A message from the editor of this section, Professor Juan Tamargo

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.


Interacting drug Pharmacodynamic interactionPharmacokinetic interaction Clinical implicaciones
AcetylcysteinePotentiates GTN-induced coronary vasodilation and may reverse nitrate tolerance No special precautions
AlcoholAdditive hypotensive effectsHigher 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-blockersAdditive hypotensive effects Higher risk of postural hypotension, dizziness and syncope. The dose of nitrates should be up-titrated gradually.
Calcium antagonists Diuretics
ApomorphineAdditive hypotensive effectsHigher risk of postural hypotension, dizziness and syncope. The dose of nitrates should be up-titrated gradually.
AspirinAspirin reduces the headaches produced by nitrates. The vasodilatory and hemodynamic effects of GTN may be enhanced by aspirinReduces the hepatic metabolism and increases GTN plasma levelsThe dose of GTN should be reduced. Monitor the vasodilator response to GTN. A confusing interaction with other NSAIDs
β-blockersDecrease 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 antagonistsDecrease 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 pectorisGTN markedly decreases the first-pass metabolism of dihydroergotamine and increases its oral bioavailabilityAvoid the combination of GTN with ergotamine and related drugs
HeparinI.V. GTN can reduce the anticoagulant effect of heparinThe 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 effectsHigher 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 ischemiaThe 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 antidepressantsAdditive hypotensive effects Higher risk of postural hypotension, dizziness and syncope. The dose of nitrates should be up-titrated gradually.



  • 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



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
- 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
- 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.
- 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
- Nefazodone
- Trazodone
May increase digoxin toxicity
Nonsteroidal anti-inflammatory agents (indomethacin), including COX-2 inhibitors They increase serum potassiumNSAIDs 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
- 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
CanagliflozinUnknown 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 levelsDecrease 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
- 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
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 SDCTherapy 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.
Decrease the Vd and renal excretion of digoxin Reduce the dose of digoxin
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


  • 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 PharmacokineticImplications
AlcoholAdditive 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.
AntiarrhythmicsIncrease 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 CCBsAppropriate dosage adjustment of the CCB is needed.
The starting dose of atorvastatin should be 10 mg od and the maximum dose 20 mg od.
BenzodiazepinesThe 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 CCBsThey 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 etexilateClose 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 .
DigoxinIncreased 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
- Ciclosporin
- Everolimus
- Sirolimus
- Tacrolimus
Increase the adverse effects of the immunosupressantsDiltiazem, 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.
- 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 verapamilMonitor 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
Increased incidence of muscular disordersDiltiazem, 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 nifedipineThey 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 drugPharmacodynamic interactionPharmacokinetic interactionClinical implications
ACE inhibitorsPotentiate the antihypertensive effect. ACE inhibitors may cause acute renal failure in patients with sodium depletion. Furosemide may interact with ACE inhibitors causing impaired renal functionRisk 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.
AliskirenReduces the plasma levels of furosemideMonitor the clinical response
AlcoholIncreases the hypotensive responseMonitor 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 levelsMonitoring of blood pressure, diuresis, electrolytes, and auditive and renal function
Amphotericin BIncreased risk of hyponatremia, hypopotassemia and nephrotoxicityReduce the dose of furosemide. Monitor serum levels of electrolytes and renal function
Antiarrhythmics: - Class IA and IIILoop diuretics produce hypopotassemia and increase the risk of torsades de pointesMonitor the ECG.
Antibiotics: - Aminoglycosides - Polymyxins - VancomycinIncreased risk of ototoxicity.Furosemide can decrease vancomycin serum levelsMonitor the auditory function
Angiotensin receptor blockers (ARBs)Potentiate their antihypertensive effect. ARBs may cause acute renal failure in patients with sodium depletionRisk of hyponatremia, hypokalemia and hypotension. Higher risk in patients with hypovolemia and sodium depletion
AntidiabeticsThe hypoglycaemic effects of antidiabetics antagonised. they may increase the requirements of insulinPlasma serum glucose levels
Anti-hypertensive agentsHypotensive effects may be enhancedIncreased risk of postural hypotension. Titrate the dose of loop diuretics
- Alcohol - Alprostadil - General anesthetics - Baclofen - Levodopa - Nitrates - MAOIs - Opioids - Phenothiazines - TADs - TizanidineThey may enhance the hypotensive effects of loop diureticsIncreased risk of postural hypotension. Monitor BP. Titrate the dose of loop diuretics
Anti-psychotic drugsHypokalaemia increases the risk of cardiac toxicity Avoid concurrent use with pimozide. Increased risk of ventricular arrhythmias with amisulpride or sertindoleMonitor the ECG Combination with caution.
β-blockers.Increase the risk of new-onset diabetesMonitor plasma glucose levels. Not recommended as monotherapy in patients with diabetes or metabolic syndrome
Bile-acid binding resins: Cholestyramine ColestipolDecrease the diuretic and antihypertensive effectsReduce the absorption of the diureticReadjust the dose of the diuretic. Administer 2 to 3 hours apart
CarbamazepineIncreased risk of hyponatraemiaMonitor serum potassium levels
Cephalosporins: Cephacetrile Cephaloridine CephalothinThese cephalosporins have nephrotoxic effectsFurosemide increases the half-life of the cephaloridinesGreater risk of nephrotoxicity. Reduce the dose of the diuretic
CiclosporinGreater risk ototoxic and nephrotoxic effects.Increase the plasma levels of uric acidMonitor renal function and uricemia
Platinum compoundsIncreased risk of nephrotoxicity and ototoxicityMonitor renal and auditive function. The e of furosemide should be reduced and a positive fluid balance should be used
CNS drugs: - Anxiolytics - Hypnotics - Phenothiazines - TADsHypotensive effects may be exacerbated Hypokalaemia increases the risk of cardiac toxicityIncreased risk of postural hypotension. Titrate the dose of loop diuretics
GlucocorticoidsThey inhibit the diuretic and antihypertensive effects of loop diuretics and produce hypopotassemia and hyperglycemia and increase potassium lossMonitor the diuretic and antihypertensive effects. Monitor the glucemia and kalemia. Administer potassium salts if necessary
CyclosporineThis combination increases the risk of kidney and/or nerve damageThis combination should be administered under medical supervision
DigoxinHypercalcemia and hypopotassemia increase the risk of digitalis intoxicationMonitor 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 - TheophyllineThese drugs increase the risk o hypokalemiaThe 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
FoodDecreases the diuretic effect of furosemideReduces the bioavailability and the Cp of furosemideFurosemide should be taken with an empty stomach
LithiumFurosemide decreases the renal clearance of lithiumIncreases the tubular reabsorption and the Cp of lithiumIncreases 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 blockersLoop diuretics increase the potency and duration of succinylcholineReadjust the dose of neuromuscular blocker. Monitor the extubation of the patient
NitratesHypotensive effects can be exacerbatedIncreased risk of postural hypotension. Titrate the dose of loop diuretics
Nephrotoxic drugs: - Aminoglycosides - Amphotericin B - Some cephalosporins - NSAIDsLoop diuretics also increase the risk of nephrotoxicity when coadministered with other nephrotoxic drugsMonitor the renal function. Loop diuretics should be used with caution in patients with impaired renal function
NSAIDsAntagonize 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 salicylatesIn rheumatic patients treated with high doses of salicylates furosemide may competitively inhibit the excretion of salicylates in the proximal tubuleAvoid 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.
PhenytoinInhibits the diuretic effect of furosemideDecreases the intestinal absorption of furosemideReadjust the dose of furosemide
Potassium-sparing diuretics: - Amiloride - Eplerenone - Spironolactone - TriamtereneExert additive diuretic effects and reduce the risk of hypokalemia and of cardiac arrhythmiasMonitor BP and electrolyte balance. Potassium-sparing diuretics are preferred to K+ supplements as they correct both hypokalemia and hypomagnesemia
ProstaglandinsEnhance the hypotensive effectMonitor BP
QTc prolonging drugsLoop diuretics produce hypopotassemia and hypomagnesemia and increase the risk of torsades de pointesMonitor the QT on the ECG. Avoid QT prolonging drugs
Sexual hormonesOestrogens and progestogens reduce the diuretic and antihypertensive effectMonitor the diuretic response. Increase the dose if needed
Skeletal muscle relaxing drugsLoop diuretics can antagonize the effect of tubocurarine and may enhance the action of succinylcholine.Monitor the response of skeletal muscle relaxants
SucralfateSucralfate decrease the gastro-intestinal absorption of furosemideThese drugs should be taken at least 2 hours apart
TheophyllineIncreased risk of hypokalemia and hypotensionIncreases the excretion and decreases the Cp of theophyllineMonitor the Cp of theophylline
Thiazide diureticsSequential 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.
VasodilatorsLoop diuretics enhance the effect of hydralazineMonitor 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 interactionClinical implications
α-blockersIncreased risk of 1st-dose hypotension with α-blockersMonitor BP
ACE inhibitors/ARBsPotentiation of the antihypertensive effectsThe 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 TADsIncrease the risk of orthostatic hypotensionMonitor BP
AllopurinolCoadministration of thiazides with allopurinol increases the risk of severe allergic reactions in patients with CKDClose monitoring of patients, particularly those with chronic kidney disease
Antiarrhythmics: - Class IA and IIIThiazides produce hypopotassemia and increase the risk of torsades de pointesMonitor the ECG.
Antigout agentsThiazides can increase uric acid levelsIt may be necessary to increase the dose of antigout agents
Antihypertensive agentsAdditive effect or potentiation of the antihypertensive effectsMonitor BP
Bile-acid binding resins: - Cholestyramine - ColestipolDecrease the diuretic and antihypertensive effectsCholestyramine and colestipol reduce the absorption of the diureticReadjust the dose of the diuretic. Administer 2 to 3 hours apart
DigitalisThiazides increase potassium and magnesium loss and may increase the risk of toxicityMonitor digitalis response
Drugs producing hypokalemia: - Antimicrobial: amphotericin B, Aminoglycosides, Penicillins* - β-adrenergic agonists - Cisplatin - Corticosteroids - Fludrocortisone - Insulin (high dose) - Laxatives - Ritodrine - TheophyllineThe increase the risk of hypokalemiaMonitor serum potassium levels and signs of hypokalemia (ECG, fatigue, muscular pain). Administer potassium salts if necessary
GlucocorticoidsGlucocorticoids inhibit the diuretic and antihypertensive effects. They produce hypopotassemia and hyperglycemia and increase potassium lossMonitor 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 drugsMonitor plasma glucose levels. Dose adjustment of the antidiabetic drug may be required.
LithiumThiazides increases the risk of lithium toxicity. In patients with lithium-induced nephrogenic diabetes insipidus, thiazides paradoxically decrease urine volume and increase urine osmolarityThiazides reduce the renal clearance of lithiumLithium levels should be monitored closely
Loop diureticsThey 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 - CisplatinTheir nephrotoxic effects may be potentiated by thiazides.Monitor the renal function.
Non-depolarizing neuromuscular blockersThiazides produce hypokalemia and potentiate their effectsMonitor the response and change the dose accordingly
NSAIDsInhibit the diuretic effects of thiazides. NSAIDs cause Na+ retention and can predispose to functional renal insufficiency and heart failureMonitor the diuretic response
Oral contraceptivesInhibit the diuretic effects of thiazides.Monitor the diuretic response and increase the diuretic dose if needed
QuinidineThiazides can increase renal tubular reabsorptionMonitor the ECG. AVoid the combination
QTc prolonging drugsThiazides produce hypopotassemia and hypomagnesemia and increase the risk of torsades de pointesMonitor the QT on the ECG. Avoid QT prolonging drugs
Potassium-sparing diuretics: - Amiloride - Eplerenone - Spironolactone - TriamtereneExert additive diuretic effects and reduce the risk of hypokalemia and of of cardiac arrhythmiasMonitor BP and electrolyte balance. Potassium-sparing diuretics are preferred to K+ supplements as they correct both hypokalemia and hypomagnesemia
Vitamin D preparations and Ca2+ saltsThiazides decrease renal Ca2+ excretion and increase the risk of hypercalcemiaThiazides decrease the urinary excretion of calciumMonitor calcium plasma levels