Clinical manifestations

Presentation and course

	• Drugs can induce 3 types of syncope: neurogenic, cardiogenic, and that due to postural hypotension.
	• Generally, the prognosis of patients with syncope due to a drug is excellent if the offending drug is discontinued.
	• Prognosis is less favorable in patients with drug-induced cardiotoxicity leading to rhythm or conduction disorders or with a preexisting cardiac disease.

Syncope may present as 3 types, which can all be caused by drugs: (1) reflex (neurally mediated) syncope; (2) cardiac syncope; and (3) syncope due to postural hypotension (29). Clinical manifestations of drug-induced syncope vary according to the mechanism involved. It may be a simple vasovagal faint from which the patient recovers promptly without any residual signs or symptoms. Syncope secondary to drug-induced cardiac arrhythmia may be less benign, and other signs and symptoms of cardiovascular disturbances may complicate the clinical state of the patient. A patient may faint during injection of a medication as a vasovagal reaction and not due to any adverse effect of the medication. Syncope is a manifestation of postural hypotension associated with some drugs such as antihypertensive medications. Dizziness is a frequent accompaniment of postural hypotension. Other symptoms of cerebral hypoperfusion are light-headedness, general weakness, and visual disturbances. Tonic or clonic movements may occur during syncopal episodes.

Prognosis and complications

The prognosis of patients with syncope due to a drug is excellent if the offending drug is discontinued. However, in patients with drug-induced cardiotoxicity leading to rhythm or conduction disorders or with a preexisting cardiac disease, the mortality rate is higher than in patients with noncardiac causes and in patients where no cause is found. Complications of syncope include the following:

	• Trauma from falls
	• Ischemic stroke due to decreased blood flow to the brain
	• Cardiovascular complications, including arrhythmias

Development of torsades de pointes due to Q-T interval prolongation is life-threatening. In a multicenter, 2-year longitudinal, observational study of elderly patients hospitalized due to syncope, total mortality was 17.2% and syncope recurrence was 32.5% (33). Cardiac syncope was more frequent in those who died as compared to survivors. Drug-induced Brugada syndrome has a good prognosis if asymptomatic; however, sudden cardiac death is possible (30).

A review of patients with cardiovascular syncope revealed that drug-induced syncope was an independent risk factor for rehospitalization, and careful follow-up of these patients for at least 1 year is recommended (24).

Clinical vignette

A 54-year-old woman, who presented with syncope and had markedly prolongation of QTc interval, was admitted for observation. She had history of depression and was treated with citalopram, which was discontinued. She had low serum potassium level that was corrected. Despite these measures, she experienced a near syncope during an episode of Torsade de Pointes. A cardioverter-defibrillator was implanted, and genetic testing identified a heterozygous KCNE1 p.D85N gene variant, a known QT modifier. The authors of this case report concluded that the combination of citalopram, hypokalemia, and a common KCNE1 QT modifier may have caused severe QTc prolongation and life-threatening arrhythmia, which presented initially as syncope (18).

Biological basis

Etiology and pathogenesis

	• A large number of drugs from various therapeutic categories are associated with syncope.
	• Two main mechanisms of drug-induced syncope are postural hypotension and cardiac arrhythmias.

Most episodes of syncope are single. It is recurrent syncope that is usually investigated as to the cause. A simple classification of syncope according to etiology is as follows:

Cardiovascular
	• Organic cardiac disease • Cardiac arrhythmias • Orthostatic hypotension
Neurogenic
	• Vasovagal (neurocardiogenic) overlaps with cardiovascular form • Situational syncope (micturition, cough, etc.) • Psychogenic syncope (anxiety and panic disorders) • Glossopharyngeal and trigeminal neuralgias • Cerebrovascular ischemia (transient ischemic attacks) • Carotid sinus syncope
Drug-induced syncope

• Syncope as a manifestation of drug-induced anaphylaxis

Syncope of unknown etiology

Vasovagal (reflex syncope) is the most common form of syncope, occurring in approximately 60% of syncope presentations; orthostatic hypotension presents in around 15%, with arrhythmic syncope in 10%, and structural heart disease as the cause of syncope in 5% (32). Besides the frankly identified drug-induced causes, orthostatic hypotension, cardiac arrhythmias, and cerebrovascular ischemia may also be drug-induced. Drugs reported to be associated with syncope are shown in Table 1.

Table 1. Drugs Associated with Syncope

• Analgesics
	- Opioid analgesics - Nonsteroidal antiinflammatory drugs
• Antineoplastic drugs: vincristine
• Cytokines: interferon-alpha
• Cholinesterase inhibitors in elderly patients with dementia (21)
• Digitalis
• Drugs that produce postural hypotension (see Table 2)
• Drugs and combinations that prolong Q-T interval/torsades de pointes (See Table 3)
• Hypnotic-sedative drugs (depressants of the CNS)
	- Barbiturates - Benzodiazepines
• Other sedative hypnotic drugs: niaprazine
• Hypoglycemic drugs
	- Insulin - Oral hypoglycemics
• Selective serotonin reuptake inhibitors
	- Fluoxetine - Citalopram
• Miscellaneous therapeutics
	- Apheresis: plasma, white cells, or red cell exchange - CNS stimulants - Gamma hydroxy butyrate - Local anesthetics - Loperamide - Meglumine antimonate (anti-leishmaniasis antimony compound) - Topical ophthalmic preparations: - Levobunolol ointment - Betaxolol ophthalmic solution - Vaccines
(12)

Drugs most significantly associated with an excess risk of syncope in the elderly are (1) fluoxetine, (2) aceprometazine, (3) haloperidol, and (4) L-dopa.

Two main mechanisms of drug-induced syncope are postural hypotension and cardiac arrhythmias. Syncope may occur in the absence of hypotension by drug-induced vasoconstriction of cerebral vessels. Drugs that produce postural hypotension are shown in Table 2.

Table 2. Drugs that Produce Postural Hypotension

Drugs used to treat hypertension:
	• Angiotensin-converting enzyme inhibitors • Beta blockers • Calcium antagonists • Diuretics
Drugs that have hypotension as an adverse effect:
	• Antidepressants • Antiparkinsonian drugs
		- levodopa - bromocriptine - selegiline (deprenyl) - anticholinergics
	• Antipsychotics
		- phenothiazines - butyrophenones
	• Drugs that induce autonomic peripheral neuropathy
		- amiodarone
		- perhexiline maleate
	• Vasodilators
		- nitrates, eg, nitroglycerine
	• Sildenafil

Hypotension. Significant hypotension is a drop in systolic pressure of at least 20 mm Hg or 10 mm Hg in diastolic pressure on standing up. An alternative definition is used because a low blood pressure is not tolerated on standing. Any systolic blood pressure in the upright position of less than 95 mm Hg, regardless of the change of posture, indicates orthostatic hypotension.

Evidence from experimental animal studies suggests that the site for induction of postural hypotension by passive upright tilt may lie in the forebrain region, whereas the primary center for the induction of postural hypotension lies in the brain stem. Orthostatic hypotension and decreased cerebral blood flow are interrelated. The critical lower limit of cerebral perfusion lies at, or close to, 50% below baseline supine (horizontal) mean cerebral blood flow velocity. At this level of cerebral hypoperfusion, unconsciousness ensues in 80% of subjects. This indicates impaired autoregulation, and there may be an unknown clinical predisposition to this condition. There was enhanced susceptibility to vasovagal reaction during upright tilt testing on patients with syncope and a positive response to tilt testing. This demonstrates that chronic vasodilator therapy predisposes to syncope.

Drug-induced hypotension. Hypotension in the elderly is significantly associated with the use of potassium-sparing diuretics, dopaminergic antiparkinsonian drugs, and butyrophenone antipsychotics. Orthostatic hypotension is often associated with hyponatremia and is found in one fifth of the elderly who take diuretics. A slight decrease in sodium levels induced by diuretics results in marked orthostatic hypotension in healthy elderly persons, but it does not affect younger adults. Nitrates dilate arterial and venous smooth muscle and reduce cardiac output by pooling blood in the periphery. This leads to a fall in blood pressure, and the risk of this is higher in the elderly. Levodopa produces orthostatic hypotension in patients with late-onset Parkinson disease who are prone to it because of autonomic dysfunction.

Oral formulation of the selective M1 agonist xanomeline, used for the treatment of Alzheimer disease, is associated with an increased incidence of syncope. Alzheimer patients, who presumably lack M1 receptor activity, usually have a reduced risk of tilt-induced syncope compared with normal subjects. Both groups, however, have enhanced susceptibility to hypotension and syncope when M1 receptor activity is pharmacologically increased such as by xanomeline administration.

Ability of bromocriptine to induce syncope in head-up tilt test is utilized in investigation of neurally mediated syncope of unknown etiology. A positive test indicates that dopaminergic supersensitivity may play a role in the pathogenesis of syncopal episodes.

An isoproterenol-mediated increase in cardiomotor tone and decrease in afterload contribute to the induction of vasovagal syncope. Contrary to conventional belief, a significant decrease in preload is not observed immediately before isoproterenol-induced syncope.

Syncope after the use of an antihypertensive drug is not always due to postural hypotension. Beta blockers may produce bradycardia in addition to hypotension. Paradoxically, beta blockers are also used in the treatment of syncope.

Paradoxical hypotension due to suppression of vasomotor outflow may occur after amphetamine intoxication.

High-dose nitroglycerin infusion, used for treatment of “sympathetic crashing acute pulmonary edema,” can produce drug-induced hypotension and syncope (25).

Cardiac arrhythmias and conduction disturbances. An important cause of syncope is drug-induced prolongation of Q-T interval (torsades de pointes). Long QT syndrome and Brugada syndrome are arrhythmia syndromes characterized by presyncope, syncope, cardiac arrest, and seizures. Besides occurrence as side effect of drugs, there is a genetic predisposition. A mutation in SCN5A gene, which encodes the cardiac sodium channel Nav1.5, is the most identified mutation in both conditions. Female gender is recognized as an independent risk factor for drug-induced long QT syndrome, which is influenced by other factors, including age, menstrual cycle, and hormone replacement therapy (17). A clinical pharmacology study during a drug's development process can assess its propensity to induce torsades de pointes using prolongation of the QT interval as seen on the ECG as a biomarker (15).

The most common cause of sudden death of a young athlete on the competitive field is cardiac illness; usually that of congenital etiology. However, the use of anabolic steroids, peptide hormones, and stimulants that can cause dangerous arrhythmias have led to initial manifestation as drug-induced syncope and, in some instances, can present as a sudden, unexpected death (07).

Andersen-Tawil syndrome is characterized by a triad of episodic periodic paralysis, ventricular arrhythmias, syncope, weakness that occurs spontaneously following prolonged rest or prolonged QT interval, and congenital anomalies. Affected individuals present in the first or second decade with either cardiac symptoms (palpitations and/or syncope) or muscle weakness that occurs spontaneously at rest (31). Clinical and ECG findings are characteristic, but pathogenic variant in KCNJ2 gene confirms the diagnosis. Medications known to prolong QT intervals and potassium-wasting diuretics that provoke drug-induced hypokalemia, which aggravate the QT interval, could precipitate syncopal attacks.

Drugs that produce cardiac arrhythmias and conduction disturbances are shown in Table 3.

Table 3. Drugs Reported to Cause Syncope by Inducing Arrhythmias and Conduction Disturbances including Torsades de Pointes

Single drugs
• Antiarrhythmic drugs
	- Ajmaline - Amiodarone - Disopyramide - Procainamide - Quinidine - Sotalol
• Antihistaminic drugs
	- Astemizole - Terfenadine - Fexofenadine, a nonsedating histamine H1 receptor antagonist
• Antimalarial or antiprotozoal
	- chloroquine/hydroxychloroquine - halofantrine - mefloquine - pentamidine - quinine
• Antimicrobials
	- Combination antiretroviral therapy for HIV-1 - erythromycin - HIV protease inhibitors - trimethoprim-sulfamethoxazole - gatifloxacin - antifungal agent isavuconazonium
• Antineoplastic drugs
	- anthracycline cardiotoxicity
• Atropine (paradoxical effect) • Cisapride (cytochrome P450 3A4 substrate), for the treatment of gastrointestinal motility disorders • Drug abuse
	- cocaine-induced bradyarrhythmia - methadone for management of heroin dependence
• Encainide • Flecainide • Psychoactive drugs
	- Amphetamines - Atypical antipsychotics - Haloperidol - Phenothiazines - Pimozide
• Miscellaneous drugs
	- Amantadine - Bromocriptine misuse - Carbamazepine - Carbimazole - Guanfacine - Probucol - Synthetic opioids - Tacrolimus - Trimethaphan - Vasopressin
Combination of drugs
	- Cisapride and diltiazem - Cisapride and ranitidine - Clozapine and cocaine - Clozapine and diazepam - Clozapine and enalapril - Fluconazole and amitriptyline - Fluoxetine and ranitidine - Loratadine and amiodarone - Terfenadine and itraconazole - Terfenadine and erythromycin - Terfenadine and astemizole

Torsades de pointes. Torsades de pointes may cause syncopal episodes and dizziness. It is characterized by polymorphic QRS complexes that change in amplitude and cycle length and may be preceded by Q-T prolongation. Torsades de pointes may result from acquired medical and genetic disorders, but it is often induced by drugs shown in Table 3.

Quinolone antibiotics have potentially serious proarrhythmic effects. Ciprofloxacin may be used because the agent is believed to be safer than other drugs in its class, although a few cases of unexplained cardiac arrest temporally related to ciprofloxacin have been reported.

Syncope in drug addicts using methadone and cocaine may not be due to effects on the central nervous system but rather on cardiac conduction. Cocaine and methadone may induce syncope by prolonging the QT interval (16).

Atropine is widely used as a parasympatholytic agent during diagnostic and therapeutic procedures. Syncope has been observed as an unexpected paradoxical response to atropine after cardiac transplantation. Various degrees of atrioventricular block have been documented in these patients. Although the underlying mechanism is not clear, these findings suggest that atropine may paradoxically cause high-degree atrioventricular block in patients after transplantation.

Syncope may occur as a side effect of guanfacine, an alpha2-adrenergic receptor agonist, and is probably due to drug-induced hypotension or bradycardia (14).

Prolongation of the QT interval caused by antipsychotics (particularly, pimozide, thioridazine, ziprasidone, and sertindole) may produce dizziness, syncope, ventricular fibrillation, and sudden death (27). Antipsychotics are associated with ventricular tachycardia because of their inhibition of the cardiac delayed potassium rectifier channel, which extends the repolarization process of the ventricles of the heart, manifested as a prolongation of the QT interval (22).

A case of syncopal attack, misdiagnosed as epilepsy, was found to be related to oral cisapride use for dyspepsia (01). Discontinuation of cisapride and normalization of serum potassium level led to disappearance of both ECG abnormalities and loss-of-consciousness episodes.

Methadone is associated with QT prolongation and higher reporting of syncope in a population of heroin addicts (06).

Use of cholinesterase inhibitors is associated with increased rates of syncope, bradycardia, and pacemaker insertion in older adults with dementia (09).

Drug-induced anaphylaxis. Syncope and hypotension are more common in drug-induced anaphylaxis, which is severe in 54.2% of cases of anaphylaxis due to all causes (13). Urticaria and other skin symptoms are significantly more common in food-induced anaphylaxis.

Epidemiology

	• Syncope occurs in approximately 20% to 50% of the population.
	• The epidemiology of hypotension, which occurs in 10% of individuals over 71 years of age, is also relevant to syncope.

Syncope occurs in approximately 20% to 50% of the population. In a certain study, using a standardized adverse drug reaction algorithm, 9 of 70 patients (13%) with syncope were rated as having probable drug-related syncope or presyncope (10). Epidemiology of hypotension is also relevant to syncope. Hypotension is common in the elderly, and in 10% of the individuals over 71 years, blood pressure values were found to be less than or equal to 122 mm Hg systolic and less than or equal to 68 mm Hg diastolic (02). An association between hypotension and drugs was found in this study.

In a study of clinically important adverse drug reactions on 393 newly introduced medicines in Japan, 101 (25.7%) showed syncope/loss of consciousness (20).

Centers for Disease Control and Prevention and the FDA have analyzed data from the Vaccine Adverse Event Reporting System for January 1, 2005, through July 31, 2007, and compared the results with reports received during 2002 through 2004 and found that reports of postvaccination syncope had increased since 2005, primarily among females aged 11 to 18 years (03). In a retrospective study of 100 patients aged 65 years or older admitted to a subacute care unit with a diagnosis of fall-related trauma, 36 had transient loss of consciousness; out of these, 10 had drug-induced orthostatic hypotension (26).

Prevention

	• The use of multiple drugs in the elderly, particularly antihypertensives, should be avoided.
	• Drugs with known effects on cardiac rhythm and conduction should be avoided in those susceptible to syncope.

The use of multiple drugs in the elderly, particularly antihypertensives and central nervous system depressants, should be avoided. Other drugs with known effects on cardiac rhythm and conduction should be avoided in those susceptible to syncope. The use of short-acting calcium antagonists, such as oral or sublingual nifedipine, is no longer recommended to be used in hypertensive patients because it can cause syncope and even more serious cardiovascular adverse effects. However, low doses of the long-acting formulations seem to be safer.

Because syncope is a common adverse effect of vaccination, it is recommended that patients be observed for 15 minutes following vaccination. Those exhibiting presyncopal signs and symptoms around the time of immunization should be evaluated carefully and may need to be assisted to sit or lie down until free of symptoms. However, a survey has revealed that few physicians are aware of recommendations for postvaccination observation for syncope, and strategies to improve this need to be developed and implemented (11).

Differential diagnosis

Confusing conditions

Although cardiovascular factors are involved in neurally mediated syncope, drug-induced syncope is more likely to be cardiovascular in origin. The following nondrug-induced disorders should be considered in the differential diagnosis of drug-induced syncope:

• Cardiac arrhythmias • Drop attacks due to brainstem ischemia • Falls • Neurally mediated syncope • Petit mal or absence epilepsy • Peripheral autonomic neuropathy • Tonic-clonic seizures • Postural hypotension/classic orthostatic hypotension • Psychogenic disorders • Situational syncope

Syncope and falls are 2 common concomitant adverse drug effects reported in elderly patients. An overlap between syncope and falls is becoming increasingly acknowledged. In the elderly, determining the cause of a fall can be difficult. A patient may be unable to recall documented falls some months later and a witness account for syncopal events is often unavailable.

Three characteristic hemodynamic features help to differentiate between classical orthostatic hypotension and vasovagal or cardioneurogenic syncope: (1) the shape of the overall fall in blood pressure; (2) the latency of blood pressure decrease; and (3) the direction of heart rate change (08). These hemodynamic contrasts likely rest on a failure of compensation mechanisms on standing in orthostatic hypotension, whereas vasovagal syncope is characterized by initial slow venous pooling followed by subsequent cardioinhibition. Drug-induced orthostatic hypotension differs from neurogenic orthostatic hypotension, which is due to failure of the sympathetic nervous system that occurs in severe in multiple system atrophy with dysautonomia (Shy-Drager syndrome) and is also commonly seen in patients with Lewy body dementia and in patients with Parkinson disease. In contrast, the sympathetic nervous system function is preserved in secondary orthostatic hypotension associated with antihypertensive or psychotropic drugs (19).

A study has shown that 35% of patients monitored with Brugada ECG showed vasovagal responses during the head-up tilt test, suggesting that some of these patients have impaired balance of the autonomic nervous system, which may relate to their syncopal episodes (34). There are case reports of patients with primary autonomic neuropathy suffering from both severe orthostatic hypotension and arrhythmic syncope (05).

Diagnostic workup

	• History of drugs taken prior to syncope
	• Blood pressure
	• Electrocardiogram
	• Head-up tilt testing
	• DNA sequencing, if cardiac channelopathies are suspected
	• Diagnostic scores for syncope

After defining the episode of syncope, the most important first step is to determine the history of drugs taken prior to the episode, particularly those with known association to syncope. Blood pressure should be evaluated carefully to detect postural hypotension. ECG is the most important laboratory test for detecting arrhythmias and conduction disturbances.

Head-up tilt testing is widely used in the clinical assessment of patients with unexplained syncope. Drug provocation can be used in conjunction with tilting. Sublingual isosorbide dinitrate and tilting is sensitive and specific in inducing a vasovagal reflex in patients with syncope of uncertain origin. Patients with spontaneous vasovagal syncope have lower blood pressure, higher frequency of reflex asystole, pronounced increases in epinephrine, as well as vasopressin during early phase of the head-up tilt test, than those with drug-potentiated positive head-up tilt test, but both groups share similar supine neuroendocrine profiles (23).

In syncope patients with suspected cardiac channelopathies, DNA sequencing is now commercially available for patient diagnosis.

The following 3 diagnostic scores for syncope have been shown to be useful in practice (28):

	(1) Calgary Syncope Seizures Score discriminates between epileptic convulsions and syncope with a sensitivity and specificity of about 94%.
	(2) Calgary Syncope Score for normal hearts discriminates between vasovagal syncope and other causes of syncope with a sensitivity and specificity of about 90%.
	(3) Calgary Syncope Score for Structural Heart Disease diagnoses ventricular tachycardia with 98% sensitivity and 71% specificity.

Management

	• Suspected drugs should be discontinued in drug-induced syncope.
	• Elastic stockings may correct orthostatic hypotension.
	• If nonpharmacological measures are inadequate, drug treatment, such as fludrocortisone, may be considered.
	• Cardiac rhythm and conduction disturbances require care in a cardiology unit.

In a patient with suspected drug-induced syncope, the drug in question should be discontinued. When assessing orthostatic hypotension in the elderly, drug treatment should always be reviewed. Whenever possible, antihypertensive drugs should be discontinued, and the dosages of essential drugs should be reduced. Wearing elastic stockings sometimes corrects orthostatic hypotension. If nonpharmacological measures are inadequate, drug treatment may be considered. Fludrocortisone (0.1 to 0.4 mg/day) is recommended. Also, a prostaglandin inhibitor such as indomethacin may be useful at a dose of 25 to 150 mg/day. Ephedrine is recommended for syncope occurring after local or regional anesthesia, particularly in obstetrical procedures. Epinephrine is used for syncope due to drug-induced anaphylaxis.

L-DOPS (L-threo-dihydroxyphenylserine) is in phase III clinical trials for the treatment of levodopa-induced neurogenic orthostatic hypotension. L-DOPS is a prodrug to the neurotransmitters norepinephrine and epinephrine with the difference that it can cross the blood-brain barrier.

Patients with cardiac rhythm and conduction disturbances require care in a cardiology unit. Drug management is complicated by the fact that several of the drugs used for the treatment of cardiac arrhythmias also have syncope as a side effect. Several drugs are used for the treatment of syncope, but if syncope is drug-induced, there may be complications and interactions if the offending drug therapy is maintained. While the patient is monitored, adjustment or discontinuation of cardiovascular medications can help in the management of falls and syncope and may obviate the need for other treatment.

Patients with Alzheimer disease have been reported to present with cardiac syncope soon after initiation treatment with donepezil, a cholinesterase inhibitor. In these cases, pacemaker implantation is recommended rather than cessation of donepezil.

Drug-drug interactions are a common cause of syncope in the elderly presenting in emergency departments. For proper management of these patients, it is important to identify these interactions.

Special considerations

Pregnancy

Although pregnancy may be suspected as a risk factor for drug-induced hypotension and syncope, there are no documented cases of drug-induced syncope in pregnant women.

Anesthesia

Local and spinal anesthesia may induce syncope due to hypotension and cardiac rhythm disorders. There is no relevant information about general anesthesia.