The three general mechanisms of drug-drug interactions include pharmacokinetic, pharmacologic, and idiosyncratic interactions.
Pharmacokinetic Interactions
Pharmacokinetic interactions include those interactions involving drug absorption wherein one drug may enhance or impair GI absorption of another. For example, drugs that reduce Gl motility may slow the transit time of another drug, allowing it to be present in the Gl tract for a longer period of time, and thereby enhancing systemic absorption of the second drug. Drugs may speed Gl motility to the extent that there is decreased absorption of another therapeutic agent. Furthermore, the coadministration of cholestyramine resin or of a gel antacid, along with a phenothiazine may result in formation of an insoluble complex which is not absorbed through the Gl tract, thereby decreasing the therapeutic effect of the administered psychotropic medication.
Another pharmacokinetic interaction involves the binding of a drug to plasma proteins with the resultant availability of a lower concentration of free drug. If another drug is administered that displaces the first drug from plasma protein binding sites, the concentration and pharmacologic action of the first drug, now freed from binding sites, is increased. A common example of this is the displacement of warfarin from plasma protein binding sites by the coadministration of chloralhydrate. In addition to protein binding, lipid solubility and binding are extremely important in that all psychotropic medications, with the exception of lithium carbonate, are quite freely lipid-soluble. As the fat-to-lean body mass ratio increases in the elderly patient, increased plasma concentrations are encountered with a variety of lipid-soluble psychotropic medications.
Interactions at the site of biotransformation are another form of pharmacokinetic drug interactions. For example, barbiturates induce a variety of hepatic microsomal enzymes, thus enhancing the rate of metabolic degradation of many drugs, including the anticonvulsant phenytoin. Inhibition of drug-metabolizing enzymes by one drug may increase plasma concentration and pharmacologic action of another drug. The MAOls not only diminish the activity of this enzyme, thereby enhancing the effects of a variety of sympathomimetic amines, but also have the ability to impair metabolic degradation of unrelated drugs, including sedatives and narcotics, thereby increasing the pharmacologic effects of a given dose of one of these compounds.
Finally, pharmacokinetic drug interactions at the site of drug elimination may enhance or impair the pharmacologic action of a variety of medicinal substances. Alkalinization of the urine by the administration of sodium bicarbonate, for instance, may hasten the excretion of long-acting barbiturates such as phenobarbital, this interaction may thus be useful in the treatment of phenobarbital overdoses. However, the same interaction may prevent the desired pharmacologic effect of a carefully chosen phenobarbital dose in a patient with a seizure disorder. Acidification of the urine by ascorbic acid or ammonium chloride increases the rate of excretion of amphetamines and phencyclidine hydrochloride (PCP). Thus the administration of acidifying agents may be an important therapeutic technique in the treatment of PCP or amphetamine intoxication.
Pharmacologic Interactions
Pharmacologic interactions occur when two simultaneously administered drugs act similarly on the same receptor site or antagonize the action of each other at the receptor site. At times, a desired therapeutic effect can be achieved by administering two drugs that act similarly at the same receptor site. Two drugs acting at the same receptor site in a similar fashion may, however, produce an unwanted additive drug interaction as in the case of a patient developing an anticholinergic delirium when receiving a combination of neuroleptic, tricyclic antidepressant, and antiparkinsonian medication. Two drugs, each with important and desired therapeutic effects, may antagonize the action of each other, thus preventing a desired therapeutic response. The classical example of this kind of drug interaction occurs when a hypertensive patient on a regimen of guanethidine receives amitriptyline or another tricyclic antidepressant and thereby loses the antihypertensive effect of guanethidine. All tricyclic antidepressants block nerve reuptake mechanisms, which are necessary to achieve the antihypertensive action of guanethidine, clonidine, and related drugs.
Idiosyncratic Reactions
Another form of drug-drug interaction is the idiosyncratic phenomenon wherein we do not understand the mechanism of interaction leading to either a diminished therapeutic response of one or the other drug or the occurrence of a toxic or adverse effect of one drug when administered in the presence of another. One form of idiosyncratic reaction involves allergic reactions to drugs, wherein the patient has presumably been sensitized by the prior administration of a similar medication to the extent that a classical immunologically mediated reaction occurs. Although in the idiosyncratic category, allergic reactions are, by definition, largely unpredictable, it should be borne in mind that familiarity with chemical structural similarities between various therapeutic agents may allow the clinician to avoid allergic reactions to a specific pharmacologic agent when the patient has previously experienced an allergic reaction to a chemically related substance. As we obtain greater understanding of the mechanism of action and adverse effects of a variety of medications, we will encounter fewer and fewer idiosyncratic drug interactions. As we understand mechanisms better, we may be able to avoid combined therapeutic application of substances that have previously been demonstrated to interact with each other in an adverse fashion.
Having reviewed some mechanisms of common drug interactions, we now focus on specific interactions between various psychotropic drugs and medications administered for nonpsychiatric illness. The role of coexisting medical and neurologic disorders in the occurrence of adverse drug reactions as well as the psychiatric complications of nonpsychotropic medications is also discussed. Those reactions under discussion have been well documented in published literature and are common enough that the average sophisticated clinician should be prepared to recognize them.
SEDATIVES
A wide variety of chemical compounds including barbiturates benzodiazepines, antihistamines, meprobamate, methaqualone, glutethimide, ethchlorvynol, chloral hydrate, and ethanol are used to treat anxiety and insomnia. Sedatives are also known as minor tranquilizers or antianxiety drugs.
All sedatives, with the exception of antihistamines, have the capability of producing a dose-related CNS depressant effect. Administration of excessive doses of these compounds or their use in combination with each other or with other centrally acting drugs may produce CNS depression and respiratory depression. Patients suffering from chronic obstructive pulmonary disease may be excessively sensitive to respiratory depression induced by these drugs and may suffer prolonged respiratory embarrassment. These drugs, with the exception of the antihistamines, are capable of inducing tolerance, physical dependence, and addiction when administered over a prolonged period of time. Patients suddenly withdrawn from any of these drugs following the appearance of an addictive syndrome, may suffer a withdrawal reaction marked by seizures, delirium, high fever, and even death. Patients who have become dependent on any of the sedative drugs require careful gradual detoxification under medical supervision. Although benzodiazepines have relatively minor anticholinergic action, confusional states and prolonged sedation resulting from their use may be reversed by the cautious IV administration of physostigmine. A toxic delirium has been reported when ethchlorvynol is used in combination with tricylic antidepressants, presumably related to the enhancement of anticholinergic action of the latter drug by the former.
Barbiturates, particularly phenobarbital, are potent enzyme inducers and may enhance metabolic degradation of a variety of drugs including phenytoin and anticoagulants, reducing the therapeutic effects of the latter compounds.
Benzodiazepines, which were initially believed to be relatively free of drug interactions, have been found to interact with a variety of therapeutic agents. https://searchfortruth.info/wp-content/uploads/2017/07/img44fd2d42019cc-300×178.jpgCimetidine inhibits benzodiazepine metabolism, producing increased and prolonged effects, particularly of longer-acting benzodiazepines such as chlordiazopoxide and diazepam Likewise, disulfiram, which decreases benzodiazepine metabolism, may enhance and prolong the pharmacologic action of these compounds. When diazopam is administered along with neuromuscular blocking drugs such as gallamine or succinylcholine, prolonged neuromuscular blockade and paralysis result.
Chloralhydrate, which displaces a variety of drugs from plasma protein binding sites may, by this mechanism, enhance the anticoagulant effects of warfarin and related compounds, and may also interact with the diuretic furosemide to produce diaphoresis and a hypertensive reaction.
Hydroxyzine, a sedating antihistamine without CNS depressant or addictive effect, has been reported to interact with phenothiazines, particularly thioridazine, tricyclic antidepressants, and lithium to increase the risk of cardiac arrhythmias.
Estrogenic hormones appear to inhibit metabolic degradation of benzodiazepines and may thereby increase their plasma concentration and pharmacologic action. The antituberculous drug isoniazid inhibits a variety of enzymes and may thereby increase the effect of coadministered benzodiazepines. Rifampin, another antituberculous drug is an enzyme inducer and may decrease the pharmacologic effect of benzodiazepines by enhancing their metabolism. Likewise, tobacco smoking may decrease benzodiazepine activity by enzyme induction. For reasons that are at this time unclear, administration of benzodiazepines along with digoxin may increase the half-life of the latter drug. Table 12-1 demonstrates some of the currently recognized interactions between sedatives and other drugs.
ANTIPSYCHOTIC DRUGS
Antipsychotic or neuroleptic drugs include five chemically distinct groups of therapeutic agents: phenothiazine, thioxanthene, butyrophenone, dihydroindolone, and dibenzoxazepine. These drugs alleviate hallucinations, delusions, disordered thinking, and other major manifestations of psychotic illness, as a result of their ability to block dopamine receptors within the brain. The various antipsychotic drugs differ from one another in their potency and selectivity with respect to dopamine receptor blockade. They also differ from one another in respect to their side effects. Chlorpromazine, mesoridazine, and thioridazine are most sedating whereas haloperidol, loxapine, molindone, and the piperazine phenothiazines such as trifluoperazine are much less sedating. If a highly sedating antipsychotic agent is used in combination with a barbiturate or benzodiazepine, the patient may experience excessive somnolence and an additive drug interaction. The patient may become difficult to arouse or may experience respiratory depression, particularly if there is underlying chronic obstructive pulmonary disease or if the patient is elderly.
Chlorpromazine, mesoridazine, and thioridazine are potent alphaadrenergic blocking agents and may thereby produce considerable hypotension. If these drugs are combined with coronary, cerebral, or peripheral vasodilators or with antihypertensive drugs, more profound degrees of hypotension may be encountered. Likewise, the combination of the previously mentioned phenothiazines with an MAOI antidepressant can produce profound hypotension that may be difficult and indeed dangerous to reverse since the MAOI may increase the risk of any pressor agent administered and the phenothiazine will reduce the response when a pressor agent is administered. Hypotension resulting from these drug interactions is best treated by keeping the patient in a recumbent position and providing IV fluid replacement through a large catheter with careful patient monitoring to avoid congestive heart failure, which may result from too vigorous fluid replacement. If pressor agents must be administered, phenylephrine is the safest to employ, but it must be used cautiously because of the need to balance reduced sensitivity to the drug as a result of phenothiazines versus the increased sensitivity to the drug resulting from monoamine oxidase inhibition. Epinephrine should be avoided because it may, as a result of its B-adrenergic stimulant effect, induce further hypotension. The use of indirect-acting agents, such as metaraminol, which release catecholamines from the adrenal medulla, may be associated with unwanted hypertensive and arrhythmic effects.
Haloperidol has the least x-adrenergic blocking effect and is least likely among antipsychotic drugs to induce hypotension. The likelihood of an additive interaction with vasodilators or antihypertensive drugs is less with haloperidol than with the previously mentioned phenothiazines. Haloperidol and the piperazine phenothiazines such as trifluoperazine are safer if used in conjunction with MAOIs than are the previously mentioned lower-potency more hypotensive neuroleptics. When used alone, haloperidol is much less likely than other neuroleptics to induce unwanted hypotensive effects. When phenothiazines are used in combination with a variety of anesthetics such as halothane, enflurane, and isoflurane, there is considerable likelihood of a profound hypotensive reaction; therefore, this drug combination should be avoided. It should be kept in mind that phenothiazines may produce an additive drug interaction with succinylcholine resulting in prolonged neuromuscular blockade in association with anesthesia employing this muscle relaxant.
Numerous drugs prescribed by psychiatrists exert a pronounced anticholinergic effect. Indeed, most antiparkinsonian medications exert their therapeutic action as a result of cholinergic blockade. Tricyclic and heterocyclic antidepressants produce pronounced anticholinergic action. Among antipsychotic drugs, thioridazine and mesoridazine are most likely to produce pronounced cholinergic blockade. Chlorpromazine is also strongly anticholinergic while the piperazine phenothiazines including trifluoperazine and the butyrophenone compound haloperidol exert much less anticholinergic action. Clinicians are generally aware that anticholinergic drugs produce blurred vision, dry mouth, tachycardia, constipation, and urinary retention. It is all too easy to forget that anticholinergic agents may also have a central effect including the production of stuttering speech and impaired memory and concentration. Since patients receiving neuroleptic drugs frequently are also receiving antiparkinsonian medication, and, not uncommonly, tricyclic antidepressants as well, there is a strong likelihood of the patient experiencing excessive cholinergic blockade as a result of a psychotropic drug regimen.