final exam comprehensive Flashcards
pharmacokinetics
how the body interacts with the administered substance
-remember ADME (absorption, distribution, metabolism, excretion/elimination)
what are some common route of administration
enteral, topical and parenteral
what route of administration bypasses all of the body’s barriers and has a greater risk for adverse effects
parenteral
-intrathecal !!
first pass metabolism and the drugs impacted by it
these drugs enter the liver prior to entering circulation which allows for any unnecessary toxins to be removed
-occurs to enteral
common barrier that need to be overcome by drugs
cell membrane, blood brain barrier (BBB), blood labyrinth barrier (BLB) and blood placental barrier
bioavailability
amount of the drug available within the circulation
-can be impacted by the route of administration, chemical form or patient factors including GI enzymes/pH metabolism
2 phases of metabolism
phase 1 : oxidation/reduction in which the chemical structure is being modified
phase 2 : conjunction/hydrolysis which inactivates the drug or enhances the drug solubility (forms a compound/breaks the bond)
cytochrome P450 (CYP) enzyme
in control of mediating oxidative reactions
-this determines the rate and extent to which an individual can metabolize various drugs
-if induced, it increases the rate of metabolism
-in inhibited, it decreases the rate of metabolism
what the equation for half life
t 1/2 = 0.693 (Vd)/elimination
what is the difference between zero order elimination and first order elimination
with zero order it is a constant amount that is eliminated whereas first order the more drug there is, the more drug that is eliminated
-zero is constant, first is adaptive
pharmacodynamics
the effects of a drug on the body
-the biochemical and physiologic actions of drugs and mechanisms of a drug action
agonist
ligand that activates the receptor
-active conformation after the drug binds to its receptor
-all NTs are agonists at their sites
antagonists (inhibitors)
prevents the action of the agonists at the receptor site but there is not effect without agonists
-can be receptor, noncompetitive or competitive
EC50 (potency) is related to the ______ of a drug ; EC50 (efficacy) is related to the __________________ by drug molecules
affinity ; receptor occupancy
pharmacogenomics
study of the role of the genome in drug response, a combination of pharmacology and genetics
-genetic polymorphisms are common in major enzymes that metabolize phase 1 and phase 2 reactions
examples of polymorphisms
inherited variation of enzymatic hydrolysis of short acting muscle relaxant (succinylcholine) by the enzymes cholinesterase AND the CYP liver enzyme
how can age impact drug metabolism
-children will have slower reactions (including slow metabolism and slow excretion)
-older adults generally have a decrease in metabolic capacity
polypharmacy
taking 5 or more medications at the same time, meaning within a 24 hour time period
-more common within older adults and younger people with chronic medical conditions such as diabetes, arthritis and autoimmune disorders
there is an ________ risk of drug-drug or drug-disease interactions with polypharmacy
increased
ototoxicity/vestibulotoxicity
drugs or other chemical substances that cause temporary or permanent damage to the cochlear or vestibular system
-exposure can result in functional impairment and cellular degeneration of the sensory organs, neurons of the cochlea and vestibular division of the 8th nerve
ototoxicity typically has SNHL, in many cases it begins as high frequency SNHL. why is this the case?
the drugs go into the inner ear damaging the basal end of the cochlea, which is the area associated with high frequencies
-will present as a HF sloping HL as the first presentation
after degeneration of the OHC’s how does damage continue to occur and how does that present clinically
damage can then spread to IHCs resulting in a mid and low frequency SNHL, degeneration of afferent nerve endings will then occur after both the OHCs and IHCs have been impacted
-as the nerve is impacted, then speech will be impacted both in quiet and in noise
-reflexes will also be impacted
audiological signs and symptoms of toxicity
SNHL that can be progressive, onset typically will occur within a few days or weeks, tinnitus, aural fullness, recruitment, abnormal/absent OAEs, abnormal/absent reflexes and poor speech perception
vestibular signs and symptoms of toxicity
light headedness/dizziness, unsteadiness/gait abnormalities, abnormal ocular tracking and nystagmus
nephrotoxicity
damage to the kidneys as a result of a drug/chemical
hepatotoxicity
damage to the liver as a result of a drug/chemical
neurotoxicity
alteration of hearing or balance by drugs/chemicals acting at the level of the brainstem or central connections of cochlear/vestibular nuclei
risk factors for ototoxicity
dosage (higher the dose, the more of a risk there is), hepatic function (liver diseases impact metabolism, increasing risk), renal function (increase risk with any renal impairment), polypharmacy, age (very young and very old are at higher risk), pre-exisiting SNHL
drugs that are primarily ototoxic
amikacin and neomycin
-both aminoglycosides
drugs that are primarily vestibulotoxic
streptomycin and gentamicin
-both aminoglycosides
what is antibiotic therapy used for
targets bacteria
-affects both gram positive and gram negative bacteria
antibiotic antagonism
when one antibiotic can cancel out desired effects of the other
-for example when tetracycline and penicillin are given together the penicillin will not be effective
antibiotic synergism
using more than one antibiotic increases the spectrum of kill and produces a desired effect of greater magnitude
-for example if penicillin is used alone to treat enterococci bacteria it will not completely remove it however, it used in conjunction with streptomycin the penicillin will completely kill the bacteria
antibiotics discussed
aminoglycosides, penicillin and macrolides
aminoglycosides
a type of antibiotic that is used to treat infections caused by gram negative bacteria that can cause life threatening infections such as endocarditis, septicemia and kidney infections
why are aminoglycosides most often administered through IM or IV
they have poor bioavailability if taken through oral administration
-absorbed within the gut this way
what are the primary toxicity reactions associated with aminoglycosides
nephrotoxic (tubular cell injury), can lead to neuromuscular blockage (respiratory paralysis) as well as both ototoxicity/vestibulotoxicity
with aminoglycosides, toxicity is generally dose dependent until there is a _______ component
genetic
-aminoglycoside included ototoxicity occurs with a point mutation within the mitochondrial DNA making an individual susceptible to ototoxicity
-only cochlea will be impacted resulting in a severe to profound SNHL
how does ototoxicity occur with aminoglycosides
cationic changes occur within the charge of the cell membranes allowing for drugs to enter the cell
-drug increases the intracellular calcium and generates toxic levels of reactive oxygen species (ROS) resulting in apoptosis and necrosis
-with gentamicin, this shows concentration within the stria vascularis and diffusing into the endolymph disrupting ion channels and disturbing the homestatic balance of the inner ear
explain the progress of damage with ototoxicity and aminoglycosides
the OHCs are damaged first, progresses to the IHC and the rest of the organ of corti
-nerve fiber will be impacted secondary to the hair cells
-once the IHCs and nerve are impacted ability to understand speech is impacted
_________ is the most limiting use factor of aminoglycosides
ototoxicity
why is HFA important within ototoxicity monitoring and aminoglycosides
HL begins in these higher frequencies, typically beginning over 16000 so by including HFA we can catch the damage prior to it reaching 8000
vestibulotoxicity with aminoglycosides
more likely to occur in people that have a history of balance problems and kidney dysfunction
-can be permanent or temporary
-can include vertigo, disequilibrium, oscillopsia or risk of falling
explain how vestibular issues can be compensated
this is a central process so if vestibular signs and symptoms are unilateral, compensatory actions can occur over time
-HOWEVER if the issue is bilateral, no compensation will occur
when aminoglycoside is given in conjunction with loop diuretics, what happens
causes toxicity at a higher rate as there is an enhanced entry of aminoglycosides into the cochlear fluid and tissues
when aminoglycosides are given in conjunction with neuromuscular blocking agents, what happens
can lead to skeletal muscle weakness and respiratory depression
when aminoglycosides are given in conjunction with vancomycin, what happens
there is a synergistic effect meaning and increase in toxicity
penicillin
produced by a fungus that has a bactericidal action, meaning it blocks bacterial cell wall synthesis
-examples include amoxicillin and augmentin
usage of amoxicillin
otitis media
-one of the most prescribed drugs in the US for OM
usage of augmentin
used for otitis media if the patient develops a resistance or no benefit from amoxicillin
is penicillin ototoxic or vestibulotoxic?
generally it does not cause toxicity
macrolides
a type of bacteriostatic meaning it does not kill the bacteria but it kills the material membrane so it cannot replicate
-example is a z-pack
usage of macrolides
otitis media, respiratory tract infections, sexually transmitted diseases and can be used when patients are allergic to penicillin
ototoxicity associated with macrolides
reversible SNHL that occurs at high doses through IV administration
-may also impact central auditory pathways
risk factors for macrolide ototoxicity
renal failure, liver impairment, receiving an organ transplant, age, female gender, concurrent use with other ototoxic drugs and a prolonged/high dose macrolide treatment
which antibiotic is most commonly used to treat otitis media
penicillin
-such as augemntin or amoxicillin
which antibiotic is most often associated with ototoxicity
aminoglycosides
classification of chemotherapeutic agents
platinum derived compounds (cisplatin and carboplatin), folate analog inhibitors and vinca alkaloids
limitation with chemotherapeutic agents
normal cells are also subjected to the effects of chemo so needing to allow time between sessions to allow the body’s cells to not be as impacted as the cancerous cells
what is the most ototoxic drug
cisplatin
cisplatin
used for germ cell tumors, bladder cancer, gynecological, lung tumors, tumors of the head/neck region and from childhood tumors such as neuroblastomas
risk factors for ototoxicity from cisplatin
high IV bolus, high cumulative dose, poor renal function, young or advanced age, co-administration of high dose of vinca alkaloids and poor cranial radiation therapy
ototoxicity with cisplatin
can be gradual, progressive, cumulative or it can present suddenly
-cochlear loss is detected in the higher frequencies first
-some degree of reversibility but is generally is permanent
-neurotoxicity and vestibulotoxicity can also occur
carboplatin
a second generation analog of cisplatin
-same uses as cisplatin
-was introduced to be less nephrotoxic however it is more vestibulotoxic
with carboplatin, there is significant ________________ toxicity
bone marrow
-take out both the T and B cells which then impacts the immune system
-can lead to anemia
mechanisms of ototoxicity with platinum derived compounds
caused by free radical generation and inhibition
-hair cells and spiral ganglion are most susceptible to apoptosis
the permanent HL associated with platinum compounds is probably caused by ….
loss of OHCs in the basal turn, damage later then spreads to the rest of the cochlea and then degeneration of the stria vascularis also occurs
what are critical issues to address when dealing with platinum compound ototoxicity
genes involved in drug transport, metabolism/DNA repair regulation, route of administration and timing relative to therapy
folate analog inhibitors
folate (vitamin B) is a vital for both cancerous and normal cells so these drugs aim to deplete folate which reduces DNA synthesis of both types of cell
-inhibition of folic acid has been used as the mechanisms for elimination of rapidly dividing cells
an example of a folate analog inhibitor is methotrexate, explain the drug
used to treat severe cancer of the blood, bone, lung, breast, head/neck, RA, psoriasis and cogan’s syndrome
-is highly ototoxic in children!!
-is also used with ectopic pregnancy
vinca alkaloids
an antitumor drug that is derived from periwinkle plant
-is often given together with other drugs such as cisplatin
-used for leukemia, lymphoma, breast/testicular cancer, neuroblastoma therapy and kaposi’s sarcoma
why is it hard to determine the exact amount of toxicity associated with vinca alkaloids
since it is often given in conjunction with other very ototoxic drugs, it is hard to know exactly how much toxicity this drug has
salicylates
a group of drugs that includes aspirin, which is used for mild to moderate pain relief, reduction of inflammation, reduction of fever and can prevent strokes
how can salicylates cause ototoxicity
they are absorbed quickly and are distributed into the cochlea through the arteries and can then accumulate within the perilymph
-shows reversible biochemical and/or metabolic changes in the cochlea with no permanent morphologic abnormality
-associated with greater than 12 regular strength aspirin tablets taken daily for several days
ototoxicity signs with salicylates
high pitched tinnitus, reversible mild to moderate HL SNHL
what is generally the first sign of ototoxicity with salicylates
tinnitus
-often becomes louder !
non-steroidal anti-inflammatory analgesics (NSAIDS)
actions include anti-inflammatory, analgesic and antipyretic effects
-examples include ibuprofen, naproxen and indomethacin
-nephrotoxic and can impact the GI by causing ulcers
ototoxicity associated with NSAIDS
reversible tinnitus and HL
-reversible dizziness is reported with indomethacin
quinine
an antipyretic used for malaria
-off label usage for nocturnal night cramps
-can be found in tonic water
toxicity associated with quinine
reversible bilateral HF hearing loss with a 4000 Hz notch, high pitched tonal tinnitus, dizziness/vertigo
-referred to as cinchonism which includes tinnitus, HL, dizziness, headache, nausea and vision changes
acetaminophen
useful for treating mild pain and fever but there is not anti-inflammatory agents
-such as tylenol
-is hepatotoxic if taken at greater than recommended doses
toxicity associated with acetaminophen
no reported temporary or permanent ototoxic or vestibulotoxic however overuse/abuse can cause rapidly progressive profound permanent SNHL
-which only occurs with multi-ingredient substances such as vicodine (acetaminophen and hydrocodone)
diuretics
preventing the reabsorption of sodium into the body which excretes water decreasing the blood volume and pressure
-used for hypertension, to reduce edema in patients with congestive heart failure, liver cirrhosis or kidney disease
what type of diuretics is believed to be ototoxic
loop diuretics
-including ethacrynic acid, furosemide and torsemide
mechanism of ototoxicity with loop diuretics
dose related and is reversibly depending on the endocochlear potential and intra-labyrinth electrolyte changes
-reduction in magnitude of the cochlear microphonic, summating potentials and 8th nerve action potentials
-recovery y of cochlear potentials occurs gradually
-can also cause dizziness/vertigo
HL can be reversible if ______________ is used alone
loop diuretics
how can blood thinners, bleeding disorders and diabetes impact the management of an audiologic patient
small nicks can lead to severe bleeding
-it is important when making impressions, particularly deep canal impression, and cerumen management
-clearance from a physician or written consent from patients informing risk is prudent
according to AAA, what is the purpose of ototoxic monitoring
allows for informed medical decisions
-performed for two purposes including early detection of changes to hearing status and audiologic intervention can occur when significant hearing impairment has occurred
ototoxic monitoring can lead to audiological intervention, this can include …..
use of HA/assistive devices, programming HA’s to adapt to changes within hearing sensitivity (i.e. progressive HL) and educational support for children with HL
patient populations that should be monitored
very old/very young patients, patients in poor general physical health, co-morbidities (in particular liver or kidney diseases), poor hydration status, genetic tendency for ototoxic susceptibility, patients that have received large or multiple doses and patients with a history of noise exposure
overview of the general timeline for ototoxic monitoring
baseline data, monitoring evaluations and post treatment evaluation
importance of having baseline data
this needs to occur in order to determine if ototoxicity has occurred
-the patient is their own control!!
timing of the baseline evaluation
should be evaluated before or no later than 24 hours after administration of chemotherapeutic agents, before or no later than 72 hours following administration of aminoglycosides and then a recheck of thresholds should occur within 24 hours to determine reliability
timeline of monitoring evaluations
should occur periodically throughout treatment and is usually prior to each dose for chemotherapy patients or 1-2 times per week for patients receiving ototoxic antibiotics
-is dependent on drug regimen and the physicians recommendations
despite the monitoring schedule, it can be warranted anytime based on what factors
if the patient reports and increased hearing difficulty, tinnitus, aural fullness or dizziness
timeline of post treatment evaluations
after treatment has stopped, evaluations should occur every 3 months for the first year then should occur annually
why is post treatment evaluations so important
ototoxic HL can be progressive and it can occur 6 to 12 months after the drug is discontinued
the national cancer institute at the national institutes of health published the common terminology criteria for adverse events (CTCAE), what is this and what does it state
a set of criteria for standardized classifications of adverse effects of the drug used in cancer therapy
-criteria is categorized based on changes in hearing, functional impact severity and the need for intervention
with pediatric monitoring, this is more urgent. what are some scenarios where monitoring should occur
newborns who are premature, children who have been diagnosed with cancer and children who have a condition that makes them vulnerable to infections
what are some important factors to consider with ototoxic monitoring
the status of patients, speed of test, cost of performing and interpreting the results and the availability of equipment/personnel
criteria for clinically significant changes in hearing due to ototoxic medications
greater than a 20 dB pure tone shift at one frequency, greater than a 10 dB pure tone shift at two consecutive frequencies or threshold response shifting to a no response at three consecutive test frequencies
when any changes in hearing are detected, what needs to occur
they need to be confirmed within 24 hours
what are the ASHA testing recommendations when it comes to ototoxic monitoring
they recommend a full audiometric evaluation for patients that are alert and responsive
-abbreviated test battery is required for patients who tire easily or show limited responsiveness/awareness
if any changes are noticed within the abbreviated test battery, what is the next step
a more complete evaluation will need to occur
importance of adding physiologic measures for ototoxic monitoring
physiologic measures should be included if there is any risk for the patient becoming less responsive over the course of treatment
what is within our test battery for monitoring
case history, otoscopy, pure tone audiometric monitoring (both conventional and extended high frequency), tympanometry, speech, OAEs and ABR
importance of high frequency audiometry with ototoxic monitoring
this detects ototoxicity much earlier than conventional audiometry because the drugs impact the basal end of the cochlea resulting in a HF SNHL
-we need to establish a baseline for this though because there are no well accepted standards
HFA will only be useful if we have _____________
the patients baseline
why is test-retest of HFA poor in children
these signals typically sound very different to children
-the differences between testing can be up to 10 dB different
when can OAEs and ABRs be used for ototoxic monitoring
younger children, patients with questionable reliability, unresponsive patients, patients with low cognitive abilities and very sick patients who cannot tolerate behavioral evaluation
advantage of using OAEs during monitoring
they are a good indicator of early ototoxic damage as they measure the outer hair cell function
when would ABRs be more appropriate for monitoring
in cases of ME dysfunction however there needs to be more caution in reading it as it could look like a conductive loss
how can cranial radiation impact the hearing structures
it can damage any of the auditory structures within the radiation field, extending from the external ear to the higher auditory pathways
how can radiation cause conductive HL
radiation can degrade the external ear and middle ear systems through thickening the TM, stenosis of the ear canal, changes in the ET and ossicles resulting in temporary or permanent conductive HL
how can radiation cause SNHL
as dose increases, it can cause degeneration of the OHCs, IHCs and the 8th nerve fibers
timeline of radiation therapy ototoxicity
typically is irreversible and progressive
-is considered a late adverse effect with onset occurring several years after treatment
tinnitus and ototoxicity
this is often the first thing that patients will report
-tinnitus ototoxicity monitoring interview (TOMI) was developed to detect tinnitus onset or changes in existing tinnitus perception during treatment with potentially ototoxic drugs
vestibular toxicity monitoring
monitoring requires assessment of the balance system including the vestibular reflexes such as VOR by caloric and rotary chair testing
pharmaceutical cognitive side effects
impaired concentration/attention, disorientation, confusion, loss of mental acuity, mental clouding, drowsiness, forgetfulness
cognitive side effects
poorer WRS, poorer pure tone thresholds, poor compliance with use of HAs
management of ototoxicity
counseling prior to therapy with ototoxic drugs to make patients aware of the risks, counseling patient/family after ototoxicity and the recommendations for rehabilitation, appropriate intervention with HAs or CIs, children with ototoxic HL will likely require the use of technology with remote microphone technology to improve SNR in the classroom, frequent follow up/counseling due to potential progressive loss
despite the patient being done with treatment, monitoring should still occur. why?
the progressive nature of HL associated with ototoxicity puts patients at risk for up to 6-12 months after treatment has stopped. that is why the post treatment evaluation is vital
examples of nephrotoxic drugs
aminoglycosides, cisplatin, MTX and NSAIDS
how are aminoglycosides nephrotoxic? how does this relate to ototoxicity?
there is injury to the tubular cells from drug accumulation, which this can be reversible
-renal toxicity causes the drug to accumulate within the body and stay longer
examples of hepatotoxic drugs
acetaminophen (if taken in greater then recommended doses)
examples of neurotoxic drugs
cisplatin, vinca alkaloids and MTX
what neurotoxic symptoms do vinca alkaloids cause
numbness, pain and dizziness
why is ototoxic HL SNHL and not conductive
the ME space does not have any sensory or vestibular organs so the ototoxicity will always be SNHL
-the ME space may be impacted however the damage will be occurring within the inner ear
examples of drugs that can cause vestibulotoxicity
aminoglycosides, cisplatin, carboplatin and quinine
differential diagnosis for ototoxicity (based on the audiogram alone)
presbycusis, ototrauma and noise induced HL
by looking at an audiogram alone, we cannot tell what caused the HL. how can we differentiate between ototoxicity or other diagnoses
through the case history and additional diagnostic testing results
-also with DD’s we will not see vestibulotoxicity symptoms
how is the blood labyrinth barrier (BLB) involved with ototoxicity
remember the BLB allows only certain things to cross however certain factors can breakdown the integrity of the barrier
-ototoxins have the ability to cross this barrier through some sort of disruption in the ions of the stria vascularis
-once inside, different parts of the cochlea will be impacted
as dosage and/or duration increases …..
IHCs can become destroyed damaging the apex causing SNHL in the mid to low frequencies
-degeneration of the afferent nerve endings follow causing tuning curse to become shallow!!
reflexes and ototoxicity
they will be impacted, may still be present but at low levels due to recruitment
-remember we expect them up to around a 50-60 dB HL
