Final Exam Flashcards
Describe how drugs interact with receptors
Drug reactions can occur if drug molecule fits into the target cell receptor
When ligand binds to a specific receptor it causes a conformational change in the cell triggering its responses
Lock and key, only a specific substrate can fit into the active site of a receptor
most abundant class of cell receptors and are involved in cell signaling
g proteins
what do g proteins do
activates production of second messengers (signaling molecules) that convey input provided by the first messenger to cytoplasmic effectors
When a first messenger (like a hormone or neurotransmitter) binds to a receptor, it triggers the production of second messengers inside the cell. These second messengers then carry the signal from the first messenger to other parts of the cell (cytoplasmic effectors) to create the desired response.
activity is regulated by factors that control their ability to bind and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP)
lock and key
only the correct drug can fit into the active site of the receptor
induced fit model
receptor is partially flexible and the drug plays a role in determing the final shape of the receptor
The same action as a natural ligand on cell receptors
agonists
Stop the effect of a natural ligand on cell receptors
antagonists
what is an agonist
ligands that activate receptors
ex of agonists
all NT that are at their respective sites - acetylcholine (ACh - excitatory)), Gamma-amino butryic acid (GABA - inhibitory), glutamate (excitatory), histamine, norepinephrine (NE), Seratonin 5 hydroxytryptamine (5-HT)
what is an antagoist
inhibit action of natural agonists at receptor sites
without an agonists there is no effect of an antagonist
can you have an antagonist without an agonist
no
Differentiate between competitive versus non-competitive antagonists receptors
Competitive antagonist - reversible binding (agonist can displace antagonist) to the same active site on the receptor as an agonist; when an antagonist competes with the ligand for agonist site binding
Noncompetitive antagonist - irreversible (cannot be displaced even with high concentrations of agonists), poisonous, bond covalently; when an antagonist binds to a receptor at a site other than the agonist site & doesn’t compete directly with an agonist for receptor binding but instead alter or inhibit receptor from responding to an agonist binding
ligand/enzyme
molecule that binds to a specific site on a target molecule
drug potency
affinity of a drug to its receptor
EC50
Higher the potency, less amounts of the drug needed to cause action
drug efficacy
drug efficacyMaximal drug receptor occupancy by drug molecules
ECmax
pharmacodynamics
what the drug does to the body
pharmacokinetics
what the body does to the drug after administration
membrane barriers that can affect drug absorption
cell
BPB
BBB
BLB
what drugs can pass the cell membrane
Nonpolar (steroids) pass easily
Smaller molecules pass easily
more lipid soluble drug = easier crossing because they are water hating
charged molecules cannot cross (mus use pores/channels), Hydrophobic drug molecules can generally pass through easily
molecular size - smaller = easier & larger = harder
drug shape - shape shifters can go through easier (induced-fit model)
what is the BLB
maintains balance of the inner ear fluids, several ototoxic drugs and bacteria can cross and enter the perilymph resulting in disruption of ion transport system of the lateral cochlear wall resulting in disruptions of IE homeostasis & auditory function
enteral
Oral & rectal
Simplest
Adv: easy self administration, portable, less likely for systemic infections
Disadv: lipid soluble drugs pass through GI tract the easiest
food in stomach can alter absorption rate
pH of stomach and drug can interfere with absorption
other drugs in stomach can cause drug interaction (in oral route)
drugs pass through first-pass metabolism in liver
Applied on the surface: otic, transdermal, nasal, ophthalmic
topical
parental
Bypasses GI track & its barriers
Usually injected w/ syringes & needles
Ad: fast onset, delivers continuous meds, useful when they cannot take the meds through GI (unconscious/coma, ER, before/after surgery
Disadv: higher addiction, most dangerous route, risk of HIV & hepatitis
inhalation, intradermal, intravenous, intrarterial, intramuscular, intraosseous, sublingual (enters venous circulation), intrathecal (injected into the spinal canal/subarachnoid space), & intraperitoneal (injected into the peritoneum),
Drug metabolism enhaces hydrophillic nature of drugs for easy elimination from body
true
Phase I and II outcomes
convert active drug to inactive - most common outcome; inactive drug formed from the parent drug
convert inactive drug form (prodrug) to active - inactive parent drug is converted to active drug after metabolism
convert active drug to active - active parent drug is converted to a second active drug
*function of Phase I and II biotransformation is to enhace the hydrophilic nature of a
hydrophobic drug so it can excrete out of the body easily
Oxidation/Reduction (Phase I)
modifies chemical structure of a drug through oxidation reduction (transfer of electrons; oxidation = gain of O2, cation, reduction = loss of O2, anion)& liver has enzymes to facilitate these rxns
CYP Enzymes
primary machine for metabolizing drug
cyp enzymes
more CYP = slower drug metabolism
false faster
less CYP = slower drug metabolism
true
Conjugation/Hydrolysis or Phase II
Conjugation
forming a compound by joining two or more chemical compounds
Hydrolysis
reaction involving breaking of a bond in a molecule using water
*phase two makes the molecule bigger and breaks it with water to make it more soluble so it can pass through the membrane
first pass effect” of drug metabolism after oral absorption
Drugs administered orally are subject to it & occurs in the liver
It inactivates a portion of the drug so drug dosage needs to be adjusted
Fxn of it is to protect body from ingested toxins
Hepatic disease affects it
bioavailability
quantity of a drug reaching the systemic circulation divided by the quantity of the drug administered
Drugs administered through IV have bioavailability of
1
affected by hepatic metabolism regardless of route of administration
bioavailability
Drug dosage is dependent on bioavailability of a drug
true
depends on the route of administration, the chemical form of drug & PT factors (GI enzymes, pH and hepatic metabolism
bioavailability
FDA mandates generic has to have 50% of the bioavailability of the parent compound
false
90%
Discuss how drugs are eliminated from the body
movement of a drug and or its metabolites out of the body
primarily through renal excretion (urine) & biliary excretion (feces
25% of the entire blood in the body goes to the kidneys
Fat soluble drug will be reabsorbed by the kidneys and put into the bloodstream
After metabolism it is excreted primarily through kidneys (urine), liver (bile), and gut (feces)
increasing the rate of metabolism would decrease the action of the drug
tru
decreasing the rate of metabolism would increase the action of the drug
true
inducer
leaves the body faster, decrease of drug action, metabolics are sped up
inhibition
stays in the body longer, increase of drug action, slows down metabolics
what is polypharmacy
taking multiply drugs together and increasing adverse drug reactions
biological “half-life” of a drug
t1/2 = 0.693 x Vd ÷ Clearance
time required for the serum drug concentration to decrease by 50% (T½)
drug is cleared (removed) from body in ~ four to five half-lives
Elimination of a constant quantity per time unit of the drug quantity present in the organism
drug is eliminated at a steady rate regardless of its concentration.
0 order elimiation kinetics
Elimination of a constant fraction per time unit of the drug quantity present in the organism
as the concentration of the drug decreases, the rate of elimination decreases.
first order elimination kinetics
95% of drugs are eliminated in this fashion
First order elimination kinetics
pharmacogenomics
study of the role of the genome in drug responses
combo of pharmacology & genetics
studies how the genetic makeup of a PT affects their response to drugs
how gene mutations affect drug actions including SNIP mutations
Cytochrome P450 (CYP) liver enzymes metabolize >30 classes of drugs
Genetic variations causing less active/inactive forms of CYP can influence drug metabolism for tons of drugs leading to overdoses
what is a snip
when one nucleotide in a specific position is exchanged for another nucleotide
Alters the function and number of proteins which alters coding sequence of transcirption or mRNA translation
benefits/current limitations affecting the field of pharmacogenomics
benefits of pharmacogenomics
Development of drugs to accurately target specific diseases based on genetic information resulting in
improved therapeutic effects
decreased damage to healthy cells
Establishing gene phenotypes before the use of certain medications
For example, identifying gene types in asthmatics to ensure that bronchiole receptors will respond to albuterol
Matching the right drug and correct dose to patients’ genotype
Removing the need to experiment with medication till patients show desired improvement (e.g., blood pressure medication)
Advanced screenings for disease or disease susceptibility to monitor conditions and maximize therapy
Developing better vaccines
Decreasing overall healthcare costs
Barriers
barriers: complex and time consuming, knowing a person’s genetic makeup will not be helpful if the two drugs available are contraindicated and no alternative is available, and there is little incentive for drug manufacturers to spend huge amounts of $$$ to bring a drug to market. Despite these barriers, research in ongoing
physiologic differences in pharmacokinetics in children and elderly patients
children
Many biotransformation reactions are slow in young children
insufficiency of phase I and II enzymes can quickly lead to toxic levels of drugs in neonates and younger children
Neonatal jaundice results from the deficiency of the phase II enzyme Uridine Diphosphate Glucuronyltransferase (UDP-GT)
adults
Age-related changes in the liver mass
Hepatic blood flow
Hepatic enzyme activity
how these physiologic differences affect drug dosing and drug effects
in children
Children have increased skin and mucous membrane permeability, which absorb medications more quickly and more readily than adults
leading to quicker dose levels
Pediatric drug dose is calculated according to the child’s weight
typically pediatric dose is half that of the adult dose but proper pediatric doses should be calculated
polypharmacy effects of the most ototoxic and vestibulotoxic drugs such as cisplatin and methotrexate, and gentamycin and loop diuretics
Gentramycin + loop diuretic = kidney failure & snhl
when loop diuretics are given along with aminoglycoside(gentamicin) there is an enhanced entry for the aminoglycoside to enter cochlear fluids which enhances ototoxicty
Define ototoxicity
Drug or other chemical substances that cause temporary or permanent damage to the cochlea or vestibular system
Define vestibulotoxicity
Drug or other chemical substances that cause temporary or permanent damage to the cochlea or vestibular system
define neurotoxicity
Distinct from ototoxicity
Alteration of hearing or balance by drugs & chemicals acting at the level of BS or central connections of the cochlear and vestibular nuclei
Ototoxicity at the brainstem level
define nephrotoxicity
Toxicity that occurs in the kidney
Kidney damage from toxic substances
define hepatotoxicity
Toxicity that occurs in the liver
Liver damage caused by toxic substances
what are risk factors for ototoxicity
dosage - higher the risk
hepatic function - liver disease can decrease metabolism
renal function -
polypharmacoloty
age - very young and very old
pre-existing snhl
Higher the dose and more prolonged administration, the greater the risk of
ototoxicity
Synergy (interaction) bw existing SNHL & ototoxic drugs increasing ototoxicity risk
true
how does the ototoxins pass to get to the IE and their disruption caused
through BLB
disruption in the ion regulatory role of the stria vascularis
Different classes of drugs act on different parts of the cochlear microstructure restulting in ototoxicity
In animal models, earliest cochlear lesion is OHC destruction at the basal end
Many ototoxic drugs are also nephrotoxic
true
Discuss the rationale for the high frequency sensorineural hearing loss related to ototoxicity
Ototoxicity causes high-frequency SNHL because the basal region of the cochlea, which processes high-frequency sounds, is anatomically more vulnerable to drug-induced damage.
This vulnerability is due to greater drug exposure, higher metabolic activity, and susceptibility to oxidative stress in the hair cells located there.
As these high-frequency hair cells are destroyed, patients experience a reduction in their ability to hear high-pitched sounds, often leading to permanent hearing loss if the exposure is significant or prolonged.
what are ex of HFSNHL related to ototoxicity
Aminoglycoside antibiotics (e.g., gentamicin, tobramycin): These are particularly known for their high-frequency ototoxic effects.
Platinum-based chemotherapy agents (e.g., cisplatin): Cisplatin is especially known for causing high-frequency hearing loss due to its ability to induce oxidative stress.
Loop diuretics (e.g., furosemide): These can cause reversible or irreversible high-frequency SNHL by affecting the ionic balance in the cochlea.
what is ototrauma
any injury or damage to the ear, affecting the outer, middle, or inner ear, caused by physical, acoustic, or barometric forces
severity and effects of ototrauma depend on the type of trauma and the structures involved. It can result in hearing loss, pain, balance problems, or other ear-related symptoms.
effects of ototrauma
Hearing Loss: Conductive (temporary) or sensorineural (permanent)
Tinnitus: Persistent ringing or buzzing
Ear Pain: Pain due to eardrum perforation or infection
Vertigo: Balance disturbances
Eardrum Perforation: Hole in the tympanic membrane
Fluid Accumulation: Possible ear infection or blood behind the eardrum
Hyperacusis: Increased sensitivity to sound
Ossicular Chain Disruption: Damage to middle ear bones affecting hearing
Increased Infection Risk: Due to trauma-related exposure
examples of drugs which are primarily ototoxic and those that are primarily vestibulotoxic
Primary site of lesion: depends on the drug
Streptomycin and gentamicin = vestibulotoxic
Amikacin and neomycin = ototoxic
these tendencies are not absolute, and the extent of toxicity can vary with each drug
All aminoglycosides can damage one or both end organs
Streptomycin and gentamicin
vestibulotoxicity
Amikacin and neomycin
ototoxic
audio signs symptoms
HL: bilateral symmetrical SNHL (rarely unilateral or asymmetrical); starts HF and progresses to LF
tinnitus
aural fullness
recruitement
abn/abs OAEs
abn/abs ARTs
Poor speech
describe the HL in ototoxicity
bilateral symmetrical SNHL (rarely unilateral or asymmetrical); starts HF and progresses to LF
Progressive HL
Can continue after drug is stopped like in aminoglycosides & cisplatiin
Onset of HL
Occurs within few days or weeks of administration - dose dependent
Delayed onset can happen months or year after drug stops
onset of hl due to ototoxicity
Occurs within few days or weeks of administration - dose dependent
Delayed onset can happen months or year after drug stops
tinnitus in ototoxicity
Change in frequency, intensity or character can exist
Acute tinnituse can precede or supersede SNHL
FIRST SIGN OF OTOTOXICITY: Usually high pitch ranging from 4-6 kHz
Can be intermittent at first but is constant later
Can stop after discontinuationi with aspirin use
what is the first sign of ototoxicity
Usually high pitch ranging from 4-6 kHz
vestib symptoms in ototoxicity
True vertigo is rare
Usually light headed or dizzy
Unsteady or gait (ataxia)
Abnormal ocular tracking on vestib tests
Nystagmus (rapid involuntary eye movements)
d/d for ototoxicity
NIHL
presbycusis
ototrauma
SSNHL
ototrauma
Define antibiotic antagonism and an ex
One antibiotic can cancel out desired effects of the other
For e.g., if tetracycline and penicillin are given together, penicillin will not be effective
Define antibiotic synergism
Using more than one antibiotic increases the spectrum of kill and produces a desired effect of greater magnitude
For e.g., enterococci bacteria may not be completely eradicated by penicillin alone
But streptomycin given with penicillin, will kill the enteroccoci bacteria completely
Use of multiple antibiotics raise the risk of polypharmacy and adverse reactions including ototoxicity
true
Aminoglycosides are isolated from bacteria of the
Streptomyces genus
Describe the target organism for antibiotic therapy
The specific bacterial that that antibiotic was designed for
Used for infections caused by aerobic gram-negative bacteria
what are aminoglycosides
bactericidal antibiotics derived from the Streptomyces genus, used to treat serious infections caused by aerobic gram-negative bacteria
what are consequences of aerobic gram negative bacteria
endocarditis, septicemia, and kidney infections which can all in turn increase the risk of ototoxicity
MOST toxic to the auditory/vestibular system
aminoglycosides
can antibiotics work against viruses
no
most aminoglycosides have poor bioavailability following oral administration because they are poorly absorbed by the gut
true
how are aminoglycosides administered and why
Due to their poor absorption in the gut & low protein binding, these drugs are typically administered intramuscularly (IM) or intravenously (IV), which raises the risk of severe adverse reactions even after just a few doses.
common primary aminoglycosides
amikacin, gentamicin, kanamycin, neomycin, streptomycin, and tobramycin.
what is Antimicrobial Combination Therapy
Use of two or more antimicrobial agents together to treat an infection
employed to achieve better therapeutic outcomes compared to using a single antimicrobial agent alone
Antibiotic synergism & antagonism are specific phenomena that can occur within the broader context of ACT
benefits & risks of ACT
Benefits: enhances efficacy, prevents resistance, covers a wider range of pathogens
Risks: increased adverse effects (ototoxicities), increased cost, normal flora is disrupted
what are the 3 primary toxic effects of aminos
nephrotoxicity
neuromuscular blockade
ototoxicity/bestibulotoxicity
how does aminos cause nephrotoxocity
(20-30% incidence): This can be reversible but can also contribute to ototoxicity by causing the drug to accumulate in the body due to impaired renal clearance.
can increase both ototoxicity and vestibulotoxicity.
A rare but severe reaction that can lead to respiratory paralysis.
Neuromuscular Blockade
Describe the target organism for antibiotic therapy
The specific bacterial that that antibiotic was designed for
Used for infections caused by aerobic gram-negative bacteria
DO NOT fight viruses
Cochlear hair cells are the primary targes of aminoglycoside antibiotics
OHCs in the cochlea from the base to the apex = HFSNHL
Type I hair cells are lost first in the vestib system causing disturbances in its function
Discuss the pathophysiology of ototoxicity/vestibulotoxicity
Hair cell loss is severe at basal turn
OHCs first
ICHS & organ of corti in more severe cases
Damage to stria vascularis, spiral ligament, reissner’s membrane
Nerve damage secondary to HC loss
Discuss the pathophysiology of ototoxicity/vestibulotoxicity for aminoglycosides
Cationic charge of the aminoglycosides interacts with anionic charge of membranes of hair cells, which allows for drug transport into the cells
Aminoglycosides form complexes with iron and other metals, which forms free radicals through redox reactions that damage hair cells
Can result in both acute physiological & permanent damage
HL can sometimes be reversible following discontinuation of the drug
Following entry into inner ear hair cells, the drug can result in a variety of acute harmful effects
The drug increases intracellular calcium and generates toxic levels of reactive oxygen species (ROS)
These physiological changes result in cell death through apoptosis and necrosis (non-programmed cell death)
Which mechanism of hair cell death is initiated depends on the type of aminoglycoside and dosage regimen
primary targes of aminoglycoside antibiotics
cochlear hair cells
aminoglycosides & cochlea
OHCs in the cochlea from the base to the apex = HFSNHL
aminoglycosides & vestibular system
Type I hair cells are lost first in the vestib system causing disturbances in its function
oto/vestib w/ aminos are dose dependent unless there is a genetic ototoxicity
true
when does oto/vestib occur
Usually happens after chronic administration
In 6-8 day treatment regimen HL might not be noticeable
Adverse affects may occur after repeated administrations through parental
or weeks after initial treatment when drug is stopped that is followed by progressive HL
why should ototoxic monitoring happen for weeks to months after the drug is stopped
because adverse affects can occur weeks after initial treatment when drug is stopped that is followed by progressive HL
common classes of antibiotics
penicillin
macrolies
quinolones
aminoglycosides
use of penicillin
Bacterial action
Blocks bacterial cell wall synthesis
Ampicillin, amoxicillin (most commonly prescribed for OM), amoxicillin w/ Clavulanic Acid (Augmentin - OM if they develop resistance or no benefits with amoxicillin)
use of macrolide antibiotics
Bacteriostatic
Erythromycin, clindamycin, azithromyzin (contained in Z-pak - OM) & clarithromycin (OM)
Used for: OM, strep, tonsillitis, pharyngitis, sexually transmitted diseases, used for PTs allergic to penicillin
is penicillin ototoxic/vestibulotoxic
generally not
ototoxicity of macrolides
reversible SNHL (some irreversible), generally in very high doses w/ IV administration
factors that increase ototoxicity w/ macrolides
Renal & liver impairment
Getting an organ transplant
Age & female
Use of these w/ other ototoxic drugs
Prolonged high dose macrolide treatment
Aminoglycoside Genetic Predisposition
Mutation in mitochondrial DNA (mtDNA) - guanine has been substituted for adenine
Mutation causes high susceptibility to aminoglycoside ototoxicity
what is effected in aminoglycoside genetic mutation
Only cochlea is effected
Severe to profound SNHL
NOT dose-depended: single injection can lead to profound deafness
Genetic susceptibility is greater in the Chinese and Japanese
Which antibiotics are commonly used to treat otitis media?
Penicillin (first and subsequent generations such as augmentin)
Cephalosporin
Macrolides
Which antibiotics are MOST often associated with ototoxicity?
Aminoglycosides
Macrolides (generally reversible)
Glycopeptide antibiotics (e.g., vancomycin)
what is erythromycin
(macrolide) - slightly ototoxic but greater risk with higher doses
Broad spectrum antibiotic to fight gram positive and gram negative bacteria
what is vancomycin
glycopeptide antibiotic
works against gram-positive bacteri
treats meticillin-resistant staphylococcus aureus (MRSA) and gut infections
what happens when vancomycin is taken with aminos
has a synergistic effect
On its own, vancomycin has a slight risk of ototoxicity
But the combination of vancomycin and aminoglycosides increases the risk for ototoxicity
what are antineoplastics
chemotherapeutic drugs
what are antineoplastics used for
Used to stop cancer cells from proliferating, invading, metastasizing & killing hosts
what does and doesn’t respond to chemo
Small rapidly dividing cells respond best (not solid tumors becuase of slow growth/divisio of cells & they need radiation/surgery as well)
Normal cells also rapidly divide & use chemo
what is metastasize
happens when tumor cells mutate
Original tumors - respond well to chemo
Metastatic lesions - less responsive & poor prognosis
what is the challenge with chemo
give a dose good enough to kill cancer cells but not killing too many healthy cells
when is cisplatin used
Germ cell tumors - ovarian & testicular tumors (including metastatic)
Bladder cancer
Gynecological
Lung tumors
head/neck & brain tumors
Many childhood tumors including neuroblastoma
what causes risk of ototoxicity in cisplatin
High IV bolus (single dose over a short time) administration
High cumulative dose
Poor renal function
Young and advanced age
Co-administration of high dose vina alkaloids
Prior Cranial radiation therapy
what does ototoxicity look like in cisplatin
Can be gradual, progressive, cumulative or sudden
Cochlear loss detected early at >/= 8000 Hz
Conventional testing shows loss at 4-8 kHz
HF tinnitus
HL usually bilaterally but some asymmetrical
Usually permanent especially if it is profound HL (some degree can be reversible)
Ototoxic & nephrotoxic (some neurotoxicicty and vestibulotoxicity)
Causes HL in 60% of peds
cisplatin
platinum based compounds
cisplatin
carboplatin
Not any less ototoxic than cisplatin
More vestibulotoxic
carboplatin
toxicity mechanism for carboplatin
reactive O2 & nitrogen species
Toxicity risk increases with previous cisplatin or aminoglycosides administration
mechanism of ototoxicty in cisplatin
NOX3 (NADPH Oxidase 3)
what is NOX3 (NADPH Oxidase 3)
Protein coding gene
The protein encoded by this gene is expressed predominantly in the IE and is involved in biogenesis of otoliths (crystalline structures of the inner ear involved in the perception of gravity.
______ is associated with NOX3
NIHL
Antitumor drug derived from periwinkle plant
vinca alkaloids
types of vinca alkaloids
Vincristine, vinblastine, vinorelbine
Used in combo chemo usually with Cisplatin
how do vinca alkaloids work
blocking mitosis, cell cycle specific action
ototoxicity of vinca alkaloids
higher doses affect primarily hair cells
can be neurotoxic (numbness, pain & dizziness)
when are vinca alkaloids used
Leukemia, lymphoma, breast & testicular cancer, in neuroblastoma combination therapy, and Kaposi’s sarcoma
what are folate analog metabolic inhibitors and how are they used
Inhibition of folic acid metabolism has been used as a mechanism for successful elimination of rapidly dividing cells, i.e., tumor cells
what is a folate analog metabolic inhibior used
methotrexate
what does methotrexate treat
Treats severe cancers of blood, bone, lung, breast, head and neck, RA, psoriasis, & Cogan’s syndrome
Given along with Vinglastine & Cisplatin
Given along with Vinglastine & Cisplatin
methotrexate
Highly ototoxic, especially in children (Moore et al, 2023), especially if given with other cancer drugs, also nephrotoxic, and neurotoxic
Teratogenic and abortifacient (used in ectopic pregnancy)
folates
what are diuretics
Prevent reabsorption of sodium in the body exreting water to decrease blood volume & pressure
Used for
Hypertension, reduce edema, liver failure, kidney disease
types of diuretics
Thiazides, potassium-sparing & loop diuretics
what are loop diuretics
Prevent reabsorption of Na+, K++, and CL- causing more fluid to be excreted from kidneys
temporary hearing loss and may reverse with drug stop
mechanism of ototoxicity with diuretics
Dose related
Reduces endocochlear potential, causes disequilibrium of electrolytes in ear, causes reduction in cochlear potentials
Cochlear potentials can recover after discontinuation
SIGNIFICANT when taken with aminos - rapid onset, flat irreversible SNHL w/ roaring tinnitus
HL associated with loops taken with aminos
rapid onset, flat irreversible SNHL w/ roaring tinnitus
Salicylates
Aspirin & therapeutic mix
Used for pain, inflammation, fever, stroke
Absorbed rapidly and goes to cochlea through arteries & accumulates in the perilymph
ototoxicity of salicylates
High pitched HF reversible SNHL
Mild to mod symmetric
Rarely permanent
Recovers w/in 72 hrs after discontinuation
Associated with >/= 12 regular strength aspirins (325 mg) taken daily for several days
what are NSAIDS
Ibuprofen (advil, motrin), indomethacin (indocin), ketoprofen (Orudis KT), Cox-2 inhibitors (celebrex), naproxen sodium (aleve, anaprox, naprosyn, pamprin)
Similar to aspirin
ototoxicity of NSAIDS
Nephrotoxic & can cause ulcers
Reversible tinnitus & HL
How can blood thinners, bleeding disorders, and diabetes impact the management of an audiologic patient?
Anticoagulants - Xarelto (rivaroxaban), Eliquis (apixaban)
Small nicks can lead to severe bleeding
Important for impressions (deep ones) & cerumen
Bleeding & diabetes need caution for the same reasons
clearance/written consent from PTs informing them of the risks of the procedure is a must
Take a medical/drug profile history before testing and making impressions
most common side effect of ototoxicity/vestibulotooxicity drugs?
tinnitus & dizziness
HL/balance deficits from medications can be temporary or permanent, mild or severe
2 classes of meds w/ greatest potential for ototoxicity & iatrogenic HL (caused by medical treatment)
aminoglycosides antibiotics (IV mode of transmission) & antineoplastic (chemotherapeutic) medications particularly platinum based drugs
where is most ototoxic monitoring occurring
cancer treatment & long term antibiotics
not chemotherapeutic but given in junction with cisplatin or other cancer medication & used in different immune conditions as a treatment & causes abortions (highly teratogenic)
methotrexate
ways to detect oto/vestib
By directly assessing hearing and balance functions
HL & cochlear damage might not be noticed until it affects speech understanding
When symptoms of dizziness occur, vestibular damage may already have occurred
Why is monitoring important?
ototoxicity/vestibulotooxicity can cause great disability resulting in
Loss of hearing (max hl seen? HF SNHL)
Debilitating tinnitus
Difficulty with understanding speech, which affects communication/socialization leading to social isolation
Altered balance and coordination
Inability to perform physical activities
Negative impact on job/educational performance
Negative impact on independence
Children consequences (ototoxic HL)
S/L acquisition
educational challenges
psychosocial challenges
economic status (future economic gains)
quality of life
Adult consequences (ototoxic HL)
occupational challenges
psychosocial challenges
economic status (current employment opportunities & retirement economic security)
quality of life
Incidence of pediatric cancers is low and remains fairly stable
true
But the 5-year survival rate, therefore, prevalence for many pediatric cancers in the U. S., has increased, reaching upwards of 80% due to advancements in the diagnosis and treatment of childhood cancers
true
one of the most common causes of acquired pediatric HL is
ototoxicity
Time line for monitoring is determined by
drug toxicity & physicians recommendations
Follow up audios are performed after drug discontinuation for
up to a year?
Performed at 3, 6, 9, & 12 mos then annually after especially for platinum based drugs
when do you stop monitoring
When the HL steadies and stops changing
What is the change? More than 5-10dB change
Purpose for ototoxic monitoring per AAA (2009)
Ototoxic monitoring allows for informed medical decisions
Audiologic monitoring for ototoxicity is primarily performed for two purposes (AAA, 2009)
early detection of changes to hearing status attributed to a drug regimen
audiologic intervention can occur when significant hearing impairment has occurred
what audio rehab do we do with ototoxicity
Use of hearing aid and assistive devices
Programming hearing aids to adapt to changes in hearing sensitivity – progressive hearing loss
Educational support for children with hearing loss
Ototoxicity is determined by
comparing baseline data, (ideally obtained BEFORE ototoxic drug administration), to the results of subsequent monitoring tests to have each person as their own control
asha guidelines for baseline evals
Occurs before or no later than 24 hours after administration of chemotherapeutic drugs
Before or no later than 72 hours following administration of aminoglycoside antibiotics
Recheck thresholds within 24 hours of the Baseline Test to determine patient reliability
ashas guidelines for monitoring evals
Periodically throughout treatment, usually BEFORE each dose of chemo
1 to 2 times per week for patients receiving ototoxic antibiotics
frequency depends on
A patient’s particular drug regimen, which can be determined by reviewing the patient’s medical chart
Physician’s recommendations
asha guidelines on tests to use for monitoring evals
Use Conventional, EHFA, ABR, OAEs
FULL audio eval (aka serial audios) when able to
Physiological measures
Rule out ME dysfunction first
If normal, OAEs are good indicator of early ototoxic damage because they measure OHC fxn
Abnormal mE & baseline HL >/=40 dB may prevent effective monitoring use of OAEs
ABR is more appropriate in such cases
DPOAE change in overall amp from 5-9dB at two or more frequencies is considered a significant change
Abbreviated test measures if needed
Conventional
EHFA - can detect much earlier and since it happens on the basal end affecting HFs
Test retest: w/in +/-10dB bw 9-14 kHz
referrals for further auditory and vestibular testing also are warranted any time when patients’ report
Increased hearing difficulties
Tinnitus
Aural fullness
Dizziness
Ototoxic medication post-treatment evaluations are necessary to confirm that hearing is stable. why
Because ototoxic hearing loss can be progressive, occurring > 6 to 12 months after drug regimen is discontinued
Typically, follow-up audiograms performed after drug discontinuation can continue for up to a year, performed at
3 months, 6 months, 9 months, and 12 months
Then annually thereafter, especially for platinum-based drugs
You typically monitor for over a year in 3 month periods and if there is no change you can stop monitoring
In order for standard criteria to be accepted:
Use of well-accepted statistical methods for determining test performance in large groups of patients receiving ototoxic drugs
Hospitalized (control) patients receiving non-ototoxic drugs
ASHA criteria for clinically significant change in hearing sensitivity due to ototoxic medication
> 20 dB pure-tone threshold shift at one frequency
10 dB shift at two consecutive test frequencies
Threshold response shifting to “no response” at three consecutive test frequencies
significant changes in hearing need to be confirmed within 24 hrs
all threshold changes must be confirmed by retest
test summary for ototoxicity
Case history (especially medical and drug history)
Otoscopy
Baseline and serial pure-tone audiometric monitoring with
Conventional audiometry
Extended high frequency audiometry (earlier detection than conventional audiometry)
Tympanometry to rule out ME dysfunction causing change in hearing sensitivity
Speech audiometry to assess communication deficits
OAEs
Very sensitive to OHC integrity and will detect ototoxicity earlier than conventional audiometry
ABR (especially young children & nonresponsive patients)
Vestibulotoxicity monitoring
can result in compensation by central vestibular system w/ minimal long term effects but some the damage is permanent (especially bilateral peripheral vestibular damage)
Balance & mobility can occur causing debilitation
Monitoring includes vestibular reflexes (VOR) through calorics and rotary chair testing
treatment for vestibulotoxicity
Medication
Vestib rehab therapy
when do we see compensation occur for vestibular dysfunction
If there is peripheral bilateral vestib damage could there be compensation
no
if there is unilateral peripheral vestibular damage is there compensation
yes
if there is a central vestibular damage is there compensation
no
Tinnitus monitoring and why?
~ 40% PTs w/ chemotherapy have tinnitus
How do we measure tinnitus change?
Objective measures - PT explains it is louder, change in pitch, etc.
Tinnitus Ototoxicity Monitoring Interview (TOMI) was developed as a clinical tool by Zaugg, Kaelin, & Henry
Developed to detect tinnitus onset or changes in existing tinnitus perception during treatment with potential ototoxic drugs
1 page instrument completed w/in 5 min
Should be administered by audiologist or ENT
Fully scripted so it can be administered by other professions as a screening tool
Timeline for radiation therapy monitoring
Baseline Hearing Assessment: Before starting radiation therapy to establish a baseline for comparison.
Regular Monitoring: Typically, hearing should be monitored every 3 to 6 months during and after the completion of radiation therapy, depending on the risk factors and the specific treatment regimen.
Long-Term Follow-Up: Continued monitoring may be necessary for several years post-treatment, as radiation-induced hearing loss can sometimes develop or progress long after the treatment has ended.
Timeline for post-treatment monitoring for drugs and radiation therapy
Long-term (up to 10 years) audiologic follow-up post treatment is recommended
Potential damage caused to the auditory system with radiation therapy
HL can present as CHL, mixed, SNHL, or retro
⅓ PTs treated w/ this radiation experience SNHL
This radiation exacerbates HL when taking along w/ platinum-based chemotherapies
HF SNHL that is irreverisble or progressive and can occur after treatment
Radiation can degrade external ear and middle ear system
Thickens ™, causes canal stenosis, changes ET & ossicles - results in temporary or permanent CHL
Radiation results in cochlear microvascular fibrosis, in turn causing degeneration of
OHCs, IHcs, and VIII N fibers (Huang, et al., 2023).
Radiation and hearing loss exhibit a dose-response relationship
As radiation dose increases, so does the risk and degree of severity of the hearing loss
Dose-response relationship
The more the dose the more risk you have
describe aminoglycoside induced ototoxicity based on the reading
Drug Uptake: Aminoglycosides enter the cochlea via the bloodstream, crossing the blood-labyrinth barrier. They also enter hair cells through mechanotransduction channels, which are involved in sound signal processing.
Reactive Oxygen Species (ROS): These antibiotics cause ototoxicity primarily through the generation of reactive oxygen species (ROS) and subsequent oxidative stress, which leads to damage and death of hair cells in the cochlea. They can also disrupt intracellular calcium homeostasis and cause mitochondrial dysfunction.
Inflammatory Response: The activation of immune cells and inflammatory pathways further exacerbates the damage to hair cells.
describe cisplatin induced ototoxicity based on the reading
Cochlear Uptake and Retention: Cisplatin enters the cochlea and becomes concentrated in the inner ear tissues, particularly in the stria vascularis and sensory hair cells, leading to sustained toxic effects even after the drug has cleared from the bloodstream.
DNA Damage and Apoptosis: Cisplatin directly binds to DNA, causing crosslinking and damage that leads to apoptosis (programmed cell death) of hair cells.
Oxidative Stress: Similar to aminoglycosides, cisplatin induces oxidative stress and mitochondrial dysfunction, resulting in cell death.
Inflammatory Mediators: Cisplatin triggers inflammatory responses, exacerbating the damage through cytokine release and immune cell activation.
