Drug–Drug Interactions in Vestibular Diseases, Clinical Problems, and Medico-Legal Implications

Peripheral vestibular disease can be treated with several approaches (e.g., maneuvers, surgery, or medical approach). Comorbidity is common in elderly patients, so polytherapy is used, but it can generate the development of drug–drug interactions (DDIs) that play a role in both adverse drug reactions and reduced adherence. For this reason, they need a complex kind of approach, considering all their individual characteristics. Physicians must be able to prescribe and deprescribe drugs based on a solid knowledge of pharmacokinetics, pharmacodynamics, and clinical indications. Moreover, full information is required to reach a real therapeutic alliance, to improve the safety of care and reduce possible malpractice claims related to drug–drug interactions. In this review, using PubMed, Embase, and Cochrane library, we searched articles published until 30 August 2021, and described both pharmacokinetic and pharmacodynamic DDIs in patients with vestibular disorders, focusing the interest on their clinical implications and on risk management strategies.


Introduction
The function of balance is regulated by the vestibular system. The main subdivision of this system, includes a peripheral portion (the posterior labyrinth, in the inner ear, and The PubMed, Embase and Cochrane library databases were searched for articles published until 30 August 2021 in English language, in agreement with our recent papers [20,21]. Secondary search included articles cited in reference lists identified by the primary search. Records were first screened by title/abstract before full-text articles were retrieved for eligibility evaluation. Remaining articles were then subject to a citation search of all reference lists. Papers were deemed eligible if they included any form of words: "adverse drug reaction", "drug interactions", "polytherapy", "vestibular disease/s", "systemic diseases". All citations were downloaded into Mendeley, and duplicates deleted. GM and PV screened all articles by title/abstract to determine their eligibility and RR reviewed a random sample of 20% to evaluate the reliability of the selection process. To avoid a bias of exclusion, the full text articles were retrieved following first round exclusions and were also subject to two independent eligibility reviews (CP 100%, LM 20%), this time with perfect agreement. The studies evaluated as eligible were enclosed in the present review. We excluded manuscript without full text and without indications of adverse drug reactions. Moreover, we also excluded manuscript not in English language. MR revised the manuscript elucidating the physiological mechanisms.

Betahistine
Betahistine dihydrochloride is an oral drug, a strong antagonist of histamine H3 receptors and a weak agonist of H1 receptors [22]. Betahistine increases vasodilation and restores microcirculation [23] and blood flow, but also facilitates vestibular compensation and inhibits spike generation in lateral and medial vestibular nuclei [24]. Its main clinical indication is represented by MD (Meniere's disease) [22], but it may be also used in BPPV (benign paroxysmal vertigo, in selected patients) [25], vestibular neuritis, and other cases of peripheral vestibular vertigo [24].
A systematic review by Murdin et al. [26] assessed betahistine's efficacy in the treatment of vertigo despite low level of evidence. According to the BEMED trial performed by Adrion et al., low and high dose betahistine seem to be not superior to placebo on reducing the incidence of attacks caused by MD. Both placebo and betahistine lowered attack ratio and this result was probably related to natural history of MD [27]. Another systematic review showed no efficacy of betahistine in MD, sustaining the need of high quality studies [28].

Antihistamines
Betahistine acts as an histamine analogue, with possible interactions with antihistamines as a consequence [23] Risk for reduced efficacy Olanzapine Coadministration with olanzapine showed a reduction of olanzapine binding to D 2 R This may prevent adverse events (weight gain) related to olanzapine, but also "dopaminergic supersensitivity" due to high stimulation on D 2 R. Despite this evidence, betahistine may also affect drugs effect on D 2 R [176]

Class effects NSAIDs
Various mechanisms including NSAID related sodium and water retention, suppression of plasma renin activity, alterations in adrenoceptor sensitivity and impaired synthesis of vasodilator prostaglandins.
Nephrotoxic effect and inhibition of natriuretic response to diuretic should be considered [31,36,40,80,177] Risk for reduced efficacy of diuretics and kidney injury Table 7. Cont.

Drug(s) Involved Mechanism of Interaction Clinical Comment
Other diuretics Diuretic therapy combined with other antihypertensive drugs may lower blood pressure [40,41,178] In case of multidrug therapy in a patient with MD and hypertension, the combination of two or more drugs acting on blood pressure should be evaluated carefully [34,36,150]. Clinicians may evaluate adding or replacing of one or more drugs used for hypertension Drugs prolonging QT, proarrhythmic drugs Hypocalcemia, hypokalemia, and hypomagnesemia may also prolong QT interval [179], so diuretic therapy (associated with electrolytic disturbances) may worsen this side effect [180,181] Caution needed. Switching to a drug which doesn't alter QT, may be a good choice HCT Drugs which lower potassium (e.g., amphotericin B, corticosteroids, diuretics, laxatives, digitalis) and sodium levels (e.g., desmopressin, antidepressants, diuretics, carbamazepine) The thiazide diuretic lowers potassium and sodium concentration [31] Risk of hypokalemia and hyponatremia Antiarrhythmic drugs (e.g., amiodarone), antipsychotics (e.g., chlorpromazine) antimalarial drugs (e.g., chinidine) Hypokalemia may facilitate torsade de points [31] Risk of torsade de points Antidiabetics or drugs raising glucose levels Increase of glucose levels [31,182] Risk of hyperglycemia or hypoglycemia Calcineurin inhibitors, corticosteroids, mycophenolate, azathioprine and (lower risk) mTOR inhibitors Immunosuppression and kidney transplant have a certain association with non-melanoma skin cancer: Thiazides, used in the management of MD, are associated with a certain skin cancer risk [183] mTOR inhibitors (sirolimus and everolimus) have a lower risk, partially reverting oncogenic effects [184]. Avoid the combination is the optimal choice. Sun protection has an important role SPL Drugs generating hyperkaliemia (e.g., trimethoprim, ARB, ACE inhibitors, other potassium sparing diuretics, heparin, NSAIDs, ciclosporin, tacrolimus) Spironolactone may increase potassium levels [33,34] Risk for hyperkaliemia Cholestyramine Cholestyramine increases the urinary excretion of bicarbonate and spironolactone favors acidosis with potassium reabsorption and reduction of urine acidity [185] Risk of hyperkalemic metabolic acidosis Table 7. Cont.

Antipsychotics and metoclopramide
Hyperprolactinemia is a possible side effect of antipsychotics, related to their inhibition on D 2 R. This condition causes several clinical manifestations including menstrual disturbances, sexual dysfunction, galactorrhea, gynecomastia, infertility [186]. Spironolactone may cause gynecomastia or sexual disturbances [34]. Metoclopramide is also associated to hyperprolactinemia and, moreover, to depression [97] Hyperprolactinemia related to antipsychotics seems to be more frequent in females and to be mainly connected with some specific compounds (risperidone, haloperidol, amisulpride) [187]. Spironolactone should be avoided in male patients in treatment with prolactin raising antipsychotics or prolactinoma [188] TRI Skeletal muscle relaxants (non-depolarizing) and preanesthetic/anesthetic agents Antidiabetic drugs, or drugs increasing glucose levels It may also raise blood glucose levels [36, 37,80]. The reason for this mechanism seems to rely in triamterene's inhibition of G-protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5) [189,190] Risk of hyperglycemia or hypoglycemia

Class effects
Xanthines contrast BDZ anxiolytic effect [45] Xanthines may give anxiety [191] Reduced clinical effect CNS depressants (opioids, antipsychotics, antidepressants, hypnotics, antiseizure drugs, anesthetics, antihistamines) When associated with other central nervous system (CNS) depressants BDZ effect may be enhanced [43,45,46,192] Risk benefit-management is needed Aminophylline and theophylline can reverse at least partially the sedation from BDZ This interaction appears to be due to the blockade of adenosine receptors by aminophylline [106] Risk for reduced efficacy DZP Dopamine levels down when administered with L-DOPA [45,193] Benzodiazepines influence dopamine release [194] Difficult management of Parkinson's disease. Coadministration of antipsychotics in this clinical setting may worsen clinical status, increasing extrapyramidal side effects [193] LOR Clozapine: concomitant use of lorazepam may produce marked sedation, excessive salivation, hypotension, ataxia, delirium, and respiratory arrest [84,195] Unknown Evaluate the real necessity of this combination, switching eventually to other compounds Risk of arrythmias, pharmacodynamic antagonism Antihypertensive/hypertensive drugs Anticholinergic drugs may increase (or lower) blood pressure and raise heart rate [54,197] Evaluate the real utility of coadministration and monitor patient PPI Chronic use of PPI may be associated with dementia, and this risk should be added to that generated using [110,198] Avoid chronic treatment with PPI and ACD

Tricyclic antidepressants
These drugs act also on histaminergic and cholinergic receptors with antagonist effect [40,199] and for this reason they may enforce side effects related to antihistamines and anticholinergics Avoid coadministration Antipsychotics Some anticholinergics drugs are used in the treatment of Parkinson's disease, whereas other are associated with parkinsonism. Antipsychotics generate extrapyramidal effects [54,193,200,201] Avoid coadministration

Opioids
Opioids and anticholinergics both lead to constipation [202,203] Avoid coadministration
Sedation is a common adverse event of antihistamines [192] Avoid coadministration

Tricyclic antidepressants
These drugs act also on histaminergic and cholinergic receptors with antagonist effect [40,199] and for this reason they may enforce side effects related to antihistamines and anticholinergics Avoid coadministration DIM Ototoxic drugs When administered with ototoxic drugs, dimenhydrinate may hide ototoxicity [57] Caution needed Table 7. Cont.

Drug(s) Involved Mechanism of Interaction Clinical Comment
Drugs prolonging QT, proarrhythmic drugs Diphenhydramine (and then dimenhydrinate) may also prolong QT, but rarely [204,205] Avoid coadministration DPH Antihypertensive drugs It may cause fatigue, that is a possible adverse event of antihypertensive drugs also [61,206] Prefer a short time of treatment Drugs prolonging QT, proarrhythmic drugs Diphenhydramine (and then dimenhydrinate) may also prolong QT, but rarely [204,205] Avoid coadministration if administered with other drugs prolonging QT. Therefore, they suggest ECG and electrolyte screening only in patients at high risk and receiving ondansetron intravenously [205,207] Tramadol, SSRI, SNRI, serotoninergic drugs Tramadol acts on serotonin reuptake, whereas ondansetron is a 5HT 3 receptor antagonist. Other authors suggest also a pharmacokinetic mechanism: competition at CYP2D6 leading to the reduction of tramadol active metabolite [208] Ondansetron may reduce tramadol's analgesic effect and increase the risk of serotoninergic syndrome [76,208] MCP L-DOPA, dopamine agonists Metoclopramide is an antagonist of dopamine D 2 receptors [40,71,72] Avoid coadministration Alcohol and CNS depressants Increase of sedative action [72,192] Avoid coadministration

Anticholinergics and morphine derivatives
These drugs may antagonize the gastrointestinal effect of metoclopramide (a pro-kinetic drug). They are also related to constipation. However, this last effect is useful to avoid diarrhea from MCP [202,203] Avoid coadministration of anticholinergics and MCP for the best clinical effect. Evaluate risk benefit or the use of another compound if patient consumes opioids for pain management Psychiatric drugs Antipsychotics may increase the risk of extrapyramidal side effects and antidepressants or serotoninergic drugs (e.g., SSRI, SNRI) may increase the risk of serotoninergic syndrome, since metoclopramide acts on dopamine and serotonin receptor [72] Avoid coadministration Table 7. Cont.

Drug(s) Involved Mechanism of Interaction Clinical Comment
Antihypertensive, hypertensive drugs Metoclopramide leads to hypotension [209] Administer carefully. Metoclopramide is administered for a short interval of time (5 days) [72].
Therefore  Table 8. Adverse drug reactions related to the most common drugs used in the management of peripheral vestibular vertigo.

Diuretic Therapy
Diuretic drugs are commonly used for the treatment of hypertension and heart failure. Their action is mainly characterized by fluid excretion [217].
Endolymphatic hydrops plays a key role in the pathogenesis of MD. Therefore, fluids reduction is a rational strategy of treatment. Diuretics showed a certain efficacy in the control of hearing loss and vertigo, especially in patients with non-advanced disease. However, further analysis demonstrated that they didn't prevent a long-term deterioration of hearing [41]. A systematic review by Crowson et al. [218] stated that diuretics are more effective in the prevention of vertigo in patient with MD, with a lower action on hearing outcomes.
Hydrochlorothiazide/triamterene, acetazolamide, spironolactone are the most important diuretics used in MD, whereas loop diuretics may be employed, but need a close monitoring of ADRs [22,41,219].
Hydrochlorothiazide and acetazolamide are carbonic anhydrase inhibitors, whereas triamterene and spironolactone have a potassium sparing mechanism (Table 1).

Acetazolamide
According to magnetic resonance imaging (MRI) study, Sepahdari et al. documented that acetazolamide reduces endolymphatic hydrops in subjects with MD. However, the action of acetazolamide could not be effective on hydrops in all patients and fluid could increase after therapy discontinuation [220].

Hydrochlorothiazide
Hydrochlorothiazide is a thiazide-type diuretic. It exerts its action inhibiting sodium chloride co-transporter in the distal convoluted tubule [31,32]. Its role in MD is well described [219,221], and it can be commonly administered with triamterene [22,41] (Tables 1-4).

Triamterene
Triamterene, a potassium-sparing diuretic, inhibits the epithelium sodium channel (ENaC), avoiding sodium-potassium exchange [35,38]. Triamterene is often administered with hydrochlorothiazide since it enhances the effect of hydrochlorothiazide in lowering blood pressure and prevents hypokalemia. In MD the two drugs are often prescribed in a coformulation [22,35,41] (Tables 1-4).

Spironolactone
Spironolactone is a potassium-sparing diuretic. It is a mineralocorticoid receptor antagonist which blocks the consequential action of aldosterone on ENaC (Epithelium Sodium Channel). Spironolactone determines the excretion of chlorine, sodium and water, whereas potassium is retained [33][34][35], ad is recommended in MD [22,41].
In an experimental study, Degerman et al. showed that spironolactone blocks the phosphodiesterase 4 (PDE4) pathway, involved in the generation of endolymphatic hydrops [222].
Other studies described a positive effect of aldosterone on endolymphatic hydrops that is related to salt-reduced diet (generating an increase of aldosterone levels), that is part of the management of MD [223] (Tables 1-4).

Benzodiazepines
Benzodiazepines (BDZ) are recommended in MD, VN and may be used for particular classes of patients in BPPV [22,25,41,42,56]. BDZ act on GABA A receptor as allosteric modulators, increasing receptor affinity for its substrate, with an increase in GABA inhibitory activity [39,106]. Despite the effectiveness of BDZ being demonstrated [22,[224][225][226][227], it has been suggested that they might impair compensation for vestibular lesions [228]. In fact, GABA B activation seems to be involved in vestibular compensation after damage [229,230]. Diazepam, lorazepam, and clonazepam are more frequently used in the treatment of vestibular peripheral vertigo [22,228], due to short onset of action [41].
BDZ main adverse events are neurologic symptoms (somnolence, motor difficulties, amnesia, difficulty concentrating, headache, vertigo, behavioral changes) and gastrointestinal symptoms. Incontinence, articular pain, hypersensitivity, hepatic damage, and hematologic alterations are rare. Abstinence, abuse, and tolerance are very common after BDZ administration. To avoid this kind of reaction physicians should use a gradual taper to discontinue BDZ, use a lower dosage. High dose and prolonged treatment are more frequently associated to these side effects [40,43,45,46,81,82,84].

Anticholinergics
Anticholinergics are used as vestibular suppressants in MD, BPPV, VN, and BV [22,25,41,42,56]. The most common anticholinergics are scopolamine, atropine and glycopyrrolate [22,41]. These drugs, acting on acetylcholine (ACh), inhibit the ACh muscarinic receptor (mAChR) [22,40]. Clinical trials showed a certain efficacy of scopolamine (transdermal route) [55] and glycopyrrolate (oral route) [50] in the control of vertigo. ACh pathways seem to have a crucial role in the activity of the mammalian vestibular system. In an experimental model, Schneider et al. described that atropine and scopolamine inhibited vestibular spike responses in mice [231]. Other authors sustain that muscarinic and nicotinic receptors are involved in both inhibitory and excitatory responses [232] ( Tables 1-4).
Glycopyrrolate does not pass the blood-brain barrier; therefore, it has less neurologic side effects. It also shows minor ocular and cardiovascular events [40,49].

Antihistamines
Antihistamines are commonly used as vestibular suppressants in the treatment of peripheral vestibular vertigo. Dimenhydrinate, meclizine and diphenhydramine (first-generation antihistamines) are the most common compounds. Diphenhydramine is a dimenhydrinate metabolite [22,25,40,41,56]. They exert their action blocking histamine receptor H 1 [40].Cinnarizine, a calcium channel blocker, may be administered in combination with dimenhydrinate: The combination was more effective than monotherapy [14,233]. Phenothiazines are antipsychotic drugs that also act on histaminergic pathways and may be employed in the treatment of vertigo (e.g., promethazine) [41].An experimental model by Takatani et al. described an inhibitory action of diphenhydramine more selectively in medial vestibular nucleus (MVN) rather than lateral vestibular nucleus (LVN). Evidence about an important role of histaminergic pathways in vestibular system come from experimental models, showing a role of H1, H2, and H3 receptors. Counterintuitively, a high expression of H1 and H2 receptors is associated with a better vestibular compensation [62,234,235]. Not only the activity of histaminergic receptors seems to be effective in improving balance, but they also seem to modulate GABA pathways [234], reducing the concentration of the inhibitory neurotransmitter [235]. However, further studies are needed.
This positive role of histamine receptors seems to assess the need of a histaminergic agonist to treat vertigo, and betahistine (strong H3 antagonist and weak H1 agonist) was the main candidate [234]. However, trials described a superiority of betahistine compared with promethazine [236], but a minor effect than cinnarizine/dimenhydrinate [237]. Furthermore, a systematic review showed that evidence for betahistine in the treatment of peripheral vestibular vertigo has a low level of quality [26].Moreover, the clinical effectiveness of the other H1 antagonists was observed in other clinical trials [22,[238][239][240].
Meclizine is an agonist for murine constitutive androstane receptor (mCAR) and an inverse agonist for human constitutive androstane receptor (hCAR), involved in the regulation of hepatic enzymes [65].

Other Antiemetics
Other drugs may be used for the management of symptoms related to vertigo. Among them, 5HT3 antagonists play an important role. This category includes ondansetron (the most used), granisetron, tropisetron, dolasetron, and palonosetron (second generation antagonist) [40]. In an experimental model by Zhang et al., serotonin had an important role in vestibular compensation: the increase of its levels was documented after semi-circular canal occlusion [241]. Ondansetron showed a better effect in the control of nausea and vomiting, but a minor efficacy in the treatment of peripheral vertigo in comparison with promethazine [238]. Nevertheless, an experimental model by Dyhrfjeld-Johnsen etal. showed a positive post-insult effect of ondansetron in vestibular neuritis [242]. Ondansetron may be also used in the management of MD [41]. It is metabolized by CYP1A2, CYP2D6 and CYP3A4 [40,75,99], and It is also a P glycoprotein (P-gp) substrate [100].
Metoclopramide is a pro-kinetic drug used in the management of nausea and vomiting. It acts on 5HT4 (agonist), 5HT3 (antagonist) and dopamine D 2 (antagonist) receptors [40,71,72]. Dopamine may have an important role in vestibular activity. Jansen et al. showed a reduction of D 2 /D 3 receptor in patients with bilateral vestibular failure. They speculate that this may obstacle vestibular compensation. Dopamine pathways are complex and regulate vestibular activity involving also cortex and basal ganglia [243]. An experimental model by Toro et al. showed a dopamine modulation of sensory hair cells activity acting in a paracrine fashion [244]. Metoclopramide had a similar efficacy to dimenhydrinate in reducing vertigo, nausea and vomiting in an emergency setting [245]. Metoclopramide (non-specific compound) is commonly prescribed in the management of MD, BPPV, VN, and other forms of vertigo [73].Metoclopramide is metabolized to monode-ethyl-metoclopramide at least in part by CYP2D6 isoform, and possibly CYP1A2 and CYP3A [97].

Corticosteroids
Glucocorticoids have anti-inflammatory, anti-pyretic, and anti-allergic activity [133]. They modulate immune response through different mechanisms, for example, encoding pro-inflammatory cytokines IL-4, IL-10, IL-13, and TGFβ or inhibiting activation of nuclear factor (NF)-κB genes [246]. They act on the hypothalamic-pituitary-adrenal (HPA) axis [105,247]. Oral corticosteroids may be used in MD to reduce inflammatory response or to treat exacerbations. Evidence about their application is limited and their usage is based on expert opinion [248]. Even if dexamethasone, methylprednisolone and prednisone are the most common corticosteroids used [41], their role in VN is controversial. In fact, some authors suggest to start the treatment until 72h [56], whereas a systematic review failed to report a strong evidence [249]. Recent works described a role of corticosteroids in accelerating the recovery, without affecting prognosis [250]. Dexamethasone, methylprednisolone, and prednisone are metabolized by CYP3A4 [131][132][133][134]. Dexamethasone induces CYP3A4 and is both a substrate and inducer of P-gp [133,147]

Other Treatment Options
Calcium antagonists other than cinnarizine (flunarizine and verapamil) may be useful in MD, especially in patients with migraine as prophylactic medications [219]. Flunarizine showed good results (clinical improvement) in a small court of 32 patients [251].
However, flunarizine efficacy was inferior to betahistine in MD in clinical trial [252]. A prostaglandin F2α analogue, latanoprost, may have a certain efficacy, since the F2 receptor has been found in inner ear. Intratympanic administration was associated with MD symptoms improvement in a small court, but further studies are needed [219].
Compounds mimicking and inducing glutathione peroxidase may exert anti-oxidant and anti-inflammatory effect in MD. Ebselen is a drug with these characteristics: Its administration in a phase 2 trial led to improvement of hearing and tinnitus in MD [219].
These drugs are not mentioned in MD guidelines [22]. Intratympanic gentamicin and intratympanic corticosteroids are two therapeutic options used in surgical setting [219,253].

Discussion
DDIs are an important concern in clinical practice. Assessing the relevance of DDIs is not easy since this task needs pharmaceutical, chemical, and clinical skills. Risk: benefit ratio should be always considered in the evaluation of DDIs. Minor interactions may be accepted, if necessary, when patients obtain a tangible improvement of their conditions [254]. Scott et al. defined deprescribing as "the systematic process of identifying and discontinuing drugs in instances in which existing or potential harms outweigh existing or potential benefits within the context of an individual patient's care goals, current level of functioning, life expectancy, values, and preferences" [254]. This kind of approach is usually needed with elderly people, since they consume multiple medications, creating space for interactions [255]. Potentially inappropriate medications (PIM) generate an important part of DDIs. Their role is crucial because the reduction of their prescription or discontinuation may consistently reduce DDIs. When evaluating a patient, physician must be aware of all the drugs taken, consider the risk related to a specific drug and, above all, the real presence of a clinical indication. In fact, PIM will not only lead to no benefit, but will probably determine adverse events [254,255]. Therefore, physician should prescribe therapies according to guidelines and specific characteristics of patient.
Ageing is associated with multiple pathophysiological changes. An increase of adipose tissue may be observed in elderly people, especially women: then, the volume of distribution (Vd) of lipophilic drugs may be increased. Conversely, the reduction of body water is associated to a reduction of Vd for hydrophilic drugs. Minor differences in CYP450 metabolism were observed, whereas significant changes may be described in hepatic first pass metabolism (with a possible increase of bioavailability), α1acid glycoprotein (often increased), renal elimination (worsening). More data about transporters activity are needed [5,127]. These factors should be held in account in the management of elderly patients.
Sex differences should be evaluated. Vd is generally higher in men due to their larger body. However, women have a major percentage of fat compared to men, but the difference decreases with older age. This factor may be important in the evaluation of lipophilic drug distribution: For example, diazepam has a larger Vd in women; therefore, it may show an increased duration of its effect. Renal processes are faster in men, whereas CYP450 activity may vary greatly based on the single isoform, or the specific substance metabolized. CYP1A, CYP2D6 metabolism and hepatic conjugation are generally faster in men, whereas CYP3A activity seems to be quicker in women. These observations were often made on young and healthy subjects [256]. Specific and generalizable data about pharmacokinetics sex differences in elderly people are lacking. However, elderly females are predicted to have the lowest elimination rates, since they live longer than men and according to age-related increase of comorbidities, clearance reduction, and decrease of body size [256]. Another important statement is that there are important differences in adaptive homeostasis between males and females. Nevertheless, these sex-related distinctions seem to be lost with age [257]. Furthermore, sex-aging related differences in genomic instability were found, including a major tendency of DNA mutations, telomere attrition and sometimes methylation in men [258]. This assumption may affect gene expression related drug development, one of the present and future direction of pharmaceutic industry [259,260]. In addition, physicians should remember that females live longer than males, but have a higher risk of frailty and morbidity. Despite being less affected by comorbidities, males are characterized by a higher level of physiological dysregulation. Authors called it "malefemale dysregulation frailty paradox" [257,261]. This concept may influence a therapy including multiple drugs.
Interaction in elderly may be various and unpredictable because this category of patients consumes multiple medications.
Drugs with anticholinergic (anticholinergic and antihistamines) effect should be avoided in patients suffering for urinary retention [262]. The concomitant consumption of cholinergic drugs is another contraindication to the use of this kind of therapy [54].In contrast, a difficulty in clinician's decisions can be described in dementia or other neurologic pathologies related to urinary incontinence [263]. In fact, anticholinergic drugs (or compounds with anticholinergic effect) may worsen cognitive impairment. Crossing the blood-brain barrier (BBB) anticholinergics block muscarinic receptors M1 and M4. Furthermore, these drugs may interact with cholinesterase inhibitors, used in Alzheimer's disease [198,263].
Diabetes is a difficult setting. If patients develop peripheral vestibular vertigo, metformin-glipizide and liraglutide are associated with dizziness. Other compounds may create difficulties in balance, affecting vision [264]. Diabetic neuropathy may cause urinary incontinence [265], since using anticholinergics to treat vertigo may be a right choice.
Acarbose is associated with flatulence and diarrhea, some of the most frequent adverse events of metoclopramide and other vestibular suppressants [72,138].
Cardiovascular setting is difficult since several interactions may happen (Tables 5-7). Despite some action of CYP450 enzymes on ACE inhibitors been described [102], they seem not to be part of important interactions, whereas angiotensin receptor blockers (ARB) may be involved in this kind of mechanism [101]. Nevertheless, the role of CYP450 enzymes on ARB metabolism is not always clear [103] and then predicting interaction is difficult.
NSAIDs are also associated with dizziness and then they may obstacle the treatment of vertigo [18].
Obstructive sleep apnea syndrome (OSAS) seems to be related to vertigo and to vestibular system. A reciprocal influence and neuroanatomical route between vestibular nuclei and orexinergic neurons have been reported. Sleep also stimulates neuroplasticity that helps vestibular compensation. Therefore, OSAS and sleep deprivation impair vestibular control, but also vestibular pathologies induce sleep disturbances [266,267]. Vestibular-evoked myogenic potentials may be used to evaluate vestibular lesions at the early stage of OSAS [268]. Furthermore, continuous positive airway pressure therapy in refractory MD patients with concomitant OSAS demonstrated an improvement of dizziness and audiometric testing [269]. According to these observations, the treatment of dizziness may improve OSAS. In this clinical situation, it is important to avoid drugs inhibiting respiratory system (e.g., opioids, barbiturates) [270]. Although characterized by a lower potential of respiratory depression, benzodiazepines may be associated with acute respiratory failure in patients with sleep apnea [40,271]. Physicians must remember it in the management of peripheral vestibular vertigo with concomitant pneumological pathologies. Furthermore, anticholinergics and antihistamines seem to reduce respiratory secretions generating rare and mild respiratory symptoms [40,49,53,54,61,214]. Atropine may generate respiratory depression [47].
Gastrointestinal symptoms or illness should be evaluated carefully. The induction of diarrhea by metoclopramide [74] may be troublesome in the management of electrolytic disturbances, gastrointestinal infections, colon cancer, and diverticulosis.
Oncologic patients may experience ototoxicity when treated with platinum compounds, surgery, or radiotherapy. This may also worsen or ingenerate vertigo [272]. Physician must pay attention to vertigo in oncologic patients since it may be the sign of brain metastasis. A series of red flags may add value to the clinical hypothesis: altered mental status, ataxia, headache, visual symptoms, seizure, and focal signs and symptoms [273]. Some of the drugs used for the management of peripheral vestibular vertigo may generate headache (e.g., ondansetron, triamterene, benzodiazepines, betahistine) [23,36,45,75,76,80,82] and blurred vision (e.g., antihistamines, anticholinergics) [274], therefore clinician must distinguish these side effects from cancer spread.
The susceptibility to infection in the elderly is increased by immune senescence as well as altered skin and mucosal barrier function [275].Among antibiotics, macrolides, aminoglycosides, and glycopeptides may generate ototoxicity, worsening clinical status of patients with peripheral vestibular vertigo [276].
An association between osteoporosis and BPPV has been reported, mainly in women [277]. Use of corticosteroids in this clinical setting may increase the risk of bone fracture [278]. Bisphosphonates undergo negligible liver metabolism [40], so no important interactions are expected. In the past, episodic vertigo after bisphosphonates intravenous administration was described [279]. On the other side, vertigo may increase the risk of falls in elderly people with osteoporosis, raising the possibility of fracture [280].
Rheumatology may be another field of interactions. For example, triamterene, anticholinergics, and antihistamines are associated with dry mouth [36,40,53,57,61], that could be an important issue in patients with Sjogren's syndrome (SS) [281]. Hydrochlorothiazide may cause skin manifestation (common in rheumatologic pathologies) and SLE exacerbations [31,282,283]. Hydrochlorothiazide and triamterene may generate hyperuricemia, that would be a trouble in the management of gout [36, 80,284].
Liver and kidney function is often altered in elderly people. CYP450 function is reduced in elderly, liver volume and blood flow decrease with age, similarly to immune response. An increased susceptibly to autoimmunity and hepatic infections is another major concern. All these factors may reduce tolerance to treatment [285]. A declination of glomerular filtration rate and a decreased number of functional glomeruli (alongside other anatomical alterations) are typical of aging and senescence [286]. Therefore, physicians must pay attention to vertigo treatment effect on liver and kidney status (Tables 2-4), especially if administered with other nephrotoxic or hepatotoxic medications [276,287].
Furthermore, hepatic cirrhosis may degenerate in hepatic encephalopathy [288] and then the use of CNS depressants drugs (see the sections before) should be avoided.
Pharmacogenomics could be used to evaluate the individual response for each treatment. Therefore, clinicians should be aware of this kind of genetic variability to perform specific analysis (genotype) and adequate dosage to the result. However, non-genetic factors may generate a phenomenon called phenoconversion [297], creating a mismatch between genetic polymorphisms and the real capacity to metabolize drugs (Table 9). However, the evaluation of low and normal expressers may be useful to dispose dose reduction (half-dose in low expressers) [299] CYP3A4*22 resulted in decreased activity [299] See the section above. See DZP section for other possible polymorphisms of CYP3A4 NAT2 NAT2*4 is associated with rapid acetylation of 7-amino-clonazepam (main metabolite), whereas NAT2*5, *6 and *7 are related to slow acetylation [299] Slow acetylation pathway, associated with high CYP3A4-induced metabolism, may lead to the accumulation of 7-amino-clonazepam. This metabolite has a partial agonist effect on GABA A receptor and may modify clonazepam effects. Furthermore, it is associated to withdrawal symptoms. In patients with high CYP3A4 activity and low NAT2 acetylation a longer dose reduction period may be needed [299,300] DZP CYP2C19 CYP2C19*1 allele is wild type (normal activity) [301] Not required Several polymorphisms have been identified (e.g., CYP3A4 1*B), but their frequency or their effect on benzodiazepines is not clear. In general isoform activity seem to be preserved [302,303]. Punctiform mutations may also affect CYP3A4 function and ethnicity is another important factor [304]. More than 856 CYP3A4 variants are documented [304] CYP3A4*1 is related to normal function [305] -CYP3A4*20 is related to loss of function. CYP3A4*22 is associated with reduced activity [305] Unknown impact on benzodiazepines, but possible dose reduction CYP3A4 1*B has an uncertain effect on enzyme's activity. Some studies described a decreased action, other an increased action (tacrolimus, ciclosporin, simvastatin) [305] Unknown impact of benzodiazepines CYP3A4 1*G seem to be associated with higher substrate clearance, but further studies are needed and some controversial results are described [305] Unknown impact of benzodiazepines, but possible dose increase

Antihistamines
Class related Elements H1 receptor Polymorphisms in this gene (rs901865 allele) were associated to increased side effects for desloratadine, and may have similar effects on other antihistamines [306] The experience of Chu showed that H1 polymorphisms (CC genotype) were associated to a better clinical response in allergic rhinitis, whereas other polymorphisms (CT + TT) generated a worse effect [307] Further studies needed in vestibular diseases

H4 receptor
The rs77041280 mutant genotype (TA + TT) and the rs77485247 mutant genotype (TA + AA) may lower drug effects and enhance adverse events after using antihistamines for allergic rhinitis [308] Further studies needed in vestibular diseases are examples of nonfunctional alleles [310].

Muscarinic receptors
There are documented polymorphisms of M 1 and M 2 in literature, whereas M 3 variants are less known. No clear link between phenotype and genotype has been described. Implications on drug responsiveness is not available [313] Further studies needed

KCNH2
This gene determines the production of a subunit of a potassium channel, whom mechanism is voltage dependent. KCNH2 seems to be a predictive factor for MCP response or side effects development. The drug may exert its action on potassium channels [315] Adequate dosage on the basis of different polymorphisms. Further studies needed ADRAID ADRAID codifies α1 D adrenergic receptor, that may be a target of MCP or matter of interaction with dopaminergic system. It seems to be related to MCP clinical efficacy [315].

Medico Legal Aspects: A Multidisciplinary Approach
DDI is a rising phenomenon due to the ageing of the population and the consequent increasing number of patients with comorbidities requiring multiple drug use [323]. For example, multiple drug use (polypharmacy) is common in diabetes mellitus (DM) patients [324]. DDIs are potentially harmful to patients, so full information is required also to improve the safety of care and to avoid malpractice claims. An essential requirement before administering or prescribing any substance is to adequately inform the patient of the expected benefits and any risks of the proposed activity. The Italian Law No. 219-"Provisions for informed consent and advance treatment directives"-specifically defines the issue of information and consent. In observance of the principles referred to in Articles 2, 12, and 32 of the Constitution and Articles 1, 2, and 3 of the Charter of Fundamental Rights of the European Union, the Law No. 2019 of 22 December 2017 not only stipulates that "no medical treatment shall be initiated or continued unless the person concerned has given free and informed consent, except in cases expressly provided for by law", but also states that "The communication time between the doctor and patient constitutes care time". Although legislation differs between countries, the promotion of a close care relationship based on informed consent should be widely considered as a goal of treatment, which requires a communicative method appropriate to the patient's condition and abilities, which can be critical in the elderly population [325]. Informed consent to pharmacological treatment should not be limited to provide a correct information about the risk:benefit ratio of the drug but should be extended on the side effects and their frequency. Clinicians should sensitize patients to alert them if any abnormal symptom appears, in order to modify current polytherapy cares. Extended knowledge of possible adverse drug reactions may improve patient adherence to therapeutic regimen even in case of interactions that may be accepted, if not unknown. By strengthening the relationship between doctor and patient, reaching a real therapeutic alliance, clinicians could guarantee the safety of treatments and reduce possible malpractice claims related to drug-drug interactions. It is necessary, then, to facilitate and promote a constant conversation with the patient [326], as well as careful clinical and laboratory monitoring in order to quickly discover any adverse event. DDIs, as previously discussed, can also determine liver or kidney overload and, therefore, require careful monitoring to quickly detect any drug interaction. The timely identification of pathological effects of drug interactions allows the right therapeutic changes, thus avoiding potential organ damage and subsequent harm to the patient. The benefits of this strategy will not only be economic, allowing to reduce the costs of compensation and civil disputes, but will strengthen the patient's trust in the doctor, thus enhancing his diagnostic and therapeutic role and making the therapeutic alliance more effective.

Conclusions
The management of peripheral vestibular vertigo in elderly requires a deep knowledge of clinical pharmacology and of multidisciplinary issues in the treatment of these patients. Pharmacogenomics are a key point of the therapeutic algorithm. Individual differences in ageing seem to be strictly related to genotype. The evaluation of the different alleles linked to CYP450 isoforms and transporters may be useful to choose the best therapeutic option [102,115,125,159,327]. Clinicians must always remember the important changes related to ageing, involving Vd, renal clearance, hepatic function, and multiple organ impairment. However, individual differences in concomitant treatment, sex, comorbidities, physician decisions, and lifestyle may add great variability to this process [5,254,256]. A good number of therapeutic options is available for peripheral vestibular vertigo. None of the mentioned drugs has shown a superiority in clinical trials; therefore, physician's challenge consists in the choice of the proper compound [14,22,25,41,[236][237][238]245]. The knowledge of DDIs can be used to select treatments for patients, thus optimizing clinical response, minimizing toxicity, and improving the safety of care. DDIs are potentially harmful to patients, so full information is an essential requirement also to enhance a therapeutic alliance and to avoid malpractice claims.
However, we need to underline that most of DDIs described do not show a clinically significant effect because in clinical practice other variables play a role (e.g., inter-individual differences, enzyme availability, concentration of drug into the site of metabolism, affinity of drugs for the enzyme [19,[328][329][330][331][332], and activity of genetic and epigenetic factors [333,334]).