Review Top 10 Prescribed Drugs: Important Interactions
Karen A. Jensen, MSc, BSP Presented at the University of Saskatchewan’s 4th Annual Peter and Anna Zbeetnoff Memorial Drug Therapy Decision-Making Conference, Saskatoon, Saskatchewan, March 2007.
ith more drugs and drug combinations Management Wbeing used than ever before, the poten - Manage this drug interaction by: tial for adverse effects due to interaction is also • using azithromycin or antibiotics from an increasing. The actual incidence of clinically alternate class, significant interaction has not been determined • discontinuing atorvastatin for the duration but it is known to be a factor in many ER visits of antibi©otic therapy, or by and hospital admissions. Patient groups at high - i•gswhitchting from atorvastatin to a “ustattiin”on er risk of serious interaction effects includey: r less likely to interact, sutchrais:b op is d, C ial D wnloa • those taking three or more drugs, -epravcastatin, can do mm users use • psychiatric patients, Co o- rrisoseudvastatin or sonal or . Auth or per • the elderly, ale hibited - fcluovpaystaftin. r S se pro ingle t fo ised u rint a s N• opatients uanduetrhtoher care of mulatinplde p Un y, view Be aware of… physicians anddispla • patients who fill prescriptions at more than Possible cases of an interaction that have been one pharmacy. reported with pravastatin; one case report of The following are examples of interactions rhabdomyolysis as a cause was associated with involving last year’s top 10 prescribed drugs. azithromycin plus lovastatin. 1 Caution those patients on any “statin” plus Atorvastatin and macrolides macrolide combination to watch for signs of myopathy. Atorvastatin and macrolides interact via the inhibition of cytochrome P450 3A4 and Levothyroxine and calcium p-glycoprotein by macrolide antibiotics. This results in elevated atorvastatin serum levels and The calcium binds to levothyroxine, decreasing an increased risk of adverse reactions, such as the amount of levothyroxine available for myopathy and rhabdomyolysis. Erythromycin absorption in the gut. Although the effect is has the strongest inhibitory activity, clar - insignificant for most people, there are case ithromycin has a moderate effect and reports of elevated thyroid stimulating hormone azithromycin has little or no effect. and symptoms of hypothyroidism.
90 The Canadian Journal of Diagnosis / May 2008 Drug Interactions
Management of these drug classes, however, have the poten - tial to increase potassium levels which can Patients should be counselled to take levothy - progress to severe hyperkalemia and life- roxine at the same time each day in relation to threatening cardiac arrythmias. Elderly, renally- meals and calcium supplements so that any impaired and diabetic patients are at higher risk. interaction effect will be adjusted for when Management titrating the levothyroxine dose. Ideally, levothyroxine should be taken on an empty stom - To avoid this interaction effect, the combination ach and at least one hour before or four hours of ACE inhibitors and the potassium-sparing after the ingestion of calcium supplements. diuretics, amiloride or triamterene is not rec - Consider the possibility of interaction ommended. Doses of spironolactone with ACE between levothyroxine and calcium when previ - inhibitors should be limited to ≤ 25 mg. ously stable patients exhibit signs/symptoms of Regular monitoring of serum potassium is hypothyroidism. essential and extra vigilance is required for Other potential interactants high-risk patients. Did you know...? Calcium-fortified orange juices, bottled waters, some cereals and breads have the potential to Elderly patients on ACE inhibitors hospitalized interact with levothyroxine, as do meal replace - with hyperkalemia are 20 times more likely ments ( e.g. , nutritional energy drinks), iron, than control patients (without hyperkalemia) to magnesium and possibly zinc supplements. have received a potassium-sparing diuretic. 2
deally, levothyroxine Amlodipine and alcohol Ishould be taken on Alcohol is reported to increase serum levels of an empty stomach and nifedipine (inhibited metabolism) and felodip - ine (increased bioavailability), but it appears to at least one hour before have no significant effect on amlodipine phar - or four hours after the macokinetics. 3 However, patients who combine ingestion of calcium amlodipine and alcohol are still susceptible to the pharmacodynamic effects of interaction, supplements. which are: • Acutely - an increased likelihood of Ramipril and potassium-sparing orthostatic hypotension diuretics • Long-term - decreased antihypertensive effect when ≥ 30 gm of alcohol daily (two The combination of ACE inhibitors and drinks) are ingested on a regular basis potassium-sparing diuretics is often beneficial for patients with congestive heart failure. Both
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Management - Fever According to the 2006 Canadian Hypertension - Diarrhea Education Program Guidelines, to avoid the • Mental status changes: pharmacodynamic effects of alcohol and - Agitation amlodipine, consumption should be limited to - Incoherent speech less than two standard drinks daily, < 14 drinks - Delirium per week for men and less than nine drinks per • Neuromuscular abnormalities: week for women. Patients should be made - Incoordination aware of the potential for exaggerated hypoten - - Tremors sive effect with alcohol. - Rigidity Did you know...? Management
Moderate alcohol intake in men with hyperten - Patients should be counselled on particular sion is associated with a decreased risk of MI, symptoms of concern and the need for immedi - but not mortality. 4 ate medical attention if any of the above symp - toms occur. lderly patients on The risk increases when therapy with ven - EACE inhibitors lafaxine is initiated, when the dose of venlafax - hospitalized with ine or the “triptan” is increased and if the patient is using additional drugs with serotoner - hyperkalemia are 20 gic activity. The actual incidence of an interac - times more likely to have tion between venlafaxine and “triptans” appears received a potassium- to be low but vigilance is required given the sparing diuretic. potential severity of the reaction. FDA alert
Venlafaxine and “triptans” In July 2006, the FDA issued an alert based on The combination of venlafaxine and “triptans” seven reported cases of serotonin syndrome (i.e. , sumatriptan, zolmitriptan, naratriptan, involving selective serotonin or serotonin- etc. ) can result in excess serotonergic activity, nor epinephrine reuptake inhibitors and the use of increasing the risk of serotonin syndrome, a “triptans.” Thirteen patients were admitted to hos - rare , but potentially serious condition involving: pital and two of these cases were life-threatening. 5 • Autonomic hyperactivity: Low-dose ASA and ibuprofen
Ms. Jensen is the Manager of the Saskatchewan Drug Ibuprofen use may counteract the beneficial CV Information Service, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan. effect of ASA by inhibiting ASA binding to platelets.
92 The Canadian Journal of Diagnosis / May 2008 Drug Interactions
Management PPIs and risk of hip fracture Acetaminophen should be substituted for An observational study reported a statistically sig - ibuprofen. For occasional use, ibuprofen may nificant increase in overall fracture rate in those be taken at least 30 minutes after the regular taking PPIs. This risk increased with high-dose ASA dose and not less than eight hours before PPIs and a longer duration of PPI therapy. The the next scheduled dose of ASA. actual individual risk appears to be minimal (num - NSAIDs less likely to interact with ASA are ber needed to harm = 1,200 elderly adults/year). 7 diclofenac or naproxen. Did you know...? Acetaminophen/codeine and CYP2D6 inhibitors Platelet function tests suggest an interaction between 400 mg of ibuprofen and low-dose ASA, 6 CYP2D6 inhibitors ( e.g. , fluoxetine, paroxe - but the significance has not been evaluated in reli - tine, hydroxychloroquine, propafenone, able outcome studies. terbinafine) prevent the hepatic conversion of codeine to morphine, reducing or nullifying the Pantoprazole and nutrients analgesic effect of codeine. Management An increased gastric pH may decrease absorption of calcium (resulting in an increased risk of frac - Try an alternate analgesic for patients on 2D6 ture), vitamin B12 (resulting in megaloblastic ane - inhibitors and discourage the use of OTC mia and neuropathy) and may possibly impair iron codeine combinations. absorption. Monitor patients Management Monitor patients who are discontinuing 2D6 PPIs are recommended at the lowest effective dose inhibitors, as these individuals are at risk of tox - and should only be used when needed. icity due to increased morphine levels. Treating physicians should ensure that those patients who must take a PPI to suppress the Salbutamol and thiazide amount of acid in their stomachs do receive the diuretics recommended amounts of calcium and vitamin D from their diet and supplements. It may be neces - High doses of inhaled ß-agonists in combina - sary to recommend a daily multivitamin, though tion with thiazide diuretics can result in iron supplements are not required unless the hypokalemia and cardiac arrhythmias. patient is iron deficient. Management Consider periodic vitamin B12 level checks for patients considered to be at higher risk ( e.g. , poten - Be aware of interaction potential, though no tial strict vegetarians, alcoholics and the elderly). action on the part of the GP is usually required (i.e. , hypokalemia induced by salbutamol is
The Canadian Journal of Diagnosis / May 2008 93 Review
generally transient). Monitor serum potassium gain, decreased urine output and increased edema . levels in patients with risk factors such as fre - Consider... quent use of salbutamol, high doses of diuretic, renal impairment and during illnesses causing Carefully consider the risk vs. benefit of this vomiting, diarrhea, and dehydration (exacer - combination of medications in patients at high - bate potassium loss). er risk ( i.e. , the elderly, those with congestive Extra caution required heart failure, renal insufficiency and cirrhosis). Extra caution is required in those with severe Conclusion asthma, chronic obstructive pulmonary disorder (the effect is potentiated with concurrent thera - Drug interactions can cause unnecessary py with theophylline and corticosteroids and patient suffering and expense to the healthcare with hypoxia) and ischemic heart disease system. The likelihood of clinically significant (hypokalemia may affect response to digoxin, interaction is largely dependent on the individ - antiarrythmics and may generate arrhythmias). ual patient situation. Identifying and monitor - ing those patients at high-risk for adverse dentifying and effects resulting from interaction is the shared responsibility of physicians and pharmacists. I monitoring those There are many good resources available, both patients at high-risk for electronic and hard copy. For more obscure or adverse effects resulting complex situations, specialists in pharmacology or drug information services can be consulted.
from interaction is the Dx shared responsibility of physicians and pharmacists. References 1. Baxter K (ed.): Stockley’s Drug Interactions . Pharmaceutical Press, London, 2006, pp.838-9. Furosemide and NSAIDs 2. Juurlink DN, Mamdani M, Kopp A, et al: Drug-Drug Interactions Among Elderly Patients Hospitalized for Drug Toxicity. JAMA 2003; 289(13):1652-8. NSAIDs decrease prostaglandin synthesis, 3. Vincent J, Colangela P, Baris B, et al: Single and Multiple Doses of Amlodipine Do Not Alter the Pharmacokinetics of Alcohol in Man. renal blood flow and diuresis as well as antago - Therapie 1995; 50(Suppl):509. 4. Beulens JW, Rimm EB, Ascherio A, et al: Alcohol Consumption and nize the diuretic and the antihypertensive effect Risk for Coronary Heart Disease Among Men with Hypertension. Ann of furosemide while increasing the risk of Intern Med 2007; 146(1):10-9. 5. FDA ALERT [7/2006]: Potentially Life-Threatening Serotonin nephropathy. Syndrome with Combined Use of SSRIs or SNRIs and Triptan Medications. [Accessed 15Feb2007] Available from: http://www.fda.gov/cder/drug/InfoSheets/HCP/triptansHCP.htm. Management 6. Catella-Lawson F, Reilly MP, Kapoor SC, et al: Cyclooxygenase Inhibitors and the Antiplatelet Effects of Aspirin. N Engl J Med 2001; BP should be regularly monitored and patients 345(25):1809-17. 7. Yang YX, Lewis JD, Epstein S, et al: Long-Term Proton Pump Inhibitor should be encouraged to report sudden weight Therapy and Risk of Hip Fracture. JAMA 2006; 296(24):2947-53.
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