The rate and degree of drug metabolism and absorption into the blood is dependent on several factors e.g. route of administration, dosage, genetics and comorbidities. Effective absorption from the oral route depends on both the chemical properties of the drug and the functional efficacy of the GI tract. Parenteral absorption is dependent on the extent of blood supply. The bioavailability of a drug is the most critical part of pharmacokinetics.
Bioavailability is the amount of the drug that is available to the body to produce the therapeutic effect. Bioavailability can be described as the percentage of the drug administered that is available therapeutically. This varies from 0% to 100%, and the route of administration affects the therapeutic dose. For many drugs, metabolism happens in two phases. Phase one reactions involve the formation of a modified functional group or cleavage, and these reactions are non-synthetic. Phase two involves conjugation with an endogenous substance. Substances that are formed in this stage are more polar and thus more readily excreted by the kidneys (Drug Metabolism – Clinical Pharmacology, 2019).
The primary site of metabolism in the body is the liver. So, any condition that affects the hepatic function will alter the rate and degree of metabolism. Drug metabolism is determined by the microsomal oxidative enzymes such as cytochrome P450 enzymes, and the liver’s capacity for conjugation.
After the drug has been absorbed in the GI, it is taken up in the bloodstream through the hepatic portal system. This is true of most substances that are absorbed from the Gi tract, the exception is lipids which enter the lymphatic system and are eventually deposited in the bloodstream via the thoracic duct system into the superior vena cover. The Hepatic portal system is designed to take digested food staff to the liver, where they can be processed. In some cases, they can be stored, before they are distributed to the rest of the body. As the liver is the main site for metabolism, some drugs may be extensively metabolised before reaching the rest of the body.
That means that there are some cases where an individual takes analgesia, might in theory never reach the site where the pain is. Some drugs that have a high hepatic first pass, sometimes never get passed the liver. This is true for most Narcotics that are taken orally. Hence the dose needed for drugs administered via the IV route is usually lower than drugs given orally, e.g. pethidine. Some drugs are completely metabolised in the liver that they cannot be given orally, otherwise, they will not have any therapeutic effect. Another example is, GTN, a medication used for angina if given sublingually, will evade the hepatic first pass and will reach the site needed fast.
Diseases of the liver can lead to either the accumulation of pharmacologically active agents to toxic levels or prolonged effect of the drugs or both. The impact is most significant for medications that need to metabolise before they are excreted, e.g. specific forms of narcotics and non-specific beta blockers.
Effects of Diseases on Drug Action
GI diseases can affect the rate and degree of oral absorption of drugs, e.g. Conditions affecting GI peristalsis, such as severe vomiting, diarrhoea or constipation. The rate of gastric emptying can alter the rate at which the drug is absorbed. An inflammatory condition that makes changes to the structure and function of the gut may also impede drug transit into the blood. But is this dependant on the region and the track affected and the usual site of drug absorption. Nutritional imbalances brought about by GI diseases can also affect drug metabolism.
Diseases like circulatory shock, congestive cardiac failure and peripheral vascular disorders often reduce tissue perfusion of blood. As a result of the blood levels may be lower than expected while the injection at the site blood levels remain high. In effect, the injection site becomes a drug reservoir. If under these conditions, perfusion was to suddenly increase, the levels of circulating blood may rise as well, leading to increased drug activity and possible toxicity.
The presence of food in the gut around the time of drug administration can affect drug absorption and metabolism. Nutritional elements compete with the drug for the sites of absorption.
However, drug solubility has a significant influence on the degree of absorption, lipid-soluble drugs are less affected by competition than water-soluble drugs. Some medications such as tetracycline antibiotics are chelated by calcium salts predominantly found in milk products but also present in some antacid preparations. Drug bioavailability is then lowered because the conjugated antibiotic is excreted in faeces.
The function of the drug can also be altered by hormonal changes that happen during pregnancy. Peristalsis and gastric emptying may slow down to the extent that it affects the amount of blood being absorbed by the gut. During pregnancy gastric emptying is also erratic, which can affect the degree of absorption for acidic drugs. So, when treating anyone in between the childbearing age, always inquire if the patient is pregnant.
Genetic variation has been identified in many drug metabolising enzymes including the cytochrome p450. This gives rise to distinct phenotypes of persons who have different metabolism capabilities ranging from extremely poor to extremely fast. Slow metabolisers have markedly reduced or no enzyme activity. Intermediate metabolisers have reduced enzyme activity. The bulk of the population are extensive metabolisers. Utra-rapid metabolisers have high enzyme activity. It is estimated that genetic factors account for 20-95% of an individual variability in response to the prescribed drug and in some cases, dosing is dependent on this genetic polymorphism.
For example, CYP2D6 plays an important role in the metabolism of codeine. Codeine needs to be activated by conversion to morphine by this enzyme super family to achieve pain relief. Individuals who have variations in this enzyme (CYP2D6) will not benefit from codeine as a pain medication. Dose adjustment here is not appropriate and another analgesia must be considered. Another important problem may arise for ultra-metabolisers; because of this increased rate of conversion from codeine to morphine, severe morphine toxicity may occur (van Schaik, 2008).
Shargel, L., Andrew, B. C., & Wu-Pong, S. (2015). Applied biopharmaceutics & pharmacokinetics (pp. 119-120). McGraw-Hill Medical Publishing Division.
Kanodia, J., Baldwin, M., Lo, A., Wang, D., Zhou, K., Lee, J., … & Bourdet, D. (2017). Safety, Pharmacokinetics and Pharmacodynamics of TD-0714, a Novel Non-Renally Cleared Neprilysin Inhibitor, in Healthy Humanvolunteers: Potential for Once-Daily Dosing and Predictable Exposure in Patients Regardless of Baseline Renal Function. Journal of Cardiac Failure, 23(8), S68.
Drug Metabolism—Clinical Pharmacology. (2019). MSD Manual Professional Edition. Retrieved May 12, 2020, from https://www.msdmanuals.com/professional/clinical-pharmacology/pharmacokinetics/drug-metabolism
van Schaik, R. H. N. (2008). 6. Dose Adjustments Based on Pharmacogenetics of CYP450 Enzymes. EJIFCC, 19(1), 42–47.