2) Ototoxicity Flashcards
(104 cards)
1
Q
What is ototoxicity?
A
- Ototoxicity is the cellular degeneration and functional impairment of the inner ear tissues caused by therapeutic agents
- Damage to the inner ear, targeting cochlear and vestibular structures as well as sensory function, due to
exposure to certain pharmaceuticals, chemicals, and/or ionizing radiation - Different substances that can be harmful to the ear or vestibular system (mainly the cochlea is affected; the high frequency hair cells and vascular system- stria vascularis)
2
Q
Ototoxicity 3 places of involvement
A
- It typically affects the inner ear.
- Central auditory pathways leading to neurotoxicity.
- Kidneys leading to renal dysfunction or nephrotoxicity.
3
Q
Ototoxicity impairs both ____ and ____
A
Structure, function
4
Q
Define pharmacokinetics (PK)
A
- PK refers to how the body processes drugs, encompassing absorption, distribution, metabolism (biotransformation), and clearance (elimination).
- The process can be different for difference drugs
5
Q
Define pharmacodynamics (PD)
A
- PD focuses on what the drug does to the body, or mechanism of action, such as the mechanisms for ototoxicity.
- what happens to different organs and structures due to different drugs
6
Q
Define pharmacogenetics (PGx)
A
- PG addresses individual/genetic variations in response to a certain medication, or study of the role of the genome in drug response.
- response to different drugs based on certain genomes
- people respond differently to drugs (bottom picture)
- there are a lot of things associated with how the body responds to different drugs
7
Q
What are the 2 outcomes of ototoxicity?
A
̶1) Cochleotoxicity: Damage of the auditory system resulting in SNHL and/or tinnitus.
̶2) Vestibulotoxicity: Injury to the vestibular system and manifesting by dizziness, vertigo, and/or loss of balance
8
Q
What is the timeline for symptom appearance for ototoxicity?
A
- During or after the end of therapy.
- Symptoms can happen months after exposure to the drug.
9
Q
Is ototoxicity bilateral or unilateral?
A
They are typically bilaterally symmetric, OR asymmetric with one ear being affected later.
10
Q
How many ototoxic drugs are there?
A
More than 200 drugs are currently known to be ototoxic.
11
Q
The 6 most common family of ototoxic drugs in clinical use:
A
̶1) Aminoglycoside antibiotics
̶2) Platinum-based chemotherapeutic/anticancer drugs (e.g., cisplatin and carboplatin)
̶3) Loop diuretics
̶4) Macrolide antibiotics and Glycopeptides
̶5) Antimalarial drugs: Quinine
̶6) Salicylate analgesics
12
Q
What drug causes ototoxicity or late onset ototoxicity?
A
Aminoglycosides
13
Q
What are the 2 consequences of ototoxicity?
A
1) health-related consequences
̶- Hearing loss: Reduced quality of life (QoL), Negative impacts on psychosocial development and school functioning.
̶- Tinnitus: Distress, anxiety, depression, and reduced QoL.
̶- Vestibular impairments: Panic and depression.
2) economic consequences
14
Q
Why is it important to study ototoxicity?
A
- Can monitor if damage is being done to the cochlea (they we can tell physician if medication needs to be changed)
- Secondary consequences
15
Q
What 2 drugs are irreversible (permanent damage to the inner ear)
A
1) Aminoglycosides
̶2) Platinum-based Anticancer Drugs, especially cisplatin.
16
Q
What 4 drugs are reversible (after drug discontinuation)
A
̶1) Loop diuretics
̶2) Macrolide antibiotics
̶3) Antimalarial Drugs: Quinine
̶4) Salicylate analgesics
17
Q
What are the 3 most frequently used anticancer drugs?
A
Cisplatin, carboplatin, and oxaliplatin
18
Q
Cisplatin is…
A
1) The first platinum-based anticancer drug that entered the clinic.
̶2) The most frequently used platinum-based compound.
̶3) More ototoxic than carboplatin and oxaliplatin.
19
Q
What is cisplatin’s clinical application?
A
Cisplatin’s Clinical Applications: It is used for the treatment of solid tumors, such as:
̶- Brain tumors
20
Q
Cisplatin can enter cells through which 3 mechanisms?
A
̶1) Passive diffusion
̶2) Active transporters, such as CTR1 and OCT2
̶3) Endocytosis receptors (receptors involved in the transportation of extracellular materials into the cell.)
21
Q
Explain the mechanism of pharmacodynamics with cisplatin (what is happening inside the cells)?
A
Inside cells, it transforms and becomes a highly reactive complex that binds to various molecules in DNA, RNA, proteins, and peptides.
22
Q
What three ways does cisplatin cause irreversible damage?
A
̶1) Block DNA replication and transcription.
̶2) Affect mitochondrial DNA and disrupt cell respiration (kill the cell).
̶3) Generate harmful Reactive Oxygen Species (ROSs) leading to apoptosis and cell death.
23
Q
What is ROS?
A
ROS is a highly toxic material, and if the cell produces it, it will be totally damaged
24
Q
What is the most targeted place of ototoxic medication?
A
the auditory vascular system, in particular, the stria vascularis
25
Schematic representation of the cisplatin entry to the cell by active transporters: ____ and ____.
CTR1, OCT2
26
Where are CTR1 and OCT2?
- CTR1 and OCT2 are expressed in the stria vascularis and spiral ganglions.
- In OHCs:
- OCT2 is expressed on the apical plasma membrane.
- CTR1 is expressed on the lateral plasma membrane.
- In IHCs:
̶ - The OCT2 is expressed on the lateral plasma membrane
27
____ and ____ are the targets and what allow the drugs into the cell
Stria vascularis, spiral ganglions
28
What are the 5 side effects of cisplatin?
̶1) SNHL
- Typically begins days to weeks after treatment
- Involves high frequencies and progresses to lower frequencies with continued treatment.
- Even after treatment ends, hearing loss may worsen
- There are rare cases of partial improvement.
̶2) Tinnitus is common
- Occurs in 25–50% of cases and persists for at least 1 year in 38% of cases.
̶3) Vertigo, with or without nausea
̶4) Vomiting
̶5) Neurotoxicity, nephrotoxicity, and ototoxicity are dose-limiting.
29
What is dose-limiting?
Dose-limiting: a little change in dose can cause significant effects
30
Overall, what does cisplatin cause?
Cisplatin causes a full presentation of symptoms in the auditory system
31
The ototoxicity incidence rate for cisplatin varies between ____ - ____%
13–95%.
Wide incidence rate (a lot of factors contribute to this)
32
What are 8 risk factors for cisplatin induced ototoxicity?
̶1) Dose (depending on the treatment protocol)
̶2) Administration route
̶ - Bolus infusions (a large volume, at once) are more ototoxic compared with gradual infusions.
̶3) Age ≤4 years
̶4) Cranial irradiation
̶5) Noise exposure (can exacerbate ototoxicity by cisplatin)
̶6) Co-administration with other ototoxic drugs (e.g.: loop diuretics, aminoglycosides, or carboplatin)
̶7) Pre-existing hearing impairment
̶8) Renal insufficiency
33
What happens if a physician sees that there is renal insufficiency in the family?
They will not provide ototoxic drugs
34
Explain four ways how pharmacogenetics vary the ototoxicity cause by cisplatin among individuals
1) Diverse genes involved
̶2) Treatment protocol (dosage, duration, and co-administration)
̶3) Detoxification pathways (major pathways, liver, kidneys, GI tract)
̶4) and risk factors
35
Should a person receive cisplatin if they have detoxification pathways?
No
36
What are aminoglycosides?
Aminoglycosides are broad-spectrum antibiotics effective against aerobic, gram-negative bacteria, including Enterobacteriaceae and Pseudomonas.
37
What is the global significance of aminoglycosides?
Global Significance: Among the most frequently used drugs worldwide due to:
̶1) Low costs
̶2) A high rate of tuberculosis infection in developing countries
- No alternative to these drugs
38
What are the three clinical applications of aminoglycosides?
Clinical Applications: Used for the treatment of:
̶1) Life-threatening sepsis in newborns or immunocompromised individuals (e.g., after chemotherapy).
̶2) Recurrent and resistant tuberculosis
̶3) Pseudomonas aeruginosa in patients with cystic fibrosis
39
Aminoglycoside mechanism of cell entry
Similar to cisplatin ototoxicity, primary through the cochlear vascular system, stria vascularis.
40
What type of HL do aminoglycosides typically result in?
Affect high frequency hearing first, then progressing to the low frequencies (causing a significant hearing loss in the end)
41
Do aminoglycosides hold a narrow therapeutic index or dose limiting toxicity?
Yes, a small change in dosage or blood concentration may lead to serious therapeutic failures.
42
What are the aminoglycoside induced ototoxicity effects?
̶1) Cochleotoxicity: Tinnitus and/or SNHL.
̶2) Vestibulotoxicity: Vertigo, nausea, nystagmus, and ataxia.
43
____ is considered the most ototoxic, followed by gentamicin> kanamycin> tobramycin.
Amikacin
44
̶____ and ____ are mainly vestibulotoxic.
Streptomycin, gentamicin
45
____, ____, and ____ are preferentially cochleotoxic.
Amikacin, neomycin, kanamycin
46
____ is equally vestibulotoxic and cochleotoxic.
Tobramycin
47
What is the incidence of aminoglycoside induced ototoxicity? Variability in what 3 things?
̶Spans between 3.2% and 47%, reflecting variability in studies:
̶- Research methods
̶- Disease nature and severity
̶- Treatment protocol (dosage, duration, and co-administration)
48
Which of the following drugs can cause nystagmus and ataxia?
Aminoglycosides
49
What are the 8 risk factors for aminoglycoside induced ototoxicity?
̶1) High doses/elevated plasma concentrations
̶2) Frequent applications
̶3) Prolonged therapy
̶4) Renal dysfunction
̶5) Higher age
̶6) Noise exposure
̶7) Pre-existing hearing impairment
̶8)Co-administration with other ototoxic or nephrotoxic drugs
50
What should be done to prevent or reduce aminoglycoside induced ototoxicity?
̶- Monitoring drug effects
̶- Adjusting treatment protocol (changes in dose, duration, or drugs) if necessary.
51
Ototoxicity with cisplatin is associated with ____, and ototoxicity with aminoglycosides is associated with ____
lower ages, higher ages
52
What is the timeline for monitoring ototoxicity?
- Timeline for monitoring: repeat all assessments every couple months (monitor for at least 1 year)
- we have to monitor over time because even after stopping treatment, there can be late onset or progressive HL
53
Two mechanisms of action (pharmacodynamics) of aminoglycosides
The exact mechanisms are unknown. It is expected they:
1) Cause oxidative stress by producing ROS leading to apoptosis and necrosis in cochlear hair cells, marginal cells, and stria vascularis.
2) Inhibit mitochondrial protein biosynthesis and impair cell respiration.
54
What are the impacts of aminoglycoside induced ototoxicity?
̶- Begins with Initial harm to OHCs affecting high-frequencies.
̶- It progresses to IHCs, causing significant Hearing loss.
55
Explain the pharmacogenetics associated with aminoglycosides (2)
People with a specific genetic mutation called A1555G in mitochondrial DNA are more susceptible to both:
̶1) Aminoglycoside-induced ototoxicity.
̶2) Age-related hearing loss.
56
Who is the pharmacognetics gene mutation for aminoglycoside induced ototoxicity found in?
̶- 10–33% of Asian patients with aminoglycoside-induced ototoxicity.
̶- 17% of white patients with aminoglycoside-induced ototoxicity.
57
Explain case 1
- This is a significant change just after 1 month of aminoglycoside administration
- Can lead to HL, anxiety, depression, communication challenges (much more than just HL)
58
Explain case 2
Bilateral HF HL, and 11 days after treatment, severe to profound HL
59
Explain case 3 and 4
There can be significant changes even after just a few days
60
Explain case 5 and 6
- Three routes for receiving ototoxic drugs
- Both received similar therapy, but affected each child differently
61
Explain case 7
62
What are salicylate analgesics?
- Salicylate (e.g., aspirin) are among the most commonly used drugs worldwide.
- They are a class of anti-inflammatory drugs.
63
A high dose of salicylate can cause what 3 things?
̶1) Mild to moderate bilateral symmetric SNHL along with tinnitus and suprathreshold changes.
̶2) It usually recedes within 24–72 hours after cessation of the drug.
̶3) However, cases with permanent hearing loss have been reported.
64
Potential Mechanisms of Action (Pharmacodynamics) for salicylate analgesics (3):
65
Explain case 8
66
Explain case 9 and 10
It is rare to see unilateral HL with aspirin (ototoxic drugs commonly lead to bilateral HL, but in random cases can be unilateral)
67
Explain case 11 and 12
- Bilateral SNHL in case 11
- Flat moderate to severe HL in case 12 (we don’t typically expect flat HL)
- It is usually steeply sloping or gradually sloping HL
68
What are 4 examples of loop diuretics?
̶1) Etacrynic acid (Edecrin)
̶2) Furosemide (Lasix)
̶3) Torsemide
̶4) Bumetanide
69
What four reasons are loop-diuretics used?
̶1) Congestive heart diseases
̶2) Renal insufficiency
̶3) High blood pressure
̶4) Edematous disorders
70
How do loop-diuretics cause HL?
A dose-dependent transient SNHL.
71
Explain the four Potential Mechanisms For loop-diuretic induced Ototoxicity (Pharmacodynamics):
̶1) They block specific transporters (Na-K-Cl co-transporter: NKCC1 and NKCC2) in the inner ear, leading to:
̶2) Reduce blood flow
̶3) Disrupt the balance of ions
̶4) Impair mechanical functions in the inner ear.
72
How do you prevent hearing damage with loop-diuretic induced Ototoxicity
- To prevent greater hearing damage, their coadministration with cisplatin and aminoglycosides should be avoided.
- Would most likely cause severe to profound bilateral SNHL
73
Studies for loop-diuretics are all based on what?
Animal studies
74
Explain case 13 and 14
- The difference between these two cases is the dosage of administration
- Both cases have full recovery after drug use (most of the drugs under loop diuretics are reversible)
- Sometimes we can see permanent HL with loop diuretics
75
Explain case 15 and 16
- Case 15: bilateral to severe bilateral HL 2 weeks after treatment
- Case 16: partial improvement after each stage of getting the audiogram (could maybe improve more, that is why we monitor for at least 1 year)
76
Effects with loop diuretics are usually a reduction in ____ to ____ dB.
10-20 dB
77
What are some examples of macrolide antibiotics?
̶1) Erythromycin
̶2) Azithromycin
78
What four things are macrolide antibiotics used to treat?
̶- Respiratory infections
̶- Skin infections
̶- chlamydia infections
̶- Syphilis
79
How does macrolide antibiotics induced ototoxicity effect hearing?
- They can lead to SNHL, tinnitus, and vertigo.
̶- Transient dose-dependent symmetrical SNHL, between 40–50 dB, and appears 2–7 days post-treatment.
̶- SNHL commonly resolves within 1–3 weeks after drug discontinuation.
̶- Irreversible SNHL has been reported with both erythromycin and azithromycin.
80
Four Potential Mechanisms For macrolide antibiotics induced Ototoxicity (Pharmacodynamics):
̶- The exact mechanisms are unknown.
̶- Erythromycin may inhibit ion transport in the inner ear.
̶- Erythromycin may cause psychiatric complications (confusion and dizziness). It may refer to central nervous system involvement as well.
- May cause neurotoxicity (may affect the central nervous system)
81
Explain case 18 and 19
82
What are anti-retroviral drugs for HIV?
- The ototoxic impacts of anti-retroviral drugs to treat human immunodeficiency virus (HIV) is uncertain.
̶- There are some supportive studies & some studies that found no association (some studies say these drugs may affect the auditory system, but some studies say that they wont)
- This is a new group of ototoxic drugs
83
What are four ototoxic chemicals?
̶- Heavy metals, such as lead and mercury, and probably germanium and tin compounds.
̶- Tetrachlorocarbon and sulfur compounds.
̶- Organic phosphates and solvents (such as styrene and toluene)
̶- Carbon monoxide
84
What do ototoxic chemicals affect?
- These chemicals also affect other body organs (kidney and liver).
- This happens if people are exposed to these chemicals
85
Evaluation and grading of ototoxicity refers to...
It refers to monitoring drug-induced hearing loss, tinnitus, and or vertigo (dizziness).
86
Why do we need baseline audiograms?
Baseline audiograms before treatment are essential, but they are not always available, potentially leading to underestimation of ototoxic drugs' impact.
87
Why is monitoring hearing status important (three)?
̶- Considering alternative treatments
̶- Modifying doses and duration of administration
̶- Using otoprotective substances
88
What are the 7 steps of a full hearing evaluation protocol?
̶1) Ear microscopy
̶2) Conventional (0.25 – 8 kHz) and extended high-frequency audiometry (up to 16 kHz)
̶3) Speech audiometry in noise
̶4) Impedance audiometry
̶5) DPOAEs and TEOAEs
̶6) ABR and ASSR, especially for cases with a lack of cooperation (could tell you if there is neurotoxicity).
7) Vestibular testing (at least behavioural assessments, but electrophysiology assessments are great to get)
89
Why do we have to do vestibular testing?
Because most drugs are ototoxic and vestibulotoxic
90
How are ototoxic medications graded?
- Grade A: top level of evidence (one or more RCT_
- Grade B: non-RCT observational studies
- Grade C: case reports/series
91
Why do we still face ototoxicity?
1. Their unique effectiveness, especially in life-threatening infections and cancer treatments.
2. Low costs
̶
For example:
̶- Aminoglycosides often have no alternatives for life-threatening infections.
̶- Aminoglycosides are crucial for the treatment of recurrent and resistant tuberculosis, due to their low cost.
92
What 3 reasons are aminoglycosides and cisplatin similar?
̶1) Causing high-frequency hearing loss (due to the loss of OHCs in the basal turn of the cochlea).
̶2) Being nephrotoxic.
̶3) Producing ROSs within the cochlea, leading to Cellular damage and apoptosis
93
Most ototoxic drugs are both ____ and ____.
cochleotoxic, vestibulotoxic
94
Some drugs are more cochleotoxic (e.g., ____), and some others are more vestibulotoxic (e.g., ____).
neomycin, streptomycin
95
Pharmacodynamics - They affect ____ and ____.
cochlear hair cells, stria vascularis
96
Pharmacodynamics - ____ are usually affected before ____.
OHCs, IHCs
97
Pharmacodynamics - Damage typically begins in the ____ of the cochlea.
Basal turn
98
Pattern of SNHL
̶1) Usually starts in high frequencies and progresses to lower frequencies.
̶2) Bilateral, symmetrical hearing loss is common, but it can also be unilateral.
99
Associated symptoms
̶Tinnitus may accompany or precede hearing loss, though not always.
100
Timing of Ototoxic Effects:
̶- Most ototoxic effects occur during or soon after drug administration.
̶- Aminoglycosides can lead to SNHL months after treatment cessation, depending on the case and treatment protocol.
101
3 Risk Factors for Ototoxicity:
1) Major factors include Dosage, treatment duration, and renal function.
̶2) Coadministration of ototoxic drugs
̶3) Noise exposure
102
Kidney Toxicity:
̶Many ototoxic drugs are toxic to the kidneys (nephrotoxic).
103
Monitoring and Evaluation:
̶- Close monitoring of patients receiving ototoxic drugs is crucial.
̶- Monitoring should include hearing status, renal function, and drug levels in the blood.
̶- Taking a baseline audiogram might be challenging in critically ill patients.
104
̶How long monitoring should be and why?
̶- It should continue months after treatment cessation (at least up to 1 year).
̶- Due to the risk of delayed onset or progressive hearing loss.
- Dependent on province
