Special Report

The Relative Ototoxicity of

Anti-Hypertensive Drugs

Neil G. Bauman
Special Report

The Relative Ototoxicity of

Anti-Hypertensive Drugs

Neil Bauman, Ph.D.

© January, 2018 (revised March, 2019)

1013 Ridgeway Drive

Lynden, WA 98264
360-778-1266
Neil@HearingLossHelp.com
http://hearinglosshelp.com
 The Relative Ototoxicity of Anti-Hypertensive Drugs

People often ask me which are the least ototoxic beta blockers (or
other classes of anti-hypertensive drugs) to take for high blood pressure
(hypertension). For example one man asked:

I have some questions about the ototoxicity of medications for high blood
pressure. My primary care physician and I have been searching for a
medication to treat my high blood pressure and so far have not been able to
find one that is not associated with ototoxicity—specifically tinnitus. Are there
some suggested ones that we can explore? I have had tinnitus for 15 years and
am concerned about taking any drugs for an extended time that could
permanently intensify my tinnitus.

I replied, in part,

I understand your concerns. As you are probably aware, all the drugs used
for reducing high blood pressure are ototoxic to some degree or other. I’m not
aware of a single one that is not ototoxic.

Therefore, since some drugs in any given drug class are much more
ototoxic than others, the trick is to find the least ototoxic drug that will do
the job of reducing your high blood pressure, and at the same time, reduce
your risk of getting any ototoxic (or other) side effects.

For example, you want to avoid getting:

 tinnitus, or making your existing tinnitus worse

 hearing loss, or making your existing hearing loss worse
 balance problems such as ataxia, dizziness, vertigo, nystagmus, etc.
 other ear problems
 negative side effects elsewhere in your body

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 Note: I just focus on ear-damaging (ototoxic) side effects (the first four
points above). There are hundreds, if not thousands, of other side effects
reported for any given drug. You have to be cognizant of these other side
effects as well, since they all can affect your body. Thus, you have to do
your own “due diligence” and search them out so you can avoid those side
effects too. In this report I just zero in on those anti-hypertensive drugs with
side effects that can damage your ears.

Before you look at the various classes of anti-hypertensive drugs and

see which ones in each class are the least ototoxic, you need to understand
where this data came from; how complete it is; and thus, how reliable it is.

Where Did This Information Come From?

The information in this report has been extracted from tens of

thousands of ototoxic drug side-effect reports that people and doctors have
submitted to the Food and Drug Administration’s (FDA) database. In
addition, this information also includes some user submissions to the
FactMed database.

Specifically, these data come from reports filed with the FDA during
the 9-year period between January, 2004 and October, 2012. Even though
I’ve extracted just ototoxic side-effect data from this enormous database, the
ototoxic side-effect information alone still consists of about 44,000 lines of
data. That comprises a whopping 1,100 pages of data to sort through and
compile.

(Imagine how much larger this pile of data would have been if it had
included all the side effect reports from say 1980 to the present—which
would have been ideal!)

All that additional information would have made these data even more
complete, and thus more accurate and useful. But just this 9-year period of
side-effect data is enough to show which drugs are particularly bad for our
ears, and which ones probably aren’t.

This is because the relative number of reported incidences between

the various drugs probably would have remained much the same, except for
new drugs, whether 9 years of data was used, or 39 years of data was used.
Thus, it is unlikely that the ranking order of the drugs shown here would
change appreciably.

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How Accurate Is This Information?
I know that some critics will say that these reported figures are not
particularly accurate, and I agree. However, these reports are still some of
the best information we have available to us on the incidence of ototoxic
side effects.

One of the reasons this information is not completely accurate is

because of mistakes some people make. For example, a person on two drugs
may (wrongly) blame one of the drugs for a given side effect when it was
actually the other drug, or some other factor and thus report the wrong
drug as the culprit.

Another reason is that a person may begin taking a drug and blame a
resulting symptom (e.g. tinnitus) on the drug when it fact, the person
caused his own tinnitus coincidentally at that time from listening to loud
music, for example.

To help counteract this, if there were only 1 or 2 reported incidences

of any given ototoxic side effect, I left it out. Thus, there had to be 3 or more
reports before I included that side effect for any given drug in this report.

Because of any inaccuracies in these data, if the reported numbers

are low, you may choose to see them as mistakes or as coincidences and
therefore not necessarily true. However, when hundreds, or thousands, of
people all report the same ototoxic side effect for a given drug, you know the
chance of these being all coincidences is extremely low. Thus, these results
are generally accurate within the limits of the data collected.

My personal view is that since side effects are grossly under-reported

(see the next section), the few false positives in these figures nowhere near
make up for the enormous number of side effects that should have been,
but were not, reported.

The Incidence of Side Effects Is Grossly Under-reported

Even though 1,100 pages of data may seem like a lot of information,
actually, it represents only a miniscule fraction of the ototoxic side effects
that actually occur.

You may find it hard to believe, but few side effects are ever reported
to the FDA for inclusion in their comprehensive database. Thus, the reports
on ototoxicity we have to work with represent only a very small fraction of
the total number ototoxic side effects that occur in real life. If more people

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experiencing side effects reported them to the FDA, the compiled statistics
would be much more numerous, and thus more accurate.

Don’t for a minute think that the figures reported here reflect the true
incidence of any given side effect for any given drug. They are grossly low
because they are grossly under-reported.

Here is a classic understatement by the FDA. “Often the FDA only

receives reports of the most critical and severe cases; these numbers
may therefore under-represent the complication rate of the medication.”

Just “may under-represent”? According to former FDA Commissioner,

David Kessler, only about 1% of serious side effects are ever reported to the
FDA! Thus, at a very minimum, you need to multiply any reported statistics
by a factor of 100.

However, since ototoxic side effects are not considered “serious”, only
a small fraction of 1% of ototoxic side effects are actually reported. That
means that you probably can multiply these figures by a factor of 1,000 and
still have very conservative results.

In fact, a study of Rhode Island doctors showed that serious side

effects are reported so infrequently to the FDA that the multiplication factor
needs to be, not just 100 times, not just 1,000 times, but 2,363 times for
serious side effects. Thus, for ototoxic side effects, that multiplier will be
much greater still.

So the truth is that the ototoxic side-effect figures I have compiled in

the tables below for each class of anti-hypertensive drugs could range from
100 times the reported figures to more than 20,000 times that figure.

Therefore, never assume that because there are only 10 reports for
tinnitus (or whatever ototoxic side effect you are interested in), for example,
for a given drug, that this reported figure represents the true number of
people getting that side effect. If you did, you might erroneously consider
the risk of getting this side effect as very small.

The numbers shown here are merely the tip of the iceberg. The true
values are always many times more than are shown here.

For example, the true figure could well be 20,000 times greater—more
like 200,000 people—if every person taking that drug and getting tinnitus
had reported that fact to the FDA, rather than the measly 10 cases of
tinnitus reported as is the case with Acebutolol.

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 The good news is that, no matter what multiplier you think is closest
to the truth, the relative number of side effects reported between drugs is
probably more or less constant. Thus, as you can see in Table 4, the Beta-
Blocker table on page 13, Carteolol has 5 reports of hearing loss, whereas
Metoprolol has a whopping 1,150 reports. So whether you apply a multiplier
of 100 or 1,000 or 20,000 or anywhere in between these figures, people
taking Metoprolol are always going to have a much higher incidence of
hearing loss than are those taking Carteolol.

The True Population Taking a Given Drug is Unknown

In order to make this data even more meaningful, we need to know

how many people actually took each of these drugs. Here’s why.

You’ll notice that some drugs have many thousands of reports and
others have few or even none. Below are several reasons for this. You have
to decide for yourself which is the most likely scenario in your case and for
the drug you are considering taking. Then you need to act appropriately.
For example, we need more information on whether:

1. The drug is widely used and is quite ototoxic, so of the many

millions of users there are a lot of side effects reported (even though that
number reflects far less than 1% of the total).

2. The drug is widely used but is not very ototoxic, so there are few
ototoxic side effects to report, and thus few are reported.

3. The drug is not widely used so although it is quite ototoxic,

there aren’t many side effects reported.

4. The drug is not widely used and is not very ototoxic so there are
few ototoxic side effects reported.

5. The drug is fairly new (since 2004) so it has not been in use long
enough to have a lot of people taking it. As a result, there are not a lot of
reports in the FDA database yet.

Unfortunately, we don’t have this detailed information.

Putting the Odds in Your Favor

Even though the information available to us on each drug is woefully
incomplete as we have just seen, it is still valuable. Thus, you’ll be glad to
know that you can figure out the worst drugs in each class based on the
data presented here.
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 This is because you can assume that drugs that have fewer reports
(scenarios 2 through 5 above) are generally safer to risk taking than those
with many reports (scenario 1).

Based strictly on the number of incidences reported in this 9-year

period, I have put the drugs in each class into one of three groupings—low
risk, medium risk and high risk.

Based on this information, you and your doctor can start with the
drugs in the low-risk section and decide which of them (if any) would likely
do the job and try them. If none of them will do the job, then go on to the
medium-risk section. This way, you are putting the odds in your favor and
are minimizing your chances of ending up with any ototoxic side effects,
including making your tinnitus worse.

Here’s another tip to reduce your risk of experiencing ototoxic side

effects. Never use a dose higher than you absolutely need. Find the
minimum dose that will do the job and stick with it. That way, you may
just fly under the ototoxic radar and not experience any obvious ototoxic
side effects such as tinnitus or hearing loss.

Anti-Hypertensive Drug Classes

I can’t tell you in advance all the drugs doctors may prescribe to
reduce blood pressure. This is because doctors are free to prescribe
whatever drugs they want, from whichever drug classes they want, if they
think it will do the job. Therefore, I don’t know specifically which drugs your
doctor may, or may not, choose to use for treating your hypertension, so the
below lists may not be complete.

However, having said that, there are five classes of drugs doctors
typically use to try to control hypertension. These five classes of drugs
come under the general heading of anti-hypertensive drugs. The drugs in
each class work a little differently from the drugs in the other classes in
order to accomplish the same job. That is why doctors sometimes prescribe
two or three drugs—each from a different drug class—so the combined effect
will bring down your blood pressure by one means or another.

These five classes of anti-hypertensive drugs include the:

1. Angiotensin-converting enzyme inhibitors. (Commonly referred
to as ACE Inhibitors.) The generic names in this class of drugs
typically end in “-pril”, e.g. Perindopril.

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 2. Alpha-adrenergic blocking drugs. (Commonly referred to as Alpha
blockers.) The generic names in this class of drugs typically end in
“-osin”, e.g. Prazosin.
3. Angiotensin-2-receptor blocking drugs. (Commonly referred to as
ARBs). The generic names in this class of drugs typically end in
“-sartan”, e.g. Irbesartan.
4. Beta-adrenergic blocking drugs. (Commonly referred to as Beta
Blockers.) The generic names in this class of drugs typically end in
“-olol”, e.g. Pindolol.
5. Calcium channel blocking drugs. (Commonly referred to as CCBs.)
The generic names in this class of drugs typically end in “-ipine”,
e.g. Nicardipine.

How to Read the Drug-Class Tables

For each drug in each class, this report lists the drugs in ascending
order of ototoxic risk, They are broken down into three groups—low risk,
medium risk and high risk.

For each generic drug name, I list the reported incidence under the
following headings.
1. Tinnitus: The number of people reporting tinnitus as a side effect of
taking this drug.
2. Hearing loss: The number of people reporting hearing loss as a side
effect of taking this drug.
3. Cochlear side effects: The total number of reports of cochlear
(hearing-related) side effects which includes the figures from the
tinnitus and hearing loss columns as well.
4. Vestibular side effects: The total number of reports of vestibular
(balance) side effects such as dizziness, vertigo, balance disorders,
ataxia, nystagmus, etc.
5. Outer/middle ear side effects: The total number of reports of
outer/middle ear side effects including ear pain, otitis, etc.
6. Grand total: The total number of reports of all ototoxic side effects
for this generic drug (the totals of 3, 4 and 5 above). This total
ranges from a low of 0 to a high of 16,353. This shows the
tremendous variation in ototoxic risk between taking one of the
drugs in a given drug class as opposed to another drug.

An asterisk (*) after a number means that I have received side-effect

information on this side effect, even though no one reported this side effect

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to the FDA’s database in the 9-year time period under consideration here.
You can assume that the incidence of side effects marked with an asterisk
is quite low, or else they likely would have been reported to the FDA data
base by now.

Also, just because a drug shows a 0 in one or more columns doesn’t

mean that drug is not ototoxic. It just means that there are no reports of
this side effect associated with this drug at this time. In the future, that
may change.

These tables give you a good indication of the relative ototoxicity of the
various anti-hypertensive classes of drugs, but there is no absolute
guarantee that you won’t experience any of these side effects if you take one
of the zero-rated ones. It’s just that the risk appears to be very low, and
thus is probably a wise place to start if you need to take one of these drugs.

Obviously you want your doctor to prescribe a drug with a zero, or a

low value so you have the least risk of damaging your ears. At the same
time, you definitely want to avoid those drugs with high values as much as
possible, as the risk of getting ototoxic side effects from taking them is
enormously greater.

Since you want to specifically reduce your risk of making your

tinnitus worse, you can focus on the first column. If you wanted to avoid
both tinnitus and hearing loss, you’d focus on the first two columns.

However, you’d do well to also focus on the sixth column—the Grand

Total—as drugs with a low grand total will also be low in the incidence of
tinnitus and hearing loss.

The following pages show five tables ranking the ototoxicity of five
classes of anti-hypertensive drugs.

Table 1: Alpha-Adrenergic Blocking Drugs (Alpha Blockers)

Table 2: Angiotensin-Converting Enzyme Inhibitors (ACE Inhibitors)

Table 3: Angiotensin-2-Receptor Blocking Drugs (ARBs)

Table 4: Beta-Adrenergic Blocking Drugs (Beta Blockers)

Table 5: Calcium Channel Blocking Drugs (CCBs)

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Table 1: Alpha-Adrenergic Blocking Drugs (Alpha Blockers)

Tinnitus Hearing Cochlear Vestibular Outer/ Grand

Loss (Hearing (Balance Middle Totals
Related) Related) Ear

Low Risk
Trimazosin 0* 0 0* 0 0 0*
Thymoxamine 0* 0 0* 0 0* 0*
Bunazosin 0* 0 0* 0 0* 0*
Prazosin 3 2 5 127 0 132

Medium Risk
Alfuzosin 19 23 42 513 28 583

High Risk
Terazosin 44 126 210 1,133 141 1,484
Doxazosin 65 130 220 1,327 113 1,660
Tamsulosin 136 275 435 3,047 323 3,805

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Table 2: Angiotensin-Converting Enzyme Inhibitors (ACE Inhibitors)

Tinnitus Hearing Cochlear Vestibular Outer/ Grand

Loss (Hearing (Balance Middle Totals
Related) Related) Ear

Low Risk
Imidapril 4 0 7 57 0 64
Cilazapril 3 4 7 14 0* 21
Moexipril 17 4 21 129 20 170
Trandolapril 7 12 28 336 28 392
Perindopril 28 21 57 742 17 816

Medium Risk
Captopril 33 66 99 690 53 842
Benazepril 34 65 109 818 118 1,045
Fosinopril 37 74 116 681 107 904
Quinapril 49 137 205 1,139 113 1,457

High Risk
Enalapril 110 224 385 2,849 240 3,474
Ramipril 141 226 424 3,197 260 3,881
Lisinopril 466 837 1,475 10,127 1,044 12,646

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Table 3: Angiotensin-2-Receptor Blocking Drugs (ARBs)

Tinnitus Hearing Cochlear Vestibular Outer/ Grand

Loss (Hearing (Balance Middle Totals
Related) Related) Ear

Low Risk
Eprosartan 4 0 4 112 0* 116

Medium Risk
Telmisartan 60 56 116 1,255 70 1,441

High Risk
Irbesartan 110 124 253 1,832 185 2,270
Candesartan 91 142 259 1,703 52 2,014
Olmesartan 91 179 318 1,920 208 2,446
Losartan 255 369 660 4,246 411 5,317
Valsartan 345 468 874 6,364 519 7,757

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Table 4: Beta-Adrenergic Blocking Drugs (Beta Blockers)

Tinnitus Hearing Cochlear Vestibular Outer/ Grand

Loss (Hearing (Balance Middle Totals
Related) Related) Ear

Low Risk
Dilevalol 0* 0 0 0 0 0
Levobetaxolol 0* 0 0 0* 0* 0
Oxprenolol 0* 0 0 0* 0 0
Levobunolol 0 0 0 20 0 20
Celiprolol 0 0 0 27 0 27
Esmolol 0 4 4 23 12 39
Pindolol 0* 4 4 50 0 54
Carteolol 0 5 5 9 1 15

Medium Risk
Betaxolol 9 10 19 87 16 122
Acebutolol 4 17 24 141 10 175
Nadolol 16 6 22 357 36 415
Labetalol 11 34 51 446 44 541
Nebivolol 29 5 34 576 7 617

High Risk
Sotolol 50 37 98 715 62 882
Timolol 71 89 163 726 39 928
Bisoprolol 89 124 228 1,712 60 2,000
Propranolol 141 158 407 1,878 292 2,577
Carvedilol 133 274 450 4,608 394 5,452
Atenolol 409 511 1,064 6,872 689 8,625
Metoprolol 695 1,150 2,160 12,744 1,449 16,353

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 Note: Dilevalol is the fourth isomer of Labetalol. Therefore, you might
expect it to have similar ototoxic properties and risk factors as Labetalol.
Thus, if you are particularly cautious, you might want to move it to the
“moderate” section with Labetalol.

This is because, as a very general rule, you could expect that drugs in
the same class will have much the same side effects. However, the intensity
and incidence of such side effects varies from one drug to another in the
same class. Thus, some beta blockers seem to be relatively free of ototoxic
side effects while others have a lot of side effects and these side effects show
up in a high proportion of the people taking them. For example, compare
the differences in the incidences between Metoprolol and Carteolol.

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Table 5: Calcium Channel Blocking Drugs (CCBs)

Tinnitus Hearing Cochlear Vestibular Outer/ Grand

Loss (Hearing (Balance Middle Totals
Related) Related) Ear

Low Risk
Bepridil 0* 0 0* 4 0 4
Nilvadipine 0* 0 0* 19 0* 19
Lacidipine 0 0 0 20 6 26
Nimodipine 0* 0 0* 30 0* 30
Nitrendipine 2 3 5 42 0* 47

Medium Risk
Nicardipine 0* 0 0* 86 0* 86
Nisoldipine 0* 1 1 178 27 206
Lercanidipine 5 0 9 212 0 221
Isradipine 9 24 33 101 0* 134

High Risk
Felodipine 39 57 103 654 57 814
Verapamil 103 142 266 1,766 221 2,253
Nifedipine 99 174 309 2,077 174 2,560
Diltiazem 173 408 613 4,380 523 5,516
Amlodipine 479 781 1,463 10,386 1,011 12,860

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