Nature of drug interactions
Anticholinergics, antihistamines with anticholinergic properties, ganglion blockers, opiates, acetylsalicylic acid slow gastric emptying.
These are the interactions that occur the most. The risk of interaction arises from the time a patient takes two or more drugs simultaneously.
Interactions affecting drug absorption
They manifest in changes in the rate of drug absorption in the gastrointestinal tract, and in the amount of drug absorbed. Thus there was a change in a pharmacokinetic parameter, i.e. bioavailability of the product. This phenomenon is commonly seen in drugs taken orally. This can be avoided by keeping an interval between doses. These interactions often cause a decrease in the effectiveness
of the drug.
Interactions affecting the absorption of drugs from the gastrointestinal tract may have several mechanisms:
Formation of difficult-to-absorb complexes
For example, tetracyclines form with calcium, aluminium, magnesium complexes that are not absorbed through the intestinal wall - Thus, it is necessary to avoid concomitant use of tetracyclines with drugs that are mainly composed of aluminium, magnesium, and other gastrointestinal mucosal drugs. calcium.
For example, a plastic substance such as cholestyramine, which is intended to keep cholesterol, can hold many drugs if taken together (oral anticoagulants, digital drugs, thyroid hormones). Preparations containing iron salts also interact by forming complexes with antacids containing aluminium, calcium, and magnesium salts.
Soluble in non-absorbable liquids
For example, long-term use of Vaseline oil can greatly reduce the absorption of fat-soluble vitamins (A, D, E, K) - Caution should be exercised in patients taking vitamin K antagonists.
Changes in pH of the stomach and intestines
For example, H2 blockers or antacids containing aluminium, magnesium or calcium salts can slow down or reduce the absorption of some active ingredients such as furosemide, indomethacin, digoxin, isoniazid...
Due to adsorption
For example, the substances Kaolin, aluminium pentasilicate, pectin, cyclamate have the effect of adsorbing some drugs (lincomycin, paracetamol, aspirin, nalidixic acid, nitrofurantoin, oral anticoagulants...)
Changes in the time of drug contact with the mucosa because on intestinal motility.
Anticholinergics, antihistamines with anticholinergic properties, ganglion blockers, opiates, acetylsalicylic acid slow gastric emptying.
Changes in blood flow in the intestinal lining
For example, substances that cause vasoconstriction and vasodilation.
The toxic effect on the intestinal mucosa, even destroying the intestinal bacteria.
Malabsorption syndromes or can prevent bacteria from producing an essential substance. For example, when taking tetracyclines for a while, it destroys bacteria in the intestine, preventing the synthesis of vitamin K by saprophytic bacteria in the intestine (changing the response of vitamin K antagonists).
Increased rate and amount of drug absorption from the gastrointestinal tract
Examples are antacids and penicillin G - ethyl alcohol and theophylline. Alkalizers and base drugs (chloroquine, imipramine, quinine, amphetamine).
Passive tubular reabsorption
Filtered drugs can be passively reabsorbed in the renal tubules, especially in the distal regions of the renal unit. The mechanisms used here are those that control the exchange across biofilms. Urine filtered by the glomerulus and excreted by the proximal tubules is concentrated by water reabsorption. This phenomenon is important for active substances that can ionize because the pH of urine is easily changed. Therefore, drugs that alter urine pH may be the source of drug interactions.
Water-soluble drugs with high molecular weight are not reabsorbed and do not cause interactions at this stage. In contrast, fat-soluble substances can be reabsorbed. This is the case of weak acids and bases in their non-ionized form.
Therefore, increasing urine pH increases the reabsorption of bases by decreasing ionization. Conversely, a decrease in urine pH increases the reabsorption of acids. Therefore, the half-life of amphetamine is doubled when the urine pH is changed from 5 to 8, and the renal clearance of quinidine is decreased from 1 to 10 when the pH is 6 to 7.5. Elimination of phenobarbital is increased with sodium bicarbonate (classic treatment of barbituric intoxication).
Interactions affecting drug distribution by competing with the drug for plasma and tissue protein binding sites
In the pharmacokinetic phase, there is a risk of interaction once the drug has been absorbed into the bloodstream. But many drugs are bound to plasma proteins, especially albumin. Drug binding to proteins is a reversible equilibrium process, like that of an enzyme with a substrate, unless the complex does not break down to form a new substance. This protein binding obeys the law of mass action.
Free drug + free protein 2 drug-protein
The drug's affinity for proteins is expressed as the coherence constant Ka .
This constant is defined as:
Ka = K1 / K2
where K1 and K2 are the rate constants of the combination and dissociation reactions of the drug-protein complex.
Although binding to albumin is much less selective than binding to various globulins, some (acidic) drugs exhibit relatively specific binding to a limited number of sites. on the albumin molecule to the extent that these sites can saturate at therapeutic concentrations in the blood.
In addition, some low-molecular-weight molecules can disturb binding capacity without competing for common binding sites, but by altering the spatial conformation of the protein. heterochromia phenomenon). The bound drug part acts as a reserve to renew the free drug part, But it should be remembered that the binding part is not distributed in the body, is not metabolized and eliminated.
On what factors should these competitive threats be predicted, and with what consequences?
The drug undergoes a strong and prolonged biological transformation. They must bind to plasma proteins at a very high rate (over 85%), where the number of binding sites plays an important role, and it is necessary to determine the affinity constant (association), the nature of association, the number of link positions. They must have a small volume of distribution for the free fraction increase to be clinically significant. For example, tricyclic antidepressants, although strongly bound to plasma proteins, have a large volume of distribution in tissues, and therefore do not cause interactions of this type in clinical practice. They must have high plasma concentrations (due to high doses or small volumes of distribution), and slow elimination; acidic in nature and used in high doses. Age (newborns and elderly), undernutrition, liver and kidney failure all significantly alter protein binding.
This effect is only evident for drugs with a narrow therapeutic range; With these agents, partial release of drug bound to plasma proteins can be detected by toxic or overdose events (risk of bleeding with anticoagulants, risk of hypoglycaemia with anticoagulants). oral diabetes).
The immediate consequences of partial release of the active drug and the binding of another drug to plasma proteins, meeting the above conditions, may be as follows:
Increased drug concentration in the serum of the active part of the drug is ejected.
Increased elimination of drugs ejected by glomerular filtration.
Increases the pharmacological effect of the drug at sensitive receptors.
Interactions due to stimulation induce changes in drug metabolism
When an absorbed drug can be eliminated intact, unchanged, or subject to biological alterations prior to elimination (formed metabolites may be active or inactive), the final can also conjugate with other substances without being altered before being eliminated.
People divide biological transformations into two stages: the first stage is the metabolic phase, which includes oxidation, reduction, hydrolysis and decarboxylation reactions; The second stage is called the conjugation phase, which is essentially the reaction of the drug or its metabolite with an endogenous substrate, usually a glucid derivative, an amine compound, or inorganic sulphate. . The second phase almost always leads to inactivation.
There are four types of reactions in the metabolic phase
This is the most common type of reaction. Microsomal oxidation is catalysed by liver microsomal enzymes. They require the presence of NADPH and cytochrome P450
Oxidation of a linear carbon chain occurs either at the terminal carbon with the formation of an acid, or at the carbon immediately adjacent to the terminal carbon with the formation of alcohol.
The N - oxidation - deamination.
The reduction of aldehydes to primary alcohols.
For example, human plasma contains enzymes such as esterase, which are nonspecific, which hydrolyse drugs such as procaine and succinylcholine (choline esterase).
Carboxyl reduction reaction.
The example of substance L-dopa speaks volumes about the importance of this issue. Orally, it is converted to the emetic dopamine, largely by enzymes located in the gastrointestinal mucosa, and does not cross the gastrointestinal barrier.
Conjugation phase Conjugation of drugs or their metabolites - The conjugation phase, like the one above, results in more water-soluble substances, thus more readily being eliminated. However, unlike the first step, conjugation always leads to the inactivation of the conjugated substances.
Conjugation with glycol
This is the main amino acid used to conjugate aromatic acids and some linear acids. In addition to glycocols, this conjugation reaction also requires the presence of CoE A and glycocol N - acetylase. Conjugation with glycuronic acid is mainly with water- or carboxyl radicals.
Sulfo conjugation: occurs in some alcohols and phenols.
The source of the methyl group is S-adenosyl methionine, whose active methyl group is transferred to the acceptor by the enzyme methyltransferase.
The acetylation of aromatic primary amines is the most important reaction in drug inactivation - It requires the presence of CoE - A, an amine of N - acetyltransferase, for example, isoniazid.
Factors capable of altering the rate of biological change
We need to distinguish between endogenous and exogenous factors
Endogenous factors Species, age, pathological status, sex, genetic makeup (eg, G6PD deficiency in some populations leads to hemolytic anemia).
They are related to drugs, including dose, the effect of combination with another drug. Thus, biotransformation reactions to drugs fall into two categories:
Phase 1 reactions (formation or change of functional groups) and phase 2 reactions (conjugation).
The majority of enzyme induction and inhibition phenomena known to date are oxidation reactions and oxygen-binding reactions, performed by cytochrome P450 monooxygenases and by conjugation with glucuronic acid.
The hydroxylation and oxygen-binding reactions carried out by cytochrome P450s require a complex enzymatic cycle - For each cycle, cytochrome P450s require one oxygen molecule and two electrons as different electron transport chains provide level. Enzyme inducers and inhibitors act differently on cytochrome P450 and electron transport enzymes.
The inducible effect seems to be enhanced by a decrease in the rate of enzymatic degradation. Since there are so many enzymes involved in drug metabolism, one can expect that each enzyme has different modes of induction.
Inducers can be classified into three groups
The most familiar agent is phenobarbital. In this group are also other drugs and insecticides.
Polycyclic aromatic hydrocarbons (benzo(a)pyrene and methyl cholantrene) are present in cigarette smoke.
The group of anabolic steroids not yet clearly characterized.
There may be other groups that are still unknown. For example, the mechanism of the induction of ethanol is still unknown.
Properties of an enzyme inducer
The induction of hepatocyte enzymes is a nonspecific process. This process requires some time to form, which varies by the inducer, from a few days to several weeks, and the induction effect persists for some time after the inducer is discontinued. Enzyme inducers are usually fat-soluble drugs, have long plasma half-lives, and relatively slow elimination. They are usually strongly protein-bound and are concentrated in the liver.
Consequences of enzyme induction are usually expressed as decreased therapeutic effect or decreased toxicity of the induced drug unless the result of enzyme induction results in more active metabolites or more toxic.
For example, in the case of epileptic treatment with phenobarbital in combination with diphenylhydantoin, the latter will be metabolized more rapidly than usual, resulting in lower plasma concentrations, and therefore a risk of ineffectiveness. It is necessary to adjust the dosage. In a patient who was treated with a vitamin K antagonist and on a regular basis with barbiturates, the dose of the vitamin K antagonist (removal of enzyme inducer) had to be reduced a few days later when the barbituric was stopped.
Finally, numerous pregnancies have been described in the literature in women taking oral contraceptives (especially in low doses) and regularly taking phenobarbital (for women with epilepsy or insomnia) or rifampicin (for tuberculosis). - Enzyme induction by these drugs increases the catabolism of contraceptive steroids, so a concentration sufficient to inhibit ovulation is not achieved.
Examples of beneficial effects of enzyme induction:
Treatment of jaundice caused by unconjugated bilirubin is with phenobarbital (stimulating glycuronyl-transferase, the enzyme responsible for bilirubin conjugation).
Treatment of some syndromes characterized by increased hormone secretion with enzyme inducers such as diphenylhydantoin, phenobarbital and OP'DDD (metabolites of DDT) have been used in the treatment of adrenal Cushing's syndrome and in adrenocortical states. increase vitamin D.
Treatment of digital toxicity (digitoxin) with spironolactone. This drug works through enzyme induction, not through changes in blood potassium levels.
Major enzyme inducers: Barbituric (especially phenobarbital) glutethimide, anticonvulsants (diphenylhydantoin), antibiotics (rifampicin), steroids (spironolactone, anabolic agents), ethanol, polycyclic aromatic hydrocarbons (especially benzoin). (a) pyrene, methyl-3-cholanthrene), chlorinated insecticide (DDT).
This mechanism is as complex as the induction mechanism. Inhibition may be nonselective, due to hepatotoxicity (e.g. carbon tetrachloride) or to decreased hepatic enzyme synthesis.
The most common inhibitors occur in monooxygenases and in particular in certain cytochrome P450s (eg, MAO).
Inhibition can be competitive, non-competitive, or even mixed. In fact, it all needs to be studied further. The problem is further complicated when it is known that some products of metabolism, especially hydroxylated metabolites, inhibit biotransformation of the parent substance or some other substrate. Thus, enzyme inhibition leads to enhanced effects of the inhibited drug, as demonstrated by increased plasma half-life, and/or increased toxicity.
Cimetidine is an inhibitor of interest that increases the duration of action of diazepam by prolonging its half-life and decreasing clearance. Cimetidine inhibits microsomal activity, which governs the dealkylation and hydroxylation reactions of benzodiazepines such as diazepam, chlordiazepoxide, dipotassium clorazepate, prazepam and medazepam. In contrast, other benzodiazepines, such as oxazepam or lorazepam, are conjugated with glucuronic acid (this phenomenon is not controlled by the liver microsomes), so their activity is not altered when coadministered with cimetidine. Likewise, cimetidine increases plasma concentrations of phenyl hydantoin, theophylline, and carbamazepine. Because these drugs have a narrow therapeutic range, these combinations should be carefully monitored, or avoided.
Need to remember
Enzyme inhibition is a phenomenon that occurs much earlier than enzyme induction.
Enzyme inhibition can occur not only in hepatocytes but also in the intestine.
The same drug may have an enzyme-inducing or inhibitory effect depending on the dose and duration of treatment (eg, alcohol).
Enzyme inhibition may be specific
Neostigmine inhibits plasma cholinesterases, thus allowing the elimination of the effects of non-depolarizing curates. Monoamine oxidase (MAO) inhibitors interact with many substances such as sympathomimetic agents, morphine-type analgesics, and barbiturates. Morphine-type analgesics cause the adrenal medulla to release catecholamines into circulation. Thus, the risk of hypertensive crisis is increased, because circulating catecholamines that are not destroyed by the MAO enzyme act on unstimulated alpha receptors (blockade by MAOIs).
Certain inhibitors of drug metabolism: Alcohol, at very high doses or at lower doses but with long-term use, acts as an enzyme inducer. Chloramphenicol, estrogens, oral estro-progestogens, diltiazem, disulfiram, cimetidine (and to a lesser extent ranitidine) valproate, erythromycin, TAO, isoniazid, verapamil, azole antifungals.
Competing interactions at the drug elimination stage (renal and biliary excretion)
The amount of drug found in the urine depends on the intensity of three renal elimination mechanisms: glomerular filtration, active tubular secretion, and passive tubular reabsorption.
Glomerular Filtration: Only the free drug fraction is filtered through the glomerulus; Furthermore, all drugs that increase glomerular blood flow facilitate the elimination of other substances.
Active tubular secretion: In the proximal tubule, some drugs pass from the blood into the urine against the concentration gradient. That transition is made possible by an active mechanism that consumes energy. This secretory process utilizes transport molecules located in the tubular cell membranes.
Two systems of transmembrane transport are distinguished: One is responsible for the elimination of acidic drugs, and the other is responsible for the elimination of base drugs.
In the presence of two drugs from the same class, they may compete for a transport site, showing that their elimination is slowed. This phenomenon has the benefit of maintaining high plasma concentrations, but can also lead to overdose.
Like probenecid, a uricosuric sulphonamide, previously used because of its inhibitory effect on penicillin elimination, has the disadvantage of retaining many acidic drugs (eg, indomethacin). Likewise, the combination of dicoumarol with an antidiabetic sulphonamide (chlorpropamide) reduces its excretion actively, to the point of potentially fatal hypoglycaemic events if dose reductions are not observed. This phenomenon has also been observed with anti-inflammatory drugs such as acetylsalicylic acid, indomethacin, phenylbutazone, oxyphenbutazone and thiazide diuretics.
Pharmacodynamic interactions can occur: due to a change in the interaction between the binding site and the active substance, or from the binding of a second substance to another site, causing an amplifying effect. or prevent interaction between the binding site and the active ingredient.
There are two features to pay attention to
Affinity: corresponds to how easily the active substance binds to the receptor.
Intrinsic activity: corresponds to the number of receptors that need to be bound to the active substance to exert a pharmacological (stimulant) effect.
These two parameters are independent variables. Simply put, the interaction can occur at the same receptor, causing a competitive mechanism, and at other receptors on the same organelle. Either way the outcome of the interaction is a synergistic or antagonistic effect.
Types of changes in active site-drug interactions.
Both substances bind to the same pharmacological sites. Two substances present in the body antagonize each other and cancel each other's effects. Thus, there is a competitive antagonism, requiring the concept of a pharmacological receptor. Examples are atropine or beta-blockers, which block the binding of active substances such as acetylcholine or adrenaline.
In everyday practice, the combination of an antagonist is not common, except in toxicology aimed at eliminating the toxic effects of one of the products (antidote). However, the projections are not so straightforward, as all receptors are still unidentified, and many substances are unknown agonists or antagonists, so potentiation may occur. effect or resistance is unknown. Such is the case with the anticholinergic activity of some antihistamines, or the recently discovered affinity of butyrophenone for the morphine receptor.
Examples of additive and enhanced effects:
The effect of hypnotics is enhanced by ethanol, opiate drugs, tranquillizers, and some antihistamines.
Combined anticholinergic effects between antispasmodics, some antihistamines, antidepressants.
The effects of antihypertensive agents are sometimes enhanced by diuretics, anaesthetics, anaesthetics, and sedatives.
Synergistic or synergistic effects between two bactericidal antibiotics: penicillin, cephalosporin, aminoside, polymyxin.
The additive or synergistic effect between two bacteriostatic substances: tetracycline, chloramphenicol, erythromycin, sulphonamide.
Examples of physiological antagonists:
Inhibition of sulfa drugs by p.aminobenzoic acid and some derivatives (such as local anaesthetics).
Interaction between vitamin K and oral anticoagulants.
Interactions between cholinesterase inhibitors and curar-type drugs.
Interactions between tricyclic antidepressants (imipramine, amitryptiline) and guanidine-derivative antihypertensives (guanethidine, debrisoquin).
Link position change
One of the substances changes the binding site of the other so that warfarin has an increased effect when combined with thyroxine. Thyroxin increased the affinity of the anticoagulant binding site.
Changes in response after drug-site interaction
It is generally due to the blockade of enzymes responsible for metabolism at the active site. For example, diuretics, amphotericin B (injected), corticosteroids, stimulant laxatives, by means of a potassium-depleting mechanism, may enhance response to cardiac heterosides by sensitizing myocardial fibers sensitive to Na+/K+ dependent ATPase inhibition.
Physical and chemical incompatibilities
These are interactions that occur, not in vivo, but in vitro before the patient takes the drug. Interaction occurs between two or more substances when combined with each other, between containers - containers, between drugs and carriers. Physical incompatibility leads to a visible change - Chemical incompatibility causes no visible changes. There are many mechanisms of physicochemical incompatibilities.
Solvents cause inactivation eg by pH: The acidic pH of glucose solutions inactivates beta-lactams and cephalosporins; sometimes only due to the low stability of some drugs in the aquatic environment (eg penicillin).
Direct interaction between two drugs: Leads to inactivation, with or without visible precipitation.
No precipitation ® Example penicillin + aminoglycoside.
Precipitation is present if the polarity is changed ® For example tetracycline + calcium salt solution (complex).
Direct interaction between acid and base groups. For example protamine (base) - heparin.
Inactivated by a drug solution preservative. For example, bisulfite - penicillin.
Inactivation due to drug binding to another substance. For example, amino acid hydrolyzate and digital drugs, tetracyclines, barbiturics... Never add drugs to the parenteral nutrition solution.
Oxidative inactivation by light, caused by some reducing agents. For example riboflavin - tetracycline (see list of medicines that need to be stored in the dark). Currently, it is possible to find infusion containers, light-blocking tubes, allowing for infusions to be carried out for quite a long time. Examples are some anti-cockroaches.
Inactivated by storage at ambient temperature. For example, hydrolysates of amino acids, hormones, vaccines, proteins (see list of medicines to be kept refrigerated).
Inactivation due to drug adsorption or absorption on glass or plastic containers. This problem has emerged and has been studied mainly with diazepam and trinitrin injected in polyvinyl chloride ampoules.
The phenomenon of insulin adsorption on glass bottles is known. The emergence of synthetic resins PVC (Polyvinyl chloride), EVA (Ethylene-vinyl acetate) for the manufacture of infusion lines and infusion bags has accelerated these studies, and these also explain the dose differences. used in different literature, especially with trinitrin. The introduction of polystyrene syringes forced the French Ministry of Health to issue regulations that for injecting solutions using a solvent other than water, the use of plastic syringes, but rather glass, was prohibited. The use of polypropylene syringes reduces this risk.
However, the problem of incompatibility has developed very strongly with the appearance of injection points in the catheters, infusion tubes, and the appearance of polyethene bottles that do not allow visual detection of precipitates or suspensions. turbidity, syringe pushers, multi-way nozzle frames, plastic peristaltic pumps.
Adsorption on plastics:
Absorption: The phenomenon of allowing a substance to enter the interior with a retained part
. The penetration of the active substance into the thickness of the plastic is the phenomenon of absorption.
Adsorption: The phenomenon of retaining a substance (gas or liquid) at the surface layer of a solid. Thus, in the first contact between the active substance and the surface of the vessel wall, adsorption occurs (so this is a surface phenomenon).
Permeation: The phenomenon in which molecules of a solution pass through the walls of the container. In adsorption, kinetics occur very quickly, and equilibrium is established quickly. In contrast, in absorption, the process takes much longer (which can be accelerated by increasing the temperature). Examples are the adsorption of heparin on glass, insulin adsorption on PVC, polyethene, polypropylene, and ethylene-vinyl acetate (EVA) polymers, and insulin adsorption on glass.
For example the adsorption and absorption of nitrosated derivatives on PVC (nitroglycerin and isosorbide dinitrate).
For example the absorption of diazepam on PVC and on cellulose propionate.
The physical and chemical phenomena that may occur during drug preparation, when the drug is at the plunger stage, at the stage of infusion and when the infusion fluid flows through the infusion line must not be forgotten.