Drugs that may cause Takotsubo

Drugs associated with the development of Takotsubo syndrome

Cardiotonic drugs

Adrenalin (epinephrine), noradrenalin (norepinephrine), isoprenaline (isoproteranol), dopamine, and phenylephrine have all been used successfully to induce TTC-like changes in rat models.1

Adrenaline (epinephrine) and noradrenaline (norepinephrine)

Catecholamines have a central role in the development of TTS, and there are many case reports linking exogenous catecholamines to the development of TTS. Reviews suggest that adrenaline, also called epinephrine, is the most commonly used drug to cause TTS.2  Reports of TTS related to adrenaline use show that the population affected are generally younger than what is commonly reported in large registry databases.3,4  Women were still the dominant gender affected, but one study found that this was in a significantly lower percentage than general TTS population reports.Some of the common indications for adrenaline use are cardiac arrest, cardiogenic shock, hypotension, anaphylaxis (life threatening allergic reactions), control of superficial bleeding in dental or surgical some procedures. Routes of administration for adrenalin are inhalation, intra-ocular, topical, local irrigation, and subcutaneous, submucosal, intramuscular and intravenous injection. Multiple cases of TTS associated with uses of adrenaline and noradrenaline (norepinephrine) have been reported in various medical conditions.

Some examples of these are listed below:

  • Accidental or inappropriate administration (adrenalin5-11 and noradrenaline12-14)
  • Airway obstruction (nebulised adrenaline)15
  • Allergic reaction or anaphylaxis (adrenaline)16-30
  • Asthma (adrenaline)31
  • Hypotension/circulatory shock/septic shock (noradrenaline)32-36
  • Surgical and dental procedures/anaesthesia (adrenaline)10,37-45

Clinicians should be aware of the potential for development of TTS related to these drugs. Adrenalin and noradrenaline are drugs that are often crucial in resuscitation, managing hypotension and treating anaphylaxis.  Use of these drugs may be unavoidable, but clinicians should explore other options and use these drugs judiciously where circumstances mandate their use.

Dobutamine and dopamine

Dobutamine is the second-most commonly reported drug to cause TTS. Dobutamine is a synthetic catecholamine that increases contractility of the heart. It is used as an intravenous infusion for the short-term treatment of patients with depressed myocardial contractility. There are few reports of dobutamine being associated with TTS in this context,46 but it is possible that TTS could be masked or signs and symptoms mistaken for the underlying illness. However, there are numerous reports of dobutamine triggering TTS when used in cardiac investigations.47-62 These have predominantly occurred in the context of pharmacological stress testing when the patient is unable to exercise on a treadmill.

Dopamine is one of the catecholamine neurotransmitters in the brain and like dobutamine has been used to support blood pressure in cases of severe hypotension.  There are rare reports63-64 of association of dopamine with TTS in the context of managing hypotension, but as with dobutamine, it is possible TTS is masked or mistaken for the underlying illness.

Other cardiotonic drugs associated with cases of TTS include:

  • dipyridamole,65
  • isoprenaline (isoproteranol),66
  • terlipressin.67

Phenylephrine, a synthetic sympathomimetic amine that acts predominantly on α-adrenergic receptors, is mainly used to treat nasal congestion, but may also be used in treating hypotension and shock and hypotension during spinal anaesthesia. It has been associated with cases of TTS in obstetrics in the setting caesarean section for anaesthetic induction-related hypotension or perioperative hypotension,68-72 but in this context, it is usually not the only drug used that has the propensity to cause TTS.  Use of phenylephrine alone has been reported in cases of TTS but is often used in combination with other drugs. Phenylephrine has also been implicated in the development of Takotsubo with nasal and intraocular use.73-44

Drugs used in the treatment of mental health conditions

 Serotonin norepinephrine reuptake inhibitors (SNRIs)
Serotonin norepinephrine re-uptake inhibitors (SNRIs) are monoamine re-uptake inhibitors and their action is to inhibit the re-uptake of serotonin and norepinephrine. SNRIs are primarily used to treat depression, anxiety, and chronic pain disorders. Although SNRIs are often referred to as “dual action agents” the degree to which re-uptake of serotonin and norepinephrine is inhibited depends upon their affinity for the serotonin transporter and norepinephrine transporter and the dose administered.75 Desvenlafaxine, duloxetine, and venlafaxine are more potent inhibitors of serotonin re-uptake than norepinephrine re-uptake, whereas levomilnacipran preferentially blocks re-uptake of norepinephrine.  Cases of TTS have been reported in association with desvenlafaxine (Pristiq),76-77duloxetine (Cymbalta),78-80milnacipran (Ixel, Savella, Dalcipran, Toledomin),81 and venlafaxine (Effexor).82-86

Other medications used to treat mental health conditions that have been suggested to possibly have had an association with the development of TTS include:

  • atomoxetine87-88
  • nortriptyline 89
  • lithium90-91

Drugs used in the treatment of cancer

Chemotherapy agents

Recent studies have described an increasing trend in the incidence of TTS among adult patients receiving chemotherapy and significantly higher mortality for cancer patients with TTS compared with those with no TTS.92-94

Several chemotherapeutic agents, monoclonal antibodies, and tyrosine kinase inhibitors have been identified as possible sole culprits of TTS. The most common chemotherapy drugs associated with TTS are 5-fluorouracil (5-FU)95-114
and its oral pro-drug capecitabine.114-123


Other drugs used in the treatment of cancer that have been associated with TTS are:

  • monoclonal antibodies bevacizumab,124 cetuximab,125 ipilimumab,126 rituximab,127 trastuzumab,128 and omalizumab129
  • tyrosine kinase inhibitors axitinib,130 pazopanib,131 and sunitinib,132 and lenvatinib133
  • combretastatin134
  • interferon alpha-2b135
  • interleukin 2136
  • oxaliplatin,137FOLFOX (modified folinic acid, 5-fluorouracil, oxaliplatin)138
  • cytarabine,139cytarabine and daunorubicin,140 lomustine, cytarabine, cyclophosphomide and etoposide141

Drugs used in obstretrics

Cases of TTS have been reported in the obstetric setting and is a serious complication that is associated with acute pulmonary oedema,142-150  cardiogenic shock,151 cardiac arrest,152-156 and death.  TTS can happen throughout pregnancy or later in the peripartum period, but the risk is greatest in during or soon after birthing. Peripartum TTS appears to be more common in women with pre-existing maternal high-risk features including age >35 years, multiple gestations, preterm birth (<37 weeks), multiple pregnancy and most reported cases are associated with caesarean delivery. 157  There are also reported cases associated with preeclampsia and HELLP syndrome (haemolysis, elevated liver enzyme levels, and low platelet levels) and vaginal delivery.158-159.

The development of TTS within 24 hours of delivery may be multifactorial.  In cases of hypotension induced by spinal anaesthesia, 160 the drugs given to counteract the hypotension are the likely trigger for TTS. 161 These include adrenaline, noradrenaline, dopamine, dobutamine, phenylephrine, and ephedrine.147 Most of these are given in combination so it is difficult to know whether it is one of these drugs alone or the combination of drugs, but all of these have a propensity to trigger TTS alone.  Similarly, in the setting of peripartum haemorrhage (PPH), drugs used to reduce the risk of PPH or control haemorrhage may have triggered TTS.

Uterotonics that have been linked with the development of TTS include oxytocin,142,143,145,153, 157 ergot alkaloids, 142,143,145,157,158,162 and prostaglandins (PGE2 or PGF2α).142, 148. 157, 161

Ritodrine, used as a tocolytic, has also been reported as a possible trigger for TTS cases. 163-166.

TTS should be considered as a possible diagnosis if symptoms of chest pain, shortness of breath and signs of haemodynamic compromise occur, particularly during or soon after birthing.

Asthma medications

Chronic obstructive pulmonary disease (COPD) and asthma been described as potential physical triggers for TTS. Medications used in the treatment of COPD and asthma including β2 adrenergic receptor agonists albuterol (salbutamol),167-173 terbutaline174 and salmeterol175 likely have a role, but in some cases appears to be due to higher than recommended doses, suggesting that medical review of unstable asthma should be sought sooner rather than taking excessive doses of β2 adrenergic receptor agonists.

Other drugs used to treat asthma and respiratory disease that have been possibly associated with TTS onset are:

  • ipratropium176
  • theophylline 177
  • aminophylline178
  • adrenaline (epinephrine)179

Illicit drugs

Cocaine,180-183methamphetamines,184-186 and cannabis187-188are known to trigger TTS.

Withdrawal syndromes

TTS can be triggered by withdrawal from alcohol,189-191methadone,192-193 opioids,194-195 baclofen, 196-197 and buprenorphine.198 TTS has also been associated with abrupt beta blocker withdrawal.199-200

Other drugs

Other drugs that have possibly been associated with TTS are

  • anagrelide201-202
  • atropine203
  • bromocriptine204
  • cortisone (epidural injection)205-206
  • entacapone207
  • flecainide208
  • influenza vaccine209
  • levothyroxine210-213
  • meperidine214
  • midodrine215
  • nandranone and stanozol216
  • nurofen and diphenhydramine overdose217
  • zolmitriptan218-219

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