Lecture 20 - Eye & Ear Toxicity Flashcards
define ototoxicity
functional impairment and cellular degeneration of the tissues of the inner ear
purpose of cochlear fluids
- conduct sound waves to the hair cells
- provide nutrients and remove waste
- control pressure
- maintain electrochemical gradient
Describe tinnitus
- result of trauma, disease or xenobiotic toxicity
- MOA unknown
- hair cell dysfunction
- streptomycin, neomycin, indomethacin, doxycycline, ethacrynic acid, furosemide, heavy metals and high dose caffeine
What is tinnitus typically caused by?
salicylates and quinine
Describe presbycusis
hearing loss
-common in the elderly (atrophy of the basal end of organ of Corti, loss of hair cells, stiffening of basilar membranes, vascular changes)
Describe symptoms of vestibular dysfunction
- lightheadedness
- headache
- whirling sensation
- patient may display nystagmus, ataxia, unsteady gait and posture
What drugs can cause reversible hearing loss?
Diuretics (acetazolamide, furosemide, bumetanide, ethacrynic acid): physiologic dysfunction, loss of hair cells and edema at the stria vascularis
Inhibition of potassium pump and G protein associated with adenylcyclase - decreased potassium activity in the endolymph and decreased endocochlear potential
-Salicylates, Erythromycin, Quinine, PDE5 inhibitors
Describe the reversible hearing loss caused by salicylates
- generally mild
- MOA unclear - effect on PG synthesis may interfere with the Na+, K+ ATPase pump function at the stria vascularis - decrease cochlear blood flow - reversible decrease in outer hair cell turgor secondary to membrane permeability changes (inhibition of otoacustic emission)
When is it reversible after salicylates
24-72 hours after d/c of the drug
Salicylates - what dose causes ototoxicity
daily doses above 2.7 grams associated with increased ototoxicity
doses above 4g/day produce tinnitus in 50% of patients and hearing loss in 25% of patients
*typically bilateral and symmetrical
Describe reversible hearing loss with Erythromycin
- MOA unclear
- incidence as high as 20-30% of patients
- bilateral impairment of hearing at all frequencies associated with slurred speech, double vision and confusion
What dose of erythromycin causes ototoxicity
PO doses > 4 gram/day (2 gram / day in renal or hepatic failure)
What are risk factors for erythromycin ototoxicity
high doses with renal or hepatic failure, IV administration, age, use with other ototoxic agents, use with inhibitors of erythromycin metabolism
Describe quinines
- PG inhibition
- inhibit phospholipase A2 enzyme (converts phospholipids to arachidonic acid)
- inhibition of calcium channels
- vasoconstriction
- inhibition of potassium channel
PDE5 inhibitors and hearing loss
- sildenafil, vardneafil, tadalfil
- sudden hearing loss (very rare)
- unilateral, first 24 hours
- causality not confirmed
What drugs can cause irreversible hearing loss
aminoglycosides (gentamicin)
cisplatinum
What are some risk factors for irreversible hearing loss with aminoglycosides
- Severity of illness (hydration state, organ failure)
- Pre-existing hearing loss
- Previous exposure to aminoglycosides (it is a lifetime risk yo)
- Duration of therapy
- Peak-valley variation (extended interval dosing)
- other ototoxic drugs (synergistic effects with loop diuretics)
- pre-existing renal failure
- age, noise exposure, previous ear infection
- genetic predisposition (cochlear toxicity)
Describe cisplatinum and irreversible hearing loss
- Clinically apparent hearing loss noted in 30-70% of patients receiving doses of 50-100 mg/m2
- Damage to the outer hair cells and stria vascularis (inhibition of adenyl cyclase in the stria vascularis, inhibition of protein synthesis and formation of free radicals)
- Usually bilaterial
- Cochlear and vestibular symptoms (2-5 days after first or second dose)
What are the 2 separate vascular systems of the eye?
- Uveal blood vessels
- Retinal vessels
Where does amiodarone precipitate in the eye
cornea and lens
_____ is very rich with enzymes (so it is highly susceptible to injury)
retina or cornea
What is the cornea?
- Transparent protective membrane (must remain transparent, allows light rays to reach the retina)
- Avascular (corneal epithelium, stroma, endothelium)
What is the lens?
- Avascular and transparent
- Focus and accomodation
How do phenothiazines affect the eye?
- change in pigmentation from white to yellow to tan (five stages) it begins on the anterior surface of the lens (cornea is involved when lenticular pigmentation reaches grade 3)
- dependent on cumulative dose; unlikely to show if total dose < 500g, 90% of patients with total cumulative dose > 2500g show ocular changes
*need to have eyes checked annually (high dose or long term therapy)
How do corticosteroids affect the eyes
- altered lens epithelium electrolyte balance
- binding to proteins of the lens (corticosteroid-crystallin adducts)
- generally reversible
- unlikely in patients who receive less than 10mg prednisone (or treated for less than a year)
- eyes examined every 6 months (if on long-term therapy)
How does Quetiapine affect the eyes
- quetiapine is structurally related to clozapine
- the manufacturer recommends an eye examination at baseline and every 6 months throughout therapy
- cataract development observed in dog model
- some human patients have developed lens changes but no cataracts
What is normal intraocular pressure
10-20 mmgHg
What pressure will cause ischemic damage of the optic nerve causing glaucoma?
> 28-30 mmHg
What is open-angle glaucoma?
- absence of pain
- slow loss of peripheral visual field
- often unnoticed by the patient
What is closed-angle glaucoma?
- happens to an individual who is genetically susceptible
- narrow anterior chamber angle, caused by anything that dilates the pupil
How can corticosteroids affect IOP
- increased resistance to aqueous humour outflow
- topical ophthalmic agents more likely than oral agents to increase IOP
- prolonged continuous use
What other agents can affect IOP
- phenothiazines
- TCAs
What is the point of tears?
- create a smooth corneal surface
- wet and protect the corneal and conjunctival epithelium
- inhibit growth of microorganisms
- provide nutrition to the cornea
Where are tears secreted from?
the lachrymal gland (stimulated by cholinergic and adrenergic nerves)
What drugs will increase tear production?
- cholinergic drugs (pilocarpine)
- adrenergic agonist (ephedrine)
What drugs can cause orange-coloured tears?
oral erythromycin and rifampin
What is in the Uvea?
iris, ciliary body, choroid
Describe anterior uveitis
eye pain, conjunctival redness, photophobia and blurred vision
pupil is small and respond sluggishly to light
How dos Rifabutin affect eye?
systemic medication more often associated with anterior uveitus
_______ can also affect the uvea
bisphosphonates
What is the retina?
- lines about 2/3 of eye ball
- highly organized structure
- poor repair mechanisms
What does macula do?
central and color vision
What does the remaining retina do?
peripheral and night vision
Describe chloroquine and hydroxychloroquine (and how they affect the retina)
- high affinity for melanin
- accumulation in the choroid, RPE, ciliary body and iris
- will cause irreversible retinopathy
*doses of lower than 400mg/day of hydroxychloroquine appear safe even after prolonged therapy
How do digoxin and digitoxin affect the retina
Visual symptoms: dychromatopsia, flickering or flashes of light, coloured spots surrounded by coronas, snowy vision, hazy or blurred vision and glare sensitivity
Vision disturbances can occur also at therapeutic doses of digoxin
Inhibition of Na+ K+-ATPase (cone receptor function)
Reversible within a few weeks after dose reduction or d/c
Describe indomethacin and retina
chronic admin of 50-200mg/day for 1-2 years can cause blue/yellow vision, alter vision fields, increase threshold for dark adaptation
MOA unknown
color disturbances return to normal after d/c
Describe tamoxifen and retina
- chronic high dose therapy (180-240mg/day) x 3 years: axonal degeneration in the macular and perimacular areas
- permanent decrease in visual acuity and abnormal visual fields
- crystallizes in the retina
Describe retinoids and the retina
- poor night vision
- glare sensitivity
- problems with color detection
- MOA: inhibition of retinol dehydrogenase which leads to reduction in 11-cis-retinal = impairment of rod cell function
Describe how the quinine affects the retina
- neurotoxic injury to the retinal ganglion cells (permanent loss) and optic nerve
- can cause retinal vasoconstriction
- blurred vision, central and peripheral scotomata and complete blindness
- sudden visual loss can occur as late as 14 hours after OD
Describe the optic nerve
- consists primarily of retinal ganglion cell (RGC) axons
- it carries visual information from the retina to several distinct areas of the CNS
- optic neuritis
- optic neuropathy
- ON atrophy
Describe ethambutol and the optic nerve
- decreased contrast sensitivity and color vision
- blue/yellow or green/red vision
- optical neuroapthy
- 10% of patients receiving 25-50mg/kg/day show loss of vision between 1-7 months - reversible upon discontinuation - biweekly high doses eliminate visual toxicity
What is a normal pupil size
3-4 mm (equal to each other in normal light condition)
What causes constriction
cholinergic innervation of the iris sphincter by the cranial nerve 3
What causes dilation
sympathetic innervation of the radial muscle of the iris
What drugs cause miosis (constriction)?
- cholinergic agents
- opiates
- phenothiazines
- sedative hypnotics
What drugs cause mydriasis (dilated)?
- anticholinergics
- antidepressants
- sympathomimetics
____ causes jerk nystagmus
phenytoin
What can cause vertical nystagmus
phencyclidine, ketamine, DM
What is nystagmus and ophthalmoplegia caused by?
thiamine deficiency
