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Systemic Management of Ocular Inflammation, Allergy & Pain

Jeff Urness, OD

College of Optometry, Pacific University

2043 College Way

Forest Grove, OR 97116

 

Contents

 

Introduction

Ocular inflammation, allergy, pain and related anxiety share many common characteristics and therapeutic interventions.  As a major component of inflammation, pain management often involves treatment of inflammation.  As an outcome of the allergic immune response, inflammation can be managed by intervention in the hypersensitivity process.  As pain perception is often modulated by anxiety, anxiolytic agents can be beneficial to pain control.

This course will be loosely divided into four categories; Inflammation, Allergy, Pain and Anxiety.

This course will review foundational terminology, anatomy and physiology of the eye and body pertinent to the management of ophthalmic inflammation, allergy, pain and related anxiety.  This knowledge will serve as the basis for presentation of successful practices and pitfalls of systemic prescriptive pharmaceutical management.  Specifically the course will present pharmaceuticals and biologicals that can be used in non-topical formulations to manage ophthalmic pain, allergy, pain and related anxiety.  The mechanism of action, common clinical use, caution and adverse effect and case examples will be addressed for each category.

Inflammation Management: Anti-Inflammatories

Inflammation is a physiological process intended to protect and repair the body when threatened, injured and or invaded by agents recognized as “foreign”.  There are three subclasses of inflammation:  Traumatic, Immunogenic and Neurogenic inflammation. 

Traumatic inflammation results from physical tissue damage.

(eg. Corneal abrasion)

 

Immunogenic inflammation develops where “foreign” substances contact and couple with immune cells. (eg. Bacterial conjunctivitis)

Neurogenic inflammation manifests when toxic substances encountered release neuropeptides that stimulate inflammation. (eg. Onion keratoconjunctivitis)

Each of these forms of inflammation can present acutely and or chronically.

Acute phase inflammatory response is frequently stimulated by an identifiable unsustained tissue insult.  The response is rapid in onset with a distinct termination.  The process is self regulated and usually abates in several days to a week following the triggering event.  It is characterized by a predominantly exudative vascular response.  The classic signs and symptoms of acute inflammation are:

Following an unsustained insult, acute inflammation unfolds in a predictable and generally well understood cascade of tissue activity.  Understanding these physiologic and anatomical responses is necessary to determine if, when and what intervention should be initiated by the clinician.

Regardless of the type of acute inflammation, the signs and symptoms arise from insult to and response of cells and their membranes.  In some instances the insult and response are localized to the same tissue (blunt trauma causing a black eye), while in others the response can manifest away from the exposure site (aspirin triggered asthma) or disseminate from the site of insult/exposure (staphylococcal septicemia).  The basic mechanism of acute phase inflammation is initiated and mediated by phospholipids richly populating cell membranes.  Whether it be physical damage, immunologic or neurgenic insult, cells produce arachadonic acid from cell membrane phosphotidyl choline combined with phosphotidyl inositol (Figure 1).  Arachidonic acid is the primary building block for the vast majority of inflammatory mediators (Eicosanoids) (Figure 2.

 

Figure 1:   Cell membrane phospholipid bilayer:  home to phosphotidylcholine and phosphotidyl inositol which combine to form arachadonic acid.

 

 

Figure 2

 

As cell membranes and the cell machinery produce arachadonic acid the acute inflammatory cascades “wind up” developing the inflammatory tissue responses of vasodilatation, vascular endothelial activation and neutrophil (white blood cell) activation.  The stages and sequence of the acute extracellular inflammatory process are seen in the following flow diagram (Figure 3).

Figure 3

Modifying or disrupting the activity of any or all of these stages will modulate the inflammatory response.  Anywhere from the initiating cellular response to potentiating cellular and extracellular activity the clinician has to potential to intervene and modify acute inflammation.

Chronic inflammatory response is more challenging to describe, assess and manage.  Inherent to the definition is prolonged duration of response.  This response can result from sustained tissue insult, failed resolution of the acute inflammation or hypersensitivity immune response.  Chronic inflammation often demonstrates slow onset with a persistent cyclical tissue destruction and repair (Figure 4).

 

Figure 4

 

 

In summary, inflammation is intended to protect and repair the body.  Acute inflammation is short in duration of rapid response and less challenging to describe and manage to resolution.  Chronic inflammation is of longer time course, sometimes indefinite, with definite resolution frequently difficult to achieve and identify.  Often seen as the adversary, inflammation can be inappropriately or improperly attacked by the clinician.  This can be minimized by always remembering the purpose of the inflammatory response and tenaciously seeking out its cause and mechanism before and during intervention.

Inflammatory intervention involves more than systemic anti-inflammatory pharmaceuticals, but this course is not prepared to address the full scope of the topic.  In the larger picture anti-infectives play a critical role in treatment of inflammation, as does surgery, restricted activity, cryotherapy, etc. 

Before the clinician initiates anti-inflammatory drug therapy they must aggressively search for the etiology of the inflammation.  Included in the discovery is a comprehensive health and medication history.  This is important to diagnosis as well as intervention.  The clinician needs to consider the impact of the modes of administration, sites of action and mechanisms of pharmaceutical neutralization and elimination.  Gastro-intestinal health and action are uniquely important to the administration of oral anti-inflammatories.  Some anti-inflammatories have erosive, anti-coagulative effects on gastrointestinal lining.  Casually prescribed they can lead to serious adverse events such as ulceration and hemorrhage.  Hepatic and renal function impact drug metabolism and elimination.  The kidney is the primary organ of elimination for drugs, while the liver is the primary organ to metabolize drugs prior to elimination.  The kidney is dependent on prostaglandins for normal function, therefore drugs that interfere with prostaglandin activity can significantly impact kidney function.   The kidney’s adrenal medulla provides the body vital glucocorticoids that can be critically impacted by administration of exogenous corticosteroids like prednisone. In addition to GI, hepatic and renal health, pulmonary and cardiovascular systems also impact and are impacted by anti-inflammatory drug activity. 

When prescribing medication for the old, the young, the fat, the thin and the medically complex the clinician must pay increasing attention to the history of present illness (HPI) and personal health history (PHHx).   If you question the suitability of a non-inflammatory medication in the context of the patients’s HPI and PHHx consider consultation with the patient’s primary healthcare provider.  If you question a failure of treatment reconsider the working diagnosis and query for the primary cause of treatment failure, non-compliance.

In general, anti-inflammatory interventions are greatest the earlier they act in they in the inflammatory cascades (Figure 5).  

 

Figure 5

 

Commonly prescribed systemic anti-inflammatory medications are divided into groups:  Salicylate non-steroidals and non-steroidals (NSAIDs), glucocorticoids (steroidals), antihistamines and anti-rheumatics (DMARDs). 

 

Salicylates:

 

In general salicylates are rapidly absorbed and distributed following oral ingestion.  They are extensively bound to plasma protein and commonly reach peak blood concentration in one to two hours.  They are metabolized in the liver and excreted by the kidney.  This class of anti-inflammatories can be formulated as a pro-drug.  A pro-drug is an agent that is converted by the body into a metabolite drug which then imparts the desired therapeutic effects.  Salicylate pro-drugs are hydrolyzed in minutes to a few hours, while the half life of most salicylates is 6 to 20 hours.  Eliminating the action of salicylates can require days to several weeks of “washout”.   Salicylates act both locally, modulating the effects of the inflammatory cascades and centrally suppressing the pain pathway.  One Of the known mechanisms of action is prostaglandin inhibition by irreversible acetylation of the cyclo-oxygenase enzyme.

Aspirin (acetylsalicylate) is used for both acute and chronic intervention.  Common dosage for acute inflammation is 325mg to 650mg every four hours not to exceed 4g/day.  Generally aspirin is not used for pediatric application, do to the risk of inciting Reyes Syndrome.  Aspirin is metabolized in the gut, blood plasma and liver, with a half-life of 15 to 120 minutes.  Its’ metabolites are excreted in the urine.  

Coated 325mg aspirin

 

 

Chronic low dose aspirin (81mg daily) is used for its’ platelet inhibitory effects to promote cardiovascular health.  Coated aspirin slows absorption decreasing the onset of therapeutic benefit, while reducing the adverse effects to the gut.  If rapid response is indicated coated aspirin should be avoided. 

 

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 Low dose 81mg coated aspirin

 

Dolobid (diflunisal)  is a long acting salicylate with a half life of 8 to 12 hours.  It is metabolized by the liver and excreted in both the feces and urine.  Usual dosing is 250mg to 500mg taken by mouth every 12 hours not to exceed 1500mg/day.  Dolobid exhibits all the actions of other salicylates though there are aspects of the mechanism of action that are still unknown.  A major effect of Dolobid to inhibition of prostaglandins.

 

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Like any pharmaceuticals, salicylates’ can produce adverse drug reactions (ADR).  Allergy to these agents can be life threatening.  Some asthmatics can be aggravated by salicylates.  Patients with severe pulmonary disease may have respiratory difficulty due to the added load salicylates place on respiration.  Salicylates are additive with steroids, NSAIDs and anticoagulants.  Patients with a history of gastro-intestinal bleeding are at risk for hemorrhagic events.

Ophthalmic indications for salicylates most commonly exploit the anti-platelet effects of the class. Amarosis Fugax, diabetic retinopathy and retinal vascular occlusions are conditions most commonly prompting prescription of salicylates. 

Non-steroidal anti-inflammatory drugs include several sub-classes and a large number of agents.  All classes have some degree of anti-inflammatory, anti-pyretic and analgesic effect.  There are seven sub-classes fenamates (eg. Ponstel), indoles (eg. Indocin), pyrazolones (eg. Butazolidin), proprionates(eg. Advil), Phenylacetates (eg. Voltaren), oxicams (eg. Feldene).  NSAIDs turn down the cyclooxygenase “valve”, reducing the production of prostaglandins and thrombaxanes.  There are two physiological pathways that require cyclooxygenase (Figure 6).  One, the COX-1 pathway, is primarily responsible for facilitating and modulating “housekeeping” activities carried out by the body.  These actions involve normal renal function, gastric protection, platelet production, to name a few.  The other pathway, COX-2, is primarily involved with inflammatory response producing and mediating prostaglandin activities, some of which produce pain, heat and swelling.

 

Figure 3: The Cyclooxygenase Pathway

Figure 6

 

In general orally administered NSAIDs are rapidly absorbed and distributed, being extensively bound to plasma protein.  Peak blood concentration is reached one to two hours following ingestion.  NSAIDs are metabolized by the liver and excreted by the kidney.  The half life is a couple of hours to a couple of days.  NSAIDs can produce a number of systemic adverse reactions.  Such responses include nausea, cramping, gastrointestinal ulceration, perforation and hemorrhage.  Some recipients may develop allergic reactions, including asthma and dermatitis.  NSAIDs will reduce blood clotting, but not to the degree that aspirin does.  Renal and cardiac function can also be adversely affected by this class of anti-inflammatory agents.  Prescibing NSAIDs for patients with GI, cardiovascular, renal or hepatic conditions must be done with added caution.

The selective COX-2 inhibitors have been implicated in cardic complications.  The mechanism of action contributing to these events is still uncertain.  Two popular theories are imbalance in COX activity leading to platelet aggregation and vasoconstriction, and elevated blood pressure secondary to sodium retention causing vasoconstriction.  From the published studies reviewed these events have overwhelmingly been connected with chronic treatment with oral COX 2 inhibitors.  It is unlikely that a short course of these medications, in a properly screened patient, would produce a clinically significant increased risk for myocardial infarction.

There are several ocular indications for oral NSAID therapy are: recalcitrant episcleritis, recalcitrant uveitis, recalcitrant cystoid macular edema and scleritis.  An example of dosing for episcleritis would be 250 mg to 500 mg of Naproxen bid to tid. An example of dosing for diffuse and nodular scleritis would be Indomethacin 25 mg to 50 mg tid.

 

                                     

 

Corticosteroid anti-inflammatory medications exploit the studies of the adrenal gland by Addison and Brown-Sequard from the 1800s.  They studied the role of adrenal glands in regulating body function, and in the early 1900s several hormones termed glucocorticoids and mineralocorticoids were isolated from the cortex of the adrenal gland.

Soon thereafter followed the discovery of the link between the adrenal glands, the pituitary gland (responsible for secreting adrenocorticotropic hormone (ACTH), which stimulates adrenal cortex corticosteroid production), and the hypothalamus (responsible for secreting corticotropin-releasing factor (CRF), which stimulates pituitary ACTH production). The hypothalamus, in turn, secretes more CRF in response to neural excitatory stimuli and reduced plasma corticosteroid concentration. This increases pituitary ACTH production which ultimately increases adrenal cortex corticosteroid production. This interdependent feedback mechanism is termed the H-P-A axis (Figure 7).                                                                                                                                                             

Figure 7

In normal individuals, the adrenal cortex secretes about 25mg of cortisol (hydrocortisone) and 5 mg corticosterone per day. Only about 5% of these steroids are biologically active, the remainder being bound to plasma protein. Naturally occurring corticosteroid hormones are critical to normal physiologic function.  Exogenous corticosteroid anti-inflammatory agents (steroids) mimic the action of naturally produced adrenocorticoid hormones, produced by the adrenal cortex.  Corticosteroid drugs impart their effects by entering cells, binding with cytoplasmic receptors, which then transport the complexes into the cell’s nucleus.  In the nucleus protein production is modified up-regulating production of anti-inflammatory proteins.  These proteins, in part, inhibit phospholipase A2 which impairs the production of Arachodonic acid the primary precursor to eicosanoid production (Figure 8).

 

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Figure 8

 

By inhibiting Arachodonate production the inflammatory cascades are inhibited very early in their path of activity, and thereby inflammation powerfully inhibited.

In equally powerful ways corticosteroid agents will up-regulate a number of other physiological mechanisms, which can lead to undesirable adverse effects from this drug class.  The prescriber must always be cognizant of the possible adverse effects of hypertension, hyperglycemia, congestive heart failure, psychosis, mood shifts, insomnia, allergy, osteoporosis, nausea/vomiting, appetite suppression, peptic ulceration, papilledema, impaired growth & healing, fat redistribution, muscle atrophy and promotion of infection.

The need for systemic steroids in the management of ophthalmic conditions is uncommon, but when indicated remarkably effective in minimizing sequelae.   In general systemic steroids are indicated when topical and/or injectable delivery is not appropriate or sufficient to achieve desired therapeutic effect.  Systemic steroids are also indicated when the ophthalmic condition is part of a more disseminated disease process requiring steroid treatment.

 

Ophthalmic conditions warranting systemic corticosteroid therapy:

Common agents and dosing for acute ophthalmic intervention:

Prednisone

Adult up to 120 mg PO QD

Child 0.05 to 2 mg/kg/day PO

Dexamethasone

Adult up to 9 mg PO QD

Child up to 0.3 mg/kg/day PO

Injection – 4 mg/cc  up to 0.5 cc SCI

Triamcinalone (Kenalog)

Adult up to 50 mg QD

Child not advised for under age 12 years

Injection – 40 mg/cc   up to 0.5 cc SCI

Methylprednisilone Dosepak (Medrol Dosepak)

Adult:  Presorted system of 4 mg tablets.  24 mg of drug are taken day one, reducing dose by 4 mg each day until the pack is completed. 

Nasal inhaler

Flonase & Beconase

2 sprays/nostril/day

Typical systemic corticosteroid adult dosing for ophthalmic conditions:  Arteritic ischemic optic neuropathy 1000 mg IV methylprednisilone per day x 3 days or 60 mg to 100 mg oral prednisone daily tapering based on response to therapy.  Highly suspect orbital pseudotumor is treated with 60 mg to 100 mg oral predisone and tapered based on clinical course.  Dramatic and rapid response of orbitopathy is strongly supportive of the working diagnosis.  Graves orbitopathy is less uniformly responsive to oral prednisone.  Maximum therapeutic benefit of 80 mg to 100 mg oral prednisone daily should be achieved in 2 weeks or less.  Prompt taper of prednisone should begin, at the latest, two weeks into treatment.  Severe type I allergic blepharoconjunctivitis usually responds rapidly to treatment with a Medrol dosepak (24 mg down to 4 mg over 6 days).

DMARDs (anti-rhematics) and immunosuppressive agents are not covered in this course.