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Pharmacology of Otologic Drugs
Leonard P. Rybak
There has been a proliferation of publications dealing with the use of new and established drugs for the therapy of inner ear diseases. Novel ways of delivery of drugs to the inner ear have been tested in the last decade. This chapter discusses the pharmacology of several agents used to treat sensorineural hearing loss and vertigo and offers perspectives for the future for drug delivery to the inner ear.
Corticosteroids
Indications
Naturally occurring corticosteroids are used to replace deficient hormone levels in patients with adrenocortical insufficiency. Various synthetic corticosteroids are used for pharmacologic effects because of their greater potency, longer duration of action, and superior efficacy in the treatment of disease states. Corticosteroids are used to treat a variety of nonotologic diseases, including disorders of the upper and lower respiratory tract, endocrine diseases, collagen diseases, skin disorders, neoplasms, allergic problems, and diseases of the eye and blood-forming organs.1
Corticosteroids are employed to treat a variety of otologic diseases, ranging from illnesses affecting the pinna and external auditory canal, such as contact dermatitis and eczema, and as an adjunct in combination with topical antibiotic solutions or powders to treat external otitis. These drugs may also be used in combination with antibiotics topically to treat otitis media in patients with an opening into the middle ear, whether it is a ventilation tube or a spontaneous perforation of the tympanic membrane. They are also frequently used to treat several inner ear disorders, including sudden sensorineural hearing loss, whether idiopathic or of suspected vascular, traumatic, or viral etiology; Meniere’s disease; autoimmune inner ear disease; and certain vestibular disorders.
Mechanisms of Action
The glucocorticoids are the corticosteroids that are most commonly utilized to treat ear disease. These drugs are derivatives of the naturally occurring hormones in the adrenal cortex. These compounds affect carbohydrate, lipid, and protein metabolism by combining with their receptors in the tissues affected. Interaction with the receptors causes a change in gene expression within the cells. The resulting effects include immune suppression, membrane stabilization, antiinflammatory effects with a reduction in tissue edema, sodium transport regulation, and increased perfusion of target tissues.2 Steroids have been shown to prevent hearing loss in patients with bacterial meningitis by inhibiting the actions of cell adhesion molecules, thereby reducing the inflammatory response to molecules released in response to the bacterial injury, such as the arachidonic acid metabolites.3,4 Nevertheless, the exact molecular mechanisms by which steroids reverse or prevent hearing loss are not yet known.2
New mechanisms for the actions of glucocorticoids have been elucidated recently. These drugs clearly act on diverse targets through multiple mechanisms to control inflammation. The glucocorticoid receptor in humans is located on chromosome 5q31–32. The details of its regulation are detailed in a recent review article.1 Glucocorticoids interacting with their receptor initiate a complex regulatory network that blocks several inflammatory pathways. The glucocorticoids can block the production of prostaglandins through three independent mechanisms: the induction and activation of annexin I, the induction of mitogen-activated protein kinase (MAPK) phosphatase 1, and the repression of transcription of cyclooxygenase 2. The latter step is accomplished by blocking the transcriptional activity of nuclear factor (NF)-кB. Glucocorticoids and their receptor also modulate the activity of other transcription factors.
By a nongenomic mechanism, glucocorticoids activate endothelial nitric oxide synthase, thus protecting against ischemia-reperfusion injury. Glucocorticoids can also decrease inflammation by decreasing the stability of messenger RNA (mRNA) for inflammatory proteins, such as vascular endothelial growth factor and cyclooxygenase 2.1
Pharmacokinetics
Corticosteroids, such as dexamethasone, are primarily metabolized in the liver and excreted by the kidneys. The most commonly used systemic glucocorticoids are hydrocortisone, prednisolone, methylprednisolone, prednisone, and dexamethasone. These drugs have good oral bioavailability. Plasma concentrations follow a biexponential pattern. Twocompartment models are used after intravenous administration, but one-compartment models are sufficient to describe pharmacokinetics after oral administration. Pharmacokinetic parameters such as the elimination half-life, and pharmacodynamic parameters such as the concentration producing the half-maximal effect, determine the duration and intensity of the effects of the glucocorticoids.5 Measurable concentrations of steroids are reached in inner ear fluids, but the concentrations are much lower than those achieved following intratympanic administration (see below).
Adverse Reactions
A host of adverse reactions has been reported following systemic administration of corticosteroids. These tend to be more frequent and more severe following chronic administration. Adverse events include increased susceptibility to infection; disturbances in fluid and electrolyte balance (hypokalemia, retention of sodium and water); congestive heart failure and myocardial rupture after recent acute myocardial infarction; muscle weakness and wasting; disturbances in bone metabolism (osteoporosis, aseptic necrosis of the heads of the femur or humerus, compression fractures of the vertebrae); and tendon ruptures.
Endocrine problems found with corticosteroid therapy include suppression of growth in children; secondary lack of responsiveness to stress, such as trauma, illnesses, or surgery by the adrenal cortex and pituitary gland; carbohydrate intolerance especially in latent or insulin-dependent diabetics, making them relatively resistant to insulin; hirsutism; cushingoid changes in body habitus, including “buffalo hump” and cushingoid facies; as well as hypertension.
Gastrointestinal complications may include nausea, perforation of the bowel, peptic ulcers (especially when combined with oral non-steroidal anti-inflammatory drugs) with hemorrhage and possible perforation, pancreatitis, and ulcers of the esophagus.
Ophthalmologic complications include posterior subcapsular cataracts, increased intraocular pressure or glaucoma, and exophthalmos.
Neurologic side effects include seizures, increased intracranial pressure, headache, and psychological changes, including severe depression.
Skin changes include petechiae, increased fragility of the skin and capillaries with petechiae and ecchymosis, impairment of wound healing, diaphoresis, and acne.
Additional side effects such as thromboembolism, weight gain, increased appetite, and malaise may occur.1,6 Dormant tuberculosis can become active.
Drug Interactions
Corticosteroids have a hyperglycemic effect and may increase the requirement for insulin or oral hypoglycemic drugs. A patient who requires insulin while taking corticosteroids may not be able to resume oral hypoglycemic drugs when steroids are stopped. The potassium balance needs to be monitored in patients receiving corticosteroids, especially when these patients are receiving concomitant diuretics, such as thiazides or loop diuretics, or when they are being treated concurrently with amphotericin B. Such combinations can cause potassium depletion.1 The hypokalemia induced by glucocorticoids may enhance the blockade of nondepolarizing neuromuscular blocking agents, which may lead to increased or prolonged respiratory depression or paralysis, resulting in apnea. Prolonged paralysis with cisatracurium for mechanical ventilation in combination with methylprednisolone resulted in acute motor axonal polyneuropathy manifested as flaccid quadriplegia with absent deep tendon reflexes.7 Patients receiving digitalis glycosides may be more likely to experience arrhythmias or digitalis toxicity associated with hypokalemia.8 The natriuretic and diuretic effects of diuretics may be decreased by the sodium- and fluidretaining effects of corticosteroids.8
Corticosteroids given in combination with salicylates can result in increased clearance of salicylates. The efficacy of anticoagulants can be diminished by steroid therapy, and the dosage of the former may need to be adjusted when steroid therapy is initiated or discontinued. The risk of gastrointestinal ulceration or hemorrhage may be increased during concurrent use. The induction of hepatic enzymes by corticosteroids may increase the formation of a hepatotoxic acetaminophen metabolite, thereby increasing the risk of hepatotoxicity when they are used concurrently with highdose or chronic acetaminophen therapy.8
The metabolism of corticosteroids is increased by drugs that induce drug metabolizing enzymes in the liver. Such drugs include phenobarbital, phenytoin, and rifampin. If one or more of these drugs is administered concurrently with corticosteroids, the maintenance dose of the latter may need to be increased to maintain the desired effect.
The simultaneous use of certain antibiotics, such as troleandomycin or erythromycin may reduce the clearance of corticosteroids, resulting in an exaggerated steroid activity or cushingoid side effects, and the dose of steroid may need to be reduced.9
Large doses of intravenous methylprednisolone can increase the plasma concentrations of cyclosporine in renal transplant patients. This may require that the physician reduce the dose of cyclosporine in the face of glucocorticoid therapy.10
Estrogens have a dual effect on the pharmacokinetics of corticosteroids. The former hormones increase the levels of corticosteroid-binding globulin, thus increasing the fraction of bound steroid and rendering it less active. On the other hand, the metabolism of corticosteroids is decreased, thus prolonging their half-life. Therefore, when estrogen therapy is begun, a reduction in the dose of glucocorticoids may be in order, and when estrogen therapy is discontinued in patients on concomitant corticosteroid therapy, the dose of the latter may need to be increased.8
Tricyclic antidepressants do not relieve, but rather may exacerbate, corticosteroid-induced mental disturbances, and they should not be used to treat these adverse effects (United States Pharmacopeia, 1999).
Aminoglycoside Antibiotics
Indications
Aminoglycosides are polyanionic amino sugars that have been derived from soil bacteria. They were first developed in 1944 to treat gram-negative bacterial infections, such as those occurring in necrotizing otitis externa and chronic otitis media. The members of this family of drugs are streptomycin, kanamycin, neomycin, gentamicin, amikacin, tobramycin, and netilmicin. Intramuscular streptomycin has been used for vestibular ablation in patients with bilateral Meniere’s disease, Meniere’s disease in an only hearing ear, or in the second ear that is symptomatic after contralateral ablation.11 Intratympanic gentamicin (see below) now has replaced intramuscular streptomycin.
Mechanisms of Action
The aminoglycosides are bactericidal. They are actively transported across the bacterial cell membrane, irreversibly bind to one or more specific receptor proteins on the 30S subunit of bacterial ribosomes, and interfere with an initiation complex between mRNA and the 30S subunit. DNA may be incorrectly read, and this can lead to the formation of non-functional proteins. Polyribosomes are split apart, resulting in inability to synthesize new proteins. This then accelerates uptake of the antibiotic molecules, disrupting the cytoplasmic membrane of the bacteria, leading to leakage of ions and other substances out of the bacterial cell, and then to cell death.12
The mechanisms of action of aminoglycosides in the treatment of Meniere’s disease are not entirely clear. These are thought to include ablation of type I hair cells of the crista ampullaris of the semicircular canals and damage to the dark cells of the ampulla.13
Pharmacokinetics
Aminoglycosides are poorly absorbed after oral administration. They are well absorbed from intramuscular injection sites. These drugs may be absorbed in significant amounts from certain body surfaces, such as from the peritoneal or pleural cavity, following local irrigation of these body cavities.12 They are absorbed through the round window membrane to a significant degree (see below).
Aminoglycosides are not significantly metabolized following systemic administration. They are not bound to serum proteins to any great extent (usually less than 10%). They are distributed to all body tissues and accumulate within cells. These drugs achieve high concentrations in highly perfused organs, like liver, lungs, and kidneys. Lower concentrations are found in muscle, fat, and bone. They are excreted by the kidney and a high concentration is found in the urine. Distribution half-life after systemic administration is quite short, 5 to 15 minutes. Elimination half-life is 2 to 4 hours in adults with normal renal function, but is significantly longer in neonates and in patients with renal insufficiency. The terminal half-life is greater than 100 hours and this is because of slow release from binding to intracellular sites.12 Animal studies have shown that aminoglycosides may be detected in inner ear tissues up to a year after systemic administration.14 To avoid systemic toxicity and to achieve selective vestibular ablation, especially in one ear only, aminoglycosides have been applied intratympanically for Meniere’s disease (see below).
Adverse Reactions
Hypersensitivity reactions to aminoglycosides occasionally occur, and, when they are documented, cross-sensitivity to other members of this class of drugs must be considered. Hearing loss and nephrotoxicity are risks with any of the aminoglycosides. All aminoglycosides cross the placenta and cause nephrotoxicity or total, irreversible congenital deafness in children born to mothers treated with these drugs during pregnancy. All aminoglycosides have the potential to cause neuromuscular blockade. Very young infants have been reported to experience central nervous system depression, with stupor, flaccidity, coma, or deep respiratory depression. Caution needs to be exercised in the treatment of elderly patients because of age-related decrease in renal function and perhaps increased susceptibility to toxicity.12
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