The rhinological side-effects of systemic drugs

Clin. Otolaryngol. 2003, 28, 381±385 REVIEW The rhinological side-effects of systemic drugs N.D. BATEMAN & T.J. WOOLFORD Department of Otorhinolaryngology, Royal Hallamshire Hospital, Shef®eld, UK Accepted for publication 14 January 2003 BAT E M A N N . D . & W O O L F O R D T . J . (2003) Clin. Otolaryngol. 28, 381±385 The rhinological side-effects of systemic drugs Patients often present to otolaryngologists with nasal symptoms where no cause is apparent. A number of patients seen in outpatient departments are taking medication for other conditions and the adverse affects of these drugs may potentially be the source of these symptoms. In this short review, we present an overview of the more common drugs that may be responsible and outline the possible mechanisms where these are known. Keywords adverse drug reactions nasal obstruction Otolaryngologists frequently see patients who report rhinological symptoms such as nasal obstruction or stuf®ness, rhinorrhoea, smell disturbance, epistaxis, sneezing or itching. In many cases the cause is unclear. A number of these patients take systemic medications for other conditions and the adverse effects of these drugs may be the source of these symptoms. Adverse drug reactions (ADRs) may be classi®ed as predictable pharmacological reactions (type A), which account for the majority1,2 or unpredictable idiosyncratic reactions (type B).3 There are several sources of information for potential adverse drug reactions including the manufacturers' information sheets, the British National Formulary4 and various textbooks and periodic reports (including the Side-effects of Drugs Annual5 and the Monthly Index of Medical Specialities6). Adverse drug reactions may be detected in the pre-marketing evaluation of a drug or during the postmarketing period. In the latter case, the most common source of information is spontaneous adverse reaction reporting. This relies on individual clinicians and prescribers providing information on case(s) of suspected ADRs. These may then be investigated by the relevant regulatory authorities if the number of cases is high, the adverse event suf®ciently serious or uncommon. Correspondence: Neil D. Bateman, FCRS, Department of Otorhinolaryngology, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF, UK (e-mail: [email protected]). # 2003 Blackwell Publishing Ltd rhinitis epitaxis This paper aims to summarize the drugs whose adverse effects may cause rhinological symptoms. The information presented was obtained by searching data sources relating to drug prescribing including the BNF, individual drug data sheets where necessary and the medical literature (via Medline and Embase). We do not, of course, claim to present a comprehensive list of all possible adverse effects but aim to summarize the common drugs that can cause diagnostic confusion. Cardiovascular system The nasal mucosa receives extensive innervation from the autonomic nervous system. Under normal circumstances there is continuous tonic sympathetic discharge to maintain vasoconstrictor tone in the nasal mucosa. Disruption of this process may therefore lead to vasodilatation and a sensation of nasal congestion, and it has been shown that disruption of cervical sympathetic nerves causes ipsilateral nasal congestion.7,8 The following drugs reduce sympathetic output as part of their primary pharmacological action and, as a result of this action, may also affect the nasal mucosa. b e ta b l o c k e r s These bind to beta-adrenoceptors to block the response to stimulation from sympathetic neurones or circulating catecholamines. The beta-blockers Carvedilol, propranolol9 and pindolol10 have been reported to cause nasal congestion as 381 382 N.D. Bateman & T.J. Woolford an adverse effect. This is often reported as being transient and mild. It is likely that the cardioselective (e.g. atenolol, metaprolol) as opposed to the non-selective (e.g. propranolol) beta-blockers have less of a tendency to cause nasal congestion. o t h e r c a r d i o va s c u l a r d ru g s The vasodilator hydralazine, used as an antihypertensive and eprosartan, an angiotensin II receptor antagonist, may cause rhintitis.4 alph a block ers Gastro-intestinal system The pharmacological effect of these drugs is to block alphaadrenoceptors and thereby lessen the effect of sympathetic discharge. Doxazosin, indoramin, prazosin, tamsulosin, terazosin11,12 phenoxybenzamine9 and phentolamine have been reported to cause nasal congestion. Rabeprazole is a proton pump inhibitor indicated for use in peptic ulcer disease and gastro-oesophageal re¯ux. It is reported to cause rhinitis and sinusitis.4 This effect is not listed for any of the other proton pump inhibitors, including omeprazole and lansoprazole. a dr e n e rg ic n e u ron e blo ck e rs Central nervous system The adrenergic neurone blockers guanethidine and debrisoquine adversely affect noradrenaline storage and release from adrenergic neurones and, by this blockade of sympathetic out¯ow, they can both cause nasal congestion.4 a n t i p s yc h o t i c d ru g s c e n t r a l ly ac t i n g a n t i h y p e rt e n s i v e s Methyldopa may cause nasal congestion.4,13±15 This drug is a centrally acting alpha(2)-agonist. Nasal congestion is one of the less serious reported adverse effects of this drug and up to 20% of patients may discontinue its use because of other unwanted adverse effects.15 Its use during pregnancy has been associated with the development of signi®cant neonatal nasal obstruction.16 Reserpine acts by depleting central catecholamine neurotransmitter stores. It may cause nasal congestion.15 Its general side-effect pro®le is such that it is rarely used. Other cardiovascular drugs may cause nasal symptoms. a n g i o t e n s i n c o n v e rt i n g e n z y m e (ac e) inhibitors The potential for ACE inhibitors to cause nasal obstruction is well recognized.4,17 By inhibiting the angiotensin converting enzyme, ACE inhibitors cause a build up of bradykinin which is a potent vasodilator. This physiological effect is most commonly reported in the well-known side-effect of a dry cough. However, this airway in¯ammation is not con®ned to the lower airways and all ACE inhibitors have the capacity to produce rhinitis. The mechanism of action of these medications is predominately the alteration of dopaminergic neurotransmitter systems. Unfortunately, other neurotransmitter systems are affected by these medications and these drugs have a number of recognized side-effects. All have the capacity to cause rhinitis and nasal congestion.4 This may be related to the autonomic effects of the drugs, many of which have alpha- and/or beta-blocking effects. These drugs are not infrequently used in depot form to counter potential problems with patient compliance, and patients may not volunteer this as being part of their `regular medication'. A large range of antipsychotic drugs are used to treat psychiatric disorders including schizophrenia, acute psychoses, affective disorders and delusional disorders. Antipsychotic drugs may be considered as phenothiazine derivatives (e.g. chlorpromazine, levopromazine, promazine, pericyazine, pipotiazine, thioridazine, ¯uphenazine, perphenazine, prochlorperazine, tri¯uoperazine), butyrophenones (benperidol and haloperidol), diphenylbutylpiperides (pimozide), thioxanthenes (¯upentixol and zuclopenthixol), substituted benzamides (sulpiride), oxypertine, loxapide and newer `atypical' antipsychotics including amisulpride, clozapine, olanzapine, quetiapine, risperidone, sertindole and zotepine. h ypnotics Chlomethiazole, a hypnotic, may cause rhinitis as part of a general increase in airway secretions. l i p i d l o w e r i n g d ru g s Niacin is used as a lipid-lowering agent. In its sustained release form it has been shown to produce rhinitis in 30 patients from a trial of 517 (4%).18 This ®nding is in contrast to that of a smaller study of 128 patients where no difference in rhinitis was found between drug and placebo.19 antidepressants Citalopram is a selective serotonin-speci®c re-uptake inhibitor. This drug can cause rhinitis. # 2003 Blackwell Publishing Ltd, Clinical Otolaryngology, 28, 381±385 Rhinological side-effects of drugs 383 o t h e r c n s d ru g s Gabapentin is used as an antiepileptic drug as well as in the management of chronic pain. It has been reported to cause rhinitis. Pergolide is an ergot derivative used in the treatment of Parkinson's disease. It may cause rhinitis and nasal congestion. Endocrine system o r a l c o n t r ac e p t i v e s (o c p) While the BNF and the data sheets for these drugs do not list nasal symptoms among their adverse effects, there are many anecdotal reports suggesting that they are often responsible for nasal congestion. Nasal congestion is often mentioned as a side-effect of oestrogen therapy20 and several authors have noted a number of women with nasal congestion while taking the OCP.21,22 This view would be supported by evidence of changes in olfactometry, nasal peak expiratory ¯ow, rhinometry and mucociliary transport time during the menstrual cycle in women both taking the OCP and during a normal cycle20,23±26 implying a hormonal effect on the nasal mucosa. This would suggest that it is possible for female sex hormones, whether in contraceptives (oral or depot) to cause rhinological symptoms. A well recognized adverse effect of the OCP is exacerbation of migraine. Patients taking the OCP may present to otorhinolaryngology clinics with episodic frontal and/or facial migraine incorrectly diagnosed as sinusitis. Cabergoline and Quinagolide are dopamine receptor stimulants and may cause epistaxis and nasal congestion respectively.4 Immunosuppressants There are reports of Mycophenolate mofetil, an antiproliferative immunosuppressant, causing rhinitis.4 Sirolimus, another immunosuppressant, may cause epistaxis.4 Patients who are taking immunosupressants often present to otorhinolaryngology clinics with rhinosinusitis due to a combination of their underlying condition and medication. Ophthalmic drugs Emedastine, a topical antihistamine has been reported to cause epistaxis.4 Brimonidine tartrate is an alpha 2 stimulant which may cause nasal dryness.4 Brinzolamide is a carbonic anhydrase inhibitor used to treat glaucoma. It may cause rhinitis.4 Dorzolamide is another carbonic anhydrase inhibitor that has been reported to cause epistaxis.4 Dermatology Dryness of the lips is a well established side-effects of retinoids. There are reports of dryness of the nasal mucosa in addition to this28,29 Acitretin is an oral retinoid for the treatment of acne. It is reported to cause rhinitis.4 Isoretinoin is another oral retinoid used for psoriasis and may cause nasal dryness and epistaxis.4 h o r m o n e r e p l ac e m e n t t h e r a p y (h rt) Analgesics There are no reports in the BNF or data sheets of HRT preparations prescribed in the UK. However, many of the principles set out above in relation to oestrogen therapy could apply to these preparations and there are anecdotal reports of rhinological symptoms in women commencing HRT. Sildena®l (Viagra) is used in erectile dysfunction. It acts as a vasodilator by blocking the breakdown of cGMP. This increase in cGMP causes relaxation of smooth muscle. Its vasodilator effects are, however, not con®ned to the corpora cavernosae and it may cause rhinitis and nasal congestion. In addition, Hicklin et al.26,27 report two cases of epistaxis following viagra use and suggest that engorgement of nasal mucosa may contribute to this. Aspirin-sensitive patients may experience rhinitis on taking aspirin or most non-steroidal anti-in¯ammatory drugs (NSAID).30,31 The well-recognized syndrome of asthma, aspirin sensitivity and nasal polyposis is also known as Samter's triad and occurs in 5±10% of asthmatic patients. The pathogenesis of this condition remains unclear. Despite the common description that these patients are `allergic' to aspirin, this not in fact the case as there is little evidence to demonstrate a hypersensitivity reaction in these patients. It may be that the syndrome derives from inhibition of intracellular cyclo-oxygenase enzymes in respiratory cells. Aspirin has a well-recognized antiplatelet action which may increase bleeding tendency and make patients more prone to epistaxis.32 This results from interference with the action of platelets by inhibition of the action of platelet cyclo-oxygenase and hence platelet activation. Inhibition of this enzyme is irreversible and occurs after a single dose of the drug. After a single dose of aspirin, the antiplatelet action continues until new platelets are produced. The half-life of the platelet population is normally 4 days. It may therefore be several o t h e r e n d o c r i n e d ru g s Risedronate sodium, a bisphosphonate, has been reported to cause sinusitis.4 # 2003 Blackwell Publishing Ltd, Clinical Otolaryngology, 28, 381±385 384 N.D. Bateman & T.J. Woolford days before a patient's haemostasis is normal after stopping aspirin. This has implications both in patients admitted with bleeding problems such as epistaxis and in patients advised to stop aspirin preoperatively. source of nasal congestion, this does not feature in the British National Formulary. References Musculoskeletal system Penicillamine is used in the treatment of rheumatic disease. It has been reported to cause severe rhinitis with profuse rhinorrhoea in association with penicillamine-induced pemphigus foliaceus.33 Drugs used in the treatment of infections The quinolones including nalidixic acid, nor¯oxacin, cipro¯oxacin, o¯oxacin and levo¯oxacin. This group of drugs may cause smell disturbance. a n t i v i r a l d ru g s Lamivudine is used in the treatment of Human Immunode®ciency Virus infection. It has been reported to produce `nasal symptoms' as a side-effect. Ribavirin is an antiviral drug for use in in¯uenza. In its oral form it may cause rhinitis.4 Discussion The wide range of medications with rhinological sideeffects con®rms the importance of a full drug history as part of the initial assessment of any patient, particularly when the cause of their rhinological symptoms is unclear. Correlation of onset of symptoms with commencement of drugs will obviously add weight to the possibility of a rhinological side-effect. In certain instances it may be appropriate to stop the offending drug or to change to an alternative with a different side-effect pro®le. In reality this may not be possible, for example with psychotropic drugs. Liaison with the prescribing physician, often the patient's general practitioner, is the best course of action. Many patients are happy to live with their symptoms once given reassurance and an explanation as to their origin and the absence of any serious disease. Although systems are in place to maintain standards of pharmacovigilance many of these rely on spontaneous reporting mechanisms. These may be subject to bias if the symptoms are not identi®ed as an adverse effect or if the symptoms are perceived as trivial by those in a position to make a report. Both of these factors may apply to the rhinological symptoms caused by drugs prescribed by other specialities. It is interesting to note that, while many rhinologists would consider oestrogen treatment as a potential 1 OGILVIE R.I. & RUEDY J. (1967) Adverse drug reactions during hospitalisation. Can. Med. Assoc J. 97, 1450 2 HURWITZ N. & WADE O.L. (1969) Intensive monitoring of adverse reactions to drugs. BMJ 1, 356 3 RAWLINS M.D. & THOMPSON J.W. (1977) Pathogenesis of adverse drug reactions. In Textbook of Adverse Drug Recations DAVIES, D.M. (ed.), p.10. Oxford University Press, Oxford, UK 4 BRITISH NATIONAL FORMULARY 43 (2002). BMA, London 5 ARONSON J.K. 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