Monitoring of AminoglycosidesA. Chemotherapeutic Agents and OtotoxicityVI. Mechanisms of Ototoxicity
B. Anti-inflammatory Drugs and Ototoxicity
C. Erythromycin Ototoxicity
D.Vancomycin Ototoxicity
E. Loop Diuretic Ototoxicity
F. Topical Agent Ototoxicity
G. Other Ototoxicity
1. To increase familiarity with drugs causing cochlear and vestibular toxicity.
2. To understand the values and pitfalls of aminoglycoside monitoring.
3. To gain familiarity with ototoxicity of topical agents.
4. To understand the therapeutic use of gentamicin in Meniere's disease.
5. To acquire information about the ototoxicity of chemotherapeutic agents.
6. To increase familiarity with mechanisms of drug-induced vestibulocochlear toxicity.
Aminoglycoside antibiotics interact with polyphosphoinositides in the hair cell membranes. The aminoglycosides increase the permeability of the membranes, causing the cells to lose magnesium, which are normally present in high concentration in the mitochondria. It is believed that the loss of magnesium ions blocks enzymatic reactions, especially oxidative phosphorylation, in which magnesium is utilized as a cofactor and leads to cell death. Studies on aminoglycoside toxicity in animals showed that giving a loop diuretic followed by an aminoglycoside does not affect cochlear toxicity any more than any drug singly. However, if the order is reversed with an aminoglycoside antibiotic first and then a loop diuretic, the drugs act synergistically to produce toxicity and the organ of Corti is severely damaged.3
Different definitions of cochlear toxicity have been employed while monitoring a large number of patients. The usual definition is a hearing loss of 10 db bilaterally, or in some patients a 20 db hearing loss. Matz and Lerner4 have shown in a number of studies that the rates of toxicity were similar for gentamicin, tobramycin, and amikacin, with netilmicin resulting in the lower incidence of cochlear toxicity.
Neomycin and kanamycin are exquisitely toxic to the cochlea and, therefore, the parenteral use of such drugs should be limited. On a personal note, my first experience with iatrogeny with aminoglycosides came in a patient who was entirely paralyzed with Guillian Barré syndrome and went on ventilatory support for a year. At that point, the patient was the longest survivor on total ventilatory support. She eventually returned to an ambulatory status, but was totally and bilaterally deaf because of the use of kanamycin to treat a gram-negative infection. Gentamicin effects the vestibular system twice as frequently as the cochlear system. At particular risk are patients with chronic osteomyelitis who are treated with gentamicin because of the long duration of therapy and the high doses required for treatment.5 It should be emphasized that due to the extremely long half-life of gentamicin in the endolymph, vestibulotoxicity is probably equally dependent on dose as well as the length of therapy and can occur even with normal peak and trough levels. There is some evidence that there is an inherited mitochondrial DNA susceptibility for aminoglycoside toxicity. It is believed that the cochlear toxicity of gentamicin may be reversible in about 50% of the patients affected with a recovery time ranging from one week to six months following discontinuation of therapy. As pointed out by Matz6,7 investigators have attempted to determine whether once-daily versus continuous aminoglycoside dosage results in reduced ototoxicity. Some believe that intermittent dosage with an aminogylcoside antibiotic causes infrequent high maximum serum concentrations. This may be less toxic and yet as efficacious as frequent dosage. Kahlmeter and Dahlager7 reviewed reports of aminoglycoside toxicity in more than 10,000 patients focusing particularly on prospective trials. The authors found the incidence of ototoxicity to be 8.6% for gentamicin, 6.1% for tobramycin, 13.9% for amikacin, and 2.4% for netilmicin. Of interest is the fact that cochlear toxicity from aminoglycoside antibiotics is less common in neonates and children.
Monitoring of Aminoglycosides
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Patients treated with aminoglycosides are monitored for two reasons: 1) to insure that levels are adequate for therapy, and 2) to detect elevated levels that may be associated with a greater risk of ototoxicity and nephrotoxicity with the belief that the dose can be altered appropriately. Matz6 states that there are no data showing that occasionally elevated peak and trough levels result in cochlear toxicity. Toxicity can occur even in patients whose serum levels remain within an acceptable range. Table 14-1 gives the suggested dosage of aminoglycosides in adults with normal, as well as, impaired renal function. These peak levels may be modified according to the nature of the infection and the pathogen according to Matz.6
Table 14-1: Dosage Of Aminoglycosides In Adults With Normal And Impaired Renal Function
| DRUG | Desirable Serum Level (üg/ml) | Maintenance Dose*' | |||||
|---|---|---|---|---|---|---|---|
| Aminoglycoside | Peak* | TroughH | Initial Dose*I | Normal Renal Function |
Impaired Renal Function2 |
After Each Hemodialysis | |
| Gentamycin Tobramycin |
|
4-8 |
<2.5 |
2.0-3.0 mg/kg | 1.7-2.0 mg/kg every 8 hr |
0.8-1.0 mg/kg at intervals (hr) approximately 4 X serum creatinine (level mg/100 ml) |
50% of the initial dose |
| Kanamycin Amikacin |
15-30 |
<7.5 |
6.0-9.0 mg/kg |
5.0-6.0 mg/kg every 8 hr; or 7.5 mg/kg every |
2.5-3.0 mg/kg at intervals (hr) approximately 4 X serum creatinine level |
50% of the initial dose |
|
H
Patients with impaired renal function may have higher trough levels.I
An initial loading dose higher than the maintenance dose is given to patients with impaired renal function or for whom rapid onset of maximum therapy is essential (e.g., septic shock). Most patients with normal renal function receive the lower maintenance dose for the initiation of therapy.'
For obese patients, the appropriate dosage may be less than that indicated on a body weight basis.2
For example, if the serum creatinine level is 3.0 mg/100 ml, the maintenance dose would be given every 12 hours. (Table modified with permission.6)1. For patients with normal renal function, the peak level is determined within the first 1 to 2 days of therapy, the trough level within 1 week, and both peak and trough levels approximately weekly thereafter.
2. For patients with impaired but stable renal function, the peak level is determined within the first 1 to 2 days of therapy, the trough level and another peak level within 1 week, and peak and trough levels approximately twice a week from then on.
3. In the case of impaired and unstable renal function, peak and trough levels are determined within the first 1 to 2 days of therapy. Determination of serum levels may have to be made as often as daily thereafter while the renal function remains unstable.
4. After any adjustments of dosage, the peak and trough levels should be determined within 1 to 2 days.
Vestibular ototoxicity is defined as a chemical substance having a destructive or damaging effect on the structure and function of the labyrinthine hair cells and their connections through the eighth nerve to the central nervous system. Vestibular toxicity can vary from minimal damage to complete loss of auditory and vestibular function. Such losses may be temporary or permanent. Vestibular toxicity, in particular, can be devastating.8-10 The historical aspects of ototoxicity are well-reviewed elsewhere.11 With vestibular toxicity, the initial and most extensive hair cell damage occurs in the apex of the cristae and the striolar regions of the maculae. Next there is further hair cell loss extending toward the periphery of the vestibular receptor and additional damage to the otoconial membrane and the otolith structures themselves. As pointed out by Black and Pesznecker,11 we may not understand the true incidence of ototoxicity as the initial ototoxic destruction of hair cells occurs well outside the speech range for the auditory system and outside the normal active and passive head movement frequency range for the vestibular system.12,13 And even though the goal is always to use the most effective drug, depending upon the pathogen, the use of specific antibiotics may, in fact, be mandated by clinical factors beyond the physician's control such as the patterns of bacterial resistance or susceptibility. Costs may also be a factor11 as these authors point out, because gentamicin is very vestibulotoxic but continues to be widely used because it is relatively inexpensive.14
Prospective studies by Black and others13 strongly suggest that vestibular ototoxicity occurs precipitously and without warning. Vestibular toxicity may be associated with and follow signs and symptoms of cochleotoxicity. Tinnitus is often the initial symptomatic manifestation of cochleotoxicity and is usually high-pitched and continuous reflecting the cochlear hair cell damage in the basilar turn. If the tinnitus is subtle and a patient is very ill, the patient may not complain of tinnitus, only becoming aware of it later when they are well.11 A majority of patients who receive potentially ototoxic antibiotics because of life-threatening infection are those patients who spend long periods hospitalized or at bed rest. It is only when the patient becomes well enough to be up and about that vestibular symptoms are first noted. They are often attributed incorrectly to the patient's general debility. Unfortunately, an accurate diagnosis of toxicity may be delayed or even overlooked. If the patient is ambulatory, the disequilibration becomes readily apparent. They may show an ataxic gait, lose their balance when turning quickly, or need to ambulate while holding on to the wall. Patients may complain of transient positional vertigo, but mainly complain of disequilibration. As the vestibular toxicity progresses, they may begin to complain of movement of the external environment or oscillopsia. The patient is no longer able to sense head movements and make compensatory ocular movements within the orbit. The symptom of jiggling or bouncing of the external environment,oscillopsia, is caused by the loss of the vestibulo-ocular reflex. With progressive loss of vestibular function, patients may have to rely entirely upon visual and proprioceptive input to control ambulation and become Avestibular cripples@ being totally unable to ambulate without danger of falling. The patients then need to be confined to wheelchairs.
Congenital ototoxicity can occur when a pregnant woman receives an ototoxic agent. If an ototoxic agent passes through the placenta to the developing embryo or fetus, damage to the auditory or vestibular system may occur, often with catastrophic results. Besides permanent deafness or balance impairment, cleft lip and palate, skeletal malformations, ocular defects, and abnormalities of the cardiovascular, genitourinary, and gastrointestinal systems have been identified. When these conditions are present in an infant, it may be prudent to query thoroughly the mother's medication history during pregnancy and to follow up with the appropriate auditory or vestibular screening tests. The first trimester, especially the 6th to 8th week, appears to be the most vulnerable period. Quinine, salicylates, streptomycin, and dihydorstreptomycin have been among the drugs implicated.
In arriving at the proper diagnosis a careful history is most important. The symptoms may have remained unnoticed when the patient was bed-ridden. For patients who complain of balance problems after hospitalization for a severe illness, it is clear that medical records need to be reviewed carefully with a review of the drugs administered and cumulative doses. A recent prototypic case is presented:
A sixty-eight year old woman was readmitted to the hospital with complaints of dizziness, nausea, and vomiting. Neurology was consulted for the possibility of new brainstem infarction. The patient had recently been discharged from the Urology Service who had treated the patient over four years for multiple urinary tract infections. The most recent admission was for another urethral infection. The initial evaluation included pelvic MRI and ultrasound studies which were negative. The patient was discharged on enteric coated aspirin and seen as an outpatient three weeks later. She then complained bitterly of Ablurry vision.@ Upon further questioning, she reported that things Ajump around@ as she looked at them. Upon examination, the patient had a greatly impaired vestibulo-ocular reflex, being unable to fixate on a target as her head was gently moved from side to side. Review of her recent admission revealed that she had been treated with gentamicin for four days. She was asymptomatic until four days following discharge. A single trough level was 4.2 was noted during her hospitalization. My impression was that the patient, whose renal function was not impaired, had an idiosyncratic sensitivity to gentamicin and a delayed vestibular toxicity. Unfortunately, she was totally unable to ambulate and had a major reduction in vestibular function, demonstrated by no response to caloric testing during standard ENG.
Vestibular testing has been discussed in detail by Black.11 Figure 14-1 shows serial responses for the vestibular ocular reflex at baseline, when the patient was ototoxic, and during recovery.13
Electrocochleography (EcoG) has been shown to demonstrate an immediate reduction in action potential and cochlear microphonic within minutes after an intravenous dose of aminoglycoside.15 Such testing is not routinely done, but may have a role as a screening tool in patients that are particularly susceptible to ototoxic drugs. In general, such drugs should be avoided in patient with risk factors or those predisposed to ototoxicity such as with end-stage renal or hepatic impairment, or a previous history of hearing or balance disorders.
Whether there will be recovery is unknown. If ototoxic damage is in complete, and this may be difficult to tell clinically, the chances of some reversibility has been quoted as 10-15% depending upon the agent involved and the risk factors.11 If damage is severe, it is said that in all likelihood that the damage would be permanent and a subject must be prepared for this eventuality.11,16 In my experience, however, significant recovery can occur in even the most severely vestibulotoxic patients. One patient with impaired renal function received gentamicin because of a shunt infection. She was inadvertently given the full dose rather than the renal dose. Severe oscillopsia and total imbalance persisted for a year, but over the next twenty-four months gradual improvement ensued. She was able to move from a wheelchair, to a walker, to two canes, and eventually to ambulation with the use of a single cane at which time she no longer complaining of oscillopsia. The recovery in this patient was unique in my experience.
Following the induced loss of vestibular function from aminoglycosides the patient becomes Avisually dependent@ relying exclusively on vision and proprioception to compensate for the loss of control.11 Such patients should be advised not to attempt to navigate in situations of reduced illumination and, because they are dependent upon proprioceptive cues, must be extremely careful when upon uneven surfaces. Black and colleagues11 indicate that they have never seen an ototoxic patient completely adapt or compensate. Because of Avisual dependence@ and oscillopsia, ototoxic patients should not climb on chairs or step stools, ladders, roofs, or other high places from which they could fall and be injured. They should also not operate dangerous machinery (e.g., power lawn mowers, construction equipment) and should not drive until balance and coordination has stabilized and until they can pass the driver=s license test. Patients should avoid swimming underwater, as the perceived Aloss of gravity@ induced by the water=s buoyance could cause a loss of orientation, so they are unable to locate the surface; in preparation for this eventuality, patients should be trained to blow out a bubble and follow it upward.@11
It is difficult to monitor for potential vestibular ototoxicity because of the expense and time-consuming nature of vestibular testing. Most patients receiving potentially ototoxic drugs are confined to bed and are unable to cooperate fully and maintain alertness for the testing. If any vestibular toxicity is suspected the decision should be made to discontinue the aminoglycoside drug unless there is no other way to treat the infection. Serum trough levels are not uniformly useful in determining whether there will be vestibular toxicity. According to Black and Pesznecker,11 on the basis of their studies, there was no correlation between serum levels and vestibular ototoxicity (unpublished data). They remarked that Aserum levels can be useful in guiding clinicians to use a systemic dose that achieves a minimum effective blood level while avoiding and reducing additional risk of ototoxicity related to excessive dosage.@
The following high risk groups should be periodically monitored:16 (1) patients with impaired renal function, evident either before or during therapy, (2) patients with elevated peak and trough serum levels, (3) patients with pre-existing sensorineural hearing loss, (4) patients receiving more than one ototoxic drug (particularly an aminoglycoside and a loop diuretic), (5) patients with a history of receiving ototoxic drugs, (6) patients who are expected to receive ototoxic agents for more than 14 days, (7) patients with symptoms of cochlear or vestibular toxicity that become obvious during treatment, and (8) patients over the age of 65. If dose and monitoring guidelines for individual drugs published in the Physician's Desk Reference17 should be followed.
IV. Therapeutic Use of Aminoglycosides in Meniere's DiseaseEven though there has been iatrogenic injury to the peripheral vestibular apparatus due to ototoxicity, this can be put to use in the therapy of Meniere's disease. Meniere's disease, a condition of unknown etiology, has the clinical spectrum of sudden attacks of severe vertigo, progressive hearing loss, roaring in the ears or tinnitus, and a sensation of fullness in the ears. While medical therapy can be beneficial to some people in the form of vestibular suppressant medication and diuretics, eventually 10% or more of persons suffering from Meniere's disease become so disabled that surgery is considered. Destructive procedures such as labyrinthectomy have been proposed for the control of Meniere's disease. However, aminoglycosides may be used to treat Meniere's disease18-21 because of the differential effect on vestibular hair cells as opposed to cochlear hair cells. Therefore, selective end organ lesion may be achieved with a relative preservation of hearing. Initially, intramuscular streptomycin was employed.18,22,23 More recently, aminoglycosides have been applied to the middle ear in unilateral Meniere's disease. Schuknecht24 initially developed a technique to administer streptomycin solution to the middle ear via catheter tubing. More recently, different protocols have been employed with gentamicin to reduce the incidence of hearing loss.25-27 Now a standard technique is to inject gentamicin through the tympanic membrane. In one series of twenty patients, with at least two years follow up, vertigo was controlled in 90%.27 Injections into the lateral semicircular canal have also been employed, however these cause hearing loss in a high proportion of patients.28 It is believed now that intratympanic administration seems to be the most promising for future development and treatment.29,30 The effects can be titrated by giving smaller doses over a period of time which, hopefully, will result in effective therapy for Meniere's disease with preservation of hearing.
V. Other Cochleovestibular Ototoxicity
A. Chemotherapeutic Agents and Ototoxicity
{Back to Outline}The most commonly reported ototoxic chemotherapeutic agents include the following:
I. Platinum compounds
A. Cis-diamminedichloraplatinum II. Permanent dose-related, cumulative cochlear toxicity.
B. Cis-diammine-1,1-cyclobutaine decarboxylate platinum II. Minimal clinical cochlear toxicity.
II. Nitrogen mustard. Cochlear toxicity.
III. 6-Amino nicotinamide (6-AN). Neurotoxic and cochlear toxic (dose-related, cumulative, irreversible sensorineural hearing loss). Not in current clinical use.
IV. Vincristine and vinblastine sulfate. Dose-related peripheral and autonomic neuropathy. Rare reports of cochlear toxicity.
V. Misonidazole. Cochlear toxic, neurotoxic (paresthesias). Not marked in the United States.
VI. %-Diflouromethylornithine (DFMO). Transient or permanent dose-related toxicity.
VII. Dichloromethotrexate (DCM). Permanent cochleovestibular toxicity. Not marketed in the United States.
VIII. Lonidamine. Questionable reversible ototoxicity. Not approved for marketing in the United States or Europe.
The most commonly used chemotherapeutic agent and a major ototoxic agent among these compounds is cisplatin. Figure 14-2 shows a progressive loss of hearing in a patient receiving cisplatin. Cisplatin is a divalent platinum compound which produces a dose-limiting permanent, high-frequency sensorineural hearing loss and peripheral neuropathy as well as a dose-related cumulative renal insufficiency with tubular necrosis and interstitial nephritis. The potential for dose-limiting and permanent cochlear (neuro) toxicity remains despite present methods of hypertonic saline, prehydration, and mannitol diuresis prior to drug administration. As pointed out by Schweitzer31 the biochemistry, pharmacokinetics, biodistribution, and immunologic mechanisms of platinum complexes are still undefined. There is significant variability in presentation and susceptibility to cisplatin-mediated ototoxicity. Ototoxicity resulting from treatment may be subjectively experienced as hearing loss and tinnitus. The tinnitus may be transient or permanent.32 Tinnitus may accompany hearing loss, particularly at high frequencies, or may be present without any sign of hearing impairment. The overall early incidence of tinnitus, where clearly specified in clinical trials, is about 7% (range 2% to 36%). The tinnitus is commonly transient, disappearing a few hours to a weeks after discontinuation of treatment.
Hearing loss due to cisplatin is well documented. The high-frequency hearing loss may cause difficulties in speech discrimination with background noise and may also involve middle-frequency ranges, with inhibition of speech communication even in quiet surroundings.32,33 The hearing loss in most cases is permanent but recovery has been described.33
Although the cochlear toxicity of cisplatin is well documented histologically and functionally there are still a few reports confirming cisplatin-induced vestibular toxicity.34,35
Nitrogen mustard, the first clinically useful chemotherapeutic agent, has limited modern application owing to severe toxicity. The toxicity has been characterized by irreversible sensorineural hearing loss and tinnitus.
Vincristine sulfate induces a dose-related peripheral and autonomic neuropathy and there are few reported case of vincristine-induced ototoxicity.36,37
B. Anti-inflammatory Drugs and Ototoxicity
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Quinine ototoxicity is manifested both by auditory and vestibular dysfunction. Toxicity is called cinconchism and presents as deafness, vertigo, tinnitus, headache, nausea, and visual loss. Transient hearing loss, usually a first side effect, occurs a few hours after initiating high-dose therapy as, for example, in the treatment of malaria. With prolonged treatment for malaria, 20% of patients can be expected to suffer hearing loss.45 The sensorineural hearing loss is usually reversible bilaterally and symmetric, particularly affecting the high-frequencies first. Tinnitus, similar to that, is caused by salicylates. Vestibular effects of quinine are also recognized. Low serum quinine concentrations, which may occur among tonic beverage drinkers, may lead to clinically significant vestibular changes. Blood quinine levels of 0.2 mg/ml found in pilots who died in aviation accidents suggested that quinine toxicity may have played a causative role.46 Prolonged administration of high-dose quinine in many patients led to loss of outer hair cells. There may also be an effect on cochlear blood flow.47
C. Erythromycin OtotoxicityEven though erythromycin was first introduced in 1952, it has been only since the mid-70's that ototoxicity has been recognized as a potential complication.48 An extensive number of case reports of transient and rarely permanent hearing loss, secondary to erythromycin as reported by Brummett.49 There are two new similar antibiotics, clarithromycin and azithromycin which have the potential for ototoxicity.50,51 Brummett suggests that when parenteral forms of these agents become available that ototoxicity may be manifest. The ototoxicity due to erythromycin and its analogues is related to dosage. Of note is the fact that the hearing losses due to erythromycin appear to occur in speech frequencies at the same time the deficit occurs at higher frequencies. For this reason, the patient can easily recognize a change in hearing, a significant difference from the hearing loss resulting from aminoglycoside antibiotics which begin at the very high frequencies and can go unnoticed for some period of time.
D. Vancomycin OtotoxicityVancomycin, originally introduced in the late 1950's and still used for partial resistance to Staphylococcus aureus infection, was initially replaced by methicillin, but reintroduced in the early 80's because of its effect against methicillin-resistance S. aureus infections. Because of its mycin suffix, vancomycin was, and still is, often mistakenly identified as an aminoglycoside antibiotic. The first case of ototoxicity due to vancomycin was reported by Geraci and colleagues.52 Other reports are catalogued by Brummett.49 It is clearly less toxic that an aminoglycoside, so the initial concern may have been because of the incorrect belief that vancomycin was an aminoglycoside. In most cases of reported permanent ototoxicity, the patients were treated before or during vancomycin therapy with erythromycin or an aminoglycoside antibiotic. It may well be that permanent ototoxicity could be the result of a vancomycin-induced augmentation of aminoglycoside ototoxicity.
E. Loop Diuretic OtotoxicityAs reported by Rybak,53 loop diuretics are organic compounds that exert potential saliuretic effects by acting on the epithelial cells in the loop of Henle of the kidney. Unfortunately, many of the loop diuretics are ototoxic, both in clinical reports and experimental studies. Ethacrynic acid, a potent loop diuretic, is recognized as causing acute and sometimes permanent hearing loss.54 One of the most widely used loop diuretics today, furosemide or Lasix, has a significant potential for hearing loss. Heidland and Wigand55 found that infusion of furosemide at a constant rate of 25 mg per minute caused noticeable hearing loss in two thirds of patients. Although most cases of furosemide ototoxicity have been reversible, a number of reports describe patients with permanent deficits.56,57 Other loop diuretics also have potential ototoxicity. One of its most significant problems is the potentiation of aminoglycoside ototoxicity by the concurrent use of loop diuretics as previously noted. As Rybak53 points out, perhaps the kidney and the cochlea have some common receptors for the loop diuretics and it appears that all loop diuretics are ototoxic to some degree.
F. Topical Agent Ototoxicity
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G. Other Ototoxicity
{Back to Outline}In addition to the normal environmental chemicals found in modern society, there exists the possibility that otological surgery can expose the inner ear to ototoxic chemicals. Scrub solutions used to sterilize the external ear may reach the middle ear through tympanic perforations and from there these substances can be absorbed into the inner ear via the round window.64 Providone iodine preparations65,66 and chlorhexidine67,68 have both been proven to be toxic to the cochlea and vestibular sensory neuroepithelium in the inner ear after reaching the middle ear space. Therefore, surgeons should be alerted to this possibility.
VI. Mechanisms of OtotoxicityThe aminoglycoside antibiotics are the first ototoxic agents which highlighted the problem of drug-induced hearing and vestibular loss. They are highly water soluble compounds and their charge prevents entry into cells via diffusion across the plasma membrane. The incidence of clinical and functional hearing loss due to aminoglycosides has been significantly diminished because some of the newer derivatives have lower ototoxic potential and perhaps efficient monitoring of serum levels of drugs have allowed for better dosing schedules. However, the problem is a significant one as they are still widely used in the treatment of serious gram-negative infections as pointed out by Schacht.69 The concentration of aminoglycoside in plasma produced by the initial or loading dose is dependent only on the volume of the distribution of the drug. Since the elimination of aminoglycosides is almost entirely dependent on the kidney, a linear relationship exists between the concentration of creatinine in plasma and the half-life of all aminoglycosides in patients with moderately compromised renal function. In anephric patients, the half-life varies from 20 to 40 times that determined in normal individuals. Because the incidence of nephrotoxicity and ototoxicity is related to the concentration to which an aminoglycoside accumulates, it is critical to reduce the maintenance dosage of these drugs in patients with impaired renal function.2
The mechanism of oto- and vestibular toxicity has been elusive. Mechanisms for acute and chronic toxicity may be different. It appears that there is an antagonistic relationship between aminoglycosides and calcium which can block the acute aminoglycoside-induced depression of microphonic potentials experimentally.70 A number of potential synaptic mechanisms are postulated.69 For example, streptomycin blocks the postsynaptic actions of excitatory amino acids on primary afferents in the vestibular system, blocks the glutamate-gated ionophore at the crayfish neuromuscular junction, and antagonizes quisqualate-induced excitation of cortical neurons. The chronic toxicity of aminoglycosides appears to target exclusively the kidney, cochlea, and the vestibular system. Aminoglycosides have been reported to affect a wide variety of intracellular reactions which are probably responsible for the permanent deficits of chronic toxicity. DNA, RNA, and protein synthesis, energy metabolism and ion transport are affected as well as synthesis or degredation of prostaglandins, gangliosides, mucopolysaccharides, and lipids. An important feature is the delayed onset of auditory and vestibular damage in almost all cases of chronic glycoside toxicity, both in experimental animals and as in patients. Early studies of aminoglycoside pharmacokinetics gave rise to the hypothesis that the toxicity of these drugs was based upon their Aaccumulation@ in inner ear fluids. This early hypothesis has been questioned.69,71 It may well be that a metabolite of the aminoglycoside is involved in the toxic action of such drugs. This hypothesis is reviewed in detail by Schacht.69 Drug metabolism may also explain the selective toxicity toward kidney and the inner ear as well as why some aminoglycosides preferentially damage the cochlea, and others the vestibular system. For example, although the vestibular system may have a preference to metabolize vestibulotoxic drugs, it may conversely have a greater capacity to detoxify those aminoglycosides that spare the vestibular system.
VII. ConclusionFigures:
Figure 14-2: Progressive hearing loss in a patient receiving Cisplatin. A, Baseline. B, one month later. C, one month later. D, one month later. Showing progressive hearing loss at the high frequencies.
Figure 14-3: Audiogram of a patient who suffered the sudden onset of unilateral hearing loss while receiving large dose non-steroidal therapy for tendonitis.
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