A. Cos

C. Tristan

Ch, Guilleminault

Committee, Joint Formulary

D. Capella

F. J. Morales-Olivas

J. M. Castel

J. R. Laporte

JF, Marti Mass6

Klein, M.

Meyboom, R.H.B.

Milner, A.D.

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Parkinsonism, tremor, and depression induced by cinnarizine and flunarizine.

Capellà Hereu, Dolors

Laporte Rosselló, Joan-Ramón

Castel Llobet, Josep Maria

Tristán, Carmen

Cos, Ángeles

Morales-Olivas, Francisco J.

Diposit Digital de Documents de la UAB

Age at diagnosis ofAIDS at thishospital to October 1987Age (years) No of patients0-19 220-24 1925-29 2630-34 4835-39 5740-44 3345-49 3 150-54 755-59 660-64 265 4transbronchial biopsy did not show any pathogen. Hewas treated with co-trimoxazole and hydrocortisone.After 14 days of co-trimoxazole he had improvedclinically and radiographically and was dischargedreceiving maintenance treatment.CommentBoth these patients were positive for HIV antibodyand had a clinical and radiological presentationsuggestive of P carinni pneumonia that responded totreatment; thus the criteria fbr a diagnosis of AIDSwere satisfied. ' In case 2 the diagnosis was complicatedby the previous amiodarone treatment, thoughpneumonitis induced by amiodarone is unusual at adaily dosage less than 400 mg.23 Chest infections arecommon in the elderly. The increasing incidence ofHIV infection and a reluctance of older homosexuals toadmit to at risk behaviour may mean that elderlypatients will die without AIDS being diagnosed. In theUnited States 10% of patients with AIDS are over 50,2-5% over 60, and 0 4% over 70. The table shows theage distribution of our patients with AIDS up toOctober 1987. Six of 235 (2 5%) patients were over 60.P carinii pneumonia should be considered in allpatients with atypical chest infections, even when thereare no apparent risk factors.We thank Miss Linda Stannard for preparing themanuscript and Dr D J R Morgan for his helpful comments.I Anonymous. Revision of the CDC surveillance case definition for acquiredimrmlunodeficiency syndrome. .7AMA 1987;258:1143-54.2 Marchinski FE, Lansten TS, Waxman HL, Josephson ME. Amiodaronepulmonary toxicity. Ann Intern Med 1982;97:839-45.3 Suarez LD, Poderoso IJ, Elsner B, Bunster AM, Esteva H, Bellotti M.Subacute pneumopathy during amiodarone therapy. Chest 1983;83:566-8.4 Moss RJ, Miles SH. AIDS and the geriatrician.Am GeriatrSoc 1987;35:460-4.(Accepted 3 May 1988)Department ofPharmacology, UniversitatAutonoma de Barcelona,CS Vall d'Hebron,08035-Barcelona, SpainDolors Capella, MD, associateprofessorJoan-Ramon Laporte, MD,professorJosep-Maria Castel, MD,research assistantService ofClinicalPharmacology, ClinicaUniversitaria, PamplonaCarmen Tristan, MD,research assistantService of ClinicalPharmacology, CMNMarques de Valdecilla,SantanderAngeles Cos, MD, researchassistantDepartment ofPharmacology, Universitatde ValenciaFrancisco JoseMorales-Olivas, associateprofessorCorrespondence to:Professor Laporte.Parkinsonism, tremor, anddepression induced bycinnarizine and flunarizineDolors Capell, Joan-Ramon Laporte,Josep-Maria Castel, Carmen Tristan,Angeles Cos, Francisco Jose Morales-OlivasCinnarizine and flunarizine are piperazine derivativeswith antihistamine properties and calcium channelblocking activity. Several recent reports have des-cribed extrapyramidal reactions and depressionassociated with their use.Methods and resultsIn Spain a system of spontaneous reporting ofadverse drug reactions has been operating since1983. Around 5000 reports have been received, ofwhich 86 refer to cinnarizine as the suspected drug,25 to flunarizine, and five to both drugs takensimultaneously. Of these 116 reports 87 describedextrapyramidal symptoms or depression, or both:cinnarizine had been taken in 70 cases, flunarizine in13, and both drugs in four.Seventy patients developed tremor and parkin-sonism while being treated with cinnarizine (see table).They were not taking other drugs likely to induceparkinsonism, except for three patients, one of whomwas also taking sulpiride, one thiethylperazineand dimenhydrinate, and one thioridazine (he sub-sequently recovered when cinnarizine was withdrawnwithout stopping thioridazine). Eight additionalpatients (two men, six women) presented withparkinsonism and three men presented with tremorwhile being treated with flunarizine (5 mg/day in onepatient and 10 mg/day in 10). Four other patientsdeveloped parkinsonism (two men) or tremor (oneman, one woman) while treated simultaneously withboth drugs.Four patients (two men, two women, aged 24 to 67)presented with depression while taking flunarizine(three patients, one of them also with tremor) orcinnarizine (one patient, who also presented withparkinsonism). The daily dose offlunarizine was 10 mgand of cinnarizine 150 mg. The intervals betweenstarting drug treatment and the appearance of the firstsymptoms ranged from two days (in this patient tremorwas also noted) to 10 months. The four patientsCharacteristics of 70 patients with parkinsonism or tremor inducedby cinnarizine. Unless otherwise stated, results are numbers (andpercentages) ofpatientsParkinsonism TremorNo of patients: 39 31Women* 24 20Men* 13 11Median age (range) (years) 78 (53-90) 68 (38-85)Dose (mg):<150 3 (8) 12 (39)150 28 (72) 14 (45)>150 6 (15) 5 (16)Unknown 2 (5)Induction period:<l month 7(18) 6(19)1-6 months 6(15) 6 (19)6-12 months 6 (15) 10(32)1-3 years 10(26) 5 (16)>3 years 5(13) 0Unknown 5 (13) 4 (13)Recovered after withdrawal of drug:Within 1st 3 months 13 (33) 17 (55)In 3-6 months 9 (23) 0In 6-18 months 2 (5) 1 (3)Unknown 4(10) 5 (16)Not within 1st 3 months 4(10) 6 (19)Not in 3-6 months .> 1 (3) 0Not in 6-12 months 1 (3) 0Not in > I year 1 (3) 0Unknown 4 (10) 2 (7)*The sex of two patients with parkinsonism was unknown.improved when treatment stopped; three of themimproved during the first month, but no exactinformation was available about the fourth. None ofthese patients were taking any other drug which couldhave contributed to their depression.CommentIn Spain cinnarizine is marketed in 10 pharma-ceutical preparations, eight of which are fixed dosecombinations with other drugs. The most commonindications are cerebral and peripheral arterialinsufficiency. The top selling preparations contain75 mg per tablet, and the recommended dose is 75 mgtwice a day. Approved indications for flunarizine arethe same as for cinnarizine. In the United Kingdomcinnarizine is marketed as 15 mg tablets for vestibulardisorders and motion sickness, with a maximumrecommended dose of 30 mg three times a day.4 InSpain 5-7% of the population over the age of 60 may bereceiving long term cinnarizine.5 The consumption offlunarizine is also high: in 1986, 1-2 million units weredispensed. Not surprisingly therefore a large numberof cases of extrapyramidal symptoms and depressionattributed to these drugs have been assembled by ournational scheme.722 BMJ VOLUME 297 17 SEPTEMBER 1988As the table shows, parkinsonism can be inducedeven by daily doses of cinnarizine of less than 150 mg.Patients with tremor tended to be younger (Mann-Whitney U test, p=0O0043), however, and seemed tohave taken lower cumulative doses than those withparkinsonism (Mann-Whitney U test, p=0O0417).Patients with flunarizine induced parkinsonism(median age 63) were younger than those affected bycinnarizine (median age 78) (Mann-Whitney U test,p=00059), and these differences were apparently notrelated to different indications for the use of each drug.Cinnarizine and flunarizine are piperazine deriva-tives structurally related to some phenothiazines, andthis may explain their extrapyramidal effects. Theircalcium channel blocking activity may also contributeto this effect. We have started a case-control study withthe aim of quantifying the risk of extrapyramidaldisorders associated with these drugs.1 Marti Mass6 JF, Carrera N, de la Puente E. Posible parkinsonismo porcinaricina. Med Clin (Barc) 1985;85:614-6.2 Chouza C, Scaramelli A, Caamauio JL, De Medina 0, Alianati R, Romero S.Parkinsonism, tardive dyskinesia, akathisia, and depression induced byflunarizine. Lancet 1986;i: 1303-4.3 Meyboom RHB, Ferrari MD, Dieleman BP. Parkinsonism, tardive dyskinesia,akathisia, and depression induced by flunarizine. Lancet 1986;ii:292.4 Joint Formulary Committee. British national formulary number 14. London:British Medical Association and The Pharmaceutical Society ofGreat Britain,1987:160.S Laporte JR, Capella D. Useless drugs are not placebos: lessons from flunarizineand cinnarizine. Lancet 1986;ii:853-4.(Accepted 9 May 1988)de Bieslandhof Nursing andRehabilitation Centre, 2612VC Delft, The NetherlandsAMM Berkhout, MD,physicianH J M Cools, MD, adjunctdirectorCorrespondence to: DrCools.Dangerous oronasal obstructionin weak senile patientsA M M Berkhout, H J M CoolsDuring routine surveillance in this 320 bed nursingcentre patients are sometimes found in a dangerouscondition of dyspnoea and cyanosis. We describe fivecases in which this condition was caused by oronasalobstruction.Case reportsCase I-An 85 year old woman with severeAlzheimer's disease was emaciated, drank little, andremained bedridden; she was receiving no drugs. Shewas found in a dangerous dyspnoeic and cyanotic state;the nostrils were sucked in during inspiration but acertain degree of inspiration was audible. Attempts toopen the tightly closed mouth met with little successand were repelled by the patient. There was a deviatednasal septum swelling of the mucosa. A disposablecatheter (Charriere 12, 13 cm long) was inserted intothe smaller nostril. Dyspnoea and cyanosis resolvedwithin several minutes, at which time the patientopened her mouth spontaneously. She had neitherteeth nor dentures. The nasal catheter was removedseveral hours later. There was no recurrence.Case 2-A 76 year old woman with severeAlzheimer's disease was dehydrated and wasted; shewas receiving 50 mg pentazocine four times daily as ananalgesic. Years ago she had broken her nose. She wasfound in bed in a highly dyspnoeic and cyanotic state.Her toothless mouth was closed tightly and the nostrilswere sucked in. The nasal mucosa was swollen. A nasalairway was introduced and the symptoms resolvedwithin five minutes.Case 3-An 89 year old woman was transferred tothe nursing centre in a weak condition after havingbeen admitted with gastric haemorrhaging. One even-ing she was found to be feverish and severely dyspnoeicand cyanotic. The nostrils were sucked in duringinspiration and her toothless mouth was closed tightly.Again a disposable catheter alleviated the obstruction.The nasal septum was deviated and the mucosa wasswollen. She suffered three more episodes the samenight. Three days later she died ofbronchopneumonia.Case 4-A 78 year old woman with heart failure,extreme polyarthrosis, and a general loss of strengthwas receiving frusemide, prazosin, haloperidol, andpromethazine (as a hypnotic). She remained bed-ridden, ate poorly, and developed a decubitus ulcer.Several days before her death she became cyanotic withtightly closed toothless mouth and pinched in nostrils.Nasal catarrh and a deviated nasal septum were found.A nasal catheter was introduced but was removed bythe patient. The nose was taped so that the nostrilscould not be pulled inwards by suction; the patient didnot protest.Case 5-An 88 year old woman who had suffered acomplete stroke was receiving digoxine and dytaurese.In the past she had broken her nose. She had neitherteeth nor dentures. One week before her death shedeveloped a respiratory tract infection. She ate anddrank little and became bedridden. The next day shesuffered an episode similar to those experienced by thepatients in case 1-4. There was no recurrence. She diedof aspiration pneumonia.CommentSince 1984 five women in this centre have beenfound suffering from dangerous oronasal obstruction:a tightly closed mouth without teeth and dentures,sucked in nostrils, a deviated nasal septum, andswollen nasal mucosa. They were bedridden, cachec-tic, and dehydrated but not unconscious. They did notraise the alarm. Three of them were in a terminalphase. Though a restrictive medical policy is followedin such cases, the obstruction can easily be eliminatedwith a disposable catheter.Upper airway obstruction may occur when, inaddition to imperfect patency of the nose, inspiratorysuction is greater than the ability of the oropharyngealmuscles to keep the mouth and throat open. In babieswith small upper airways this phenomenon can beobserved during sleep and can lead to their suddendeath2; factors other than suction within the nose,mouth, and throat can also contribute to sudden infantdeath.3 Weak senile patients can suffer this oronasalobstruction even while awake if there is also a catarrhalinflammation of the nose and a pre-existing deviatednasal septum. Though the oral cavity is softer withoutteeth or dentures, it is not clear why patients withnasal obstruction do not breathe through the mouth.The first patient (like the others usually a nasalbreather) did this on another occasion when her nosewas carefully blocked by pinching.1 Klein M, Reynolds LG. Relief of sleep related oropharyngeal airway obstruc-tion by continuous insufflation of the pharynx. Lancet 1986;i:935-9.2 Guilleminault Ch, Heldt G, Powell N, Riley R. Small upper airway in near misssudden infant death syndrome infants and their families. Lancet 1986;i:402-7.3 Milner AD. Recent theories on the cause of cot death. Br Med J 1987;295:1366-8.(Accepted 24 May 1988)BMJ VOLUME 297 17 SEPTEMBER 1988 723

Parkinsonism, tremor, and depression induced by cinnarizine and flunarizine

Parkinsonism, tremor, and depression induced by cinnarizine and flunarizine

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