Absorption

The amount of drug absorbed and the speed at which it is absorbed can be affected by other drugs. One drug may speed gastric emptying which, as most drugs are absorbed in the small intestine, may speed up its absorption and therefore potentially its action. Metoclopramide increases gut motility and if taken with paracetamol will speed the passage of the analgesic from the stomach to the intestine where it is absorbed potentially leading to a faster action. This is shown in the BNF Appendix 1 as an interaction (listed under analgesics) but it’s a positive one and the combination product is available for sale as a single unit. However, increasing gut motility may also have the effect of decreasing the absorption of digoxin from tablets with more being excreted in the faeces (Manninen 1973). The clinical significance of this is mentioned in Stockley (2010) but is not listed in the BNF as potentially serious. This suggests you need caution to make a clinical decision based on risk benefit and you may need to contact medicines information for further advice. Drugs such as antacids slow or prevent the absorption of, for example, ciprofloxacin by forming an insoluble chelate.

Distribution

The next pharmacokinetic element to consider is distribution. After the first drug has been absorbed, some is distributed around the body attached to proteins in the plasma. You will remember that only free drug can have an action at receptors. If a second drug competes for the binding sites on the plasma proteins, it can displace the first drug leading to an increased concentration of free drug able to act. In the past this was thought to be of major significance. However, as the drug is displaced into the plasma it is quickly metabolised. Drug still attached to the protein is then released to create equilibrium in the plasma. It is difficult to identify any clinically significant drug interactions specifically due to plasma protein displacement. It may be important in therapeutic drug monitoring for example with phenytoin and in some cases where the drug is given intravenously.

Metabolism

A much more important aspect of pharmacokinetic drug interactions involve metabolism in the liver and in particular the cytochrome P450 isoenzymes (of which there are more than 50). Drugs are mainly, but not exclusively, metabolised in the liver. A second drug might have the effect of inducing or inhibiting liver enzymes. Those that induce enzymes will cause the breakdown of the first drug to occur more rapidly. Consider the effect of an enzyme inducer such as rifampicin on a substrate for example ciclosporin. The anti-rejection effect of ciclosporin will be reduced and therefore the potential for organ rejection is increased. Another example is the effect of rifampicin - an enzyme inducer - on oral contraceptives. This can lead to a failure of the contraceptive and additional contraceptive advice will be required. Drugs that inhibit the cytochrome P450 enzymes such as clarithromycin will have the effect of reducing the metabolism of the first drug, say ciclosporin, leading to an increase in plasma concentration of the ciclosporin and potential toxicity. Another example is the effect of allopurinol on azathioprine. In this case the enzyme inhibitor, allopurinol, can lead to a reduction in metabolism of the azathioprine (and its active metabolites) potentially leading to toxicity.

Elimination

Many drugs and their metabolites are excreted by the kidney. If drugs are to be reabsorbed in the kidney tubules, they need to be in an unionized lipid soluble form. If the pH of the urine is changed by another drug or food leading to a greater degree of ionization there can be changes in reabsorption and therefore elimination. Weakly acidic drugs will exist in a mainly ionized (thus non lipid soluble) form if the urine is alkaline. They will not be reabsorbed and will therefore be eliminated in the urine. The clearance of weak bases is greater in acidic urine. Another action with regard to elimination is where one drug prevents the tubular secretion of another and therefore increases the serum concentration of the second drug. An example of this is probenecid with penicillin.

Interactions involving P-Glycoprotein (P-gp) Transporters

This is the last pharmacology section but is important to understand how some drug interactions may actually happen. Drugs and other substances cross membranes by carrier mediated processes. We have known for some time that, for example, vitamin B12 need ‘intrinsic factor’ to transport it across the gut wall and if this is absent the patient can develop pernicious anaemia. Whereas intrinsic factor can transport B12 into the cells, the P-gp transporters are able to remove substances from cells. They are large protein molecules found in the cells of the gut, gonads, kidneys, biliary system, brain and other organs. Interfering with this protein can prevent the elimination of drugs or harmful substances from cells and thus lead to potential toxicity. P-gp can be induced - eliminating more drug from cells, or inhibited - preventing removal of drugs and other substances. Atorvastatin is a P-gp inhibitor while rifampicin is a P-gp inducer. Although not considered a significant interaction, omeprazole inhibits P-glycoprotein function and therefore less of the carbamazepine will be blocked from being absorbed into cells so more absorption of carbamazepine can result. The blood level of carbamazepine increased significantly - What do you think would be the effect of the P-gp inducer rifampicin on the concentration of digoxin in cells? As an inducer, rifampicin increases the ejection of digoxin from cells into the gut and thus to elimination which lowers the digoxin plasma concentration. Whether this is clinically significant is not clear. More recently it has been shown that ticagrelor, a P-gp inhibitor, can increase the plasma concentration of digoxin and ciclosporin significantly and appropriate clinical and/or laboratory monitoring is recommended when given concomitantly (SPC ticagrelor 2011). We are continuing to find out more about these transporter proteins and therefore understand more about drug interactions.

Drug-Food and Drug- Herb interactions

The absorption of drugs can be affected by the presence of food. For example, calcium in milk or other metals such as magnesium or aluminium in many antacids interact with the molecules of tetracycline to form an insoluble chelate. This well known interaction can be avoided by taking the antibiotic on an empty stomach and avoiding milk or antacids for say 2 hours after taking the drug. Other drugs that form chelates with milk and antacids are bisphosphonates and ciprofloxacin. Other food can enhance absorption. For example if the drug requires an acid environment to be absorbed such as itraconazole it would be best to take with food. Most medicines are absorbed in the small intestine so a drug that can reduce gastric emptying can delay passage to the small intestine and thus slow or delay absorption. Cranberry juice is listed in the BNF Appendix 1 as something that interacts with anticoagulants. The BNF says it possibly enhances anticoagulant effect of coumarins (warfarin) avoid concomitant use. The evidence to support this interaction is weak but as the BNF is currently advising you to avoid, it is best to remain cautious. As a prescriber you need to be aware of this so you can advise patients accordingly. Pharmacists will add the warnings and advice to labels when the medicine is dispensed but verbal emphasis can enhance adherence. Herbs such as St John’s Wort have been known for some time to interact with the oestrogens and progestogens but look at Appendix 1 of the BNF and find St John’s Wort. As it’s an abbreviation, it appears as the first drug in the S section of Appendix 1. Note that there are a large number of interacting drugs and that many have black dots showing that they are potentially serious. Let’s consider the evidence for one particular potential interaction St John’s Wort and Emergency Hormonal Contraception.