pH and Neuronal Excitability - Therapy in Autism, Epilepsy, Mitochondrial Disease and ASIC mutations. Plus GPR89A

 

Diamox or Meldonium would make it easier

 

Several times recently the subject of pH (acidity/alkalinity) has come up in my discussions with fellow parents. It is not a subject that gets attention in the autism research, so here is my contribution to the subject.

If your child has a blood gas test a day after a seizure and it shows high pH, this is not the result of the seizure, but a likely cause of it. Treat the elevated pH to avoid another seizure and likely also improve autism symptoms. It may be respiratory alkalosis which is caused by hyperventilation, due to stress, anxiety etc.

The regulation of pH inside and outside brain cells is a delicate balance with far-reaching consequences. Subtle shifts toward acidity (low pH) or alkalinity (high pH) can alter calcium handling, neuronal excitability, and ultimately drive seizures, fatigue, or even inflammation. This interplay becomes especially important in conditions like autism, epilepsy, and mitochondrial disease, where metabolism and excitability are already dysregulated.

You can measure blood pH quite easily, but within cells different parts are maintained at very different levels of pH and this you will not be able to measure. Blood pH is about 7.4 (slightly alkaline) the gogli apparatus is slightly acidic, whereas the lysome is very acidic (pH about 4.7).

 

pH and Calcium Balance

Calcium (Ca²⁺) is central to neuronal excitability. Small pH changes shift the balance between intracellular and extracellular calcium:

• Alkalosis (↑ pH): reduces extracellular calcium availability, destabilizes neuronal membranes, and promotes hyperexcitability and seizures.
• Acidosis (↓ pH): activates acid-sensing ion channels (ASICs), leading to Na⁺ and Ca²⁺ influx and further excitability.

Thus, both too much acidity and too much alkalinity can increase seizure risk, though through different mechanisms.

Your body should tightly regulate its pH. You can only nudge it slightly up or down. Even small changes can be worthwhile in some cases.

When extracellular (ionized) calcium enters neurons through ion channels it can drive inflammation, excitability, and mitochondrial stress. Calcium needs to be in the right place and in autism it often is not, for a wide variety of reasons.

 

 

Mitochondrial Disease and pH

Mitochondria produce ATP through oxidative phosphorylation. Dysfunction can impair this process and lead to accumulation of lactate (acidosis) or, paradoxically, reduced proton flux (relative alkalosis). In autism, mitochondrial dysfunction is reported in a significant minority (10–20%) of cases.

 

Hyperventilation and Alkalosis

Another often-overlooked contributor is hyperventilation. By blowing off CO₂, blood pH rises (respiratory alkalosis), leading to reduced ionized calcium and increased excitability. This is the reason why hyperventilation is used during EEG testing to provoke seizures in susceptible individuals.

 

Therapeutic Approaches - Adjusting pH

Several therapies—old and new—intentionally alter pH balance:

1. Sodium and Potassium Bicarbonate

• Mechanism: Buffers acids, increases systemic pH (alkalinization).
• Applications: Beneficial in some cases of autism and epilepsy, as reported in blogs and small studies.
• Note: Raises extracellular pH, which can reduce ASIC activation but may increase excitability if alkalosis is excessive.
• Beyond buffering, sodium bicarbonate (baking soda) has been shown to trigger anti-inflammatory vagal nerve pathways. This effect may be especially valuable in neuroinflammation seen in autism and epilepsy.

 

2. Acetazolamide (Diamox)

• Mechanism: A carbonic anhydrase inhibitor that causes bicarbonate loss in the urine, lowering blood pH (mild acidosis).
• Neurological Effects: Used as an anti-seizure drug, especially in patients with channelopathies and mitochondrial disorders.
• In Climbers: At altitude, the body tends toward alkalosis due to hyperventilation (blowing off CO₂). Diamox counteracts this by inducing a mild metabolic acidosis, which stimulates ventilation, improves oxygenation, and prevents acute mountain sickness (AMS). This is why mountaineers often describe Diamox as helping them “breathe at night” in the mountains.

3. Zonisamide

• Mechanism: Another carbonic anhydrase inhibitor, with both anti-seizure and mild acidifying effects.
• Benefit: Often used in refractory epilepsy.

 

ASICs: Acid-Sensing Ion Channels

ASICs are neuronal ion channels directly gated by protons (H⁺). Their activity is pH-sensitive:

• Low pH (acidosis): Activates ASICs → Na⁺/Ca²⁺ influx → excitability and seizures.
• High pH (alkalosis): Reduces ASIC activity, but destabilizes calcium balance in other ways.

 

ASIC Mutations

Mutations in ASIC genes can alter how neurons respond to pH shifts. In theory, modest therapeutic modulation of pH (via bicarbonate or acetazolamide) could normalize excitability in patients with ASIC mutations.

 

ASIC2 is seen as a likely autism gene. There is even an ASIC2 loss of function mouse model.

Give that mouse Diamox!

 

Meldonium vs Diamox — Two Paths to Survive Altitude

During the Soviet–Afghan war in the 1980s, Russian troops were supplied with meldonium, while American soldiers and climbers commonly used acetazolamide (Diamox) for altitude adaptation. The Mujahideen and Taliban need neither, because they have already adapted to the low oxygen level.

Meldonium is a Latvian drug made famous by the tennis star Maria Sharapova who was found to be taking it for many years. It is a very plausible therapy to boost the performance of your mitochondria and so might help some autism. I know some people have tried it.

Although both drugs were used to improve performance under hypoxia, they worked in almost opposite ways:

 

At high altitude without Diamox

• You hyperventilate to compensate for low oxygen.
• Hyperventilation ↓ CO₂ in the blood → respiratory alkalosis (↑ pH).
• The alkalosis suppresses breathing (since the brainstem senses “too alkaline, slow down”), which is why people breathe shallowly at night, leading to periodic apnea and low oxygen saturation.

With Diamox

• Diamox blocks carbonic anhydrase in the kidneys → you excrete more bicarbonate (HCO₃⁻).
• This causes a metabolic acidosis (↓ pH).
• The brainstem now senses blood as “acidic,” which stimulates breathing.
• So, you hyperventilate more, but this time it’s sustained, because the metabolic acidosis counterbalances the respiratory alkalosis.

The net effect

• Without Diamox: hyperventilation → alkalosis → suppressed breathing → poor oxygenation.
• With Diamox: hyperventilation + mild metabolic acidosis → balanced pH → sustained ventilation and better oxygen delivery.

 So, the key is that Diamox shifts the body’s set point for breathing, letting climbers breathe harder without shutting down from alkalosis.

The Irony

• Meldonium - indirect alkalinization to reduce stress on cells.
• Diamox - deliberate acidification to stimulate respiration.
• Both approaches improved function under low oxygen, but they pulled physiology in opposite pH directions.

 

Another irony is that not only is Meldonium banned in sport, but so is Diamox. Diamox is banned because it is a diuretic and so can be used to mask the use of other drugs.

Now an example showing the impact of when pH control within the cell is dysfunctional.

 

GPR89A - the Golgi “Post Office” gene that keeps our cells running

When we think about genes involved in neurodevelopment, most people imagine genes that directly control brain signaling or neuron growth. But some genes quietly do their work behind the scenes, keeping our cellular “factories” running smoothly. One such gene is GPR89A, a gene that plays a critical role in regulating Golgi pH — and when it malfunctions, the consequences can ripple all the way to autism and intellectual disability (ID).

 

The Golgi Apparatus: The Cell’s Post Office

To understand GPR89A, it helps to picture the cell as a factory:

• The endoplasmic reticulum (ER) is the protein factory, producing raw products — proteins and lipids.
• The Golgi apparatus is the post office, modifying, sorting, and shipping these products to their proper destinations.

Just like a real post office, the Golgi must maintain precise conditions to function. One key condition is pH, the acidity inside the Golgi.

 

GPR89A: The Golgi’s pH Regulator

Inside the Golgi, acidity is carefully balanced by:

• V-ATPase pumps, which push protons (H⁺) in to acidify the lumen.
• Anion channels like GPR89A, which allow negative ions (Cl⁻, HCO₃⁻) to flow in, neutralizing the electrical charge and keeping the pH just right.

Think of GPR89A as the electrical wiring in the post office: without it, the machinery may be overloaded or misfiring, even if the raw materials (proteins) are fine.

 

When Golgi pH Goes Wrong

If GPR89A is mutated:

1.     The Golgi cannot maintain its normal acidic environment.

2.     Enzymes inside the Golgi — responsible for adding sugar chains to proteins (glycosylation) — cannot work properly.

3.     Proteins may become misfolded, unstable, or misrouted. Some may be sent to the wrong destination, while others are degraded.

This is akin to a post office with wrong sorting labels: packages (proteins) either go to the wrong address or get lost entirely.

 

Consequences for the Brain

Proteins are not just passive molecules; many are receptors, ion channels, adhesion molecules, or signaling factors essential for brain development. Mis-glycosylated proteins can lead to:

• Disrupted cell signaling
• Impaired synapse formation
• Altered neuronal communication

The end result can manifest as intellectual disability, autism spectrum disorders, or other neurodevelopmental conditions, because neurons are particularly sensitive to these trafficking and signaling errors.

 

Could Modulating Blood pH Help?

Since Golgi pH depends partly on cellular bicarbonate and proton balance, I have speculated whether small changes in blood pH could indirectly influence Golgi function:

• Sodium/potassium bicarbonate
• Increases extracellular bicarbonate and buffering capacity.
• Might slightly influence intracellular pH and indirectly affect Golgi pH.
• Acetazolamide (Diamox):
• Inhibits carbonic anhydrase, altering H⁺ and bicarbonate handling in cells.
• Could theoretically shift intracellular pH including Golgi pH

 

Systemic pH changes are heavily buffered by cells, so the impact on Golgi pH is likely to be modest at best.

Neither approach has been validated in human studies for improving glycosylation. Currently, there is no established therapy for GPR89A mutations.

Because there is no treatment, a reasonable option is a brief, carefully monitored trial.

• Try both interventions (bicarbonate then Diamox) for a short period.
• Observe for any measurable benefit in function or clinical outcomes.
• If there is no benefit, stop the trial — nothing is lost.

This approach allows cautious exploration without committing to a long-term therapy that may be ineffective.

 

The Bigger Picture

Even though GPR89A itself is not classified as a major autism or ID gene, its role in Golgi ion balance and glycosylation highlights how basic cellular “infrastructure” genes can profoundly affect brain development.

GPR89A reminds us that neurodevelopment is not only about neurons or synapses but also about the tiny cellular logistics systems that make them function. Maintaining Golgi pH is not glamorous, but without it, the entire cellular supply chain collapses, illustrating a pathway from a single gene mutation → cellular dysfunction → potential autism and ID outcomes.

Manipulating blood pH with bicarbonate or Diamox is an intriguing idea, will it provide a benefit?

 

Conclusion

pH regulation is a critical but underappreciated factor in autism, epilepsy, and mitochondrial disease. Subtle shifts in acidity or alkalinity affect calcium handling, ASIC activation, and neuronal excitability. Therapeutic strategies—from bicarbonates to carbonic anhydrase inhibitors—show that intentionally modulating pH can be both protective and symptomatic. Understanding the individual’s underlying metabolic and genetic context (eg mitochondrial function, ASIC mutations etc) will help determine whether a person might benefit more from raising or lowering pH.

For people with inflammatory conditions like some autism, or even MS, the simple idea of using baking soda to activate the vagus nerve is interesting.

·      Sodium bicarbonate → slight systemic alkalization.

·      Alkalization → reduced acidosis-related inflammatory signals.

·      Sensory neurons detect the pH change → activate vagus nerve.

·      Vagus nerve triggers cholinergic anti-inflammatory pathway → lowers pro-inflammatory cytokines.

We saw this in an old post and the researchers even went as far as severing the vagus nerve to prove it.

Potassium bicarbonate is a better long-term choice than sodium bicarbonate (baking soda) since most people lack potassium and have too much sodium already. It is cheap and OTC.

Diamox, Meldonium and Zonisamide are all used long term.

If you mention any of this to your doctor, expect a blank look coming back! Unless he/she is a mountaineer or perhaps a Latvian sports doctor!

 

Can you safely take Bumetanide or Acetazolamide (Diamox) if you have a Sulfonamide allergy?

I was contacted by a reader in Italy whose child with autism may respond to bumetanide, but has a sulfonamide allergy and got a skin reaction (hives). She had to stop giving the drug, but wanted to know how she could re-start bumetanide.

Other readers have pointed out how they dare not try bumetanide because they know their child has a sulfonamide allergy. I think our longtime reader Tanya is one example.

 

Key Point to Note

Most people discover their sulfonamide after being giving an antibiotic in early childhood.

It is now well established that many (but not all) people with an allergy to sulfonamide antibiotics can safely take a sulfonamide diuretic like Bumetanide or Diamox/Acetazolamide. This is presented in case studies later in this post.

 

Sulfonamide Drugs

Many common drugs are “sulfonamides”. Their chemical structure includes a sulfonyl (–SO2) group attached to an amine group (–NH2). They include common antibiotics, like erythromycin, many diuretics (bumetanide, furosemide, acetazolamide (Diamox), some anticonvulsants (zonisamide) and some anti-inflammatory drugs (sulfasalazine).

 

Sulfonamide Allergy

Many parents discover early in their child’s life that their child has a sulfonamide allergy. Sometimes this is abbreviated to a “sulfa allergy.”

The symptoms of a sulfonamide allergy can vary but may include:

• Skin reactions (rash, hives, or itching)
• Fever
• Swelling
• Respiratory issues (shortness of breath)
• Anaphylaxis (in severe cases)

Usually the symptoms are minor, but once diagnosed the parents usually take note never to give their child any sulfonamide drug.

 

If you have the allergy must you avoid all sulfonamide drugs?

The standard assumption has been that if you have a sulfonamide allergy you cannot take Bumetanide or Acetazolamide (Diamox).

Upon further investigation in the research, this may not always be true.

 

What happens when there is no alternative drug?

When treating ion channel/transporter dysfunctions there may not be a non-sulfonamide alternative.

Acetazolamide (Diamox) is documented in the literature as a case in point. Bumetanide has not yet made it to the literature.

Furosemide fortunately has been researched and a safe desensitization protocol exists. Furosemide is a very similar drug to bumetanide.

 

Desensitization strategies

I did recently write about enzyme potentiated desensitization, which is an old, mostly overlooked, technique to overcome allergic reactions. I was interested in pollen allergy.

The best-known kinds of desensitization are allergy shots and more recently overcoming nut allergies, which gets media attention. 

Oral immunotherapy for peanut allergy in young children

The study also found that the youngest children and those who started the trial with lower levels of peanut-specific antibodies were most likely to achieve remission. 

“The landmark results of the trial suggest a window of opportunity in early childhood to induce remission of peanut allergy through oral immunotherapy,” says NIAID Director Dr. Anthony Fauci. “It is our hope that these study findings will inform the development of treatment modalities that reduce the burden of peanut allergy in children.”

 

I did wonder that if it works for nuts then why not bumetanide.

It turns out that I am not the first to consider desensitization to a drug allergy. The best known method is rapid drug desensitization (RDD), usually intravenous, which opens a window to be able to start taking a drug you are allergic to. Once you stop taking the drug, you then again become allergic to it.

The other approach is more like dealing with nut allergies, it is called slow drug desensitization (SDD) and involves taking a tiny initial dose and then slowly increasing it over weeks and months.

Drug desensitization is normally done in hospital as part of some therapy when you absolutely must have a drug that you are allergic to.

The paper below contains information on a very large number of common drugs where drug desensitization has been successfully carried out.

 

Desensitization for the prevention of drug hypersensitivity reactions

Drug desensitization is the temporary induction of tolerance to a sensitized drug by administering slow increments of the drug, starting from a very small amount to a full therapeutic dose. It can be used as a therapeutic strategy for patients with drug hypersensitivity when no comparable alternatives are available. Desensitization has been recommended for immunoglobulin E (IgE)-mediated immediate hypersensitivity; however, its indications have recently been expanded to include non-IgE-mediated, non-immunological, or delayed T cell-mediated reactions. Currently, the mechanism of desensitization is not fully understood. However, the attenuation of various intracellular signals in target cells is an area of active research, such as high-affinity IgE receptor (FcɛRI) internalization, anti-drug IgG4 blocking antibody, altered signaling pathways in mast cells and basophils, and reduced Ca²⁺ influx. Agents commonly requiring desensitization include antineoplastic agents, antibiotics, antituberculous agents, and aspirin/nonsteroidal anti-inflammatory drugs. Various desensitization protocols (rapid or slow, multi-bag or one-bag, with different target doses) have been proposed for each drug. An appropriate protocol should be selected with the appropriate concentration, dosage, dosing interval, and route of administration. In addition, the protocol should be adjusted with consideration of the severity of the initial reaction, the characteristics of the drug itself, as well as the frequency, pattern, and degree of breakthrough reactions.

Two categories of desensitization protocols are currently available: RDD and slow drug desensitization (SDD). RDD is recommended for immediate reactions, both allergic and nonallergic. The most widely used RDD protocol is doubling the dosage every 15 minutes until the therapeutic dose is achieved. SDD is recommended for type IV delayed hypersensitivity reactions with T cell involvement, and can be performed both orally and intravenously. There is as yet no consensus on SDD protocols, including the initial dose, dose increments between steps, and dosing interval. Further clinical experience and research are required to establish the role and efficacy of desensitization for delayed reactions.

H1 blockers, H2 blockers, and glucocorticoids can be used as premedication. Aspirin and montelukast block the end products of the arachidonic acid cascade and decrease the incidence and severity of BTRs. NSAIDs can help to control the symptoms of cytokine release syndrome. Glucocorticoids alone are not recommended because they cannot prevent the initial degranulation of mast cells. 

The desensitization process is known to be antigen-specific, as the level of drug-specific immunoglobulin E (IgE) decreases but the levels of other allergen-specific IgE remain consistent throughout the treatment period. However, the cellular and molecular mechanisms underlying drug desensitization are not yet fully understood.

Aspirin/NSAID desensitization is considered for patients with cardiovascular or musculoskeletal diseases who require aspirin or NSAID administration for prolonged periods.

The temporary tolerance to aspirin/NSAIDs lasts 48 to 72 hours after desensitization. Therefore, hypersensitivity reactions can recur 2 to 5 days after discontinuation if the therapeutic dose is not continued.

 

DHR to β-lactams, such as penicillin or cephalosporin, is more common than that to non-β-lactams. Desensitization can be performed for both immediate and delayed hypersensitivity reactions. The protocol should be selected based on patient characteristics, hospital capacity, and physician preferences. It is generally started with 1/1,000 of the therapeutic dose and then increased by 2 to 3-fold every 15 minutes to 5 hours. Oral administration is preferred due to its ease, safety, and effectiveness. Desensitization to penicillin and cephalosporins has been well established. Successful desensitization has also been reported for other β-lactams, such as carbapenem and monobactam, and non-β-lactams, such as vancomycin, clindamycin, metronidazole, macrolides, aminoglycosides, tetracycline, and ciprofloxacin.

Successful desensitization to other antimicrobials has also been reported for antifungals, such as amphotericin B, fluconazole, itraconazole, voriconazole, and micafungin, and for antivirals, such as acyclovir, valganciclovir, ribavirin, and nevirapine.

 

Furosemide desensitization

There is no literature specific to bumetanide but there is on the very similar drug furosemide.

 

RAPID ORAL DESENSITIZATION TO FUROSEMIDE

Furosemide is a commonly used loop diuretic that contains a sulfonamide group. Although there are rare reports of hypersensitivity to furosemide, severe reactions, including anaphylaxis, have been reported. Ethacrynic acid, the only loop diuretic without a sulfonamide moiety, is no longer available in oral formulation, thus posing a dilemma in the outpatient treatment of patients with furosemide allergy.

Published protocols for furosemide desensitization include rapid intravenous administration and oral protocols lasting 3 to 10 days.3–5 The oral protocols were performed in patients with non–type I hypersensitivity reactions. We present a rapid, oral protocol for desensitization in a patient with presumed type 1 furosemide allergy manifesting as urticaria.

 

Desensitization to sulfonamide-containing antibiotics has been extensively used, but desensitization to furosemide is uncommon. The oral protocols previously described took 3 to 10 days and were performed in patients with non–type I hypersensitivity reactions, one with pancytopenia and the other with pancreatitis. The patient with a type I hypersensitivity reaction underwent an intravenous desensitization protocol. Rapid oral desensitization to a loop diuretic has not been previously described. The potential advantages of oral desensitization are that it is probably safer than intravenous desensitization, it may be more cost-effective in terms of monitoring and staff requirements, and it may be possible to perform in an outpatient setting. We propose our protocol as a novel approach to furosemide desensitization therapy for patients with non–life threatening reactions to furosemide. Further progress in the diagnosis and treatment of hypersensitivity to sulfonamide drugs will require identification of the major antigenic determinant and standardization of skin testing and specific IgE testing.

I think we should say good work to Dr Naureen Alim, then at Baylor College of Medicine Houston, Texas.

If anyone wants to desensitize to a bumetanide allergy I think she is the one to contact for advice. She is easy to find via Google. 

Here is another case example. 

Desensitization therapy in a patient with furosemide allergy

Allergy to furosemide is a rare phenomenon. Desensitization to this sulfa-containing drug has not been frequently performed. We describe a patient with severe congestive heart failure and type I allergy to furosemide. Because of the severity of her condition, we decided to use a rapid intravenous desensitization protocol. Following the desensitization, the patient was treated with intravenous and oral furosemide with a dramatic improvement in her clinical state. We suggest that rapid desensitization may be a safe and effective way of introducing furosemide to allergic patients for whom loop diuretics are urgently indicated.

 

In the case of Acetazolamide, here is one published desensitization method:

  

Desensitization to acetazolamide in a patient with previous antimicrobial sulfonamide allergy

Acetazolamide is a carbonic anhydrase inhibitor that is frequently used in the management of idiopathic intracranial hypertension. Acetazolamide is a sulfonamide agent; specifically, it is a non sulfonylarylamine, which lacks the amine moiety found at the N4 position that is seen in sulfa antibiotics. 

Sulfonamide antibiotics contain a substituted ring at the N1 position that is thought to be the driving factor in immediate hypersensitivity reactions.  

Although sulfa allergies are commonly reported, there is no evidence to suggest cross-reactivity between sulfonamide antibiotics and sulfonamide nonantibiotics. However, patients can report a history of allergy to both categories of drugs. We present a rapid desensitization protocol to acetazolamide in a patient with history of immediate hypersensitivity reactions to both a sulfonamide antibiotic and acetazolamide. 

We formulated a 12-step intravenous protocol that was performed in the intensive care unit setting (Table 1). Informed consent was provided by the patient, and she tolerated the procedure well without any adverse reactions. The desensitization procedure took 395 minutes or approximately 6.5 hours. She was monitored overnight in the hospital and was observed the following morning after taking 500 mg of acetazolamide orally to ensure tolerance. She was thereafter able to continue her recommended dose of acetazolamide without any issues to date.

 

Allergy to a sulfonamide antibiotic does not always mean you will be allergic to the non-antibiotic sulfonamide drugs.

  

Use of Acetazolamide in Sulfonamide-Allergic Patients With Neurologic Channelopathies

The 3 patients had been considered for carbonic anhydrase inhibitor treatment but a pharmacist had refused to fill a prescription for acetazolamide for 1 patient and the other 2 patients were denied treatment because of the allergy history. All 3 patients were prescribed acetazolamide and had no adverse reaction. Two patients improved substantially and are continuing treatment. A review of the pharmacology literature suggests that cross-reactivity between antibiotic and nonantibiotic carbonic anhydrase inhibitors is unlikely. Moreover, a review of case reports does not suggest cross-reactivity. Previous reports in the ophthalmology literature also indicate that acetazolamide can be administered to patients with a history of antibiotic sulfonamide allergic reaction.

Conclusions

These 3 cases confirm that the carbonic anhydrase inhibitor acetazolamide can be given to patients with a history of allergic skin rash with antibiotic sulfonamide.

 

Acetazolamide has been used for the treatment of episodic ataxia type 2, with benefit in 50% to 75% of patients. In episodic ataxia type 1, acetazolamide was also effective in decreasing attack frequency. Acetazolamide is also effective in the periodic paralyses. Carbonic anhydrase inhibitors have been used to prevent altitude sickness, to lower intraocular pressure in open-angle glaucoma, and to treat refractory absence, myoclonic, and catamenial epilepsy as part of multidrug regimens. Acetazolamide has recently been used for hemiplegic migraine and idiopathic intracranial hypertension. 

The lack of available clinical or pharmacological evidence to support cross-reactivity between sulfonamide antibiotics and acetazolamide lends supports to the use of acetazolamide to treat patients with episodic ataxia and periodic paralysis. Of our 3 sulfonamide-allergic patients, 2 improved in symptoms after treatment with acetazolamide and none of the 3 had a hypersensitivity reaction. We conclude that a sulfonamide allergy should not be a contraindication to treatment with acetazolamide in patients with neurologic channelopathies. 

 

Acetazolamide and sulfonamide allergy: a not so simple story

 Allergies and adverse reactions to sulfonamide medications are quite common. Two distinct categories of drugs are classified as sulfonamides: antibiotics and nonantibiotics. The two groups differ in their chemical structure, use, and the rate at which adverse reactions occur. Cross-reactivity between the two groups has been implied in the past, but is suspect. Acetazolamide, from the nonantibiotic group, is routinely used in the prevention and treatment of high altitude issues and may not need to be avoided in individuals with a history of sulfonamide allergy. This review addresses the differences between the groups and the propensity for intergroup and intragroup adverse reactions based on the available literature. We also examine the different clinical presentations of allergy and adverse reactions, from simple cutaneous reactions with no sequelae through Stevens-Johnson syndrome and anaphylaxis, with risk for significant morbidity and mortality. We offer a systematic approach to determine whether acetazolamide is a safe option for those with a history of allergy to sulfonamides.

Sulfonamide-containing antibiotics are the second most frequent cause of allergic drug reactions, after the b-lactams (penicillins and cephalosporins). In one large study, the incidence of reactions to trimethoprim–sulfamethoxazole (TMPSMX) was 3% of patients exposed, compared with 5% for amoxicillin. The incidence of reactions to nonantibiotic sulfonamides is not well established; it is clearly less than with antibiotics.

 

There are several approaches to the use of sulfonamide drugs (specifically acetazolamide) in patients with past reactions to this class of medications. The choice of strategy depends on the type and severity of the previous reaction, as well as the class of drug (antibiotic versus non antibiotic) and the risk–benefit profile for the patient. However, regardless of the approach, the risks of subsequent reactions cannot be completely eliminated, and a thorough discussion between the medical provider and the patient should include this point so that an informed decision regarding the use of acetazolamide can be made. The safest approach for the patient with any prior reaction to a sulfa drug, multiple drug allergies, or penicillin allergy would be to avoid all drugs in the sulfonamide group, including acetazolamide.

 

Avoidance of the entire sulfonamide drug group is warranted for individuals whose previous reaction included a serious and/or life-threatening condition such as anaphylaxis, SJS, and TEN. Any form of reexposure to the precipitating drug or a sulfonamide in the same group is strictly contraindicated. Published evidence has shown that SJS/TEN can recur with even minor reexposures and may be more severe in the second episode. Even though SJS/TEN reactions are so far not associated with nonantibiotic sulfonamides, because of the severity and life-threatening nature of these reactions, a safe practice is to avoid all sulfonamides in patients with past SJS or TEN from sulfonamide containing medications.

 

This paper was published in a journal on high altitude medicine. That is why the suggested alternatives are staged ascents of the mountain and oxygen.

  

Conclusion

The first key point is that you can have an allergy to sulfonamide antibiotics and have absolutely no negative reaction to sulfonamide drugs like bumetanide and acetazolamide (Diamox).

If you do have a mild allergic reaction to a sulfonamide drug, there are desensitization strategies that are proven to work in many people.

It looks like rapid oral desensitization to bumetanide and acetazolamide is likely possible, based on what has been shown possible with furosemide and a wide variety of other drugs.

Clearly the level of sensitivity and hence the nature of the allergic reaction can vary massively from person to person, this is why rapid desensitization usually takes place in hospital.

If you opt for the slower process, much less is known, because it is not generally used. If you did it in hospital it would require a very long stay and so would be hugely expensive.

It is suggested that slow drug desensitization (SDD) should be much more long lasting and hopefully might become permanent – as is the hope for nut allergy treatment.

When posed the initial question by our reader wanting to use bumetanide, I was thinking along the lines of slow drug desensitization (SDD), because this is how you would treat a pollen allergy. If rapid oral desensitization will work for taking bumetanide once a day that would be great. To maintain the protection from allergy it might be safer to take a small second daily dose.

 

Here is a quick overview of desensitization options for sulfonamide allergy:

• Rapid Desensitization (RDD):
• Faster process (hours)
• Temporary tolerance achieved
• May be repeated if needed
• Slow Desensitization (SDD):
• Slower process (days, weeks, or months)
• Might offer a greater chance of longer-lasting
• Still requires close monitoring

Important Considerations:

• Always consult your doctor: They can assess your allergy severity, treatment options, and the suitability of desensitization if necessary.
• Desensitization is not without risks: It requires careful monitoring.

 

I for one found this an interesting investigation and with promise for parents of those with severe autism who have been unable to trial Bumetanide due to a sulfonamide allergy. 

Hopefully our reader Dr Antonucci will follow up on this and make a bumetanide desensitization protocol for those people with autism and a sulfonamide allergy. Maybe he has already done it. It looks very achievable.

Enhancing the effect of Bumetanide in Autism

Many readers of this blog, and some of those who leave comments, are using the Bumetanide therapy proposed by Ben-Ari and Lemonnier.

At some point it should become an approved autism drug and Ben Ari has already patented it for use in Down Syndrome, so I guess that will come later on.

I have been developing my own add-on therapies that might help people for whom a high level of intracellular chloride is part of their autism, or indeed Down Sydrome.  If Bumetanide has a profound impact on your autism, this is almost certainly you.

Monty, aged 13 with ASD

After 4 years of Bumetanide, it continues to be effective and if Monty stops taking it there is a gradual cognitive decline over a few days, presumably as chloride concentration gradually increases.

In spite of an odd temporary Tourette’s type verbal tic that developed after an infection before Christmas, I have been getting plenty of feedback that Monty has got cleverer in 2017.  So it looks like some bumetanide add-on does indeed work.

The Colosseum

Monty’s big brother continues to be a fan of Lego and indeed Nanoblocks from Japan.  Nanoblocks is like extremely small Lego.

Having completed the Colossuem, his latest Nanoblocks model, he asked Monty “where is it?”.

Back came the answer, unprompted, “Italy”.

This was a big surprise.

That was not the answer big brother expected, he expected no answer or a silly answer like “over there”.

Add-ons

The first is potassium bromide (KBr) which was the original epilepsy therapy 150 years ago.  One of its effects is that the bromide (Br^-) part competes with chloride (Cl-) to enter neurons and bromide is known to be faster.  As a result some of the chloride inside cells is replaced by bromide.  Bromide is extremely similar to chloride, but is not reactive; this is why it can be used with any anti-epileptic drug (AED) without fear of negative interactions.

KBr has an extremely long half-life, meaning that if you take it every day it will take 4-6 weeks to reach its stable level in your body.

KBr is used for pediatric epilepsy in Germany and Austria and for epilepsy in pet dogs all over the world.  

A dose of 8mg/kg is far below the dose used for epilepsy, but does have a bumetanide enhancing effect in one 50kg boy.

The even more recent add-on is based on the experience of our reader Petra’s son with Asperger’s, who found that taking his bumetanide with Greek coffee seemed to make it more effective.

It turns out that dopamine is known to increase the effect of diuretics on the chloride cotransport NKCC2 in your kidneys.  There is a myth that coffee is a diuretic, but it is clear where this myth has come from.  Coffee will increase diuresis and so does caffeine.

In the brain it is the chloride cotransporter NKCC1 that is also blocked by bumetanide.  So it would be plausible that dopamine/coffee/caffeine it might have the same effect on NKCC1 as it does on the very similar NKCC2.

The cheap and widely available 50mg caffeine tablets do seem to serve as a proxy for a steaming cup of Greek coffee.  Indeed 50mg of caffeine is more like a weak cup of instant coffee.

I did much earlier propose the use of Diamox/ Acetazolamide to reduce chloride.  It seems that in some neurons 2/3 of the chloride enters via NKCC1 and 1/3 via the exchanger AE3.  Diamox/ Acetazolamide works via AE3.

Diamox has some other ion channel effects, making it useful in some epilepsy.

Some readers of this blog use Diamox, but in Monty it seems to cause reflux.

Caffeine is a very simple add-on to try.