STUDY - Technical - New Dacian's Medicine
Principles
of Drug Therapy (5)
Translation Draft
Let's talk today about drug interactions!
The effects of some medicines can be marked by the administration of other agents. Such interactions may compromise the therapeutic intention by amplifying the action of the drug (with adverse effects) or decreasing it, up to therapeutic inefficiency. Medicinal interactions should be taken into account in the differential diagnosis of unexpected therapeutic responses to medicines, taking into account the fact that patients often come to the doctor with a legacy of prescription drugs during previous medical experiences.
A meticulous anamnesis regarding the medications received will minimize the unknown elements of the therapeutic spectrum. This should include the examination of previous medicinal treatments and, if necessary, the call of the pharmacist to identify prescriptions. There are two main types of drug interactions. Pharmacokinetic interactions result from changes in the distribution of medicinal products at their places of action. Pharmacodynamic interactions are due to changes in the reactivity of the target organ or system.
Let's start by discussing pharmacokinetic interactions that lead to decreased availability of medications. Here we have several "situations" represented by A. low gastrointestinal absorption, B. induction of liver enzymes that intervene in the metabolism of drugs and C. inhibition of cellular capture or binding.
So, let's start with low gastrointestinal absorption. Colestiramine, an ion-exchange resin, binds thyroxine, triiodothyronine and cardiac glycosides with an affinity high enough to decrease their absorption from the gastrointestinal tract. This resin also probably interferes with the absorption of other medicines, so it is advisable that patients do not receive cholesteramine for 2 hours after taking them. Aluminum ions present in antacids form chelators insoluble with tetracyclines, therefore preventing their absorption. Ferrous ions similarly block the absorption of tetracycline.
The suspensions of caolin-pectin bind digoxin and, when administered together, the absorption of digoxin is reduced to about half. When caolin-pectin is administered 2 hours after digoxin, its absorption is not altered. Ketoconazole is a weak base that dissolves well only at acid pH. H2 histamine receptor antagonists, such as cimetidine and ranitidine, decrease the dissolution and absorption of ketoconazole. In contrast, the absorption of fluconazole is not decreased by the increase in gastric pH. Oral administration of aminosalicylates interferes with the absorption of rifampicin by an unknown mechanism.
We have come to the induction of liver enzymes that interfere in the metabolism of drugs. When the drug is purged, for the most part, by metabolism, an increase in the rate of metabolism reduces its availability at the places of action. The metabolism of most drugs occurs mainly in the liver, due to its mass, high blood flow and concentration of metabolizing enzymes. The first step in the metabolic process of many drugs is mediated by a group of cytochrome P450 oxidases with mixed function, localized in the endoplasmic reticulum.
These enzyme systems oxidize the drug's molecules through a variety of reactions, including aromatic hydroxylations, N-demethylations, O-demethylations and sulphoxidations. Reaction products are generally more polar than the original compounds (and thus more suitable for renal excretion). The expression of isomorphic mixed-function oxidase (CYP) is regulated and their content in the liver can be increased by a number of drugs. Phenobarbital is the prototype of these inductors and all barbiturates used in the clinic increase the activity of mixed-function oxidases. Induction of these enzymes by phenobarbital can be achieved with a low dose of 60 mg/ day.
Mixed-function oxidases may also be induced by rifampycin, carbamazepine, phenytoin and glutetimide, as well as tobacco, exposure to chlorinated insecticides such as DDT and chronic alcohol intake. Phenobarbital, rifampicin and other inductors decrease the plasma levels of many drugs, such as warfarin, quinidine, mexiletin, varapamone, ketoconazole, intraconazole, cyclosporin, dexamethasone, methylprednisolone, prednisolone (active metabolite of prednisone), oral contraceptive steroids, methadone, metronidazole and methon All these interactions have obvious clinical significance.
When taking coumarinic anticoagulants, the patient is placed in an increased risk category when the appropriate level of anticoagulation is achieved, under the conditions of association with an inductor, and it is then discontinued, for example, after the patient's release from the hospital. Plasma levels of coumarin anticoagulant will increase as the inductor effect is erased, leading to excessive anticoagulation. There are considerable inter-individual variations in the extent to which the metabolism of the drug is induced. In some patients, phenobarbital causes a marked acceleration in the rate of drug metabolism, while in others induction is weak. In addition to the definite inductor effect of the isoenzymes of mixed-function oxidases, phenobarbital has other effects on liver functions. It increases liver blood flow, bile flow and hepatocellular transport of organic anions. The conjugation of drugs and bilirubin can also be intensified by inductors.
And we've also come to inhibit cellular capture or binding. Guanidid antihypertensives (guanetidine and guanadrel) are transported to their places of action in adrenergic neurons through a membrane transport system for biogenic monoamines with energy consumption. Although the physiological function of the transporter system is the reuptake of adrenergic neurotransmitters, it transports to the adrenergic neuron a variety of cyclic basic substitutes, including guanetidine and guanidic compounds, against a concentration gradient. Norepinephrine capture inhibitors prevent the capture of guarid antihypertensives in adrenergic neurons and block their pharmacological effects. Tricyclic antidepressants are powerful inhibitors of norepinephrine capture.
Consequently, concomitant administration of therapeutic doses of tricyclic antidepressants, such as desipramine, protiptilin, nortriptilin and amitriptyline, almost completely abolishes the antihypertensive effects of guanetidine and guanadrel. Although they are weaker inhibitors of norepinephrine capture, doxepine and chlorpromazine are dose-dependent antagonists compared to guanidine antihypertensives. Ephedrine, a component of many drug combinations used in asthma, also antagonizes the effect of guanetidine. In patients with severe hypertension, the loss of control over blood pressure caused by these drug interactions may be the cause of ictus and malignant hypertension. The antihypertensive effect of clonidine is partially antagonized by tricyclic antidepressants. Clonidine lowers blood pressure by reducing sympathetic impulses from blood pressure control centers in the posterior brain. This central hypotensive action is antagonized by tricyclic antidepressants.
Another group of "conflicts" is pharmacokinetic interactions that cause increased drug availability by: A. inhibition of drug metabolism, B. inhibition of renal elimination and C. inhibition of clearance through multiple mechanisms.
In the case of inhibition of the metabolism of the drugs, if the active form of the drug is predominantly purged by biotransformation, inhibition of its metabolism results in reduced clearance, prolonged half-life and accumulation of the drug during maintenance treatment. Excessive accumulation due to inhibition of metabolism may be the cause of adverse effects. Cimetidine is a powerful inhibitor of oxidative metabolism of many drugs, including warfarin, quinidine, nifedipine, lidocaine, theophylline and phenytoin. Adverse reactions, many of them severe, resulted from the administration of these drugs in association with cimetidine.
This medicine is a stronger inhibitor than ranitidine of mixed-function oxidases, while ranitidine, administered in doses of 150 mg twice daily, does not inhibit the oxidative metabolism of the two drugs (when reduced drug treatment has been observed, the effect of ranitidine was weaker than that of cimetidine and lacks significant pharmacological consequences). However, doses of ranitidine greater than 150 mg may produce a higher inhibition of drug oxidation. Famotidine and nisatidine do not produce a clinically relevant inhibition of drug metabolism. Knowledge of isoenzyme P450 (CYP), which catalyzes the main pathway of drug metabolism, provides a basis for predicting and understanding drug interactions. For example, the CYP3A isoenzyme family catalyzes the metabolism of many drugs, which become toxic when their metabolism is blocked.
Medications that depend on CYP3A as the main route of metabolism include cyclosporin, quinidine, lovatatine, warfarin, nifedipine, lidocaine, terfenadin, astemizol, cisaprida, erythromycin, methyl-prednisolone, carbamazepine, midazole and triazolam. Erythromycin, ketoconazole and intraconazole are powerful inhibitors of enzymes in the CYP3A family. Some calcium channel blockers, diltiazem, nicardipine and verapramil, may also inhibit CYP3A, as can some of its substrates such as cyclosporin. Thus, cyclosporin can cause severe toxic phenomena when its metabolism is inhibited by erythromycin, ketoconazole, diltiazem, nicardipine and verapramil.
Lovastatin causes severe myopathy with rhabdomyolysis when administered with erythromycin and cyclosporin, and it is highly likely that other known CYP3A inhibitors may decrease the availability of lovastatin. polymorphic ventricular tachycardia (torsade of the tips) produced by terfenadin, astemizol and cisaprid can occur when their metabolism is blocked by CYP3A inhibitors, such as intraconazole, ketoconazole and erythromycin. Whenever erythromycin, intraconazole or ketoconazole is given to patients, the doctor should be cautious about the serious potential for interaction with cyp3A metabolised medicines. The isoenzyme CYP2D6, which catalyzes the polymorphic metabolism of debrisoquine, is highly inhibited by quinidine and is also blocked by a number of neuroleptic drugs such as chlorpromazine, fluoxetine and haloperidol. The analgesic effect of codeine depends on its metabolism in morphine, via CYP2D6, in people with strong metabolising phenotype (MP). Therefore, quinidine prevents the analgesic effect of codeine in powerful metabolizers (MP). Since diszipramide is widely purified by metabolism by CYP2D6 to MP, its levels increase substantially by concomitant administration of quinidine, fluoxetine or other neuroleptic drugs blockers of P450 2D6.
Some drugs are inactivated by other mechanisms, besides metabolizing liver enzymes. Azatioprina is converted in the body into an active metabolite, 6-mercap-topurine, which is oxidized by xanthinoxidase, with 6-tiouric acid formation. When simultaneously taking allopurinol, a powerful inhibitor for xanthinoxidase, and standard doses of azatioprise or 6-mercaptopurine, toxic phenomena with lethal risk (medullary suppression) may occur. Other drugs that inhibit the biotransformation of pharmacological compounds (with examples of drugs that have metabolism blocked by inhibitors listed in parentheses) are: amiodarone (warfarin, quinidine), clofibrate (phenytoin, tolbutamide), excessive ingestion of ethanol (warfarin), isoniazide (phenytoin), metronidazole, cotrimoxazole (warfarin) and phenylbutazone (warfarin, phenytoin, tolbutamide).
We've come to inhibit renal elimination. A number of drugs are secreted by renal tubular transport systems for organic anions. Inhibition of this tubular transport system can cause excessive accumulation of the drug. Phenylbutazone, samplenecid and salicylates competitively inhibit this transporter system. Salicylates, for example, reduce renal clearance of methotrexate, an interaction that may increase the toxicity of methotrexate. Tubular secretion contributes substantially to the elimination of penicillin, which can be inhibited by samplenecid. Inhibition of the tubular transport system of cations by cimetidine decreases the renal clearance of procainamide and its active metabolite, N-aethylprocainamide.
And finally, about inhibiting clearance through multiple mechanisms. The plasma concentration of digoxin is increased by quinidine, largely due to inhibition of renal elimination and, in part, bile secretion. When quinidine is administered in association with a cardiac glycoside there is a risk of arrhythmias. Adidarone, cyclosporin and verapramil also inhibit the clearance of digoxin and increase the concentration of digoxin in plasma.
Now let's present some elements about pharmacodynamic interactions and other drug interactions. Useful therapeutic interactions occur when the effect of two associated drugs is greater than that of the sum of their effects when used individually. These favorable drug associations are described in specific therapy sections, and what follows is directed to those interactions that create undesirable effects. Two drugs can act on separate components of the same process, producing a greater effect than each separately. For example, low doses of aspirin (less than 1g/ day) do not appreciably alter the time of prothrombin in patients undergoing warfarin therapy, however the risk of bleeding increases because aspirin inhibits platelet aggregation.
Thus, the combination of diminished platelet function and defective clotting system increases the potential for hemorrhagic complications in patients receiving warfarin treatment. Nonsteroidal anti-inflammatory drugs cause gastric and duodenal ulcers and, in patients treated with warfarin, the risk of bleeding from peptic ulcers is increased almost 3 times by concomitant use of nonsteroidal anti-inflammatory drugs. This is certainly a drug interaction with serious consequences. Indomethacin, pyroxicam and perhaps other nonsteroidal anti-inflammatory drugs antagonize the antihypertensive effects of beta-adrenergic receptor blockers, diuretics, conversion enzyme inhibitors and other drugs.
It results in a variable increase in blood pressure, from mild to severe. However, aspirin and sulindac do not increase blood pressure in hypertensive patients undergoing treatment. Polymorphic ventricular tachycardia (torsade of the tips) during quinidine administration occurs most frequently in patients receiving diuretics, probably as a consequence of potassium and/ or magnesium loss. Additional potassium administration more frequently leads to a much more severe hyperkalemia when the elimination of potassium is reduced by concomitant treatment with angiotensin conversion enzyme inhibitors, spironolactone, amyloride or triamterene.
I will complete this post with the presentation of some elements about the plasma concentration of drugs as a therapeutic guide. Optimal individualization of therapy can be achieved by measuring the plasma concentration of certain drugs. Genetic variations in treatment rates, interactions with other medicines, conditions that cause changes in purification and distribution, and other factors combine to produce a wide variety of plasma levels in patients receiving the same dose. In addition, the problem of non-compliance with treatments prescribed during prolonged therapy is an endemic and hard-to-detect cause of therapeutic failure. Clinical indicators help to titrate some drugs within the desired range and no chemical determination is a substitute for careful observation of the response to treatment.
However, the therapeutic and adverse effects cannot be precisely quantified for all medicines and, in complex clinical situations, the estimation of the action of the drug may be wrong. For example, a pre-existing neurological condition may hide the neurological consequences of phenytoin poisoning. because clearance, half-life, accumulation and steady plasma levels are difficult to predict, measuring plasma levels is often a useful guide to optimal dosage. This method applies especially when there is a narrow area between plasma levels that produce therapeutic effects and those that produce adverse effects. For medicines with such characteristics, e.g. digoxin, theophylline, lidocaine, aminoglycosides and anticonvulsants, dose optimisation should involve the modification of the standard dose, based on the pharmacokinetic principles described in previous posts.
In certain situations, predictive algorithms and diagrams have been developed to facilitate the necessary changes. However, the most flexible and accurate method for individualizing the dosing of the drug appears to be the retro-related approach (feedback), using a small number of data on previously obtained plasma levels and Bayesian prediction. In controlled studies, this type of computer-assisted dosing has proven useful for improving patient care. However, the cost/benefit ratio of these methods in the routine therapeutic approach remains to be proven. For medicines with a narrow therapeutic window, which are purified by an order I process, dose adjustment can be made on the assumption that there is a linear relationship between the average, maximum and minimum concentrations and the dosing rate.
Thus, the dose can be adjusted on the basis of the ratio between the desired concentration and the measured concentration according to the formula: [Cpss (optimal)/ Cpss (measured)] = [dose (nine)/ dose (previous)]. For medicines with a dose-dependent kinetics (e.g. phenytoin and theophylline), changes in plasma concentrations are disproportionately higher than changes in the dosing rate. Not only should dose changes be lower to minimize the degree of contingency, but monitoring plasma concentration should also ensure appropriate changes. Variability between individual responses at certain given plasma levels must be identified.
This is illustrated by the theoretical/hypothetical population concentration-response curve and its relationship with the therapeutic zone or therapeutic window of the desired plasma levels. The defined therapeutic window should include levels at which most patients achieve the expected pharmacological effect. However, there are a small number of people sensitive to therapeutic effects who respond to lower levels, while others are refractory enough to require levels that can cause adverse effects. For example, a small number of patients with high comitiality require plasma levels of phenytoin exceeding 20 mg/ ml to control seizures. The dosage required to achieve this effect may be useful.
Some patients may experience susceptibility to adverse effects at levels that are tolerated by the vast majority of the population, so increasing these levels to those with a high probability of therapeutic effect may produce adverse and therapeutic effects in these patients. There are many medicines that have plasma concentrations associated with adverse and therapeutic effects in most patients, their use within the limits of medical guidelines being necessary to allow a more effective and powerless therapy for patients who do not belong to the "average".
In addition, the patient's effective participation in the therapeutic program is necessary. Measuring the plasma concentration of the drug is the most effective way to determine when the patient failed to take the drug. This "non-compliance" is a common problem in the long-term treatment of diseases such as hypertension and epilepsy, occurring in 25% of patients or more in hospital environments where no special efforts are made to empower patients to their own health. Occasionally, noncompliance can be discovered by friendly, non-incriminating questioning, but much more frequently it is recognized only after the dosing of the plasma concentration of the drug shows null or low values repeatedly.
Since other factors may cause plasma levels to be lower than expected, comparison with levels obtained during hospital patient treatment may be necessary to confirm that in fact noncompliance has occurred. Once the doctor is sure of this fact, an unaccusing discussion of the problem with the patient can elucidate the reason for non-participation and can serve as a basis for more effective cooperation with the patient. Many approaches have been tried to increase patient responsibility for their own treatment, most based on improved communication on the nature of the disease and the likelihood of therapeutic success or failure.
This communication may also be an opportunity for the patient to report the problems associated with treatment. Improvements can be made by involving nurses and paramedical staff in the process. Minimising the complexity of the regimen is useful both in terms of the number of medicines and their frequency of administration. Educating patients to take the primary role in the care of their own health requires a combination of the art of communication and medical science.
That's it for today... Next time we "treat" drug side effects.
Let's talk today about drug interactions!
The effects of some medicines can be marked by the administration of other agents. Such interactions may compromise the therapeutic intention by amplifying the action of the drug (with adverse effects) or decreasing it, up to therapeutic inefficiency. Medicinal interactions should be taken into account in the differential diagnosis of unexpected therapeutic responses to medicines, taking into account the fact that patients often come to the doctor with a legacy of prescription drugs during previous medical experiences.
A meticulous anamnesis regarding the medications received will minimize the unknown elements of the therapeutic spectrum. This should include the examination of previous medicinal treatments and, if necessary, the call of the pharmacist to identify prescriptions. There are two main types of drug interactions. Pharmacokinetic interactions result from changes in the distribution of medicinal products at their places of action. Pharmacodynamic interactions are due to changes in the reactivity of the target organ or system.
Let's start by discussing pharmacokinetic interactions that lead to decreased availability of medications. Here we have several "situations" represented by A. low gastrointestinal absorption, B. induction of liver enzymes that intervene in the metabolism of drugs and C. inhibition of cellular capture or binding.
So, let's start with low gastrointestinal absorption. Colestiramine, an ion-exchange resin, binds thyroxine, triiodothyronine and cardiac glycosides with an affinity high enough to decrease their absorption from the gastrointestinal tract. This resin also probably interferes with the absorption of other medicines, so it is advisable that patients do not receive cholesteramine for 2 hours after taking them. Aluminum ions present in antacids form chelators insoluble with tetracyclines, therefore preventing their absorption. Ferrous ions similarly block the absorption of tetracycline.
The suspensions of caolin-pectin bind digoxin and, when administered together, the absorption of digoxin is reduced to about half. When caolin-pectin is administered 2 hours after digoxin, its absorption is not altered. Ketoconazole is a weak base that dissolves well only at acid pH. H2 histamine receptor antagonists, such as cimetidine and ranitidine, decrease the dissolution and absorption of ketoconazole. In contrast, the absorption of fluconazole is not decreased by the increase in gastric pH. Oral administration of aminosalicylates interferes with the absorption of rifampicin by an unknown mechanism.
We have come to the induction of liver enzymes that interfere in the metabolism of drugs. When the drug is purged, for the most part, by metabolism, an increase in the rate of metabolism reduces its availability at the places of action. The metabolism of most drugs occurs mainly in the liver, due to its mass, high blood flow and concentration of metabolizing enzymes. The first step in the metabolic process of many drugs is mediated by a group of cytochrome P450 oxidases with mixed function, localized in the endoplasmic reticulum.
These enzyme systems oxidize the drug's molecules through a variety of reactions, including aromatic hydroxylations, N-demethylations, O-demethylations and sulphoxidations. Reaction products are generally more polar than the original compounds (and thus more suitable for renal excretion). The expression of isomorphic mixed-function oxidase (CYP) is regulated and their content in the liver can be increased by a number of drugs. Phenobarbital is the prototype of these inductors and all barbiturates used in the clinic increase the activity of mixed-function oxidases. Induction of these enzymes by phenobarbital can be achieved with a low dose of 60 mg/ day.
Mixed-function oxidases may also be induced by rifampycin, carbamazepine, phenytoin and glutetimide, as well as tobacco, exposure to chlorinated insecticides such as DDT and chronic alcohol intake. Phenobarbital, rifampicin and other inductors decrease the plasma levels of many drugs, such as warfarin, quinidine, mexiletin, varapamone, ketoconazole, intraconazole, cyclosporin, dexamethasone, methylprednisolone, prednisolone (active metabolite of prednisone), oral contraceptive steroids, methadone, metronidazole and methon All these interactions have obvious clinical significance.
When taking coumarinic anticoagulants, the patient is placed in an increased risk category when the appropriate level of anticoagulation is achieved, under the conditions of association with an inductor, and it is then discontinued, for example, after the patient's release from the hospital. Plasma levels of coumarin anticoagulant will increase as the inductor effect is erased, leading to excessive anticoagulation. There are considerable inter-individual variations in the extent to which the metabolism of the drug is induced. In some patients, phenobarbital causes a marked acceleration in the rate of drug metabolism, while in others induction is weak. In addition to the definite inductor effect of the isoenzymes of mixed-function oxidases, phenobarbital has other effects on liver functions. It increases liver blood flow, bile flow and hepatocellular transport of organic anions. The conjugation of drugs and bilirubin can also be intensified by inductors.
And we've also come to inhibit cellular capture or binding. Guanidid antihypertensives (guanetidine and guanadrel) are transported to their places of action in adrenergic neurons through a membrane transport system for biogenic monoamines with energy consumption. Although the physiological function of the transporter system is the reuptake of adrenergic neurotransmitters, it transports to the adrenergic neuron a variety of cyclic basic substitutes, including guanetidine and guanidic compounds, against a concentration gradient. Norepinephrine capture inhibitors prevent the capture of guarid antihypertensives in adrenergic neurons and block their pharmacological effects. Tricyclic antidepressants are powerful inhibitors of norepinephrine capture.
Consequently, concomitant administration of therapeutic doses of tricyclic antidepressants, such as desipramine, protiptilin, nortriptilin and amitriptyline, almost completely abolishes the antihypertensive effects of guanetidine and guanadrel. Although they are weaker inhibitors of norepinephrine capture, doxepine and chlorpromazine are dose-dependent antagonists compared to guanidine antihypertensives. Ephedrine, a component of many drug combinations used in asthma, also antagonizes the effect of guanetidine. In patients with severe hypertension, the loss of control over blood pressure caused by these drug interactions may be the cause of ictus and malignant hypertension. The antihypertensive effect of clonidine is partially antagonized by tricyclic antidepressants. Clonidine lowers blood pressure by reducing sympathetic impulses from blood pressure control centers in the posterior brain. This central hypotensive action is antagonized by tricyclic antidepressants.
Another group of "conflicts" is pharmacokinetic interactions that cause increased drug availability by: A. inhibition of drug metabolism, B. inhibition of renal elimination and C. inhibition of clearance through multiple mechanisms.
In the case of inhibition of the metabolism of the drugs, if the active form of the drug is predominantly purged by biotransformation, inhibition of its metabolism results in reduced clearance, prolonged half-life and accumulation of the drug during maintenance treatment. Excessive accumulation due to inhibition of metabolism may be the cause of adverse effects. Cimetidine is a powerful inhibitor of oxidative metabolism of many drugs, including warfarin, quinidine, nifedipine, lidocaine, theophylline and phenytoin. Adverse reactions, many of them severe, resulted from the administration of these drugs in association with cimetidine.
This medicine is a stronger inhibitor than ranitidine of mixed-function oxidases, while ranitidine, administered in doses of 150 mg twice daily, does not inhibit the oxidative metabolism of the two drugs (when reduced drug treatment has been observed, the effect of ranitidine was weaker than that of cimetidine and lacks significant pharmacological consequences). However, doses of ranitidine greater than 150 mg may produce a higher inhibition of drug oxidation. Famotidine and nisatidine do not produce a clinically relevant inhibition of drug metabolism. Knowledge of isoenzyme P450 (CYP), which catalyzes the main pathway of drug metabolism, provides a basis for predicting and understanding drug interactions. For example, the CYP3A isoenzyme family catalyzes the metabolism of many drugs, which become toxic when their metabolism is blocked.
Medications that depend on CYP3A as the main route of metabolism include cyclosporin, quinidine, lovatatine, warfarin, nifedipine, lidocaine, terfenadin, astemizol, cisaprida, erythromycin, methyl-prednisolone, carbamazepine, midazole and triazolam. Erythromycin, ketoconazole and intraconazole are powerful inhibitors of enzymes in the CYP3A family. Some calcium channel blockers, diltiazem, nicardipine and verapramil, may also inhibit CYP3A, as can some of its substrates such as cyclosporin. Thus, cyclosporin can cause severe toxic phenomena when its metabolism is inhibited by erythromycin, ketoconazole, diltiazem, nicardipine and verapramil.
Lovastatin causes severe myopathy with rhabdomyolysis when administered with erythromycin and cyclosporin, and it is highly likely that other known CYP3A inhibitors may decrease the availability of lovastatin. polymorphic ventricular tachycardia (torsade of the tips) produced by terfenadin, astemizol and cisaprid can occur when their metabolism is blocked by CYP3A inhibitors, such as intraconazole, ketoconazole and erythromycin. Whenever erythromycin, intraconazole or ketoconazole is given to patients, the doctor should be cautious about the serious potential for interaction with cyp3A metabolised medicines. The isoenzyme CYP2D6, which catalyzes the polymorphic metabolism of debrisoquine, is highly inhibited by quinidine and is also blocked by a number of neuroleptic drugs such as chlorpromazine, fluoxetine and haloperidol. The analgesic effect of codeine depends on its metabolism in morphine, via CYP2D6, in people with strong metabolising phenotype (MP). Therefore, quinidine prevents the analgesic effect of codeine in powerful metabolizers (MP). Since diszipramide is widely purified by metabolism by CYP2D6 to MP, its levels increase substantially by concomitant administration of quinidine, fluoxetine or other neuroleptic drugs blockers of P450 2D6.
Some drugs are inactivated by other mechanisms, besides metabolizing liver enzymes. Azatioprina is converted in the body into an active metabolite, 6-mercap-topurine, which is oxidized by xanthinoxidase, with 6-tiouric acid formation. When simultaneously taking allopurinol, a powerful inhibitor for xanthinoxidase, and standard doses of azatioprise or 6-mercaptopurine, toxic phenomena with lethal risk (medullary suppression) may occur. Other drugs that inhibit the biotransformation of pharmacological compounds (with examples of drugs that have metabolism blocked by inhibitors listed in parentheses) are: amiodarone (warfarin, quinidine), clofibrate (phenytoin, tolbutamide), excessive ingestion of ethanol (warfarin), isoniazide (phenytoin), metronidazole, cotrimoxazole (warfarin) and phenylbutazone (warfarin, phenytoin, tolbutamide).
We've come to inhibit renal elimination. A number of drugs are secreted by renal tubular transport systems for organic anions. Inhibition of this tubular transport system can cause excessive accumulation of the drug. Phenylbutazone, samplenecid and salicylates competitively inhibit this transporter system. Salicylates, for example, reduce renal clearance of methotrexate, an interaction that may increase the toxicity of methotrexate. Tubular secretion contributes substantially to the elimination of penicillin, which can be inhibited by samplenecid. Inhibition of the tubular transport system of cations by cimetidine decreases the renal clearance of procainamide and its active metabolite, N-aethylprocainamide.
And finally, about inhibiting clearance through multiple mechanisms. The plasma concentration of digoxin is increased by quinidine, largely due to inhibition of renal elimination and, in part, bile secretion. When quinidine is administered in association with a cardiac glycoside there is a risk of arrhythmias. Adidarone, cyclosporin and verapramil also inhibit the clearance of digoxin and increase the concentration of digoxin in plasma.
Now let's present some elements about pharmacodynamic interactions and other drug interactions. Useful therapeutic interactions occur when the effect of two associated drugs is greater than that of the sum of their effects when used individually. These favorable drug associations are described in specific therapy sections, and what follows is directed to those interactions that create undesirable effects. Two drugs can act on separate components of the same process, producing a greater effect than each separately. For example, low doses of aspirin (less than 1g/ day) do not appreciably alter the time of prothrombin in patients undergoing warfarin therapy, however the risk of bleeding increases because aspirin inhibits platelet aggregation.
Thus, the combination of diminished platelet function and defective clotting system increases the potential for hemorrhagic complications in patients receiving warfarin treatment. Nonsteroidal anti-inflammatory drugs cause gastric and duodenal ulcers and, in patients treated with warfarin, the risk of bleeding from peptic ulcers is increased almost 3 times by concomitant use of nonsteroidal anti-inflammatory drugs. This is certainly a drug interaction with serious consequences. Indomethacin, pyroxicam and perhaps other nonsteroidal anti-inflammatory drugs antagonize the antihypertensive effects of beta-adrenergic receptor blockers, diuretics, conversion enzyme inhibitors and other drugs.
It results in a variable increase in blood pressure, from mild to severe. However, aspirin and sulindac do not increase blood pressure in hypertensive patients undergoing treatment. Polymorphic ventricular tachycardia (torsade of the tips) during quinidine administration occurs most frequently in patients receiving diuretics, probably as a consequence of potassium and/ or magnesium loss. Additional potassium administration more frequently leads to a much more severe hyperkalemia when the elimination of potassium is reduced by concomitant treatment with angiotensin conversion enzyme inhibitors, spironolactone, amyloride or triamterene.
I will complete this post with the presentation of some elements about the plasma concentration of drugs as a therapeutic guide. Optimal individualization of therapy can be achieved by measuring the plasma concentration of certain drugs. Genetic variations in treatment rates, interactions with other medicines, conditions that cause changes in purification and distribution, and other factors combine to produce a wide variety of plasma levels in patients receiving the same dose. In addition, the problem of non-compliance with treatments prescribed during prolonged therapy is an endemic and hard-to-detect cause of therapeutic failure. Clinical indicators help to titrate some drugs within the desired range and no chemical determination is a substitute for careful observation of the response to treatment.
However, the therapeutic and adverse effects cannot be precisely quantified for all medicines and, in complex clinical situations, the estimation of the action of the drug may be wrong. For example, a pre-existing neurological condition may hide the neurological consequences of phenytoin poisoning. because clearance, half-life, accumulation and steady plasma levels are difficult to predict, measuring plasma levels is often a useful guide to optimal dosage. This method applies especially when there is a narrow area between plasma levels that produce therapeutic effects and those that produce adverse effects. For medicines with such characteristics, e.g. digoxin, theophylline, lidocaine, aminoglycosides and anticonvulsants, dose optimisation should involve the modification of the standard dose, based on the pharmacokinetic principles described in previous posts.
In certain situations, predictive algorithms and diagrams have been developed to facilitate the necessary changes. However, the most flexible and accurate method for individualizing the dosing of the drug appears to be the retro-related approach (feedback), using a small number of data on previously obtained plasma levels and Bayesian prediction. In controlled studies, this type of computer-assisted dosing has proven useful for improving patient care. However, the cost/benefit ratio of these methods in the routine therapeutic approach remains to be proven. For medicines with a narrow therapeutic window, which are purified by an order I process, dose adjustment can be made on the assumption that there is a linear relationship between the average, maximum and minimum concentrations and the dosing rate.
Thus, the dose can be adjusted on the basis of the ratio between the desired concentration and the measured concentration according to the formula: [Cpss (optimal)/ Cpss (measured)] = [dose (nine)/ dose (previous)]. For medicines with a dose-dependent kinetics (e.g. phenytoin and theophylline), changes in plasma concentrations are disproportionately higher than changes in the dosing rate. Not only should dose changes be lower to minimize the degree of contingency, but monitoring plasma concentration should also ensure appropriate changes. Variability between individual responses at certain given plasma levels must be identified.
This is illustrated by the theoretical/hypothetical population concentration-response curve and its relationship with the therapeutic zone or therapeutic window of the desired plasma levels. The defined therapeutic window should include levels at which most patients achieve the expected pharmacological effect. However, there are a small number of people sensitive to therapeutic effects who respond to lower levels, while others are refractory enough to require levels that can cause adverse effects. For example, a small number of patients with high comitiality require plasma levels of phenytoin exceeding 20 mg/ ml to control seizures. The dosage required to achieve this effect may be useful.
Some patients may experience susceptibility to adverse effects at levels that are tolerated by the vast majority of the population, so increasing these levels to those with a high probability of therapeutic effect may produce adverse and therapeutic effects in these patients. There are many medicines that have plasma concentrations associated with adverse and therapeutic effects in most patients, their use within the limits of medical guidelines being necessary to allow a more effective and powerless therapy for patients who do not belong to the "average".
In addition, the patient's effective participation in the therapeutic program is necessary. Measuring the plasma concentration of the drug is the most effective way to determine when the patient failed to take the drug. This "non-compliance" is a common problem in the long-term treatment of diseases such as hypertension and epilepsy, occurring in 25% of patients or more in hospital environments where no special efforts are made to empower patients to their own health. Occasionally, noncompliance can be discovered by friendly, non-incriminating questioning, but much more frequently it is recognized only after the dosing of the plasma concentration of the drug shows null or low values repeatedly.
Since other factors may cause plasma levels to be lower than expected, comparison with levels obtained during hospital patient treatment may be necessary to confirm that in fact noncompliance has occurred. Once the doctor is sure of this fact, an unaccusing discussion of the problem with the patient can elucidate the reason for non-participation and can serve as a basis for more effective cooperation with the patient. Many approaches have been tried to increase patient responsibility for their own treatment, most based on improved communication on the nature of the disease and the likelihood of therapeutic success or failure.
This communication may also be an opportunity for the patient to report the problems associated with treatment. Improvements can be made by involving nurses and paramedical staff in the process. Minimising the complexity of the regimen is useful both in terms of the number of medicines and their frequency of administration. Educating patients to take the primary role in the care of their own health requires a combination of the art of communication and medical science.
That's it for today... Next time we "treat" drug side effects.
Love, Gratitude and
Understanding!!
Dorin, Merticaru