism. Therefore, drugs with a high oral bioavailability are stable in the GI tract, are well absorbed and undergo minimal first-pass metabolism (Figure 2.2). First-pass metabolism may be increased and oral bioavailability reduced through the induction of hepatic enzymes (e.g. phenobarbital induces hepatic enzymes, reducing the bioavailability of warfarin). Conversely, hepatic enzymes may be inhibited and bioavailability increased (e.g. cimetidine may increase the bioavailability of propranolol).
Figure 2.2 First-pass metabolism may occur in the gut wall or in the liver to reduce the amount of drug reaching the circulation.
Extraction Ratio
The extraction ratio (ER) is that fraction of drug removed from blood by the liver. ER depends on hepatic blood flow, uptake into the hepatocyte and enzyme metabolic capacity within the hepatocyte. The activity of an enzyme is described by its Michaelis constant, which is the concentration of substrate at which it is working at 50% of its maximum rate. Those enzymes with high metabolic capacity have Michaelis constants very much higher than any substrate concentrations likely to be found clinically; those with low capacity will have Michaelis constants close to clinically relevant concentrations. Drugs fall into three distinct groups:
Drugs for which the hepatocyte has rapid uptake and a high metabolic capacity, for example, propofol and lidocaine. Free drug is rapidly removed from plasma, bound drug is released to maintain equilibrium and a concentration gradient is maintained between plasma and hepatocyte because drug is metabolised very quickly. Because protein binding has rapid equilibration, the total amount of drug metabolised will be independent of protein binding but highly dependent on liver blood flow.
Drugs that have low metabolic capacity and high level of protein binding (>90%). This group includes phenytoin and diazepam. Their ER is limited by the metabolic capacity of the hepatocyte and not by blood flow. If protein binding is altered (e.g. by competition) then the free concentration of drug increases significantly. This initially increases uptake into the hepatocyte and rate of metabolism and plasma levels of free drug do not change significantly. However, if the intracellular concentration exceeds maximum metabolic capacity (saturates the enzyme) drug levels within the cell remain high, so reducing uptake (reduced concentration gradient) and ER. Those drugs with a narrow therapeutic index may then show significant toxic effects; hence the need for regular checks on plasma concentration, particularly when other medication is altered. Therefore for this group of drugs extraction is influenced by changes in protein binding more than by changes in hepatic blood flow.
Drugs that have low metabolic capacity and low level of protein binding. The total amount of drug metabolised for this group of drugs is unaffected by either hepatic blood flow or by changes in protein binding.
Sublingual
The sublingual, nasal and buccal routes have two advantages – they are rapid in onset and, by avoiding the portal tract, have a higher bioavailability. This is advantageous for drugs where a rapid effect is essential, for example, GTN spray for angina or sublingual nifedipine for the relatively rapid control of high blood pressure.
Rectal
The rectal route can be used to avoid first-pass metabolism, and may be considered if the oral route is not available. Drugs may be given rectally for their local (e.g. steroids for inflammatory bowel disease), as well as their systemic effects (e.g. diclofenac suppositories for analgesia). There is little evidence that the rectal route is more efficacious than the oral route; it provides a relatively small surface area, and absorption may be slow or incomplete.
Intramuscular
The intramuscular route avoids the problems associated with oral administration and the bioavailable fraction approaches 1. The speed of onset is generally more rapid compared with the oral route, and for some drugs approaches that for the intravenous route.
The rate of absorption depends on local perfusion at the site of intramuscular injection. Injection at a poorly perfused site may result in delayed absorption and for this reason the well-perfused muscles deltoid, quadriceps or gluteus are preferred. If muscle perfusion is poor as a result of systemic hypotension or local vasoconstriction then an intramuscular injection will not be absorbed until muscle perfusion is restored. Delayed absorption will have two consequences. First, the drug will not be effective within the expected time, which may lead to further doses being given. Second, if perfusion is then restored, plasma levels may suddenly rise into the toxic range. For these reasons, the intravenous route is preferred if there is any doubt as to the adequacy of perfusion.
Not all drugs can be given intramuscularly, for example, phenytoin. Intramuscular injections may be painful (e.g. cyclizine) and may cause a local abscess or haematoma, so should be avoided in patients with abnormal clotting. There is also the risk of inadvertent intravenous injection of drug intended for the intramuscular route.
Subcutaneous
Certain drugs are well absorbed from the subcutaneous tissues and this is the favoured route for low-dose heparin therapy. A further indication for this route is where patient compliance is a problem and depot preparations may be useful. Anti-psychotic medication and some contraceptive formulations have been used in this way. Co-preparation of insulin with zinc or protamine can produce a slow absorption profile lasting several hours after subcutaneous administration.
As with the intramuscular route, the kinetics of absorption are dependent on local and regional blood flow, and may be markedly reduced in shock. Again, this has the dual effect of rendering the (non-absorbed) drug initially ineffective, and then subjecting the patient to a bolus once the perfusion is restored.
Transdermal
Drugs may be applied to the skin either for local topical effect, such as steroids, but also may be used to avoid first-pass metabolism and improve bioavailability. Thus, fentanyl and nitrates may be given transdermally for their systemic effects. Factors favouring transdermal absorption are high lipid solubility and a good regional blood supply to the site of application (therefore, the thorax and abdomen are preferred to limbs). Special transdermal formulations (patches) are used to ensure slow, constant release of drug for absorption and provide a smoother pharmacokinetic profile. Only small amounts of drug are released at a time, so potent drugs are better suited to this route of administration if systemic effects are required.
Local anaesthetics may be applied topically to anaesthetise the skin before venepuncture, skin grafts or minor surgical procedures. The two most common preparations are topical eutectic mixture of local anaesthetic (EMLA) and topical amethocaine. The first is a eutectic mixture (each agent lowers the boiling point of the other forming a gel-phase) of lidocaine and prilocaine. Amethocaine is an ester-linked local anaesthetic, which may cause mild, local histamine release producing local vasodilatation, in contrast to the vasoconstriction seen with EMLA. Venodilatation may be useful when anaesthetising the skin prior to venepuncture.
Inhalation
Inhaled drugs may be intended for local or systemic action. The particle size and method of administration are significant factors in determining whether a drug reaches the alveolus and, therefore, the systemic circulation, or whether it only reaches the upper airways. Droplets of less than 1 micron diameter (which may be generated by an ultrasonic nebuliser) can reach the alveolus and hence the systemic circulation. However, a larger droplet or particle size reaches only airway mucosa from the larynx to the bronchioles (and often is swallowed from the pharynx) so that virtually none reaches the alveolus.
Local Site of Action
The bronchial airways are the intended site of action for inhaled or nebulised bronchodilators. However, drugs given for a local or topical effect may be absorbed resulting in unwanted systemic effects. Chronic use of inhaled steroids may lead to Cushingoid side effects, whereas high doses of inhaled β2-agonists (e.g. salbutamol) may lead to tachycardia and hypokalaemia. Nebulised adrenaline, used for upper airway oedema causing stridor, may be absorbed and can lead to significant tachycardia, arrhythmias and hypertension, although catecholamines are readily metabolised by lung tissue. Similarly, sufficient quantities of topical lidocaine applied prior to fibreoptic intubation may be absorbed and cause systemic toxicity.
Inhaled nitric oxide reaches the alveolus and dilates the pulmonary vasculature. It is absorbed into the pulmonary circulation but does not produce unwanted systemic effects as it has a short half-life, as a result of binding to haemoglobin.
Systemic Site of Action
The large surface area of the lungs (70 m2 in an adult) available for absorption can lead to a rapid increase in systemic concentration and hence rapid onset of action at distant effect sites. Volatile anaesthetic agents are given by the inhalation route with their ultimate site of action the central nervous system.
The kinetics of the inhaled anaesthetics are covered in greater detail in Chapter 9.
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