Quinidine

General adverse effects and adverse reactions

Gastrointestinal symptoms, including anorexia, nausea, and vomiting, are common.

Quinidine has a negative inotropic effect on the heart and can cause heart failure and hypotension. It prolongs the QRS complex and QT interval and can cause cardiac dysrhythmias, which can result in syncope (so-called “quinidine syncope”).

“Cinchonism” is the term used to describe a cluster of adverse reactions that occur at high dosages, including nausea, vomiting, diarrhea, tinnitus, dizziness, and blurred vision; in severe cases there may be deafness and toxic amblyopia in addition to cardiac abnormalities.

Other adverse reactions that have been described include dementia, psychosis, esophagitis, sometimes resulting in stricture, and exacerbation of myasthenia.

Various hypersusceptibility reactions have been attributed to quinidine, including fever, rashes, various types of hematological abnormalities (particularly thrombocytopenia), hepatitis, asthma, and anaphylactic shock. Quinidine has rarely been reported to cause a lupus-like syndrome.

Observational studies

In 652 consecutive inpatients 91 adverse reactions to quinidine occurred in as many patients (14%); of these, 51 were gastrointestinal, 16 dysrhythmic, 11 febrile, six dermatological, and one hematological; there were six cases of cinchonism [ ]. Although there were four cases of potentially fatal dysrhythmias, there were no deaths.

In 245 patients, the most common adverse reactions were diarrhea (35%), upper gastrointestinal distress (22%), and light-headedness (15%). Other common adverse reactions included fatigue (7%), palpitation (7%), headache (7%), angina-like pain (6%), weakness (5%), and rashes (5%) [ ].

Of 35 patients given hydroquinidine for Brugada syndrome, seven had diarrhea, five during the first month, and two withdrew as a result [ ]. One patient had hepatitis during the first month, which reversed after withdrawal. Two patients had syncope during long-term treatment, one associated with prolongation of the QT interval.

Comparative studies

Quinidine and sotalol have been compared in a prospective multicenter trial of 121 patients after conversion of atrial fibrillation [ ]. Patients with low left ventricular ejection fractions (below 0.4) or high left atrial diameters (over 5.2 cm) were excluded. After 6 months the percentages of patients remaining in sinus rhythm were similar in the two groups (around 70%), but when the dysrhythmia recurred it occurred later with sotalol than with quinidine (69 versus 10 days). There was also a difference between patients who had been converted from recent-onset atrial fibrillation, in whom sotalol was more effective than quinidine, and in patients who had had chronic atrial fibrillation for more than 3 days, in whom quinidine was more effective. There were significant adverse effects requiring withdrawal of therapy in 17 patients, of whom nine were taking quinidine; three patients had gastrointestinal symptoms, two had central nervous symptoms, two had allergic reactions, one had undefined palpitation, and one had QT interval prolongation. One patient taking quinidine, a 65-year-old man, had frequent episodes of non-sustained ventricular tachycardia.

Placebo-controlled studies

In a prospective multicenter study 1033 patients (mean age 60 years, 62% men) with frequent episodes of symptomatic paroxysmal atrial fibrillation were randomized to quinidine + verapamil 480/240 mg/day (n = 263), quinidine + verapamil 320/160 mg/day (n = 255), sotalol 320 mg/day (n = 264), or placebo (n = 251) [ ]. The three treatments were equally effective and the incidences of adverse reactions were the same. There were four deaths, 13 cases of syncope, and one case of ventricular tachycardia; one death and the ventricular tachycardia were related to quinidine + verapamil in the higher doses.

In a prospective, multicenter, double-blind, placebo-controlled, randomized study in 1182 patients with persistent atrial fibrillation, 848 were successfully cardioverted and then randomized to sotalol (n = 383), quinidine plus verapamil (n = 377), or placebo (n = 88) [ ]. Quinidine plus verapamil was significantly superior to both placebo and sotalol in preventing recurrence. Adverse events were comparable (about 24% in each group), except that all nine cases of torsade de pointes occurred in patients taking sotalol.

Quinidine has relatively poor efficacy in maintaining sinus rhythm after cardioversion of atrial fibrillation [ ], and can have serious adverse effects, including cardiac dysrhythmias (“quinidine syncope”), thrombocytopenia, and liver damage. These studies do not rehabilitate it in the management of atrial fibrillation, despite arguments to the contrary [ ], since apparent efficacy may have been largely due to the verapamil with which quinidine was combined in both these studies.

Cardiovascular

Quinidine prolongs the QRS complex and QT interval, the effect being related to plasma quinidine concentrations [ ] and being greater in women [ ]. As a result, torsade de pointes or other ventricular tachydysrhythmias can occur and may lead to syncope (“quinidine syncope”). The minimum risk of torsade de pointes has been estimated at 1.5% per year [ ].

The relation between serum quinidine concentrations and QT interval dispersion has been studied in 11 patients with atrial dysrhythmias and subtherapeutic or therapeutic serum quinidine concentrations (1.48 and 3.78 μg/ml respectively) [ ]. The baseline QT _c interval was 430 ms. At subtherapeutic and therapeutic serum quinidine concentrations, mean QT _c intervals were 451 and 472 ms respectively. Mean QT dispersion was 47 ms at baseline, 98 ms at subtherapeutic concentrations, and 71 ms at therapeutic concentrations. Despite QT interval lengthening with increasing serum quinidine concentrations, QT dispersion was greatest at subtherapeutic concentrations.

Quinidine has also been incriminated in cases of sinoatrial block and sinus arrest, but it was not clearly established that quinidine was responsible [ , ]. The anticholinergic effects of quinidine can increase the risk of dysrhythmias [ ].

Treatment of tachydysrhythmias secondary to quinidine is problematic. Other class I antidysrhythmic drugs are theoretically contraindicated. Some success has been reported with bretylium and with a combination of a beta-adrenoceptor antagonist and phenytoin [ , ]. Overdrive pacing has also been reported to be of value [ ].

• Quinidine syncope in a 46-year-old woman, associated with bradycardia and torsade de pointes due to prolongation of the QT interval (660 ms), responded to intravenous sodium bicarbonate and pacing [ ].

Intravenous quinidine has been used to study the susceptibility to QT interval prolongation in 14 relatives of patients who had safely tolerated chronic therapy with a QT interval-prolonging drug (controls) and 12 relatives of patients who had developed acquired long QT syndrome [ ]. The interval from the peak to the end of the T wave, an index of transmural dispersion of repolarization, was significantly prolonged (from 63 to 83 ms) by quinidine in the relatives of those with acquired long QT syndrome but not in control relatives (from 66 to 71 ms). The time from the peak to the end of the T wave as a fraction of the QT interval was similar in the two groups at baseline but was longer in the relatives of those with acquired long QT syndrome after quinidine. The authors concluded that first-degree relatives of patients with acquired long QT syndrome have greater drug-induced prolongation of terminal repolarization than control relatives, supporting a genetic predisposition to acquired long QT syndrome.

Hydroquinidine has been used to treat the short QT syndrome in six patients and has been compared with other antidysrhythmic drugs [ ]. Hydroquinidine prolonged the QT _c interval from 290 to 405 ms and ventricular fibrillation was no longer inducible. Diarrhea was the main adverse effect.

Quinidine has a negative inotropic effect on the heart and causes peripheral vasodilatation. Hypotension can occur secondary to these effects [ ].

Nervous system

Quinidine rarely causes effects on the nervous system when used in therapeutic dosages, although there have been occasional reports of dementia [ ]. However, in toxicity it can cause vertigo and tinnitus [ ].

Sensory systems

Quinidine rarely affects vision, but can cause scotomata, impaired color vision, and toxic amblyopia [ ], altered vision [ ], sicca syndrome [ ], keratopathy [ ], and granulomatous uveitis [ ].

Hematologic

Hypersusceptibility reactions to quinidine include thrombocytopenia, hemolytic anemia, and neutropenia.

The overall annual incidence of acute thrombocytopenia has been estimated at 18 cases per million [ ], and two possible mechanisms have been invoked:

• 1.

  direct combination of quinidine with platelets, causing the production of antibodies, which then cause platelet lysis;

• 2.

  formation of quinidine-antibody complexes, which are then deposited on the platelet (the so-called “innocent bystander” mechanism).

There is evidence in favor of both of these mechanisms [ ].

• A 72-year-old woman developed repeated bouts of thrombocytopenia; quinidine-dependent antibodies were found after it transpired that she had been taking her husband’s tablets intermittently to treat bouts of palpitation [ ].

Sensitization may have occurred because of the intermittent nature of exposure in this case.

Other hematological reactions are much less common, and include hemolytic anemia [ , ], neutropenia [ , ], and eosinophilia [ ].

Withdrawal of quinidine and the administration of glucocorticoids is the usual treatment for thrombocytopenia [ ], although intravenous immunoglobulin has also been used [ ].

In a review of all English-language reports on drug-induced thrombocytopenia, excluding heparin, 561 case articles reporting on 774 patients were analysed [ ]. A definite or probable causal role for the drug used was attributed in 247 case reports, and of the 98 that were implicated quinidine was mentioned in 38 cases. The next most common drugs involved were gold salts (11 cases) and co-trimoxazole (10 cases).

Mouth and teeth

A blue–black pigmentation of the oral mucosa has been reported with quinidine [ ].

Gastrointestinal

Anorexia, nausea, vomiting, and diarrhea are common adverse reactions to quinidine and occur in up to 30% of patients [ ]. They can be minimized by the use of modified-release formulations [ ].

In one series diarrhea was reported commonly [ ], and it can occur late in treatment [ ].

Quinidine sometimes causes esophagitis [ , ], especially when there is some abnormality of the esophagus or cardiomegaly. This sometimes results in esophageal stricture [ ].

The quinidine derivative hydroquinidine had some beneficial effects in 10 patients with myotonic dystrophy with slow saccadic eye movements, apathy, and hypersomnia [ , ]. However, two patients had nausea and epigastric pain and withdrew while taking the active treatment. Although there were no cases of cardiac abnormalities, the authors raised the concern that in patients with myotonic dystrophy, who have a high frequency of cardiac disturbances, the risk of cardiac dysrhythmias with quinidine derivatives may be too high to take.

Liver

Hypersusceptibility reactions to quinidine include granulomatous hepatitis. In one retrospective series of 487 patients, 32 had evidence of hypersusceptibility, 10 of whom had hepatotoxicity [ ]. In another series of 1500 patients, quinidine-induced hepatitis was identified in 33 (2.2%) [ ]; these represented one-third of all cases of drug-induced hepatitis in those patients. In all cases the liver damage resolved on withdrawal.

Urinary tract

Glomerulonephritis has been reported in association with Henoch–Schönlein purpura [ ] and nephrotic syndrome, possibly as part of a lupus-like syndrome [ ].

Skin

Rashes are uncommon [ ], but can occur as part of a hypersusceptibility reaction. In a review of drug-induced skin disorders, from a list of 26 drugs or groups of drugs, only quinidine was mentioned of all antidysrhythmic drugs [ ]. The reaction rate was quoted as 12 per 1000 recipients. Several different kinds of rash have been reported, including photosensitivity [ ], which can result in a variety of types of rash, contact dermatitis [ ], pigmentation [ ], urticaria [ ], exfoliative dermatitis [ , ], granuloma annulare [ ], and exacerbation of psoriasis.

Musculoskeletal

Quinidine is a neuromuscular blocking drug and can exacerbate myasthenia gravis [ ]. It can also cause an increase in the serum activity of the muscle-specific isoenzyme of creatine kinase [ ].

• A 56-year-old man who took quinidine 324 mg five times daily for prevention of paroxysmal atrial fibrillation developed a syndrome similar to polymyalgia rheumatica which settled on drug withdrawal [ ].

Quinidine can cause polyarthropathy [ ], both in association with and independent of a lupus-like syndrome.

Immunologic

A variety of immune syndromes have occasionally been reported with quinidine, including a lupus-like syndrome, polymyalgia rheumatica, and vasculitis [ ].

Life-threatening vasculitis has been attributed to quinidine in a healthy volunteer taking part in a clinical trial [ ].

• A 58-year-old man took quinidine 200 mg tds for 7 days as part of an interaction study with a new alpha-blocker. He developed widespread maculopapular purpuric lesions on the limbs, trunk, and ears. His temperature rose to 38.4 °C and some of the lesions on his fingers, toes, ears, and nose became necrotic. He had peripheral edema with a bluish purpuric discoloration of the hands and feet. There was mucous membrane involvement with purpuric, partially necrotic lesions on the tongue and palate. A skin biopsy showed necrotizing vasculitis with focal leukocytoclasia. Direct immunofluorescence showed microgranular deposits of IgA, IgM, and C3 around the superficial skin vessels. Quinidine was withdrawn and he was given intravenous methyl prednisolone followed by oral prednisone for 1 month. He recovered completely within 3 weeks.

There has been a report of a dermatomyositis-like illness in a man taking quinidine [ ].

• A previously healthy 63-year-old man, who had taken quinidine gluconate 972 mg/day for 9 months, developed diffuse edematous erythema on the extensive surfaces of the hands, arms, and face, with marked accentuation over the joints. His nail-fold capillaries were dilated and the shoulder abductors were slightly weak. His erythrocyte sedimentation rate was slightly raised (29 mm/hour) and there was a positive ANA titer (1:640) with a speckled pattern. There were no antibodies to Sm, ribonucleoprotein, SSA or SSB antigens, or histones. There was no evidence of inflammatory myopathy on electromyography, and a skin biopsy showed a mild, superficial, perivascular, lymphocytic inflammation with positive direct immunofluorescence for IgG and IgM at the dermoepidermal junction. There was no evidence of malignancy. All these abnormalities resolved rapidly after quinidine withdrawal.

Antiphospholipid antibodies have been reported in patients taking quinidine [ ]. A 68-year-old woman with easy bruising and hematomas provoked by minimal trauma, who had been taking quinidine for 18 years had antiphospholipid antibodies and antiprothrombin antibodies [ ].

A lupus-like syndrome has occasionally been reported in patients taking quinidine [ , , ]. It usually presents with polyarthralgia, a raised erythrocyte sedimentation rate, and a raised antinuclear antibody titer. It can occasionally be associated with antihistone antibodies and a circulating coagulant. In two cases [ ] the syndrome was associated with quinidine and not with procainamide. Lupus anticoagulant has been reported with the use of quinine and quinidine, and an associated antiphospholipid syndrome has been described [ ].