The Provider Primers Series: Medications that impact mast cell degranulation and anaphylaxis

A number of medications can induce mast cell degranulation and histamine release. Other medications increase the risk of anaphylaxis and can increase the severity of anaphylaxis.

Medication reaction profile is very individual and not all mast cell patients react to the medications listed below. Additionally, there may be a need for some mast cell patients to take  medications listed below if the benefit outweighs the risk.

Medications that are reported to induce mast cell degranulation and histamine release
Alcohol[i] Amphoterecin B[ii] Aspirin[i] Atracurium[iii]
Caine anesthetics (esters)[iv] Codeine[v] Colistin (polymyxin E)[vi] Dextran[iii]
Dextromethorphan[iii] Gelatine[iii] Iodine based radiographic dye[vii] Meperidine[viii]
Miconazole[ix] Mivacurium[iii] Morphine[iv] Nefopam[iii]
NSAIDs[x] Phentolamine[xi] Polymyxin B[v] Reserpine[xii]
Rocuronium[iv] Succinylcholine[iv][xiii] Thiopental[iv] Tolazoline[v]
Vancomycin[xiv] (especially when given intravenously)

 

Patients on beta blockers are more likely to experience anaphylaxis and more likely for that anaphylaxis to be severe and treatment resistant. Beta blockers also impede treatment of anaphylaxis by interfering with the action of epinephrine[xvi]. Patients at risk for anaphylaxis who are on beta blockers should get a glucagon pen to use prior to epinephrine[xv].

Beta adrenergic blockers[xvi] (Note: List is not exhaustive)
Acebutolol Atenolol Betaxolol Bisoprolol
Bucindolol Butaxamine Cartelol Carvedilol
Celiprolol Esmolol Metoprolol Nadolol
Nebivolol Oxprenolol Penbutolol Pindolol
Propranolol Sotalol Timolol

 

Alpha blockers impede treatment of anaphylaxis by interfering with the action of epinephrine[xvii].

Alpha-1 adrenergic blockers[xvii] (Note: List is not exhaustive)
Alfuzosin Amitryptiline Amoxapine Atiprosin
Carvedilol Chlorpromazine Clomipramine Clozapine
Dapiprazole Dihydroergotamine Doxazosin Doxepin
Ergotamine Etoperidone Fluphenazine Hydroxyzine
Imipramine Labetalol Loxapine Mianserin
Nefazodone Olanzapine Phentolamine Prazosin
Quetiapine Risperidone Silodosin Tamsulosin
Thimipramine Thioridazine Trazodone

 

Alpha-2 adrenergic blockers[xvii] (Note: List is not exhaustive)
Buspirone Chlorpromazine Clozapine Esmirtazapine
Fluophenazine Idazoxan Loxapine Lurasidone
Mianserin Mirtazapine Olanzapine Phentolamine
Risperidone Thioridazine Yohimbe

Patients on angiotensin-converting enzyme (ACE) inhibitors are also more likely to experience anaphylaxis and more likely for that anaphylaxis to be severe and treatment resistant. The exact reason for this is unclear but ACE inhibitors impede appropriate bradykinin metabolism which may contribute to anaphylaxis[xvi].

Angiotensin converting enzyme (ACE) inhibitors[xvi] (Note: List is not exhaustive)
Benazopril Captopril Enalapril Fosinopril
Lisinopril Moexipril Perindopril Quinapril
Ramipril Trandolopril

Special notes:

Aspirin use in mast cell patients to suppress prostaglandin production is becoming increasingly common[xviii]. In some situations, other NSAIDs are also used.

Fentanyl, sufentanil, remifentanil and alfentanil are the preferred opioids for mast cell patientsiv. Hydromorphone releases minimal histamine and is also used in mast cell patients.[xix]

References:

[i] Valent P. (2014). Risk factors and management of severe life-threatening anaphylaxis in patients with clonal mast cell disorders. Clinical & Experimental Allergy, 44, 914-920.

[ii] Lange M, et al. (2012). Mastocytosis in children and adults: clinical disease heterogeneity. Arch Med Sci, 8(3), 533-541.

[iii] Dewachter P, et al. (2014). Perioperative management of patients with mastocytosis. Anesthesiology, 120, 753-759.

[iv] Eggleston ST, Lush LW. (1996). Understanding allergic reactions to local anesthetics. Ann Pharmacother, 30(7-8), 851-857.

[v] Brockow K, Bonadonna P. (2012). Drug allergy in mast cell disease. Curr Opin Allergy Clin Immunol, 12, 354-360.

[vi] Kwa A, et al. (2014). Polymyxin B: similarities to and differences from colistin (polymyxin E). Expert Review of Anti-infective Therapy, 5(5), 811-821.

[vii] Kun T, Jakubowski L. (2012). Pol J Radiol, 77(3), 19-24.

[viii] Blunk JA, et al. (2004). Opioid-induced mast cell activation and vascular responses is not mediated by mu-opioid receptors: an in vivo microdialysis study in human skin. Anesth Analq, 98(2), 364-370.

[ix] Toyoguchi T, et al. (2000). Histamine release induced by antimicrobial agents and effects of antimicrobial agents on vancomycin-induced histamine release from rat peritoneal mast cells.  Pharm Pharmacol, 52(3), 327-331.

[x] Grosman N. (2007). Comparison of the influence of NSAIDs with different COX-selectivity on histamine release from mast cells isolated from naïve and sensitized rats. International Immunopharmacology, 7(4), 532-540.

[xi] Powell JR, Shamel LB. (1979). Interaction of imidazoline alpha-adrenergic receptor antagonists with histamine receptors. J Cardiovasc Pharmacol, 1(6), 633-640.

[xii] Muroi N, et al. (1991). Effect of reserpine on histamine metabolism in the muse brain. J Pharmacol Exp Ther, 256(3), 967-972.

[xiii] Sadleir PH, et al. (2013). Anaphylaxis to neuromuscular blocking drugs : incidence and cross-reactivity in Western Australia from 2002 to 2011. Br J Anaesth, 110(6), 981-987.

[xiv] Sanchez-Borges M, et al. (2013). Hypersensitivity reactions to non beta-lactam antimicrobial agents, a statement of the WAO special committee on drug allergy. World Allergy Organization Journal, 6(18), doi:10.1186/1939-4551-6-18

[xv] Thomas M, Crawford I. (2005). Glucagon infusion in refractory anaphylactic shock in patients on beta-blockers. Emerg Med J, 22(4), 272-273.

[xvi] Lieberman P, Simons FER. (2015). Anaphylaxis and cardiovascular disease: therapeutic dilemmas. Clinical & Experimental Allergy, 45, 1288-1295.

[xvii] Higuchi H, et al.(2014). Hemodynamic changes by drug interaction of adrenaline with chlorpromazine. Anesth Prog, 61(4), 150-154.

[xviii] Cardet JC, et al. (2013). Immunology and clinical manifestations of non-clonal mast cell activation syndrome. Curr Allergy Asthma Rep, 13(1), 10-18.

[xix] Guedes AG, et al. (2007). Comparison of plasma histamine levels after intravenous administration of hydromorphone and morphine in dogs. J Vet Pharmacol Ther, 30(6), 516-522.

Gastroparesis: Treatment (part 2)

Initial management of gastroparesis often focuses on treating dehydration and electrolyte and nutritional deficits.  One study found that 64% of gastroparesis patients were not consuming enough daily calories to support the needs of their bodies, which can worsen symptoms.  Vitamins A, B6, C, and K, as well as iron, potassium and zinc are frequently deficient in this population.  Small meals low in fat and fiber are recommended for gastroparesis patients.  Liquids or blended solids often empty normally from the stomach.

For cases in which oral diet is unable to provide sufficient calories and nutrition, placement of a feeding tube may be necessary.  Jejunal feeding tubes are often used successfully.  Prior to surgical placement of a feeding tube, a nasojejunal tube should be used successfully.  PEG-J or Jet-PEG tubes allow venting of gastric secretions to reduce vomiting and nausea while providing a feeding route.

TPN (total parental nutrition) is given intravenously, but carries risks, including central line infections.  For patients in whom oral feeding is not feasible, a feeding tube is often considered the safer option.

Metoclopramide, a dopamine D2 receptor antagonist, is approved for treatment of gastroparesis.  However, treatment beyond 12 weeks should be considered only if the improvement on this medication is significant enough to outweigh risks.  Metoclopramide can cause dystonia and tardive dyskinesia.  Benzodiazepines and antihistamines are sometimes used to treat these side effects.  Domperidone is also a dopamine D2 receptor antagonist, but has lower incidence of side effects.  It is not approved in the US, but can be obtained via special FDA approval for US patients.

Medications to increase gastric motor activity, like erythromycin, are often used in gastoparesis patients.  When taken orally, erythromycin often becomes less effective after several weeks of relief.  Proton pump inhibitors and H2 antihistamines may provide some relief as gastroparesis is often associated with and irritating to GERD.

Medications for management of nausea and vomiting are mainstays for many gastroparesis patients, with phenothiazines or antihistamines often used for this purpose.  5-HT3 receptor antagonists like ondansetron are also widely used.  The neurokinin receptor-1 antagonist aprepitant is sometimes used after failing other antiemetics.  Scopolamine patches and dronabinol are also options.  Tricyclic antidepressants can be used to manage nausea, vomiting and abdominal pain, with nortriptyline and desipramine often preferred over amitriptyline, which can cause delayed emptying.  Mirtazapine has been reported as successful in a case study.

Abdominal pain associated with gastroparesis can be difficult to manage because opiates can induce gastroparesis.  Gabapentin, tramadol, tapentadol, pregabalin and nortriptyline are non-opiate options for pain management.

For some patients, more invasive treatment is indicated.  Some patients with gastroparesis have increased tone in the pyloric canal, which can contribute to delayed gastric emptying.  Injection of botulinum toxin (Botox) into the pyloric sphincter is sometimes tried.  In double-blind studies, use of Botox increases gastric emptying but does not improve symptom profiles.

There are surgical options to manage gastroparesis, with varying results.  Gastric electrical stimulation is considered for patients with long term symptoms that have not improved despite treatment.  These devices are implanted and provide low grade electrical stimulation to the stomach and increase motility.  In diabetic gastoparesis patients, this method improved quality of life and decreased symptoms.  Patients who acquired gastroparesis following surgery, or whose gastroparesis is idiopathic, were less likely to improve using GES.  Pyloroplasty and gastrectomy (partial or complete) have been trialed in some patients, but there is not a clear trend in the data.

Acupuncture has been shown to benefit gastroparesis patients in a number of studies, including one blinded, randomized study. Symptom severity was improved in those receiving acupuncture and gastric emptying time was decreased.  Autogenic retraining using the program developed by NASA for space motion sickness has shown some benefit.  Autogenic retraining was found to be more successful in patients with intact autonomic function.

References:

Sarosiek, Irene, et al. Surgical approaches to treatment of gastroparesis: Gastric electrical stimulation, pyloroplasty, total gastrectomy and enteral feeding tubes.  Gastroenterol Clin N Am 44 (2015) 151-167.

Pasricha, Pankaj Jay, Parkman, Henry P. Gastroparesis: Definitions and Diagnosis. Gastroenterol Clin N Am 44 (2015) 1-7.

Parkman, H. P. Idiopathic Gastroparesis. Gastroenterol Clin N Am 44 (2015) 59-68.

Nguyen, Linda Anh, Snape Jr., William J. Clinical presentation and pathophysiology of gastroparesis.  Gastroenterol Clin N Am 44 (2015) 21-30.

Bharucha, Adil E. Epidemiology and natural history of gastroparesis. Gastroenterol Clin N Am 44 (2015) 9-19.

Camilleri, Michael, et al. Clinical guideline: Management of gastroparesis. Am J Gastroenterol 2013; 108: 18-37.

All the favors in pharmacy land

For most of my adult life, I have had the feeling that I didn’t have any money. I worked full time in college, and two full time jobs in grad school. I worked full time for a biotech company after I graduated, while also working side jobs. I certainly worked a lot for not having money.

At some point, I sat down and went through all my finances in detail. I looked at years of bank statements, credit card statements and student loan agreements. I tallied how much I spent on gas, on car repairs, on food, on fun. But none of those were the issue. I had one expense that was more than all of those put together: medical bills.

I literally just sighed as I typed that sentence. And you know what? I bet all the sick kids reading this sighed along with me. I don’t even get mad about it anymore. I am just resigned. Sigh.

I accepted a temporary position at my current company about two years ago. After six months as a contractor, I accepted a full time position. My contractor insurance was garbage and I needed comprehensive coverage badly. I eagerly flipped through the insurance information packets, basking in the golden glow of great medical coverage. It was overwhelming and wonderful. It was also a little sad that I was barely 30 years old and so excited about copayments and yearly out-of-pocket maximum costs that only had three zeros at the end.

I signed up for PPO insurance, which for our non-American readers means I can pick which doctors I see without being referred by my primary care physician (PCP, usually called general practitioner in other countries). There are caveats to PPO plans, but it is overall less restrictive and therefore desirable for me, as I often need specialist appointments on short notice.

In the US, it is not unusual for your medical insurance (doctor visits, hospital stays, medical supplies) to be managed by a different and completely separate company from your prescription coverage. So when I picked my PPO insurance, I also had to pick a large prescription carrier that forced upon the unwitting masses the bane of my existence: mail-order prescriptions.

I worked in pharmacy for about ten years. In that time, prescription insurance companies directly caused most of the issues that made my job frustrating and difficult. The prescription carrier I got along with my (amazing, approves everything) PPO is well known for rejecting claims for stupid reasons. But I needed a PPO and this was the corresponding prescription insurance. I didn’t have a choice.

So I got my new prescription insurance card and used it to fill my monthly medications at my local pharmacy. That went okay for a couple of months. Then I got a notification that my insurance would only pay for three fills of a maintenance medication (one that is taken all the time as part of your baseline care). Any fills after that would have to be filled with a mail order pharmacy.

Because I need a million strange things, I called my health insurance case manager. She sympathized but had nothing to do with pharmacy benefits. I told her that I had called the prescription company and asked for a case manager. They wouldn’t give me one. She couldn’t do anything.

The mail order pharmacy got new prescriptions for my meds from my doctors. They filled them and shipped them out to me. I opened the first huge box of meds and immediately knew something was wrong. I take ondansetron (zofran) 8mg three times a day every day. I have done this for years. I have tried to decrease and it always goes very badly. I have a prior authorization done every year to approve for 270 tablets/90 days for four total fills to coverage three a day dosing for the entire year. The pharmacy received a prescription that said that.

Except the person filling the prescription looked at it and thought, nobody takes three of these a day every day. Surely this is a mistake! And bless their hearts, they did me the huge favor of correcting that prescription from 270 with 3 refills to 27 with 30 refills. That’s much better.

So I had nine days of zofran. I called them and told them what happened. I was on the phone for two hours. They told me it was all set and they were sending the rest. Three days later, a package arrived. It had one bottle of 27 ondansetron.

I’m not going to bore you with the sordid details because I bet you all know where this is going. You know, right? Yup. Nine phone calls and every single one of them went exactly the same way except by the ninth, I was crying in frustration. I was out of my medication and every time I called, they told me it was all set and they fixed the error. And then nine more tablets would show up and we would start all over again.

This is a repeating cycle. The mail-order pharmacy is forever filling my 270 tablet (insurance approval obtained) prescription for 27 tablets.

So, mail order pharmacies are difficult. I don’t think that is surprising anyone here. But at the same time as this was going on in what I assume was a distant state where everyone is brainwashed to reassure me that they are fixing my problem right before they throw my precious bottles of ondansetron into a bottomless pit, I started having some problems closer to home.

I still got some prescriptions filled at my local pharmacy (this is entirely at the discretion of the pharmacy insurance.) There were only three I got filled locally regularly – prednisone, fluticasone nasal spray, and Epipens. Last October, I was counting out my prednisone 1mg tablets to put into my pill organizer when I realized there were a bunch of 5mg tablets mixed in with the 1mg tablets. I had been sick for three weeks and wondering why I felt decent one day and miserable the next. That would be because I was dispensed two strengths of a medication for which 1mg differences matter a lot. So that sucked. I called the pharmacist and she apologized and filled my script with 1mg tablets instead of both and I got on with my life. I understand that mistakes get made sometimes. It’s fine.

Then in December, this same pharmacy lost a prescription from my PCP. In May, they lost a prescription for prednisone for premedication before surgery. I had called the previous week to make sure it was there and sent my mother to pick it up on the Monday before my Wednesday surgery. It was gone. So that was quite a circus getting that straightened out the day before major surgery. The district pharmacy supervisor called me and we had a long conversation about my weird diseases and surgery and she apologized and I needed to go have surgery so I just let it go.

Two weeks ago, I called to get my Epipens filled. I had a new prescription that was on file from March. Guess what, guys? GUESS WHAT. That prescription was gone, too.

At this point, I just hung up the phone because I was about to start screaming. I called the district pharmacy supervisor on Monday and she went by the pharmacy to pull the original prescription book from the day it was sent over in March. It was there. It was filled, returned to stock and never put on hold. This was three prescriptions, all from different offices, in under a year, with a dispensing error right off the top.

While I was dealing with the Epipen situation, I ordered refills for all of my mail order meds and GUESS HOW MANY ONDANSETRON CAME IN MY ORDER. JUST. GUESS.

I called the poor nurse at my PCP’s office who does all my prior authorizations and I literally sobbed over how sick I was of fighting for things like meds to not vomit up everything I eat. This woman is a saint and she tag teams my insurance company with me to get things taken care of. To demonstrate my gratitude, I hereby bestow upon her the internet moniker of Nurse Amazing.

In the last two weeks, Nurse Amazing and I made over a dozen phone calls between us and had the same conversation over a dozen times. After one particularly hopeless day, she asked if my IV meds were covered under my medical benefit. They are. “If we have to, maybe we can just call in enough IV Zofran to get you through.” HOW DO I LIVE IN A WORLD WHERE IT IS EASIER TO GET IV MEDS THAN NON-CONTROL SUBSTANCE TABLETS WITH NO POTENTIAL FOR ABUSE? HOW IS THE WORLD LIKE THIS?

The Universe cut me a break this time. I finally got the rest of my ondansetron delivered Saturday.

While Nurse Amazing was on the phone with my insurance, she noticed my Enbrel prescription was about to expire so she gave them a new one over the phone. “She hasn’t taken this since last year,” the agent told the nurse so apparently they are also throwing away any record of my monthly order for this (refrigerated, requires signature and scheduled delivery) medication. My Enbrel arrived expediently with no paperwork of any kind. Just a labelled box of prefilled syringes, an ice pack and nothing else.

I just went to pick up my Epipens. The pharmacist did not apologize and did not look the least bit like she gave a shit that I have spent over 65 hours in the last three weeks trying to fill my medications at SIX pharmacies as required by insurance (for those keeping score: retail pharmacy, mail order pharmacy, specialty mail order pharmacy for Enbrel, a second retail pharmacy that stocks one of my harder to source meds, compounding pharmacy for ketotifen, IV pharmacy for IV push meds/infusions). And you know what? It’s one thing to make consecutive mistakes, and it’s another thing to make consecutive mistakes and act like I am an asshole for expecting my medications to be filled and tracked correctly.

“This copay is high but I can only charge you half because of what happened,” she said. Where ‘what happened’ meant they lost the prescription for my lifesaving epinephrine autoinjectors.

“I would appreciate it if you would waive the copay in light of all the time spent getting this straightened out,” I said in my most exhausted voice both because I am so exhausted and also because it was either exhaustion or screaming vulgarities.

“Fine,” she said. You know that voice people use when they think they’re doing you a favor, like they’re giving you something that you shouldn’t expect? It was that voice. “Fine.” In that voice. I signed, took my Epipens and left.

On my way home, I remembered that I got shorted needles by my IV pharmacy (which has never made a mistake with my meds or supplies.) I stopped by the other pharmacy in walking distance because I just did not want to go back to the one where the pharmacist was doing me favors.

In Massachusetts, you can buy syringes without a prescription if you’re over 18. I walked up to the counter with my license out and prepared myself for the inevitable condescension that usually accompanies buying syringes without a prescription.

The technician came right over. “I need twenty syringes, inch long needle, any gauge you want,” I said.

“Okay,” she said, smiling. “Any specific volume?”

“It doesn’t really matter. My infusion pharmacy just didn’t send me enough for this week.”

“Well, that’s not okay,” she said and you know what? SHE ACTUALLY MEANT IT. “I’ll bring over a few and you can pick.”

She brought over a few types and I picked the one I wanted and she rang me out.

As a demonstration of my appreciation for her smile and sympathy, she shall hereafter be known as Technician Amazing throughout all the lands. I have a dream that one day she will be successively promoted to the position of Supreme Pharmacy Ruler and she will decree that it shall be illegal to provide any less than 270 tablets of ondansetron when the prescription says 270 tablets of ondansetron.

Probably won’t happen like that. But it’s okay to dream.

Mast cell medications: Everything but antihistamines

The following medications listed are available in oral, intramuscular or intravenous formulation. Not all medications are available in the US or Europe. Topical and inhaled medications are not included in these lists.

Mast cell stabilizers interfere structures on the cell membrane required for degranulation and thus prevent the release of granule contents, including histamine.

Mast cell stabilizers
Cromolyn sodium/ Cromoglicic acid/ Nedocromil
Ketotifen
Omalizumab*
Quercetin
*mechanism unclear

 

Beta-2 adrenergic agonists cause smooth muscles to relax, which allow airways to open. These are used almost exclusively in asthma and pulmonary disease, which a secondary use in controlling uterine contractions in labor.

Beta-2 adrenergic agonists
Albuterol
Terbutaline

 

Leukotriene receptor antagonists work by interfering with the function of leukotrienes by blocking the CysLT1 receptor. Leukotrienes are heavily involved in airway reactivity and inflammation.

Leukotriene receptor antagonists
Montelukast
Pranlukast
Zafirlukast

 

5-lipoxygenase inhibitors prevent leukotrienes from being made.

5-lipoxygenase inhibitor
Curcumin
St. John’s Wort
Zileuton

 

Corticosteroids interfere with the activity of mast cells and production of mast cell mediators.

Mast cell stabilizers
Budesonide*
Dexamethasone
Hydrocortisone
Prednisone
Prednisolone
*taken orally, with effects local to the GI tract

 

Proton pump inhibitors reduce the production of gastric acid and treat heartburn, nausea and reflux. This can also be achieved by H2 antihistamines and for this reason, the two classes are often confused. The following medications, which are taken often by mast cell patients, have no known antihistamine effect. They can safely be taken with H2 antihistamines and help many mast cell patients, but it is important to clarify that they are NOT antihistamines.

Proton pump inhibitors
Dexlansoprazole
Esomeprazole
Ilaprazole
Lansoprazole
Omeprazole
Pantoprazole
Rabeprazole

Mast cell medications: Antihistamines by receptor activity

The following medications listed are available in oral or intravenous formulation. Not all medications are available in the US or Europe. Topical and inhaled medications are not included in these lists.

H1 antihistamines interfere with the action of histamine at the H1 receptor. This can help with many symptoms, including flushing, itching, hives, burning skin, nasal congestion, sneezing, constriction of airway, shortness of breath, GI cramping, diarrhea, gas, abdominal pain, tachycardia, blood pressure variability or dizziness. What symptoms are best alleviated varies with the medication; they do not all address all symptoms equally.

First generation Second and third generation Atypical antipsychotics
Alimemazine Acrivastine Aripiprazole
Azatadine Astemizole Asenapine
Benztropine Azelastine Clozapine
Bepotastine Bepotastine Iloperidone
Brompheniramine Bilastine Olanzapine
Buclizine Cetirizine Paliperidone
Captodiame Clemastine Quetiapine
Carbinoxamine Clemizole Risperdone
Chlorcyclizine Clobenztropine Ziprasidone
Chloropyramine Desloratadine Zotepine
Chlorpheniramine Ebastine
Chlorphenoxamine Emedastine
Cinnarizine Epinastine Typical antipsychotics
Clemastine Fexofenadine Chlorpromazine
Cyclizine Ketotifen Flupenthixol
Cyproheptadine Latrepirdine Fluphenazine
Dexbrompheniramine Levocabastine Perphenazine
Dexchlorpheniramine Levocetirizine Prochlorperazine
Dimenhydrinate Loratadine Thioridazine
Diphenhydramine Mebhydrolin Thiothixene
Diphenylpyraline Mizolastine
Doxylamine Rupatadine
Embramine Setastine Tetracyclic antidepressants
Etodroxizine Talastine Amoxapine
Ethylbenztropine Terfenadine Loxapine
Etymemazine Maprotiline
Flunarizine Mianserin
Histapyrrodine Tricyclic antidepressants Mirtazapine
Homochlorcyclizine Amitriptyline Oxaprotiline
Hydroxyethylpromethazine Butriptyline
Hydroxyzine Clomipramine
Isopromethazine Desipramine
Meclizine Dosulepin
Mequitazine Doxepin
Methdilazine Imipramine
Moxastine Iprindole
Orphenadrine Lofepramine
Oxatomide Nortriptyline
Oxomemazine Proptriptyline
Phenindamine Trimipramine
Pheniramine
Phenyltoloxamine
Pimethixene
Prometheazine
Propiomazine
Talastine
Thonzylamine
Tolpropamine
Tripelennamine
Triprolidine

 

H2 antihistamines interfere with the action of histamine at the H2 receptor. This helps mostly with symptoms affecting the GI tract, such as abdominal pain, nausea, and diarrhea. To a lesser extent, H2 antihistamines can decrease vasodilation.

H2 antagonists
Cimetidine
Famotidine
Lafutidine
Nizatidine
Ranitidine
Roxatidine

 

There are few H3 antihistamines and for this reason, their exact effects are largely unknown.  However, in research, H3 antihistamines modulate nerve pain and may normalize the release of several neurotransmitters, including serotonin.

The only medication with known H3 activity available for patient use as an antihistamine anywhere in the world is betahistine. It is anti-vertigo drug used mostly in treatment of Meniere’s disease and other balance disorders. Betahistine actually increases release of histamine and for this reason has been associated with the risk of severe allergic events while taking it.

A 2014 paper described for the first time the H3 reverse agonist/ selective antagonist effects of two antiarrhythmic drugs, amiodarone and lorcainide. This is a very new finding and has not been investigated yet in humans; however, this behavior would explain some of the neurologic effects of these two medications.

H3 antihistamines
Amiodarone*
Betahistine
Lorcainide*

 

Thioperamide has shown promise in research as an H3 and H4 antihistamine, but is not available for patient use.

I have seen blurbs on forums and the internet in which people state that amphetamines are H3 antagonists and doxepin is an H4 antihistamine. I cannot find any evidence that this is the case. Amphetamines interact with the transport of histamine in a very complex way, and that can theoretically interfere with the ability of cells to use histamine. However, this is not the same as a true antihistamine, and the effect of amphetamines on histamine has been difficult to quantify.

A comprehensive list of antihistamines: H1 receptor (part 2)

Chloropyramine is a first generation H1 antagonist. It is used for allergic eye and nasal symptoms, bronchial asthma, Quincke’s edema, and allergic reactions to food, medications and insect bites. It is available in several European countries as an oral or IV/IM preparation for emergent situations. It has the typical anticholinergic side effects seen in older H1 antihistamines. It is available under several names, including Allergosan, Suprastin, Supralgon and Avapena, in several countries, including Georgia, Hungary, Lithuania, Latvia, Russia, Croatia, Serbia, Bosnia and Herzegovina, Bulgaria and Mexico.

Chlorpheniramine is a first generation H1 alkylamine antihistamine. It is less sedating than other first generation antihistamines. It is sometimes used off label as an antidepressant and anti-anxiety medication as it has serotonin-norepinephrine reuptake inhibiting properties. It is available alone and in various combinations in the US, Canada, throughout Europe and Asia.

Chlorphenoxamine, more commonly known as Systral, is a medication with structural similarities to diphenhydramine. It is mostly used as an anti-Parkinsonian drug and is available in Latin American and Caribbean countries, as well as some European countries and Thailand.

Cinnarizine is an H1 antagonist that functions as both an antihistamine and also as a calcium channel blocker. It is a piperazine derivative. It improves blood flow to the brain and is used for cerebral apoplexy, cerebral symptoms following trauma and cerebral arteriosclerosis. It is also used for nausea and vomiting due to several causes. It is also antiserotinergic and antidopaminergic. Due to its action of dopamine receptors, it can cause parkinsonism if used frequently. It is not available in the US or Canada, but is available under a number of names in many countries, including Brazil, Peru, Philippines, Malaysia, China, Bangladesh, India, and Israel, among several others.

Clemastine is an H1 anthistamine. Though it can be sedating, it has fewer side effects than several other H1 medications. It is also a functional inhibitor of acid sphingomyelinase. It is available in many countries without prescription under brand names such as Tavist, Tavegil or Agasten. It is particularly effective for itching.

Cyclizine is an H1 antihistamine mostly used for nausea, vomiting and dizziness from motion sickness or medications, such as anesthesia. It is also used to potentiate the effects of opiates and opioids. It is a piperazine derivative and is available in the US and UK as IM/IV and oral formulations.

Cyproheptadine is a first generation H1 antihistamine. It is also antiserotonergic and for this reason is used to manage serotonin syndrome. It has a variety of unusual uses, including as a local anesthetic, to treat nightmares in children and due to PTSD, for hyperhidrosis, and to prevent migraine.

Dexbrompheniramine is a widely available medication with structural similarities to chlorpheniramine. It is used to manage general allergic symptoms. It is available in the US and Canada as Drixoral.

Dexchlorpheniramine is the one form of the drug chlorpheniramine. It is available in the US and Canada as Polaramine.

 

A comprehensive list of antihistamines: H1 receptor (part 1)

Alimemazine, also called trimeprazine, is a phenothiazine derivative, placing it in the same class as the more well known promethazine. It is used for a variety of purposes, including antipruritic (prevents itching), sedative, antiemetic, anxiety disorders, organic mood disorders and sleep disorders. It is a first generation H1 antagonist. It is not available for use in the US, but is available in many other countries, including several European countries, Japan, Taiwan, South Africa, Australia, New Zealand and throughout the Middle East.

Azatadine is a first generation H1 antagonist with structural similarities to loratadine. It is available as Zadine in India (note: Zadine is a brand name used in several countries for multiple drugs). It is used to treat allergic symptoms.

Bamipine is a first generation topical H1 antagonist used for itching and allergic rashes. It is sometimes combined with hydrocortisone and sold as a cream or gel. It is available in Austria, Germany and Poland.

Benztropine, also called benzatropine, is a first generation H1 antagonist. It is most commonly used in the treatment of Parkinson’s disease, and Parkinson-like symptoms, particularly tremors. It can also be used to treat dystonia. Benztropine is a widely acting medication. It also acts as a dopamine reuptake inhibitor, which can be helpful in treating narcolepsy and attention disorders, and a functional inhibitor of acid sphingomyelinase, which is sometimes used to treat depression. One study found that benztropine decreased symptoms and encouraged nerve re-myelination in MS patients.

Bepotastine is a non-sedating, second generation H1 antagonist. It is available as an oral and ophthalamic mediction in several Asian countries under the brand name Talion, with ophthalmic preparation only available in the US as Bepreve. Bepotastine has been well studied. In adult models, it inhibited histamine, antigen and PAF induced skin reactions, systemic shock, airway constriction and maintained appropriate vascular permeability. It may also inhibit leukotriene B4, NO production and substance P.

Brompheniramine is a first generation propylamine H1 antagonist. It is used for general allergic symptoms and is found over the counter in many countries. Additionally, it functions as a serotonin and norepinephrine reuptake inhibitor, giving it antidepressant properties. The first SSRI was derived from brompheniramine. It also potentiates the effects of opioid pain medication so less pain medication can be used.

Buclizine is an H1 antagonist derived from piperazine. It is mostly used for nausea. It is available in several countries, including India, Taiwan, Singapore and multiple European nations. In the UK, buclizine is available in a combination migraine medication, Migraleve.

Captodiame is an H1 antagonist derived from diphenhydramine. It is also a serotonin receptor antagonist and dopamine receptor agonist. It has antidepressant effects via a unique mechanism that raises brain-derived neurotrophic factor in the hypothalamus only. It can also mitigate CRF activity in the hypothalamus.

Carbinoxamine is an H1 antagonist readily available in many countries, including in the US. It is often combined with other medications, such as decongestants. It is used for urticarial, angioedema, dermatographism, hay fever and allergic rhinitis and conjunctivitis.

Chlorcyclizine is a first generation H1 antagonist derived from phenylpiperazine. It is used for general allergic symptoms and as an antiemetic. It also has local anesthetic properties and antagonizes serotonin receptors.

Anticholinergic use and dementia

I am going to take a quick break from the Lyme series to discuss something that has a lot of people concerned: whether or not antihistamines cause dementia.

A paper released online this week (“Cumulative use of strong anticholinergics and incident dementia,” by Gray and colleagues, JAMA Internal Medicine) was widely interpreted by the general media as proving that anticholinergic use causes dementia. It doesn’t. Studies like this get a lot of attention by the media – including reputable media – and they get sensationalist headlines.   This is generally not helpful. I think I have established well my distaste for tactics that scare the general public and this is a good example. Whether it is misinterpreted or intentionally misrepresented, news articles reporting on papers like this usually get it wrong.

Let’s look at what the paper actually says.

I actually like studies like this, because they have huge data sets to work with, and scientists usually like big data sets. (I’ll explain why that is in another post.) The study included 3434 patients 65 years of age or older who had no history of dementia when the study began. They were recruited to the study from 1994-1996 and then again from 2000-2003. Patients were followed up with every two years.

The purpose of this study was to determine if cumulative anticholinergic exposure over 10 years was linked to dementia, including Alzheimer’s disease. What is also interesting about this study is that the researchers had access to computerized pharmacy records for all these patients. This is important because it removes the uncertainty associated with patient reported information.   The researchers developed values for anticholinergic medications so that different medications could be compared meaningfully.

A lot of medications are anticholinergic. The more common medications include some antihistamines, tricyclic antidepressants, some antipsychotics, antispasmodics for the GI tract, bladder antimuscarinic medications, and medications used to treat Parkinson’s disease. In various studies, 8-37% of adults over the age of 65 have been found to regularly use anticholinergics. Cognitive disturbances (with memory, attention, “feeling slow,” etc) are well known side effects of anticholinergic medications. Older adults are thought to be more sensitive to these effects because of age related changes to the central nervous system.

Most researchers feel that these cognitive deficits are reversible by discontinuing the offending medication. However, some researchers have found that these deficits may be sustained, culminating in a range of effects from mild cognitive impairment to dementia. These studies had some noted limitations: they did not have solid proof of medication dosages or usage; they did not have information regarding dose or duration of therapy; the follow up periods were short; and they did not account for anticholinergic use to manage insomnia and depression, which can be seen in early, undiagnosed Alzheimer’s. This last one is very important because then the association would not be that anticholinergics cause dementia, but that they are used to manage symptoms of dementia.

The researchers also tried to control for health status, like a self-reported “poor” health status; hypertension; diabetes; APOE gene status; coronary heart disease; depressive symptoms; and benzodiazepine use, among other things. Some of these data were self-reported and some used a proxy, like the use of benzodiazepines for sleep or anxiety disorders.

78.3% of patients filled at least one anticholinergic prescription in the ten years before the study started. Antidepressants, antihistamines and bladder antimuscarinics accounted for more than 90% of all anticholinergic exposure. The most common medications from each of those categories were doxepin, chlorpheniramine and oxybutynin.

23.2% of patients (797 people) developed dementia in a mean period of time of 7.3 years from entry into the trial. 79.9% of those patients (637) were diagnosed with Alzheimer’s disease. This study found that patients in the highest exposure category had a statistically significant increased risk for dementia or Alzheimer’s. Participants in the next highest exposure category had a slightly elevated risk for dementia and Alzheimer’s compared to people who did not use any anticholinergics.

This is the take home message: this study found that people who used higher amounts of anticholinergics had an increased risk of dementia. They found that people with the most exposure took at least one of the following medications daily for more than three years: oxybutynin chloride, 5mg; chlorpheniramine maleate, 4mg; olanzapine, 2.5mg; meclizine hydrochloride, 25mg; doxepin hydrochloride, 10mg.

However, the study does not find that the medications CAUSED dementia. This is really important. It’s important because it’s possible that the conditions that required these medications may be linked to dementia. Or that these medications taken in conjunction with other medications to treat specific conditions might cause the increased risk of dementia. This study found an association. It found that high use of anticholinergics was correlated to increased risk of dementia. It did not find that high use of anticholinergics CAUSED increased risk of dementia. Associations like this are called correlative, not causative.

This study was well done. This was good science. I am a big believer in reducing anticholinergics where possible. I have a lot of lower GI problems and my need for huge doses of anticholinergics pretty much ground my motility to a halt. So I think it’s a good idea to examine medication regimens and reduce anticholinergics if possible, simply for the fact that they cause a lot of side effects.

The reality is that mast cell patients generally cannot avoid taking high doses of anticholinergic medications. I did a previous post on anticholinergic activity of antihistamines, so feel free to refer there. This is a topic I will keep an eye on, but I want to be clear: there is not yet any proof that anticholinergic medications cause dementia or Alzheimer’s disease.

 

References:

Grey, Shelley L., et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015.

Campbell, Noll L., Boustani, Malaz A. Adverse cognitive effects of medications: Turning attention to reversibility. JAMA Intern Med. 2015.

Cai X, et al. Long-term anticholinergic use and the aging brain. Alzheimers Dement. 2013; 9(4):377-385.

Fox C, et al. Anticholinergic medication use and cognitive impairment in the older population: the Medical Research Council Cognitive Function and Ageing Study. J Am Geriatr Soc. 2011;59(8):1477-1483.

 

 

MCAS: Pain

Pain is an unfortunate fact of life with MCAS. Muscle fatigue and weakness are common complaints, but myositis and rhabdomyolysis are rare. Some patients have elevated creatine kinase and/or aldolase, but have no related symptoms.

Bone pain is frequently reported with MCAS. Osteopenia and osteoporosis are common findings. Focal osteosclerosis is also sometimes found, but less frequently. Joints are often painful, which can lead to diagnoses of osteoarthritis, seronegative rheumatoid arthritis, fibromyalgia and polymyalgia rheumatica. Pain can migrate and is often poorly localized. Patients often feel pain in joints, bones and soft tissues, sometimes inconsistently.

Mast cells have been implicated in several pain disorders. Chronic lower back pain has been hypothesized to be related to mast cell activation for over a decade. Complex regional pain syndrome Type I, formerly known as reflex sympathetic dystrophy (RSD) and reflex neurovascular dystrophy (RND), is the most painful long term condition described. It is marked by neurogenic inflammation (nervous system swelling), sensitization of pain receptors and circulatory problems that cause swelling and color changes. It can affect any part of the body. Mast cells have been linked to the inflammatory response seen in CRPS patients.

Neurons with noradrenaline, serotonin and opioidergic receptors inhibit transmission of pain signals. (This is why taking opiates works for pain – it binds to these opioidergic receptors and suppresses the pain signals.) In the spinal cord, pain signals from the peripheral pathways meet up with the spinal pain signals to send to the brain. Here is where molecules like GABA, opioids made in the body and serotonin control pain transmission.

In chronic pain, serotonin acts to amplify the peripheral pain signals instead of suppress them. Increased serotonin levels and mast cell counts are found in many patients with chronic abdominal pain. About 95% of serotonin in the body is found in the peritoneal cavity, which explains the chronic pain many people feel in this region. Mediators released from colon biopsies in IBS patients were proven to excite the local nerves and activate pain receptors. Serotonin is one of these mediators.

Some antidepressants are known to affect serotonin secretion from mast cells. In particular, tricyclic antidepressants inhibit serotonin release in a dose dependent manner at higher concentrations. Clomipramine was seen to be the most effective, with amitriptyline and doxepin inhibiting release of serotonin and histamine at higher doses. All three were found to affect both uptake and reuptake of serotonin by mast cells and therefore lowering the relative concentration of serotonin in the local environment.

MCAS pain is often difficult to treat with typical pain medications. Antihistamines and cromolyn should be used to manage pain where possible. For bone related pain, bisphosphonates are usually effective. There is some data to suggest hydroxyurea can help manage pain in MCAS patients.

 

References:

Xinning Li, MD; Keith Kenter, MD; Ashley Newman, BS; Stephen O’Brien, MD, MBA. Allergy/ Hypersensitivity Reactions as a Predisposing Factor to Complex Regional Pain Syndrome I in Orthopedic Patients. Orthopedics 2014: Volume 37 · Issue 3: e286-e291

Giovanni Barbara, et al. Mast Cell-Dependent Excitation of Visceral-Nociceptive Sensory Neurons in Irritable Bowel Syndrome. Gastroenterology Volume 132, Issue 1, January 2007, Pages 26–37.

Ferjan, F. Erjavec . Changes in histamine and serotonin secretion from rat peritoneal mast cells caused by antidepressants. Inflammation Research 1996, Volume 45, Issue 3, pp 141-144.

Barbara, V. Stanghellini, R. De Giorgio et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology, vol. 126, no. 3, pp. 693–702, 2004.

Barbara, B. Wang, V. Stanghellini et al. Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome. Gastroenterology, vol. 132, no. 1, pp. 26–37, 2007.

Afrin, Lawrence B. Diagnosis, presentation and management of mast cell activation syndrome. 2013. Mast cells.

How to get out of a reaction cycle

If you have mast cell disease, your basic arsenal for managing your disease should include elimination of/ avoidance of known triggers, low histamine diet, second generation H1 antihistamines and H2 antihistamines.  Leukotriene inhibitors, aspirin, mast cell stabilizers, steroids and anti-IgE are also possibilities for maintaining a baseline.
As a mast cell patient, a decent baseline is what you are going for.  A reasonable baseline does not always mean that you can live the same way you did before your diagnosis.  It means that you are somewhat functional on a day to day basis.  What this looks for is different for everyone, but I aim for not being in bed for 20 hours a day, not being in 5/10 pain every day, being mentally coherent.  Most importantly, you should not have to take rescue meds frequently.  If you need rescue meds often, then you are not covering your mast cells well enough with your regular meds.  If you have eliminated triggers, then this usually involves tweaking your meds. 
I’m going to give you my insights on what that looks like, but please keep in mind that any med changes should be discussed with your treating physician.  We are all different people and med dosing can be affected by many factors. 
Part of why mast cell patients are prescribed second generation H1 antihistamines is because they are usually not sedating, have little anticholinergic activity and are, to be honest, pretty safe.  Mast cell patients often take several times the recommended daily dose on medications like loratadine and cetirizine.  (Please note: the daily recommended dose for Benadryl, which is a first generation H1, should be respected – overdosing can have serious consequences.)  So while the average person may take one Zyrtec a day for allergies, a mast cell patient may take 3 or 4 a day.  The same is true for the H2 antihistamines, like ranitidine and famotidine.  It’s not unusual to dose very high on those. 
If you have uncontrolled symptoms on second generation H1 and H2, changing the meds to something else in the same class may help.  Sometimes Pepcid works better than Zantac, or whatever.  Some people find that using one Allegra and one Zyrtec works better than two Allegras.  Consider also that inactive ingredients can be triggering and thus decreasing the effectiveness of a med.
If you have screwed around with H1 and H2 meds and have increased doses, adding leukotriene inhibitors, cromolyn or atypical H1 meds, like promethazine or doxepin, may help.  If that fails, ketotifen helps a lot of people, and anti-IgE (Xolair) has benefited some mast cell patients.  Beyond this, you are looking at things like regular IV fluids, steroids, and less palatable choices.
As I mentioned before, having a good baseline means not using rescue meds regularly.  This is really important to feeling as well as possible.  Serious reactions take a while to recover from, even if they don’t need epi.  So if you’re having one every day, it is impossible to get to your baseline without serious intervention.  The meds used to control serious reactions, including Benadryl, can cause rebound reactions that look like anaphylaxis, but are not anaphylaxis.  Let’s talk about this.
Benadryl can cause rebound reactions for two primary reasons.  The first is because it is a very strong antihistamine and it stops histamine release symptoms really well.  One of the things Benadryl does is it stops mast cells from releasing histamine.  So when it wears off, mast cells tend to release a lot of that histamine at once.  Another release is that Benadryl has very strong anticholinergic action.  When your dose wears off, you can have what’s called “cholinergic rebound.”  This can cause headache, nausea, vomiting, diarrhea, brain fog and other symptoms.  Sound familiar?  This is why people feel “hung over” when their Benadryl wears off.  Second generation H1 antihistamines, like cetirizine and fexofenadine, have almost no appreciable anticholinergic activity so they tend to not have this side effect.
Mast cell patients get hit with the double whammy of sizeable histamine release at the same time as they get hit with cholinergic rebound.  So rebound reactions can feel like anaphylaxis, but they’re not the same thing.  If you take Benadryl every day, you are going to have a rebound reaction every day.  It may not be severe, but this is not uncommonly the culprit in patients who say they always get sick around the same time every day. 
Another reason why it is generally not recommended for mast cell patients to take Benadryl every day is because it can stop working.  This is called tachyphylaxis and it basically means your body gets used to it.  When you need to use epinephrine, you are counting on Benadryl and steroids to help control the effects of anaphylaxis on your body.  Patients in whom Benadryl is ineffective get into very dangerous situations when they anaphylax.  I have a few friends like this and it is seriously not pretty. 
It is possible for anaphylaxis to be biphasic or protracted.  Biphasic reactions are not common, but seem to be more common in mast cell patients than the general population.  (This is my personal observation.)  In these reactions, once the reaction is stopped with epi, you can have another anaphylactic episode of the same or worse intensity without a trigger.  This generally happens within 24 hours and is the original reason Epipens were sold in pairs.  In protracted (sometimes called multiphasic) reactions, this can continue to happen for a number of days.  I find in my personal experience that use of epi early is the best way to avoid multiphasic reactions. 
If you absolutely must take a medication that causes a serious reaction (by which I mean not a typical side effect), desensitization is usually recommended for mast cell patients as opposed to taking antihistamines with each dose.  This method really just suppresses the immediate symptoms, not the inflammatory response.  Drug reactions for mast cell patients can be serious and any reaction can escalate even when it has been mild in the past.  For patients who react to salicylates, but need to take aspirin, Dr. Castells has written an aspirin desensitization protocol that is frequently used.
Part of why people get into these cycles with rescue meds is that they often don’t understand why they are having reactions.  Mast cell patients need to keep careful inventory of their daily histamine level because things that may not cause reactions individually can cause a reaction when you have them all together.  For example, if you have a relaxing day with no stress, maybe you can eat a spinach salad.  But if you go for a walk outside in the heat, and you eat that same spinach salad, you may have a reaction.  This doesn’t just happen to mast cell patients – there are plenty of recorded instances of patients having allergic reactions to food ONLY IF THEY EXERCISED THAT SAME DAY.  This is because exercise increases histamine.  Heat increases histamine.  Eating increases histamine. Stress increases histamine.  Sex increases histamine.  So all of this histamine adds up.  So you may be able to drink a beer, or you may be able to walk two miles, but if you try to do both the same day, you may have a reaction. 
Of course, there is also an idiopathic aspect to mast cell reactions, which means that some people have symptoms for truly unexplained reasons.  However, I find these happen a whole lot less when you really track activities/histamine and try to eliminate triggers. 
Part of how I evaluate my “histamine baseline” for any particular day is by certain physical parameters that I refer to as my “mast cell dead giveaways.”  If these are present, I know I am already starting out as reactive and need to lay low and avoid histamine that day.  Allergic shiners, which look like black eyes, or dark circles under the eyes, are one for me.  Swelling in my fingers tells me I’m having some edema from mast cell degranulation.  The taste of metal in my mouth often precedes reactions.  Skin being more reactive than usual is a very clear indicator for me.  On a reactive day, squeezing my arm with my hand will make my entire arm turn red.  I take my blood pressure in the morning and if my whole arm is red or has hives when I take off the cuff, it is a clear sign to me to not take risks that day.  Any type of “cold symptoms” (cough, stuffiness, clearing of the throat, sore throat) and I have to assume infection, which contributes to mast cell activation and thus to your histamine quota. 
I have written before about how to manage mast cell reactions with medication, so please refer to that post for more details.
Keep track of your histamine inventory.  Learn the “dead giveaways” for your body so you can self check.  If you’re taking Benadryl every day for symptoms, it can often be resolved with increasing meds/ adding other meds.  Taking Benadryl every day should be avoided, especially because it causes rebound reactions that can mimic anaphylaxis symptoms.