A message from the editor of this section, Professor Juan Tamargo
Old and new drugs need to demonstrate to be not only efficacious but also safe. Adverse effects, just like the therapeutic effects, of drugs, are a function of dosage or drug levels at the target organs. As Paracelsus (1493-1541) says, “All things are poison, and nothing is without poison; only the dose permits something not to be poisonous”. As doctors, one of our main interests is to protect public health and to promote the judicious use of drugs. This section exists for that reason.
Drug Interactions were the focus of the programme at the ISCP Annual Meeting 2017 held in Barcelona.
Nitrates
| Interacting drug | Pharmacodynamic interaction | Pharmacokinetic interaction | Clinical implicaciones |
|---|---|---|---|
| Acetylcysteine | Potentiates GTN-induced coronary vasodilation and may reverse nitrate tolerance | No special precautions | |
| Alcohol | Additive hypotensive effects | Higher risk of postural hypotension, dizziness and syncope. The dose of nitrates should be up-titrated gradually. | |
| Alteplase (t-PA) | I.V. GTN decreases the thrombolytic effect of alteplase in patients with acute MI | GTN decreases the bioavalilability of t-PA | Caution should be observed in patients receiving GTN during alteplase therapy. |
| Anticholinergic drugs: Disopyramide Tricyclic antidepressants (amitriptyline, desipramine, doxepin, others) | They cause dry mouth and diminished salivary secretions and reduce the effects of sublingual GTN. | Reduce the absorption of GTN tablets | Increase salivation with chewing gum or artificial saliva products. Use transdermal formulations of GTN |
| Antihypertensives: ACE inhibitors/ARBs β-blockers | Additive hypotensive effects | Higher risk of postural hypotension, dizziness and syncope. The dose of nitrates should be up-titrated gradually. | |
| Calcium antagonists Diuretics | |||
| Apomorphine | Additive hypotensive effects | Higher risk of postural hypotension, dizziness and syncope. The dose of nitrates should be up-titrated gradually. | |
| Aspirin | Aspirin reduces the headaches produced by nitrates. The vasodilatory and hemodynamic effects of GTN may be enhanced by aspirin | Reduces the hepatic metabolism and increases GTN plasma levels | The dose of GTN should be reduced. Monitor the vasodilator response to GTN. A confusing interaction with other NSAIDs |
| β-blockers | Decrease myocardial O2 demands, increase subendocardial coronary blood flow and suppress the tachycardia induced by nitrates | The combination increase the antianginal effects of each agent | |
| Calcium antagonists | Decrease myocardial O2 demands and increase coronary blood flow | The combination increase the antianginal effects of each agent | |
| Ergot alkaloids (ergonovin, ergotamine, dihydroergotamine) | They produce coronary vasospasm and can precipitate angina pectoris | GTN markedly decreases the first-pass metabolism of dihydroergotamine and increases its oral bioavailability | Avoid the combination of GTN with ergotamine and related drugs |
| Heparin | I.V. GTN can reduce the anticoagulant effect of heparin | The heparin dosage must be adjusted and the activated partial thromboplastin time (APTT) should be monitored when GTN is added or discontinued. After discontinuation of GTN, it can be necessary to reduce the heparin dose | |
| Morphine-like analgesics. | GTN may slow their metabolism | Monitor the clinical response | |
| Neuroleptics (phenothiazines) | Additive hypotensive effects | Higher risk of postural hypotension, dizziness and syncope. The dose of nitrates should be up-titrated gradually. | |
| Phosphodiesterase type 5 inhibitors: Sildenafil Taladafil Vardenafil | They potentiate the hypotensive effects of organic nitrates. Increased risk of life-threatening hypotension and myocardial ischemia | The combination is contraindicated. They should not be given concurrently (within 24 hours for sildenafil and vardenafil, 48 hours for taladafil) with nitrates. In emergency situations α-adrenergic agonists (norepinephrine) may be needed.
In patients with prostatism taking tamsulosin nitrates can be prescribed | |
| Tricyclic antidepressants | Additive hypotensive effects | Higher risk of postural hypotension, dizziness and syncope. The dose of nitrates should be up-titrated gradually. |
Cautions
- GTN activity decay when tablets are exposed to air and opened containers should be discarded within 3 months; keep GTN in airtight containers
- Patients should be carefully instructed about how to use short-acting sublingal GTN for acute relief of symptom
- In patients previously treated with organic nitrates, a higher dose of GTN may be necessary to achieve the desired hemodynamic effect.
- Symptoms and hemodynamics should be monitored frequently during the administration of IV nitrates
- Hypotension associated with GTN overdose is due to venodilatation and hypovolemia; thus, therapy should be directed to increase central fluid volume.
ACEI: angiotensin-converting enzyme inhibitors. ARBs: angiotensin receptor blockers. GTN: nitroglycerin. I.V.: intravenous. MI: myocardial infarction. NSAIDs: nonsteroidal anti-inflammatory drugs
Digoxin
Drugs that increase serum digoxin concentrations
| Drug/condition | Pharmacodynamic interaction | Pharmacokinetic interaction |
|---|---|---|
| ACE inhibitors Angiotensin receptor blockers | They cause hyperkalaemia which reduces cardiac binding of digoxin and increase SDC. | Decrease renal excretion |
|
Antiarrhythmics: - Disopyramide, Quinidine - Flecainide, Propafenone - β-blockers - Amiodarone, Dronedarone | Increase the risk of proarrhythmia. Some antiarrhythmics antagonize the inotropic effect of digoxin. Dofetilide increases the risk of torsades de pointes. The combination of digoxin and dronedarone increases the risk of sudden death | Reduce both renal and non-renal excretion and Vd of digoxin Amiodarone, Dronedarone and Quinidine increase SDC by reducing P-gp-mediated efflux of digoxin into the gut and kidneys, resulting in increased absorption and decreased elimination of digoxin. Amiodarone and propafenone reduce clearance of digoxin and increase SC (25–75%); Reduce the dose of digoxin by 50% and closely monitor SDC Avoid the combination with dronedarone |
| Antibiotics:
- Aminoglycosides (Amikacin, Gentamycin, Kanamycin, Roxithromycin, Tobramycin) - Cephalosphorines - Macrolides (Azithromycin, Clarithromycin, Erythromycin, Roxithromycin, Telithromycin) - Tetracyclines - Quinolones (Gemifloxacin, Levofloxacin) - Sulfonamides: Sulfadiazine, Sulfisoxazole - Aztreonam, Dapsone, Fosfomycin, Metronidazone, Nafcillin, Paromomycin, Trimethoprim, Vancomyn | Itraconazole may also oppose the positive inotropic effects of digoxin. |
Increase digoxin absorption by inactivating the Eubacterium lentum. Trimethoprim decreases the renal excretion of digoxin. |
| Antimalarials: - Choroquine - Hydroxychloroquine - Quinine | Decrease non-renal clearance | |
| Atorvastatin | Decrease the Vd and the renal clearance of digoxin | |
| Anticholinergic drugs:
- Propantheline - Diphenoxylate | Increase digoxin absorption by decreasing gut motility | |
| Antidepressants:
- Nefazodone - Trazodone | May increase digoxin toxicity | |
| Nonsteroidal anti-inflammatory agents (indomethacin), including COX-2 inhibitors | They increase serum potassium | NSAIDs reduce the renal clearance of digoxin. |
| Atazanavir | Increase the risk of AV block | |
| β-blockers | β-blockers increase the risk of bradycardia and AV block . They also increase serum potassium | Carvedilol enhances GI absorption and decreases renal clerance |
| Benzodiazepines:
- Alprazolam - Diazepam | Decrease digoxin clearance | |
| Calcium channel blockers - Felodipine, Nicardipine, Nifedipine, Nitrendipine | Decrease the Vd and renal clearance of digoxin | |
| - Diltiazem - Verapamil | Increase the risk of bradycardia, and AV block | Verapamil inhibits P-gp and the active tubular secretion and non-renal clearance of digoxin |
| Canagliflozin | Unknown | Unknown |
| Calcium salts | Increase the risk of arrhythmias | |
| Cyclosporine | Inhibits P-gp, decreases renal clearance of digoxin | |
| - Antifungals: Itraconazole, Ketoconazole
- Antiretroviral treatment: Etravirine, Indinavir, Ritonavir, Saquinavir, - Antihepatitis C: Boceprevir, Daclatasvir, Sofosbuvir/Velpatasvir, Simeprevir - BCR-Abl tyrosine kinase inhibitors: Bosutinib, Nilotinib, Ponatinib - Cobicistat - Crizotinib - Lomitapide - Loratadine - Tyrosine kinase inhibitors: Lapatinib, Neratinib - Ranolazine - Tacrolimus - Ticagrelor - Vasopressin receptor antagonists : Conivaptan, Tolvaptan - Vemurafenib | Inhibit P-gp, increase digoxin absorption and increase SDC | |
| Non-potassium-sparing diuretics
- Azetazolamide - Loop diuretics - Thiazides | Produce hypokalemia and potentiates the cardiac effects of digoxin. Increase the risk of arrhythmias | They may also reduce the renal tubular secretion of digoxin. |
| Prazosin | Decreases digoxin binding to plasma and tissue proteins | |
| Potassium-sparing diuretics - Amiloride - Spironolactone - Triamterene | These diuretics and digoxin increase serum potassium levels | Decrease digoxin clearance |
| Proton pump inhibitors | Cause hypomagnesemia and increase the risk for digoxin toxicity | Increase the absorption and inhibit the metabolism and of digoxin. |
| Sympathomimetic agents | Can increase the risk of cardiac arrhythmias | |
| Teriparide | Increase the risk of arrhythmias | |
| Vitamin D and analogs (Paricalcitol) | Increase the risk of arrhythmias | Vitamin D analogues can also increase DSC |
Clinical implications
- The increase in SDC increases the risk toxicity and the proarrhythmic effects of digoxin.
- Measure SDC when the dose of concomitant drugs is initiated, changed or discontinued.
- Reduce SDC by decreasing the starting and/or maintenance dose (30-50%) or by modifying the dosing frequency.
- Regular monitoring for signs and symptoms of digoxin toxicity, clinical response and ECG. Monitor SDC more frequently if renal function is impaired and in the elderly
* Patients should be monitored for hypokalemia and given potassium supplements when necessary.
Drugs that decrease serum digoxin concentrations
| Drug/condition | Pharmacodynamic interaction | Pharmacokinetic interaction |
|---|---|---|
| Aldosterone antagonists | May protect against digoxin-induced arrhythmias | Produce hyperkalemia |
| Anticancer drugs:
- Carmustine, Cyclophosphamide, Cytarabine, Doxorubicin, Methotrexate, Vincristine | Alter the intestinal epithelium. Decrease GI absorption | |
| Clotrimazole | Induces P-gp | |
| Inducers of drug metabolism*:
- Barbiturates, Phenytoin, Rifabutin, Rifampicin, St John’s wort | Rifampicin and St John’s wort induce P-gp and thereby decrease SDC. Increase nonrenal clearance of digoxin | |
| Gastrointestinal drugs: - Antiacids - Acarbose - Activated charcoal - Carbenoxolone - Carbimazole - Cimetidine - Eribulin - Kaolin-pectin - Metoclopramide - Neomycin - Resins: Cholestyramine, Cholestipol - Sulfacrate - Sulfasalazine | Decrease digoxin absorption from the gastrointestinal tract | |
| Drugs that produce hypokalemia**: - Amphotericin B - Selective β2-adrenergic agonists (albuterol, salbutamol, Terbutaline) - Carbenoxolone - Glucocorticoids - Laxatives - Insulin - Lithium salts | They increase cardiac sensitivity to cardiac glycosides.
Corticosteroids cause sodium and water retention increasing the risk of digoxin toxicity and heart failure. | Salbutamol increases SDC |
| Neuromuscular blocking drugs*: - Atracuronium, Pacuronium, Suxamethonium | Increase potassium efflux from the cardiac cell causing cardiac arrhythmias | |
| Tizanidine | Excessive bradycardia and atrioventricular block | |
| Topiramate | Reduces the bioavailability of digoxin | |
| Vasodilators: - Hydralazine, Nitroprusside | Increase renal clearance of digoxin |
Clinical implications
- Increase the dose of digoxin. Monitor ECG and SDC.
- The interaction with resins can be prevented by separating the doses of digoxin and anion exchange resin by about 2 hours.
* Avoid concomitant use. ** Give potassium supplements when necessary
Factors predisposing to digoxin toxicity
| Condition | Pharmacodynamic interaction | Pharmacokinetic interaction | Clinical Implications |
|---|---|---|---|
|
Acute hypoxemia Acute myocardial infarction Cardiac amyloidosis Hypercalcemia Hyperthyroidism Hypokalemia Hypomagnesemia Increase in sympathetic tone Severe myocarditis Severe respiratory disease | Sensitizes the heart to the effects of cardiac glycosides. Increase the risk of cardiac arrhythmias | Hyperthyroidism: increases the Vd and renal elimination of digoxin resulting in lower SDC | Therapy with digoxin should be administered cautiously. Decrease the dose of digoxin and monitor SDC, serum electrolytes and renal function periodically during the treatment with digoxin.
During the treatment of thyrotoxicosis, digoxin dosage should be gradually reduced as thyroid function comes under control. |
| Hypothyroidism Obesity | Decrease the Vd and renal excretion of digoxin | Reduce the dose of digoxin | |
| Hypocalcemia Hyperkalemia | Decrease sensitivity to cardiac glycosides | Monitor SDC, serum potassium and ECG | |
| Hypothyroidism | Decreases the Vd and plasma clearance of digoxin | Digoxin should be initiated at lower dosages monitoring SDC. Treatment of hypothyroidism may increase the dose requirements of digoxin. | |
| Renal impairment | Increased risk for digoxin toxicity, including ventricular arrhythmias and AV conduction disturbances | Decreases digoxin excretion | Digoxin should be administered cautiously in patients with impaired renal function. Dosage increments should be made very gradually. Monitor SDC and ECG |
| Children | Children are especially sensitive. | Increase the Vd and renal clearance of digoxin | Decrease the dose of digoxin. Monitor SDC |
| Elderly | Increased risk of digoxin toxicity | Decreased renal function and low lean body mass leads | Reduce the dose |
Cautions/notes
- Digoxin has a narrow therapeutic index, increased monitoring of serum digoxin concentrations and for potential signs and symptoms of clinical toxicity is necessary when initiating, adjusting, or discontinuing drugs that may interact with digoxin. Prescribers should consult the prescribing information of any drug which is co-prescribed with digoxin for potential drug interaction information.
- Patients with malabsorption syndrome or gastrointestinal reconstructions may require larger doses of digoxin.
- Digoxin should be withheld for 24 h before cardioversion and the lowest effective energy should be applied when attempting DC cardioversion. DC cardioversion is inappropriate in the treatment of digitalis-induced arrhythmias.
- Rapid IV digoxin can cause vasoconstriction and hypertension. Administer digoxin at a slow injection rate in hypertensive patients with HF and acute MI
- Avoid digoxin in patients with HF associated with beri-beri, cardiac amyloidosis, myocarditis or constrictive pericarditis
- Avoid digoxin in hypertrophic obstructive cardiomyopathy or constrictive pericarditis unless it is used to control the ventricular rate in AF or to improve systolic dysfunction.
AF: atrial fibrillation. COX2: Cyclooxygenase 2. DC: electrical. GI: gastrointestinal. HF: heart failure. IV: intravenous, MI: myocardial infarction. P-gp: glycoprotein P. Vd: volume of distribution.
Calcium channel blockers
| Drug | Pharmacodynamic | Pharmacokinetic | Implications |
|---|---|---|---|
| Alcohol | Additive effect on BP | Verapamil and diltiazem inhibit the metabolism and increase ethanol plasma levels. Alcohol may increase the rate of diltiazem release from the prolonged release preparation. | The effects of alcohol may be exaggerated. Avoid alcohol in patients receiving these CCBs |
| Alpha-adrenergic blockers:
- Prazosin - Terazosin | Exert an additive hypotensive effect with verapamil | Verapamil may increase the plasma concentrations of prazosin and terazosin with an additive hypotensive effect. | Close monitoring of blood pressure |
| Anesthetics | Diltiazem and verapamil potentiate the depression of cardiac contractility, AV block, bradycardia and hypotension produced by general anesthetics. | The combination should be avoided. | |
| Antiarrhythmics | Increase the risk of bradycardia, AV block, hypotension and heart failure. Coadministration of verapamil with either disopyramide or flecainide increases the risk of myocardial depression and asystole. | Nifedipine decreases the plasma levels of quinidine Diltiazem and verapamil increase quinidine plasma levels Verapamil may decrease the clearance of flecainide | The combination should be made with caution. Monitor clinical, hemodynamic and ECG changes. Diltiazem and verapamil are antiarrhythmics and its co-prescription with other antiarrhythmics is not recommended |
| Anti-H2 agents: - Cimetidine - Ranitidine | They may potentiate the antihypertensive effect of nifedipine | Cimetidine decreases hepatic blood flow and metabolism and increases the plasma levels of diltiazem, nifedipine, nisoldipine, nitrendipine and verapamil | Reduce the dose of the CCB and monitor BP. Replace cimetidine and ranitidine by famotidine or nizatidine. Amlodipine do not interact with cimetidine |
| Anti-hypertensives | Additive vasodilator response | Monitor BP. Reduce the dosage of other antihypertensives to avoid the risk of hypotension | |
| Antineoplastic drugs | Verapamil reduces the resistance to doxorrubicin | Cyclophosphamide, vincristine, procarbazine, doxorubicin and cisplatin reduce the absorption of verapamil | Increase the dose of verapamil. Use another CCB. |
| Aspirin | Coadministration of diltiazem and verapamil with aspirin may increase the risk of bleeding. | Caution with this combination. Monitor the bleeding risk | |
| Azole antifungals:
- Fluconazole, Itraconazole, Ketoconazole, Posaconazole, Voriconazole | They inhibit CYP3A4 and increase the plasma levels of CCBs | Appropriate dosage adjustment of the CCB is needed. The starting dose of atorvastatin should be 10 mg od and the maximum dose 20 mg od. | |
| Benzodiazepines | The effects of midazolam and triazolam are markedly increased by diltiazem or verapamil | Diltiazem and verapamil inhibit CYP3A4 and increase the plasma levels of midazolam and triazolam | Special care in patients treated with these short-acting benzodiazepines. This interaction does not occur with diazepam. Diltiazem does not interact with temazepam. |
| Beta-blockers | Additive effects on BP (hypotension), heart rate (bradycardia), AV conduction and/or cardiodepressant effects when combined with verapamil or diltiazem. | Diltiazem increases the bioavailability of oral propranolol.
Verapamil may increase the plasma concentrations of metoprolol and propranolol. | Coadministration of β-blockers with DHP-CCBs is usually well tolerated.
This combination should be administered under close medical (ECG) supervision, particularly at the beginning of treatment Verapamil is best combined with atenolol or nadolol that are excreted by renal route than with β-blockers that are metabolized in the liver (carvedilol, metoprolol, propranolol). IV β-blockers should not be given in patients treated with diltiazem or verapamil |
| Bile-acid binding resins | Reduce the bioavailability of diltizem and verapamil | Monitor the response to CCBs. Separate the doses of CCB and resins by about 2 hours. | |
| Boceprevir | The maximum dose of atorvatatin should be limited to 40 mg. | ||
| Buspirone | Diltiazem increases the AUC and the elimination time of buspirone | Dose adjustments are needed. | |
| Calcium salts | Antagonize the antiarrhythmic effects of CCBs | Monitor for a reduced response when large doses of calcium are given | |
| Calcium channel blockers | Diltiazem can be combined with DHPs in patients with resistant coronary artery vasospasm | Diltiazem increases nifedipine plasma levels | Monitor for increased nifedipine effects |
| Carbamazepine | Increase carbamazepine toxicity (nausea, visual disturbances, dizziness, or ataxia) | Some CCBs (diltiazem) can inhibit CYP3A4 and increases carbamazepine plasma levels | Monitor the plasma levels and reduce the dosage of carbamazepine |
| Clonidine | Cases of bradycardia and complete AV block when diltiazem or verapamil and clonidine are combined | No interaction exist between nifedipine and clonidine | |
| Colchicine | Cases of myopathy, including rhabdomyolysis, when atorvastatin and colchicine are co-administered | Verapamil inhibits CYP3A4 and P-gp and increases the exposure to colchicine | This combination is not recommended. |
| Corticosteroids (methylprednisolone) | Diltiazem can increase methylprednisolone levels through inhibition of CYP3A4 and P-gp | Monitor the patient when initiating methylprednisolone treatment. Adjustment of the methylprednisolone dose may be necessary. | |
|
Cytochrome P450 3A inducers: - Barbiturates - Efavirenz - Rifampin - St John's wort) | Decrease the effects of CCBs | They increase the metabolism and decrease the plasma levels of CCBs | Increase the doses of CCBs as appropriate. Patients should be carefully monitored where initiating or discontinuing the inducer. |
| Dabigitran etexilate | Verapamil increases the Cmax and AUC of dabigatran when both drugs are coadministred. However, no chages are observed when verapamil was administered 2 hours after dabigatran etexilate | Close clinical surveillance is recommended when both drugs are combined, particularly in patients at risk of bleeding (mild to moderate renal impairment) | |
| Dantrolene (I.V.) | The combination with verapamil increases the risk of hypotension, myocardial depression and hyperkalemia. Ventricular fibrillation when combined with verapamil | This combination should be avoided . | |
| Digoxin | Increased risk of bradycardia and AV block | Bepridil, nifedipine, nitrendipine, nisoldipine and verapamil inhibit digoxin clearance, reduce its volume of distribution and increase digoxin plasma levels. Diltiazem does not interact with digoxin | Monitor digoxin plasma levels and the ECG. reduce the maintenance dose of digoxin. |
| Dofetilide | Increases the risk of arrhythmias | CCBs increase dofetilide plasma levels | The combination is contraindicated. |
| Diuretics | Additive antihypertensive effects | Reduce the dosage as appropriate to avoid the risk of hypotension. | |
| Ezetimibe | The risk of muscular events increases with concomitant use of ezetimibe and atorvastatin | Clinical monitoring is recommended. | |
| Fentanyl | Diltiazem and verapamil increase or prolong their effects and may cause potentially fatal respiratory depression | Diltiazem and verapamil inhibit CYP3A4 increasing fentanyl exposure | The doses of fentanyl should be carefully monitored, and adjusted as needed |
| Fibrates | Increased risk of muscular adverse effects | Use the lowest dose of atorvastatin. Patients should be appropriately monitored | |
| Fluoxetine | It increases the adverse effects of CCBs | Fluoxetine reduces the clearance and increases CCB plasma levels | Reduce the dose of CCBs if necessary |
| Grapefruit juice | Inhibits CYP3A4 and increases the plasma levels of felodipine, nicardipine, nifedipine, nimodipine, nitrendipine, nisoldipine and verapamil | Avoid grapefruit juice. Amlodipine and diltiazem plasma levels are only minimally affected. | |
| Halofantrine | Increased risk of QT interval prolongation and ventricular arrhythmias | Verapamil and diltiazem inhibit CYP450 3A4 and increase halofantrine plasma levels | Monitor the ECG for 8-12 hours after completion of therapy |
| Hepatitis C protease inhibitor - Boceprevir | The maximum dose of atorvatatin should be limited to 40 mg. | ||
| Imipramine | Increased risk of hypotension, AV block and cardiodepression | Diltiazem and verapamil decrease the clearance of imipramine and increase its plasma levels | Monitor the patients for increased imipramine toxicity (tachycardia, dry mouth, sedation) and ECG (AV block). Reduce the dosage of diltiazem/verapamil |
|
Immunosuppressants: - Ciclosporin - Everolimus - Sirolimus - Tacrolimus | Increase the adverse effects of the immunosupressants | Diltiazem, nicardipine, nifedipine and verapamil inhibit the metabolism of the immunosuppressants and increase their plasma levels.
Diltiazem and verapamil increase the oral absorption and exposure to everolimus Cyclosporin inhibits CYP3A4 and increases the plasma levels of CCBs. | Frequent monitoring of BP and adjust the dose as appropriate.
The plasma levels of these drugs should be closely monitored. Reduce the dose of immunosuppressants. Cyclosporin plasma levels and renal function should be closely monitored. Amlodipine does not present this interaction. |
| Ivabradine | Additional slowing of heart rate when coadministered with diltiazem or verapamil | Avoid this combination | |
| Lithium | Diltiazem and verapamil increases the risk of lithium-induced neurotoxicity | Monitor the plasma levels and neurotoxic effects of lithium. Dose adjustments are needed. | |
|
Macrolides: - Chlarithomycin - Erythomycin - Telithromycin | Increase the effects of CCBs. Telithromycin produces hypotension and bradycardia when combined with verapamil | Macrolides inhibit CYP3A4 and increases the bioavailability of some CCBs (verapamil) | Reduce the dose of CCBs if these macrolides are prescribed.
The starting dose of atorvastatin should be 10 mg od and the maximum dose 20 mg od. |
| Nefazodone | Nefazodone inhibits the CYP 3A4 and increases plasma levels of nifedipine | Monitor blood pressure when both drugs are coadministrated. Consider to reduce the dose of nifedipine | |
| Neuromuscular blockers | Some CCBs can reduce the release of acetylcholine and potentiate the neuromuscular blockade of pancuronium | Risk for an increased neuromucular blockade during surgery | |
| Nitrates | Additive vasodilator effects | Increase the dosage of nitrates gradually. Monitor BP | |
| Phenothiazines | Additive vasodilator effects | Increased risk of hypotension. Monitor BP | |
| Phenytoin | Increase phenytoin toxicity (e.g., drowsiness, visual disturbances, change in mental status, seizures, nausea, or ataxia) | Diltiazem and verapamil inhibit CYP3A4 and increase phenytoin plasma levels. Phenytoin induces CYP 3A4 and may decrease the plasma levels of nifedipine and verapamil | Monitor the effects and plasma levels of phenytoin.
Increase the dose of nifedipine. Reduce the dose of nifedipine when phenytoin is discontinued. |
| Pimozide | Increases the risk of proarrhythmia | Diltiazem and verapamil increase plasma levels of pimozide | Avoid the combination |
| Ranolazine | Diltiazem and verapamil increase the plasma levels of ranolazine | Careful dose titration of ranolazine is recommended | |
| Sildenafil | CCBs increase its plasma levels | Reduce the doses of these drugs | |
|
Statins Atrovastatin Lovastatin Simvastatin | Increased incidence of muscular disorders | Diltiazem, isradipine and verapamil inhibit CYP3A4 and increases the plasma levels of these statins.
Atorvastatin increases verapamil levels. | Treatment with simvastatin, atorvastatin or lovastatin in a patient taking verapamil should be started at the lowest possible dose and titrated upwards. Max dose of simvastatin: 10-20 mg/day.
Use fluvastatin, pravastatin, and rosuvastatin that are not metabolized by CYP3A4. Caution when atorvastatin and verapamil are concomitantly administered. |
| Sulfinpyrazone | Antagonizes the antihypertensive effect of verapamil | Reduce the plasma concentrations of verapamil | Avoid the combination |
| Theophylline | CCBs increase the adverse effects of theophylline | Diltiazem and verapamil reduce its clearance and increase its plasma levels | Monitor theophylline plasma levels. The dose of diltiazem and verapamil should be adjusted if necessary. |
| Tobacco | Reduces the antianginal effect of CCBs | Patient must stop smoking | |
| VIH protease inhibitors:
- Atazanavir, Indinavir, Nelfinavir, Ritonavir, Saquinavir -Saquinavir+ritonavir, darunavir+ritonavir, lopinavir+ritonavir, fosamprenavir+ritonavir | Prolong the PR interval of the ECG. Orthostatic hypotension with the combination of nelfinavir or ritonavir/indinavir and nifedipine | They increase the bioavailability of diltiazem and verapamil. | Ritonavir and saquinavir should not be used with other agents that prolong the PR interval
The starting dose of atorvastatin should be 10 mg od and the maximum dose 20 mg od |
| Warfarin | Atorvastatin (80 mg/day) causes a small decrease in prothrombin time which returned to normal within 15 days of treatment. | Uncertain clinical meaning | |
| Vitamin D (at high doses) | May reduce the response to CCBs | Monitor the effects of CCBs |
BP: blood pressure. CCB: calcium channel blocker. Cmax: peak plasma levels. I.V.: intravenously. AUC: area under the curve.
Loop diurectics
Furosemide, Bumetanide, Piretanide, Torasemide
| Interacting drug | Pharmacodynamic interaction | Pharmacokinetic interaction | Clinical implications |
|---|---|---|---|
| ACE inhibitors | Potentiate the antihypertensive effect. ACE inhibitors may cause acute renal failure in patients with sodium depletion. Furosemide may interact with ACE inhibitors causing impaired renal function | Risk of hyponatremia, hypokalemia and arterial hypotension. Higher risk in patients with hypovolemia and sodium depletion. Loop diuretics should be stopped or the dose reduced before starting an ACE-inhibitor. | |
| Aliskiren | Reduces the plasma levels of furosemide | Monitor the clinical response | |
| Alcohol | Increases the hypotensive response | Monitor BP | |
| Aminoglycosides: | Loop diuretics can increase the risk of ototoxicity and nephrotoxicity (particularly if impaired renal function) | Diuretics decrease the renal excretion of gentamicin and tobramycin, increasing their plasma levels | Monitoring of blood pressure, diuresis, electrolytes, and auditive and renal function |
| Amphotericin B | Increased risk of hyponatremia, hypopotassemia and nephrotoxicity | Reduce the dose of furosemide. Monitor serum levels of electrolytes and renal function | |
| Antiarrhythmics: - Class IA and III | Loop diuretics produce hypopotassemia and increase the risk of torsades de pointes | Monitor the ECG. | |
| Antibiotics: - Aminoglycosides - Polymyxins - Vancomycin | Increased risk of ototoxicity. | Furosemide can decrease vancomycin serum levels | Monitor the auditory function |
| Angiotensin receptor blockers (ARBs) | Potentiate their antihypertensive effect. ARBs may cause acute renal failure in patients with sodium depletion | Risk of hyponatremia, hypokalemia and hypotension. Higher risk in patients with hypovolemia and sodium depletion | |
| Antidiabetics | The hypoglycaemic effects of antidiabetics antagonised. they may increase the requirements of insulin | Plasma serum glucose levels | |
| Anti-hypertensive agents | Hypotensive effects may be enhanced | Increased risk of postural hypotension. Titrate the dose of loop diuretics | |
| - Alcohol - Alprostadil - General anesthetics - Baclofen - Levodopa - Nitrates - MAOIs - Opioids - Phenothiazines - TADs - Tizanidine | They may enhance the hypotensive effects of loop diuretics | Increased risk of postural hypotension. Monitor BP. Titrate the dose of loop diuretics | |
| Anti-psychotic drugs | Hypokalaemia increases the risk of cardiac toxicity Avoid concurrent use with pimozide. Increased risk of ventricular arrhythmias with amisulpride or sertindole | Monitor the ECG Combination with caution. | |
| β-blockers. | Increase the risk of new-onset diabetes | Monitor plasma glucose levels. Not recommended as monotherapy in patients with diabetes or metabolic syndrome | |
| Bile-acid binding resins: Cholestyramine Colestipol | Decrease the diuretic and antihypertensive effects | Reduce the absorption of the diuretic | Readjust the dose of the diuretic. Administer 2 to 3 hours apart |
| Carbamazepine | Increased risk of hyponatraemia | Monitor serum potassium levels | |
| Cephalosporins: Cephacetrile Cephaloridine Cephalothin | These cephalosporins have nephrotoxic effects | Furosemide increases the half-life of the cephaloridines | Greater risk of nephrotoxicity. Reduce the dose of the diuretic |
| Ciclosporin | Greater risk ototoxic and nephrotoxic effects. | Increase the plasma levels of uric acid | Monitor renal function and uricemia |
| Platinum compounds | Increased risk of nephrotoxicity and ototoxicity | Monitor renal and auditive function. The e of furosemide should be reduced and a positive fluid balance should be used | |
| CNS drugs: - Anxiolytics - Hypnotics - Phenothiazines - TADs | Hypotensive effects may be exacerbated Hypokalaemia increases the risk of cardiac toxicity | Increased risk of postural hypotension. Titrate the dose of loop diuretics | |
| Glucocorticoids | They inhibit the diuretic and antihypertensive effects of loop diuretics and produce hypopotassemia and hyperglycemia and increase potassium loss | Monitor the diuretic and antihypertensive effects. Monitor the glucemia and kalemia. Administer potassium salts if necessary | |
| Cyclosporine | This combination increases the risk of kidney and/or nerve damage | This combination should be administered under medical supervision | |
| Digoxin | Hypercalcemia and hypopotassemia increase the risk of digitalis intoxication | Monitor ECG, renal function and kalemia. Use K+ supplements or K+-sparing diuretics | |
| Drugs producing hypokalemia: - ACTH - Amphotericin B - β2-agonists - Carbenoxolone - Corticosteroids - Laxatives - Reboxetine - Tacrolimus - Theophylline | These drugs increase the risk o hypokalemia | The combination with K+-sparing diuretics reduce the risk of hypokalemia. Loop diuretics should be used with caution. Monitor signs of hypokalemia (ECG, fatigue, muscular pain) Administer potassium salts if necessary | |
| Food | Decreases the diuretic effect of furosemide | Reduces the bioavailability and the Cp of furosemide | Furosemide should be taken with an empty stomach |
| Lithium | Furosemide decreases the renal clearance of lithium | Increases the tubular reabsorption and the Cp of lithium | Increases the toxicity of lithium. Close monitoring of serum lithium levels and electrolytes. Lithium dose reductions may be required Avoid the combination unless plasma levels can be monitored |
| Neuromuscular blockers | Loop diuretics increase the potency and duration of succinylcholine | Readjust the dose of neuromuscular blocker. Monitor the extubation of the patient | |
| Nitrates | Hypotensive effects can be exacerbated | Increased risk of postural hypotension. Titrate the dose of loop diuretics | |
| Nephrotoxic drugs: - Aminoglycosides - Amphotericin B - Some cephalosporins - NSAIDs | Loop diuretics also increase the risk of nephrotoxicity when coadministered with other nephrotoxic drugs | Monitor the renal function. Loop diuretics should be used with caution in patients with impaired renal function | |
| NSAIDs | Antagonize the diuretic and antihypertensive effect of the diuretics by inhibiting the renal synthesis of prostaglandins. NSAIDs increase the risk of acute renal failure. Risk of ototoxicity with high doses of salicylates | In rheumatic patients treated with high doses of salicylates furosemide may competitively inhibit the excretion of salicylates in the proximal tubule | Avoid dehydration, monitor patient's renal function and blood pressure. If renal insufficiency or hyperkalemia develops, both drugs should be discontinued until the condition is corrected. |
| Phenytoin | Inhibits the diuretic effect of furosemide | Decreases the intestinal absorption of furosemide | Readjust the dose of furosemide |
| Potassium-sparing diuretics: - Amiloride - Eplerenone - Spironolactone - Triamterene | Exert additive diuretic effects and reduce the risk of hypokalemia and of cardiac arrhythmias | Monitor BP and electrolyte balance. Potassium-sparing diuretics are preferred to K+ supplements as they correct both hypokalemia and hypomagnesemia | |
| Prostaglandins | Enhance the hypotensive effect | Monitor BP | |
| QTc prolonging drugs | Loop diuretics produce hypopotassemia and hypomagnesemia and increase the risk of torsades de pointes | Monitor the QT on the ECG. Avoid QT prolonging drugs | |
| Sexual hormones | Oestrogens and progestogens reduce the diuretic and antihypertensive effect | Monitor the diuretic response. Increase the dose if needed | |
| Skeletal muscle relaxing drugs | Loop diuretics can antagonize the effect of tubocurarine and may enhance the action of succinylcholine. | Monitor the response of skeletal muscle relaxants | |
| Sucralfate | Sucralfate decrease the gastro-intestinal absorption of furosemide | These drugs should be taken at least 2 hours apart | |
| Theophylline | Increased risk of hypokalemia and hypotension | Increases the excretion and decreases the Cp of theophylline | Monitor the Cp of theophylline |
| Thiazide diuretics | Sequential nephron blockade. Synergistic diuretic effect. Increased risk of hypopotassemia. It may be needed in patients with resistant peripheral edema. | Careful monitoring of fluid status and serum electrolytes to avoid dehydration, hypokalemia, hyponatremia, hypovolemia, hypotension or renal dysfunction. | |
| Vasodilators | Loop diuretics enhance the effect of hydralazine | Monitor BP. Titrate the dose of loop diuretics |
BP: blood pressure. NSAIDs: non-steroidal anti-inflammatory drugs. TADs: Tricyclics antidepressants
Thiazide diuretics
Thiazides: Bendroflumethiazide, Chlorothiazide, Hydrochlorothiazide, Hydroflumethiazide, Polythiazide
Thiazide-like: Chlorthalidone, Indapamide, Metolazone, Xipamide
| Interacting drug | Pharmacodynamic interaction | Pharmacokinetic interaction | Clinical implications |
|---|---|---|---|
| α-blockers | Increased risk of 1st-dose hypotension with α-blockers | Monitor BP | |
| ACE inhibitors/ARBs | Potentiation of the antihypertensive effects | The risk of hypotension can be minimized by discontinuing or reducing the dose of the diuretic, gradual titration of RAAS inhibitors and careful monitoring of BP | |
| Alcohol General anesthetics Baclofen Barbiturates MAO inhibitors Opioids Tizanidine TADs | Increase the risk of orthostatic hypotension | Monitor BP | |
| Allopurinol | Coadministration of thiazides with allopurinol increases the risk of severe allergic reactions in patients with CKD | Close monitoring of patients, particularly those with chronic kidney disease | |
| Antiarrhythmics: - Class IA and III | Thiazides produce hypopotassemia and increase the risk of torsades de pointes | Monitor the ECG. | |
| Antigout agents | Thiazides can increase uric acid levels | It may be necessary to increase the dose of antigout agents | |
| Antihypertensive agents | Additive effect or potentiation of the antihypertensive effects | Monitor BP | |
| Bile-acid binding resins: - Cholestyramine - Colestipol | Decrease the diuretic and antihypertensive effects | Cholestyramine and colestipol reduce the absorption of the diuretic | Readjust the dose of the diuretic. Administer 2 to 3 hours apart |
| Digitalis | Thiazides increase potassium and magnesium loss and may increase the risk of toxicity | Monitor digitalis response | |
| Drugs producing hypokalemia: - Antimicrobial: amphotericin B, Aminoglycosides, Penicillins* - β-adrenergic agonists - Cisplatin - Corticosteroids - Fludrocortisone - Insulin (high dose) - Laxatives - Ritodrine - Theophylline | The increase the risk of hypokalemia | Monitor serum potassium levels and signs of hypokalemia (ECG, fatigue, muscular pain). Administer potassium salts if necessary | |
| Glucocorticoids | Glucocorticoids inhibit the diuretic and antihypertensive effects. They produce hypopotassemia and hyperglycemia and increase potassium loss | Monitor serum potassium and plasma glucose levels as well as the diuretic and antihypertensive effects | |
| Insulin and oral hypoglycaemic agents. | Thiazides inhibit the release of insulin from the pancreas and may reduce the effectiveness of hypoglycaemic drugs | Monitor plasma glucose levels. Dose adjustment of the antidiabetic drug may be required. | |
| Lithium | Thiazides increases the risk of lithium toxicity. In patients with lithium-induced nephrogenic diabetes insipidus, thiazides paradoxically decrease urine volume and increase urine osmolarity | Thiazides reduce the renal clearance of lithium | Lithium levels should be monitored closely |
| Loop diuretics | They deliver a greater fraction of filtered Na+ to the site of action of thiazides in the distal tubule. Their combination produces a synergistic diuretic effect. | This combination can be used in patients resistant to diuretic monotherapy | |
| Nephrotoxic drugs: - Aminoglycosides - Cisplatin | Their nephrotoxic effects may be potentiated by thiazides. | Monitor the renal function. | |
| Non-depolarizing neuromuscular blockers | Thiazides produce hypokalemia and potentiate their effects | Monitor the response and change the dose accordingly | |
| NSAIDs | Inhibit the diuretic effects of thiazides. NSAIDs cause Na+ retention and can predispose to functional renal insufficiency and heart failure | Monitor the diuretic response | |
| Oral contraceptives | Inhibit the diuretic effects of thiazides. | Monitor the diuretic response and increase the diuretic dose if needed | |
| Quinidine | Thiazides can increase renal tubular reabsorption | Monitor the ECG. AVoid the combination | |
| QTc prolonging drugs | Thiazides produce hypopotassemia and hypomagnesemia and increase the risk of torsades de pointes | Monitor the QT on the ECG. Avoid QT prolonging drugs | |
| Potassium-sparing diuretics: - Amiloride - Eplerenone - Spironolactone - Triamterene | Exert additive diuretic effects and reduce the risk of hypokalemia and of of cardiac arrhythmias | Monitor BP and electrolyte balance. Potassium-sparing diuretics are preferred to K+ supplements as they correct both hypokalemia and hypomagnesemia | |
| Vitamin D preparations and Ca2+ salts | Thiazides decrease renal Ca2+ excretion and increase the risk of hypercalcemia | Thiazides decrease the urinary excretion of calcium | Monitor calcium plasma levels |