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Psychotropic Drug Interactions Graylands Hospital Drug Bulletin 2006 Vol

Psychotropic Drug Interactions Graylands Hospital Drug Bulletin 2006 Vol

Graylands Hospital

DRUG BULLETIN

Pharmacy Department Brockway Road Mount Claremont WA 6010 Telephone (08) 9347 6400 Email [email protected] Fax (08) 9384 4586 Psychotropic Drug Graylands Hospital Drug Bulletin 2006 Vol. 14 No. 2 July ISSN 1323-1251 Drug Interactions Overview A drug can be beneficial, harmful, or have A occurs when the toxicity or no significant effect. There are numerous known effectiveness of a drug is altered by the concurrent interactions involving psychotropic drugs. Many administration of another drug. Drug interactions can interactions have minor clinical significance; however, be classified as pharmacokinetic or pharmacodynamic there are many potentially hazardous interactions that in nature. A pharmacokinetic drug interaction occurs should always be considered. The significance of a when a drug alters the absorption, distribution, drug interaction can also vary between individuals or of another drug. depending on factors such as comorbidities, gender or Pharmacodynamic interactions occur when two drugs age. It is important to consider drug interactions when act on interrelated sites resulting in either initiating drug therapy, changing a dose, changing the 1 additive or antagonistic effects. route of administration or ceasing therapy . Table 1: Pharmacokinetic Interactions Mechanism Interaction Effect Absorption Changes in Psychotropics with properties can increase the gastric pH. An increase in gastric pH can: gastrointestinal • Reduce the absorption of drugs such as through reduced dissolution; pH • Damage enteric coatings on tablets Complexing and adsorb with containing magnesium or aluminium salts when given within mechanisms 2 hours, resulting in reduced absorption. Changes in Psychotropics with anticholinergic properties delay gastric emptying time, this can: gastrointestinal • Reduce the rate of absorption of other drugs; motility • Cause degradation of -labile drugs. Distribution Protein binding Competition for binding sites may result in an increase in unbound plasma levels of drugs that are highly protein- bound (>90%). Protein-binding interactions may only be significant for drugs with a small volume of distribution or where a temporary increase in plasma levels may result in unacceptable adverse effects and include drugs such as , , sulfonylureas or phenytoin. Most psychotropics are protein-bound to a certain extent with the exception of and . Metabolism Induction increases the metabolism of the drug, causing reduced plasma levels. induction This is significant for drugs where a reduced plasma level may result in treatment failure and includes drugs such as: the oral contraceptive pill, , , corticosteroids, digoxin, protease inhibitors, immunosuppressants and . Enzyme induction of psychotropic drugs may result in reduced efficacy. Enzyme Inhibition decreases the metabolism of the substrate drug, leading to increased plasma levels. inhibition This is significant for drugs with a low , where there is a low ratio between a therapeutic and toxic dose. Notable drugs involved in this reaction include: warfarin, phenytoin and theophylline. The effect of enzyme inhibition on psychotropic drugs is an increase in dose-dependent adverse effects. Changes in Certain drugs such as reduce hepatic blood flow. blood flow This may result in an increased availability of drugs that have a high rate of hepatic first-pass metabolism such through as , , and . Excretion Changes in • Increase in urinary pH decreases of and increases clearance of lithium urinary pH • Decrease in urinary pH increases clearance of amphetamines Changes in NSAIDs including COX-2 inhibitors inhibit synthesis of prostaglandins, reducing renal excretion of lithium. blood flow Changes in Drugs that alter the ability of the proximal renal tubule to reabsorb sodium or that cause volume depletion can active kidney affect the elimination of lithium. tubule excretion • Drugs that reduce lithium excretion and increase levels include: ACE inhibitors, Angiotensin II receptor antagonists, NSAIDs, COX-2 inhibitors, and low-sodium diets. • Drugs known to increase the elimination of lithium and decrease levels include: bicarbonate and sodium salts Biliary excretion There are few clinically significant interactions involving psychotropic drugs by this mechanism.

Graylands Hospital Drug Bulletin 2006 Vol 14 No.1 - 1 - levels6. Other psychotropic substrates of Pharmacokinetic interactions phase II glucuronidation include sodium , 7 Table 1 outlines the mechanisms of pharmacokinetic , oxazepam and . interactions involving psychotropic drugs2,3. Of the pharmacokinetic drug interactions, the most clinically Metabolic Drug Interaction Considerations significant interactions include metabolism Enzyme inhibition has the effect of increasing the interactions, and elimination interactions involving levels of the substrate that is metabolised by the lithium. Metabolism interactions are also the most inhibited enzyme. Enzyme inhibition begins to occur frequently encountered pharmacokinetic interactions, with the first dose of the inhibitor and is maximal when and these are discussed further below. the inhibitor reaches steady state, which is usually 2 after four to seven half-lives . Enzyme induction Metabolism occurs when a drug stimulates the synthesis of more Very few drugs are excreted from the body unchanged . The effect of enzyme induction is an in the urine; most are metabolised within the body to increase in the rate of metabolism of the substrate, less lipid-soluble compounds that are excreted by the resulting in potentially reduced efficacy. The effects of kidneys. an enzyme-inducing drug are less predictable than for enzyme inhibitors. The time course of enzyme The most clinically significant and well-studied induction onset and offset is related to the plasma metabolism interactions involve phase I metabolism, concentration of the inducer as well as the half-life of which mainly involve hepatic microsomal enzymes. enzyme production and degradation. These enzymes belong to the (CYP450) family of isoenzymes, of which there are With metabolic interactions, it is important to note that about thirty. However, only a few subfamilies are many drugs are substrates for more than one enzyme, responsible for the metabolism of the majority of so often there is an alternative route of CYP450 drugs2. Table 2 lists psychotropic drugs that inhibit, metabolism, and many drugs are also metabolised by induce or are substrates for metabolism according to phase II conjugation reactions. An example of this is isoenzyme3,4. A more comprehensive list of CYP450 sodium valproate, which is metabolised 40-60% by interactions can be found at glucuronidation and hence inhibition of CYP450 http://medicine.iupui.edu/flockhart/. metabolism does not have a significant effect on clearance of valproate, as it is considered to be a 2 Phase II drug interactions are not as well studied as minor secondary pathway of metabolism . the CYP450 interactions, although many psychotropics are substrates for, or inducers or Drugs can also have different affinities for the inhibitors of this pathway, in particular isoenzymes and therefore differ in their potential for glucuronidation5. An example of a glucuronidation significant interactions. For example, , interaction occurs between sodium valproate and and are considered potent lamotrigine. These drugs compete for metabolism by CYP450 inhibitors whereas , , glucuronidation, with a resultant increase in , and reboxetine are weak inhibitors; hence, there is a lower likelihood of Table 2: Psychotropic drugs that are substrates, inhibitors and inducers of cytochrome P450 isoenzymes CYP1A2 CYP2B6 CYP2C19 CYP2C9 CYP2D6 CYP3A4,5,7 Substrates , , amitriptyline, amitriptyline, amitriptyline, , amitriptyline, chlorprmazine, methadone citalopram, fluoxetine, , , aripiprazole, , clomipramine, phenytoin , , buspirone, , , , , fluvoxamine, , clomipramine, clomipramine, , moclobemide, , donepizil, , clozapine, imipramine, phenobarbitone fluoxetine, fluvoxamine, diazepam, donepezil, methadone, galantamine, haloperidol, galantamine, haloperidol, olanzapine, imipramine, , imipramine, methadone, pimozide, olanzapine, paroxetine, midazolam, mirtazapine, , sertraline, pimozide, , thioridazine, venlafaxine, reboxetine, sertraline, triazolam, zolpidem, Inhibitors fluvoxamine fluoxetine, fluoxetine, bupropion, fluoxetine, fluvoxamine, fluvoxamine, fluvoxamine, chlorpromazine, valproate , paroxetine, citalopram, clomipramine, paroxetine, sertraline , duloxetine, , escitalopram, fluoxetine, valproate haloperidol, methadone, moclobemide, paroxetine, reboxetine, sertraline, thioridazine, valproate Inducers , phenobarbitone carbamazepine barbiturates barbiturates, cigarette smoke, carbamazepine, modafinil modafanil, phenytoin, St John’s Wort

Graylands Hospital Drug Bulletin 2006 Vol 14 No.1 - 2 - significant metabolic drug interactions with these drugs3. Seizures may result from the additive effects of two or more drugs that lower the threshold. Most It is also important to consider the effect of stopping and can reduce the an enzyme-inducing or enzyme-inhibiting agent after . Of the antipsychotics, clozapine long-term therapy, as this can affect the levels of the and chlorpromazine have the greatest epileptogenic substrate. An example of this is the average of 72% potential and for antidepressants, the increase in clozapine levels that is observed when antidepressants (TCAs) pose the greatest risk11. cigarette smoking is stopped due to reversal of Patients that require a combination of drugs that CYP1A2 induction8. reduce the seizure threshold should be maintained on the lowest effective dose, using a slow rate of There is also large inter-individual variation in the introduction and withdrawal8. High-risk drugs and amount of isoenzymes that individuals possess; combinations in patients with underlying conditions different individuals can be poor metabolisers or ultra- that might predispose them to seizures should be fast metabolisers with respect to particular CYP450 avoided. enzymes. syndrome Pharmacodynamic interactions Serotonin syndrome can occur with one or more The most commonly encountered interactions in drugs. Serotonin syndrome is a practice are pharmacodynamic interactions. Clinically potentially life threatening condition characterized by significant pharmacodynamic drug interactions with mental state changes, , , psychotropic drugs are discussed below. hyperreflexia, fever, sweating, shivering and diarrhoea. All of the antidepressants, except Antagonistic interactions reboxetine, can contribute to serotonin syndrome, and there is a greater risk of serotonin syndrome with Antipsychotics that are potent D2 antagonists oppose the effect of dopamine combinations of selective serotonin reuptake inhibitors used in Parkinson’s disease. When used together, the (SSRIs) and monoamine oxidase inhibitors (MAOIs) or SSRIs and serotonergic TCAs (clomipramine, therapeutic effect of both drugs will be diminished. 3 amitriptyline, and imipramine) . Other drugs such as Psychotropics with anticholinergic properties can (, , and dextromethorphan), pharmacodynamically oppose the effects of stimulants (phentermine, diethylpropion, anticholinesterase drugs used in Alzheimer’s disease amphetamines, and sibutramine), 5HT1 agonists as well as prokinetic agents such as (, , and ) and others used for motility disorders. (illicit drugs, selegiline, trytophan, buspirone, lithium, and St John’s wort) can also contribute to 12 antagonizes postsynaptic serotonin serotonin syndrome . Combined use of serotonergic receptors. Concomitant use of cyproheptadine with drugs should be avoided or monitored carefully. drugs that possess serotonin-enhancing properties might be expected to result in a pharmacodynamic Hypertension interaction. Lack of efficacy has been The concomitant use of MAOIs and tyramine reported when cyproheptadine was given concurrently containing food, or drugs that increase the level of with fluoxetine and paroxetine9. monoamines (serotonin, noradrenaline, or dopamine) can result in interactions that have the potential to 6 Additive Pharmacodynamic Interactions cause hypertensive crisis . Combinations of MAOIs Oversedation and these drugs are contraindicated. The severity and Oversedation due to the additive effects of drugs with consequences of such interactions vary among properties is often encountered when individuals. If substantial and rapid increases in blood combining psychotropic drugs. Oversedation may pressure (an increase of 30 mm Hg or more in systolic also occur as the result of inhibition of metabolism of blood pressure within 20 minutes) occur, patients may experience symptoms associated with subarachnoid the sedating drug through CYP450 metabolism. 9 Severe oversedation can lead to falls, injury, venous haemorrhage or cardiac failure . thromboembolism or hypostatic pneumonia10. Anticholinergic effects Neurotoxicity Caution should be used when combining drugs with Concurrent use of lithium and antipsychotics or anticholinergic properties due to enhanced carbamazepine may result in neurotoxicity anticholinergic effects such as dry mouth, urinary characterized by weakness, dyskinesias, increased retention and . There is also an increased , encephalopathy, and brain risk of developing , or central anticholinergic damage. This interaction is rare and is more likely to characterised by cognitive changes as well as occur with higher plasma levels of lithium8. symptoms including: hot, dry skin; dry mucous membranes; dilated pupils; tachycardia; and absent 13 bowel sounds .

Graylands Hospital Drug Bulletin 2006 Vol 14 No.1 - 3 - Caution should be used when combining drugs with Conclusions an antihypertensive effect. Hypotension is a common of many psychotropic drugs due to While there are numerous theoretical and documented alpha- blockade. Hypotension is a dose- drug interactions, many are of little clinical related and additive adverse effect. It is a potentially significance. Assessment of the pharmacodynamic serious adverse reaction due to the risk of falls, and pharmacokinetic profile of psychotropic and other 8 cerebral ischaemia or myocardial ischaemia . drugs can help determine the clinical significance of any interactions and prevent the serious QTc prolongation consequences of drug interactions. Many psychotropic drugs including certain antidepressants, antipsychotics and lithium have been associated with lengthening of the cardiac QTc Acknowledgment interval, which increases the risk of ventricular This article was prepared by Karolina Golebiewski, arrhythmias such as . Drug Information and was reviewed by Psychotropics with the greatest effect on QTc interval members of the Pharmacy Department and include chlorpromazine, haloperidol, , 11 Dr Ancy John pimozide and thioridazine . The risk of cardiac Comments are welcome at the e-mail address: arrhythmia and sudden death may be further [email protected] increased when these drugs are used concomitantly with other QTc prolonging drugs, and in most cases, References available on request combinations are contraindicated. A complete list of drugs that affect the QTc interval can be found at www.qtdrugs.org. QTc prolongation is a dose Armstrong SC, Cozza KL, Sandson NS. Six patterns dependent effect; hence inhibition of of drug-drug interactions. Psychosomatics. is also an important interaction to consider. 2003;44(3):255-258 2 Stockley I, editor. Stockley’s drug interactions. Bath: Indirect pharmacodynamic interactions with Pharmaceutic Press; 2002 psychotropics that prolong the QTc interval should 3 Therapeutic Guidelines:Psychotropic Version 5 2003 also be considered. These interactions involve drugs 4 Drug Interactions. Available at: that affect the electrolyte balance, or that cause http://medicine.iupui.edu/flockhart/. bradycardia, thereby increasing the risk of 5 Liston HL, Markowitz JS, Devane CL. Drug arrhythmia11. glucuronidation in clinical psychopharmacology. Journal of Clinical Psychopharmacology. Haematological effects 2001;21(5):500-515 Psychotropic drug-induced haematological problems are rare; however consideration should be given to 6 Mims Online. Donahoo E, editor.: Health additive drug effects, in particular, effects on white Communication Network; 2005 blood cells and platelets14. 7 Liston HL, Markowitz JS, Devane CL. Drug glucuronidation in clinical psychopharmacology. Of greatest clinical significance are interactions Journal of Clinical Psychopharmacology. between clozapine and drugs known to be 2001;21(5):500-515 myelosupressive, and due to the risk of , these combinations are 8 Bazire S. Psychotropic Dug Directory 2005 Fivepin contraindicated. Many other psychotropic drugs have also been associated with agranulocytosis, most 9 DRUG-REAX® System: notably carbamazepine and the phenothiazines. Klasco RK (Ed): DRUG-REAX® System. Thomson Micromedex, Greenwood Village, Colorado (2006]). Serotonergic drugs and valproate can affect platelet 10 Cadwick B, Waller DG, Edwards JG. Potentially function. SSRIs can inhibit serotonin reuptake into the hazardous drug interactions with psychotropics. Advances platelets, reducing platelet aggregability. When SSRIs in Psychiatric Treatment. 2005;(11)440-449 are used in combination with NSAIDs or 11Taylor D, Paton C, Kerwin R. Maudsley Prescribing anticoagulants the risk of bleeding may increase Guidelines 2006-2006 8th ed Taylor and Francis although this interaction is usually uneventful12. 12 AMH 2006 Valproate can inhibit the second stage of platelet 13 Lieberman J. Managing anticholinergic side effects. aggregation and increase bleeding time. Caution is Journal of Clinical Psychiatry. 2004;6(suppl2):20-23 required when valproate is used with other drugs that affect coagulation or platelet function. 14 Oyesanmi O, Kunkel JS, Monti DA, Field HL. Hematologic side effects of psychotropics. Psychosomatics. 1999;40(5):414-421

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