๐ Drug Interaction Checker
๐Click To Know About Drug Interaction
Drug Interaction
Interactions can result in the potentiation or antagonism of one drug by another, or result in another effect, such as renal impairment.
Drug interactions may develop either through pharmacokinetic or pharmacodynamic mechanisms.
Pharmacodynamic interactions
These are interactions between drugs which have similar or antagonistic pharmacological effects or side-effects. They might be due to competition at receptor sites, or occur between drugs acting on the same physiological system. They are usually predictable from a knowledge of the pharmacology of the interacting drugs; in general, those demonstrated with one drug are likely to occur with related drugs.
Pharmacokinetic interactions
These occur when one drug alters the absorption, distribution, metabolism, or excretion of another, thus increasing or decreasing the amount of drug available to produce its pharmacological effects. Pharmacokinetic interactions occurring with one drug do not necessarily occur uniformly across a group of related drugs.
Affecting absorption
The rate of absorption and the total amount absorbed can both be altered by drug interactions. Delayed absorption is rarely of clinical importance unless a rapid effect is required (e.g. when giving an analgesic). Reduction in the total amount absorbed, however, can result in ineffective therapy.
Affecting distribution
Due to changes in protein binding:
To a variable extent most drugs are loosely bound to plasma proteins. Protein-binding sites are non-specific and one drug can displace another thereby increasing the proportion free to diffuse from plasma to its site of action. This only produces a detectable increase in effect if it is an extensively bound drug (more than 90%) that is not widely distributed throughout the body. Even so, displacement rarely produces more than transient potentiation because this increased concentration of free drug will usually be eliminated.
Displacement from protein binding plays a part in the potentiation of warfarin by sulfonamides but these interactions become clinically relevant mainly because warfarin metabolism is also inhibited.
Induction or inhibition of drug transporter proteins:
Drug transporter proteins, such as P-glycoprotein, actively transport drugs across biological membranes. Transporters can be induced or inhibited, resulting in changes in the concentrations of drugs that are substrates for the transporter. For example, rifampicin induces P-glycoprotein, particularly in the gut wall, resulting in decreased plasma concentrations of digoxin, a P-glycoprotein substrate.
Affecting metabolism
Many drugs are metabolised in the liver. Drugs are either metabolised by phase I reactions (oxidation, reduction, or hydrolysis) or by phase II reactions (e.g. glucuronidation).
Phase I reactions are mainly carried out by the cytochrome P450 family of isoenzymes, of which CYP3A4 is the most important isoenzyme involved in the metabolism of drugs. Induction of cytochrome P450 isoenzymes by one drug can increase the rate of metabolism of another, resulting in lower plasma concentrations and a reduced effect. On withdrawal of the inducing drug, plasma concentrations increase and toxicity can occur.
Conversely, when one drug inhibits cytochrome P450 isoenzymes, it can decrease the metabolism of another, leading to higher plasma concentrations, resulting in an increased effect with a risk of toxicity.
Isoenzymes of the hepatic cytochrome P450 system interact with a wide range of drugs. With knowledge of which isoenzymes are involved in a drugโs metabolism, it is possible to predict whether certain pharmacokinetic interactions will occur.
For example, carbamazepine is a potent inducer of CYP3A4, ketoconazole is a potent inhibitor of CYP3A4, and midazolam is a substrate of CYP3A4.
Carbamazepine reduces midazolam concentrations, and it is therefore likely that other drugs that are potent inducers of CYP3A4 will interact similarly with midazolam. Ketoconazole, however, increases midazolam concentrations, and it can be predicted that other drugs that are potent inhibitors of CYP3A4 will interact similarly.
Less is known about the enzymes involved in phase II reactions. These include UDP-glucuronyltransferases which, for example, might be induced by rifampicin, resulting in decreased metabolism of mycophenolate (a substrate for this enzyme) to its active form, mycophenolic acid.
Affecting renal excretion
Drugs are eliminated through the kidney both by glomerular filtration and by active tubular secretion. Competition occurs between those which share active transport mechanisms in the proximal tubule. For example, salicylates and some other NSAIDs delay the excretion of methotrexate; serious methotrexate toxicity is possible.
Changes in urinary pH can also affect the reabsorption of a small number of drugs, including methenamine.