Steph’s Note: For this post, we welcome a new writer to tl;dr! Goravpaul Chatrath is a third-year pharmacy school student from Texas Tech’s School of Pharmacy in Amarillo, Texas. After graduation, he plans to pursue a residency in either critical care or psychiatry. When he’s not studying, Goravpaul likes to binge whole seasons on Netflix, travel, and drink copious amounts of caffeine.

Right there with you, Goravpaul. But until the next season of British Baking is released, let’s learn some pharmacy!

I have a love-hate relationship with cats. These mean-spirited fluffballs and I share the same personality, but on the other hand, I look like something out of a classic rom-com next to them whenever I forget to take my cetirizine.

And apparently I’m not alone.

The American Academy of Allergy, Asthma, and Immunology (AAAAI) and the American College of Allergy, Asthma, and Immunology (ACAAI) estimate that about 14% of adults and 13% of children in the United States experience allergic rhinitis (AR).

AR has also been shown to be an independent risk factor for development of asthma. So not quite the annoying (but overall benign) entity we tend to think it is!

Because AR is so prevalent (and of course annoying), one of the most common questions in a retail pharmacy or from family and friends scouring WebMD is how to conquer allergies.

Ready to wage war?

Allergic Rhinitis Pathophysiology

Fun fact: You cannot be allergic to a substance that your body has never seen before. Allergic responses only happen after sensitization. This refers to the production of antibodies to a foreign object (dust, pollen, dandruff, your crazy aunt, etc), which would not normally cause an immune response.

This immune response consists of an antigen presenting cell (APC), such as a dendritic cell, presenting the allergen to a helper T cell. The cell then goes full John Wick and transforms to a TH2 cell hellbent on getting rid of that damn pollen molecule.

The TH2 cell secretes cytokines that cause B cells to produce antibodies. In the case of allergies, the antibody is IgE. This antibody then binds to mast cells. Upon binding, the mast cell degranulates and releases inflammatory mediators (histamine, leukotriene, prostaglandins…oh my!).

These inflammatory mediators initially cause symptoms such as a runny nose and sneezing. This phase is called the early reaction and manifests in ~30 minutes. The same inflammatory mediators released in the early phase then bring in other immune cells such as eosinophils, more mast cells, neutrophils, and T cells.

All of these cells then throw a rager, which leads to the break down and remodeling of nasal tissue, aka a stuffy nose. This phase is called the late phase, which can last for several hours (which is just absolutely perfect for when you are trying to fall asleep).

Allergic Rhinitis Treatment

Intranasal Corticosteroids

While many patients will reach for an oral antihistamine first, intranasal corticosteroids (INCS) are actually recommended first-line due to increased efficacy and improved tolerability. These drugs include fluticasone (Flonase), triamcinolone (Nasacort), and budesonide (Rhinocort). Simply put, these over-the-counter medications work by dampening down the immune response to inciting substances, such as pollen or that damn cat dander.

INCS are non-sedating and reduce allergic symptoms more effectively than antihistamines. Continuous use is recommended rather than just using when the worst symptoms hit, but any use has still been shown to be better than nothing at all. INCS are even useful for patients who have both nasal and extra-nasal symptoms since they also can improve watery or itchy eyes.

However, there are reasons why people shy people away from these medications. INCS are more expensive than antihistamines. Plus they can cause nasal dryness, stinging, and sometimes even nosebleeds.

Most people misuse INCS. It is critical that patients blow their nose before use as they are ineffective if stuck in mucus. Furthermore, it is advised to not blow your nose for at least 15 minutes after use.

To put that in more concise terms; you’re literally blowing money.

The non-gross Google image of septal perforation. But you can imagine the complications of having wear and tear in the tissue between your nostrils… (Image)

Hee hee.

It’s also important to make sure patients do not direct the mist onto the septum of the nose.

Not only is drug not getting where it needs to go, but this practice can also lead to septal perforations down the road.

Yowsers.

All in all, INCS should generally be your first recommendation, unless coordination is an issue or an oral drug is preferred.

Second Generation Oral Antihistamines

Next up, we will discuss the top three second-generation antihistamines: loratadine (Claritin), cetirizine (Zyrtec), and fexofenadine (Allegra).

These oral antihistamines can be used as needed rather than on a scheduled basis, and their effects are usually seen more quickly than with corticosteroids. These drugs cause decreased drowsiness compared to their first-generation cousins, which will be discussed later.

They can either be added on to INCS or used as monotherapy, although the most recent AR treatment guidelines do not recognize any additional benefit of the combination over INCS monotherapy. These drugs have their own personalities, so we will go through them individually.

Loratadine is the cheapest of the bunch, and at recommended doses, it does not cause drowsiness.

While it does cross the blood brain barrier, it’s a substrate of the P-gp efflux pump, so it is spit right out before it can make patients too awfully tired.

The price for this lack of sedation?

Welllll, it is typically the least effective compared to the other two options.

But if price is an issue, loratadine is a good first try.

Cetirizine is as effective as fexofenadine (but is happily less expensive than fexofenadine). Unfortunately, as a metabolite of the first-generation antihistamine hydroxyzine, cetirizine is also the most sedating of the second-generation oral antihistamines - but this does vary between patients.

Still, this sedation should be a consideration when making recommendations for elderly patients or for those who are already taking sedating medications. Don’t want to give them the double whammy!

Our third option, fexofenadine, is generally considered the least sedating oral second-generation antihistamine option and has been shown to be as effective as cetirizine. It’s also one of the most expensive - of course.

However, if a patient hasn’t improved on other options or cannot tolerate them, it could be worth a fexofenadine trial.

Fun fact: fexofenadine absorption is impaired by citrus, so patients need to separate the use of this drug and orange juice (or any citrus juice, obvi).

Whoops. I lied. There is actually a 4th oral second generation antihistamine. SURPRISE!

Levocetirizine (Xyzal) is the active enantiomer of cetirizine. As such, it is just as effective as cetirizine but potentially has an improved side effect profile, including decreased drowsiness.

So why not levocetirizine for everyone?

Even though it is now available over-the-counter, it is brand name only and PRI-CEY. ($13 for just 10 tabs at CVS!) #sadface

So when should we actually consider levocetirizine?

Maaaaybe when someone says cetirizine works for them, but the sedation is just too much. Although I’d still ask them which other medications they’d tried before jumping to levocetirizine.

There is also desloratidine (Clarinex) as an option. If you were prepping for the SAT, you’d make an analogy like this:

Claritin : Clarinex :: Zyrtec : Xyzal

Or you could do this:

Claritin : Zyrtec :: Clarinex : Xyzal

Make sense?

But Clarinex is only available with a prescription, and Xyzal is OTC now-a-days. Just keep it in mind as an option.

As an FYI, there is a debate in the literature as to if tolerance (aka tachyphylaxis) occurs with antihistamines. Regardless, IF a patient complains that a drug no longer works for them, you can recommended to cycle through these 4 options monthly.

First Generation Oral Antihistamines

The most common medications in this group are diphenhydramine (Benadryl) and chlorpheniramine. These oldies (but sometimes goodies) have a plethora of effects, some of which are desired and some of which aren’t.

Of course, as antihistamines, they bind tightly to the H1 receptor for therapeutic effect. But that tight binding in central H1 receptors is also in part what causes droWwzzZZzzinessSSss…

Oh sorry. Started nodding off there. Back to it!

These first generation antihistamines also have the happy effect of reducing the production of mucus in the body. Which is what you want when your nose just won’t stop running, right?

In some cases, yes. But the reason they have this effect is because they’re so nonspecific in their receptor binding.

Not only do they bind histamine receptors as above, but they also bind to cholinergic, adrenergic, and serotonergic receptors! This can lead to some undesirable side effects, including the classic pharmacy saying:

Can’t see (blurry vision, dry eyes)
Can’t spit (dry mouth)
Can’t pee (urinary retention)
Can’t $h!t (constipation)

Because of binding to adrenergic receptors, tachycardia is also possible. Not to mention, a 2015 analysis published in JAMA discussed an increased risk of dementia with chronic use of first generation anticholinergic antihistamines!

So along with being long-standing members of the American Geriatric Society’s Beer’s list of medications to use with caution in the elderly, there may actually be an association with dementia.

No bueno.

So, after talking so much smack about these first generation oral antihistamines, do they actually have a place in therapy?

Well, they certainly can be helpful as sleep aids.

Diphenhydramine and its brother doxylamine are commonly used as sleep medications due to their sedating effects. They may also be included in nighttime variations of cold and cough syrups for those suffering from the cold or flu with heavy mucus production since they can help patients rest while also drying up the sniffles.

Unfortunately, neither diphenhydramine nor chlorpheniramine lasts very long, which is why they require frequent (about every 4-6 hour) doses.

Probably not what patients want to do if they’re just trying to ameliorate some allergy symptoms. (SO many phone alarms!) Especially when better, once daily medications are available.

Antihistamine Eye Drops

Next up, we have antihistamine eye drops. These can be an ideal choice for patients who just experience localized eye symptoms, like itchiness or watering. They can also be helpful if someone’s itchy, watery eyes aren’t relieved with other medications.

Ketotifen (Zaditor or Alaway) is available over-the-counter and is dosed twice daily. The other ophthalmic option, olopatadine (Pazeo), is prescription only and is dosed once daily.

Decongestants

Allergic rhinitis is often characterized by a stuffy nose. Decongestants work by stimulating alpha-1adrenergic receptors in the respiratory mucosa and causing vasoconstriction, which can be useful in the nose.

However, the downside is that this adrenergic stimulation can also lead to elevated blood pressure, and effects on beta adrenergic receptors can also cause tachycardia. As such, they should not be used, or at least used cautiously, in those with hypertension or cardiac disease in general.

Furthermore, decongestants can also cause rebound congestion.

What is that!? That seems like the OPPOSITE of what patients need!

Rebound congestion (aka rhinitis medicamentosa) refers to worsening nasal congestion with continuous use of decongestants. This happens because the nasal passages come to rely on medication to keep them clear.

When this happens, patients keep taking decongestants to clear their nose, and it’s just a vicious cycle! It often leads to dependence on these medications. This is why it is so important to ensure patients know to take a break after a few days of use to avoid developing this phenomenon.

Pseudoephedrine (Sudafed) is a great option but can keep patients up at night. To account for this, it should be dosed in the morning. It is available in numerous formulations, especially in useful combinations with antihistamines.

However, due to the potential for pseudoephedrine to be diverted and converted into illicit drugs (methamphetamines), it is no longer available over-the-counter.

Rather, it is behind-the-counter, which refers to the FDA’s requirement that pharmacies log all purchases and restrict the amount of daily/monthly sales to individuals.

Ephedrine is another member of the decongestant class. It is available as a tablet in combination with guaifenesin (Bronkaid).

It is available over-the-counter, but it’s usually targeted more towards patients with asthma, as ephedrine contains strong alpha 1 and beta 2 activity. Beta 2 agonism causes bronchodilation in the lungs (similar to albuterol). (On an only semi-related note, ephedrine has also been used as a weight loss supplement, due to its stimulant properties.)

As it relates to allergic rhinitis, ephedrine is NOT recommended as a decongestant due to its stronger effects on heart rate and blood pressure in comparison to pseudoephedrine.

Closely related, is ephedrine’s cousin epinephrine. It is available OTC as an inhalation aerosol (Primatene Mist). It’s also used primarily for asthma, and it has all of the same hypertension cautions as ephedrine.

Oxymetazoline (Afrin) is available as a nasal spray. It is generally considered to be effective and does not raise blood pressure as much as the other members of the decongestant class. This is because, as a nasal spray, it acts more locally than the other options.

Rebound congestion develops after two to three days on oxymetazoline and is generally more severe than pseudoephedrine, so counseling on a max of 3 days’ use is essential. As such, it’s really best for short-term relief rather than chronic rhinitis.

Phenylephrine is found in numerous over-the-counter products and in combination with everything under the sun (for example, Coricidin). That’s because it has less cardiac impact than pseudoephedrine and therefore is the drug of choice when it comes to safety in individuals with a cardiac history.

Unfortunately, the flip side of this improved safety is that it just isn’t as effective as the real deal. So it comes down, as always, to risk versus benefit and what has the patient already tried.

Reach into the Vault

In this section, we’ll go over some less common options, for when nothing seems to be calming those allergies.

First, we have the nasal antihistamines, azelastine (Astelin) and olopatadine (Patanase). These cause less drowsiness than their oral counterparts due to their local effects. They are ideal for nasal and ophthalmic symptoms.

Unfortunately, they are only available by prescription, and not too many people want to take two nasal sprays to get both nasal corticosteroids and antihistamines. (There is one combo product, Dymista (fluticasone/azelastine), but it is expensive and it’s also prescription only.)

Next, there is the leukotriene receptor antagonist class.

Prescription-only montelukast (Singular) blocks leukotrienes, which are involved in the inflammatory response in both asthma and allergic rhinitis.

Montelukast has been shown to be as effective as antihistamines and is also a great addition to INCS or antihistamines, especially in patients who have concomitant asthma or other reactive airway disease.

Of note, montelukast is available by prescription only primarily due to risk of suicidal ideations, so patients (and/or parents) need to be counseled on reporting any changes in mood when starting this drug.

It is typically dosed at night because its primary use is for asthma which tends to be more severe at night; however if taking it for allergies, patients can take it whenever is most convenient.

What it’s like to recommend cromolyn. (Image)

Finally, we have cromolyn sodium oral inhalation.

This is like reaaaaally reaching in the bottom of the bucket because, even though it is generally regarded as safe, it’s also been referred to as “inhaling water”.

It’s (supposedly) a mast cell stabilizer, which means it prevents mast cells from releasing inflammatory mediators, and on the rare occasions it is recommended, it’s usually for prevention of allergy-induced asthma attacks.

So not really just for your run of the mill person with allergies. Also, good luck finding it - it’s usually not stocked at most pharmacies.

Allergic Rhinitis: Final Points

While there are many options for allergy medications, the most important consideration is individualizing the therapy to your patient. Often, these medications are taken together in a trial-and-error fashion until relief is obtained.

Patients respond differently and response may even change with time (tachyphylaxis!), but I hope this guide will give you a good starting point for knowing the options.

Now that you know the defenses, have fun playing with cats! Or at least helping your patients play with cats.

Preparing for Spring: Allergic Rhinitis