Download New Concepts in Ocular Surface Infection and Inflammation

Oral Pharmaceuticals in Anterior
Segment Disease
Blair B Lonsberry, MS, OD, MEd., FAAO
Diplomate, American Board of Optometry
Pacific University College of Optometry
[email protected]
OSDs are Difficult to Tell Apart: Overlapping
Signs/Symptoms
Signs
Hyperemia
Chemosis
Lid Swelling
Symptoms
Foreign Body Sensation
Burning
Dry, Gritty Ocular
Surface
Itchy Eyes
Photophobia
Tearing
CASE
Case
• 20 year old male presents
with a red painful eye
– Started that morning when he
woke up
– reports a watery discharge, no
itching, and is not a contact lens
wearer
• SLE:
– See attached image with NaFl
stain
Herpes Simplex Keratitis: Clinical
Features
• Characterized by primary outbreak and subsequent
reactivation
• Primary outbreak is typically mild or subclinical
• After primary infection, the virus becomes latent in
the trigeminal ganglion or cornea
• Stress, UV radiation, and hormonal changes can
reactivate the virus
• Lesions are common in the immunocompromised
(i.e. recent organ transplant or HIV patients)
Dendritic Ulcers
6
Pediatric HSV Keratitis
• pediatric herpes simplex keratitis has an 80% risk
of recurrence, a 75% risk of stromal disease, and
a 30% rate of misdiagnosis
• 80% of children with herpes simplex keratitis
develop scarring, mostly in the central cornea
– results in the development of astigmatism
– 25% of children have more than 2 D of astigmatism,
most of which is irregular
• consider pediatric HSV when a patient has
unilateral recurrent disease in the anterior
segment
Herpes Simplex Keratitis Management
• Topical:
– Viroptic (trifluridine) q 2h until epi healed then
taper down for 10-14 days.
• Viroptic is toxic to the cornea.
– Zirgan (ganciclovir) available, use 5 times a
day until epi healed then 3 times for a week
(US only)
Anti-Viral Medication
Drug
Mechanism of Action
Acyclovir
Bioavailability
Dosing
Side Effects
Acyclovir interferes with 10-30% gets
DNA synthesis inhibiting absorbed
viral replication
Short ½ life
*Metabolized in
kidneys
Simplex:
400 mg
5x/day
Zoster:
800 mg
5x/day
Overall very safe
Nausea, vomiting,
headaches,
dizziness,
confusion
Valacyclovir
Acyclovir pro-drug
Equivalent to acyclovir
but better for pain
management
Simplex:
500 mg tid
Zoster:
1 g tid
Same as acyclovir
Famciclovir
(Famvir)
Inhibits DNA chain
Superior to
elongation
acyclovir*
It is metabolized to
penciclovir where it is
active 10-20x as long as
acyclovir
Simplex:
250 mgTID
Zoster:
500 mg TID
Same as acyclovir
95% converted to
acyclovir*
Better
bioavailability and
longer 1/2 life
HSV Stromal Disease
• HSV Stromal disease is an immune-mediated disease
• Increased risk of scarring and high risk of poor visual
prognosis
• Requires corticosteroids (HEDS: corticosteroid reduced risk of
progression by 68%)
– Without epithelial defect: corticosteroids and prophylactic anti-viral
dosage
– With epithelial defect: active infection anti-viral dosage with judicious
corticosteroids
How much to dose steroid?
• HEDS used QID of prednisolone phosphate
• Current Recommendations:
– Mod – severe (especially with neo): 1%
Prednisolone or Lotemax QID to 6x/day
– Want the lowest dose needed to control the
inflammation
– AAO EBM Treatment Guideline 2014
• Topical steroid for 10 weeks (this is based on HEDS results) with oral
antiviral
Herpes Simplex Epithelial Keratitis
• Treatment Regimen:
– Zirgan 5x/day until the ulcer heals, then 3x/day for one week
– Oral Valtrex 500 mg 3x/day for 7-10 days
– Artificial tears
– L-Lysine 2 grams daily?
• Proven to “slow down” and retard the growth of the herpes virus and
inhibit viral replication
– Debride the ulcer?
• Prior to topical antiviral therapy debridement was treatment of choice
• Generally try to avoid use of sharp instruments and use of cotton swab
and anesthetic
• RTC 1 day, 4 days, 7 days
Herpes Simplex Keratitis
• Prophylactic Treatment:
– Reduces the rate of recurrence of epithelial and stromal
keratitis by ≈ 50%
• Acyclovir 400 mg BID
• Valtrex 500 mg QD
• Famvir 250 mg QD
• L-lysine 1 gram/day:
– Proven to “slow down” and retard the growth of
the herpes virus and inhibit viral replication
• Frequent debilitating recurrences, bilateral
involvement, or HSV infection in a monocular patient
Prophylaxis??
• Pitfalls to Prophylaxis:
– Reduction of recurrence does not persist once drug
stopped
– Resistance????
• van Velzen, et. al., (2013) demonstrated that longterm ACV prophylaxis predisposes to ACV-refractory
disease due to the emergence of corneal ACVR HSV-1.
Herpes Zoster
Herpes Zoster Ophthalmicus
18
Herpes Zoster
• Presents with:
– pain and tingling in region of skin supplied by V
few days before lesions,
– malaise and fever,
– papulomacular then pustular rash,
– mucopurulent conjunctivitis,
– uveitis, glaucoma, episcleritis, keratitis, and retinitis
can all occur.
– neurological complications include cranial nerve
palsies and optic neuritis.
Herpes Zoster
• Associated factors include increasing age, immune deficiency and
stress.
• Only people who had natural infection with wild-type VZV or had
varicella vaccination can develop herpes zoster.
• Children who get the varicella vaccine appear to have a lower risk
of herpes zoster compared with people who were infected with
wild-type VZV.
• A person's risk for herpes zoster increases sharply after 50 years of
age.
• Almost 1 out of 3 people in the United States will develop herpes
zoster during their lifetime.
• A person’s risk of developing post-herpetic neuralgia also increases
sharply with age.
Herpes Zoster
• Management includes:
– oral antivirals:
• 800mg acyclovir 5x/day
• valacyclovir (Valtrex) 1g TID,
• famciclovir (Famvir) 500 mg TID
– effectiveness of therapy is best started within 72 hours
• Valacyclovir and famciclovir are preferred because of better
bioavailability and convenience
– Pain management:
• tricyclic antidepressants,
• Gabapentin
• oral steroids
Herpes Zoster Ophthalmicus (HZO)
• Topical ganciclovir 5 times a day until healed, and
then twice daily for 2 to 4 weeks is effective for
dendriform keratitis, even in cases that have
been unresponsive to oral antivirals
• Topical corticosteroids:
41
– management of stromal keratitis and uveitis,
– often need to be continued at a low-dose chronically
and
– require close monitoring for safety and efficacy
Herpes Zoster Ophthalmicus (HZO)
• Secondary glaucoma (16% to 56%) can occur
because of inflammation or topical
corticosteroids.
• Neurotrophic keratopathy:
– complicated by persistent epithelial defects,
– corneal melting with or without perforation, and
– microbial superinfection
– challenging to manage
Vaccine (Zostavax®)
• The Advisory Committee on Immunization
Practices (ACIP) recommends zoster vaccine
(Zostavax®) for people aged 60 years and older.
• The vaccine reduced the overall incidence of
shingles by 51% and the incidence of PHN by 67%
• Even people who have had herpes zoster should
receive the vaccine to help prevent future
occurrences of the disease.
• In adults vaccinated at age 60 years or older,
vaccine efficacy wanes within the first 5 years
after vaccination, and protection beyond 5 years
is uncertain
Corneal Ulcers
•
•
Infective bacterial and fungal corneal lesions cause severe
pain and loss of vision
Signs and Symptoms:
– Pain, photophobia, tearing
– Mucopurulent discharge with generalized conjunctival
injection
– Decreased VA (esp if on visual axis)
– Possible AC reaction and hypopyon
– Dense infiltrate
– Satellite lesions around main lesion may indicate fungal
infection
Associated Factors
• Contact lens wear, especially soft and extended wear
lens
• Recent history of corneal trauma
• Topical steroid use
• History of exposure to vegetative matter (fungal
etiology)
When to culture?
•
1,2,3 Rule:
•
•
•
•
•
•
1 mm from visual axis
2 infiltrates (or more)
3mm or greater in size
Nosocomial infections
Immuno-compromised patient
Post-surgical
Sterile vs Infectious Infiltrates
Peripheral (Sterile) Corneal Ulcer
Infectious Corneal Ulcer
Corneal Ulcers
• The Steroids for Corneal Ulcers Trial (SCUT)
• Conclusions:
– no overall difference in 3-month BSCVA and no safety
concerns with adjunctive corticosteroid therapy for
bacterial corneal ulcers
– researchers did find significant vision improvement for one
specific subgroup of the study by using steroid therapy on
patients with severe ulcers
• Application to Clinical Practice:
– Adjunctive topical corticosteroid use does not improve 3month vision in patients with bacterial corneal ulcers
unless in the severe category
Management
• Infective ulcers need to be cultured!
• If contact lens wearer, consider culture of
contact lens
• Intensive topical antibiotic regimen,
consider fortified preparations,
subconjunctival injections.
– loading dose of
Vigamox/Moxeza/Zymaxid/Besivance 2gtts q 15
min x 1 hour,
– 1gt q 30 min x 6 hours,
– 1 gt q 1 hr until f/u in 24 hours.
ARMOR
• Antibiotic Resistance Monitoring in Ocular
Microorganisms (ARMOR)
• Approximately 42% of isolates were determined
to be MRSA
• Newer fluoroquinolones have better activity than
earlier generations
• Besivance has the lowest MIC values of all the
fluoroquinolones
• Vancomycin is drug of choice if MRSA present
• Azithromycin had very poor activity against Staph
Anti-inflammatory effects
• Degrade extracellular proteins
• Tetracyclines inhibit MMPs
• Anti-inflammatory
Pseudomonas case report
“Doxycycline as an adjunctive
therapy…may help to stabilize
corneal breakdown and prevent
subsequent perforation.”
AM. McElvanney
750
Anti-inflammatory Efficacy
• Cortisol (hydrocortisone) is the standard of
comparison for glucocorticoid potency and is given
an anti-inflammatory score of 1
• All of the other medications are given relative
scores that allow direct comparison
– Prednisone has a relative anti-inflammatory efficacy of 4
• Much easier to compare for systemic medications
than topical because of the vast differences in tear
films, drop delivery, etc.
Anti-Inflammatory Efficacy
Generic Name of
Medication
Anti-Inflammatory
Activity
Equivalent
Dose (mg)
Relative Sodium
Retaining Activity
Hydrocortisone
1.0
20 mg
1.0
Prednisone
4.0
5 mg
0.8
Prednisolone
4.0
5 mg
0.8
Triamcinolone
5.0
4 mg
0.0
Methylprednisolone
5.0
4 mg
0.0
Dexamethasone
25.0
0.75 mg
0.0
Betamethasone
25.0
0.75 mg
0.0
Bioavailability of Systemic Steroids
• Corticosteroids are readily absorbed from the intestinal
tract which makes oral dosages very effective
• They are metabolized by the liver (must consider
function before prescribing) and excreted via the
kidneys
• Long term steroid treatment must be tapered to avoid
side effects
– Even at doses as low as 15 mg of prednisone if the patient
has been dosed for several weeks
• High dose oral steroids should be considered for initial
therapy
– 1 mg/kg therapy and continued until uveitis has resolved
Systemic Corticosteroids
• Prednisone
– Available as Oral: 1, 2.5, 5, 10, 20, 50 mg tablets (1
and 5 mg/mL solution and syrup, if needed)
• Ocular Treatment Guidelines
– Mild to Moderate: Initial dose of 20-40 mg
– Moderate to Severe: 40 – 60 mg
– Severe: 60-100 mg
• IV Methylprednisolone 250 mg IV q6hours for 12 doses for arteritic ischemic optic
neuropathy (giant cell arteritis)
• Similar dose given for active optic neuritis 2⁰ to MS
Steroid Treatment Pearls
• Specific type and location of inflammation
determine route of administration
• I.e. treat the problem!
– Topical, Systemic, Periocular, Intravitreal, etc.
• Must institute treatment immediately and at a
high enough dose and frequency to suppress
the inflammation
Indications for oral and IV steroids
• Inflammation of the posterior segment, optic
nerve, or orbital tissues
–
–
–
–
–
–
Stubborn anterior uveitis
Posterior uveitis and/or chorioretinitis
Scleritis
Arteritic Ischemic Optic Neuropathy – temporal arteritis
Optic neuritis
Orbital inflammatory pseudotumor
• Also recommended for hypersensitivity reactions
– Contact dermatitis, etc
Why Taper?
• To prevent rebound inflammation
– Corticosteroids reduce the quantity and activity of
leukocytes
– Stopping cold turkey causes these white cells to
proliferate and increase the production of
inflammatory cytokines
– This means more steroids for a longer period of
time which increases the risk of side effects
What is the “right way” to taper
oral prednisone?
• Tapering is VERY case specific – no cookie-cutter method
• If the inflammation is mild and a low dose oral steroid is
prescribed for less than a week, tapering is usually not
needed
• Do NOT start tapering until the inflammation is resolved
Medrol Dosepak
• Methylprednisolone
• Dosepaks have six 4 mg tablets that the
patients takes on day one, with the number of
tablets reduced by 1 each day over the next 6
days in a tapering schedule (21 tablets total)
• Convenient dosing regimen with built in
tapering
Side Effects of Systemic Corticosteroids
• Incidence increases with
long-term high-dose therapy
• Length of use has greater link to developing
side effects than dosage amount
Side Effects of Systemic Steroids
• Metabolic Effects:
–
–
–
–
HYPERglycemia can occur
Increased appetite, Weight Gain, and Redistribution of fat
Decreased calcium absorption – leads to Osteoporosis
Hyperlipidemia
• Mineralocorticoid Effects:
– Fluid Retention (Increased Sodium Retention)
– Hypertension
– Edema (If liver/kidneys can’t keep up)
• CNS Symptoms: Euphoria, Insomnia, Psychoses,
Depression, and Restlessness
Therapy Considerations
• Diabetes
– Educate all Type 2 Diabetes patients that their blood sugar
will likely become elevated
– Educate all Type 1 Diabetes patients they made need to
alter their insulin levels
• Peptic Ulcers
– Consider prescribing an H2 Blocker or a Proton Pump
Inhibitor if prednisone dose ≥60 mg or ≥30 mg over 2
weeks
• PPI’s: Omeprazole (Prilosec), Esomeprazole (Nexium), and
Lansoprazole (Prevacid)
• H2 Blockers: Cimetidine (Tagamet), Famotidine (Pepcid), and
Ranitidine (Zantac)
Steroid Considerations
• Also use caution in patients with:
– Any Infectious disease
– Pregnancy (Orals are Category C)
– Chronic renal failure
– Congestive Heart Failure
– Systemic Hypertension
– Osteoporosis
– Psychoses
Allergic Conjunctivitis
Prevalence of Allergic Conjunctivitis
• Allergies affect as many
as 40 to 50 million
Americans
• Incidence and
prevalence of allergic
conjunctivitis has been
rising over the last 40
years
Signs and Symptoms of Allergic Conjunctivitis
Clinical presentation – bilateral
Signs:
–
–
–
–
–
Symptoms:
Conjunctival edema
Conjunctival hyperemia
Chemosis
Lid edema
Watery discharge
Lid edema and bilateral hyperemia
–
–
–
–
–
Hyperemia
Itching
Burning
Photophobia
Foreign body sensation
Blurred vision
Chemosis
Mast Cell Cascade
Treatment
• Ocular allergy sufferers need;
– fast relief of signs and symptoms,
– long-lasting therapeutic effects,
– comfortable and safe topical drugs,
– convenient treatment regimen
• Therapeutic focus is mostly confined to the
suppression of mast cells, their degranulation
and the effects of histamine and other mast-cell
derived mediators.
Treatment of Ocular Allergy
Medications:
• Topical OTC drops
• Oral antihistamines (prescription and OTC)
• Topical NSAID drops
• Topical antihistamines
• Topical mast cell stabilizers
• Topical steroid drops
• Topical dual-action drugs (antihistamine/mast cell
stabilizers)
Oral Allergy Medications
• Oral antihistamines (pills and liquids) ease
symptoms such as:
–
–
–
–
swelling,
runny nose,
itchy or watery eyes, and
hives (urticaria).
• Some oral antihistamines may cause dry mouth
and drowsiness.
• Older antihistamines such as diphenhydramine
(Benadryl), chlorpheniramine (Chlor-Trimeton)
and clemastine (Tavist) are more likely to cause
drowsiness and slow reaction time.
– these sedating antihistamines shouldn't be taken when driving or
doing other potentially dangerous activities.
OTC Allergy Medications
Generic
Brand
Diphenhydramine
Benadryl
Chlorpheniramine
Chlor-Trimeton
Clemastine
Tavist
Loratadine
Claritin
Cetirizine
Zyrtec
Fexofenadine
Allegra (both OTC and Rx)
Prescription Allergy Medications
Carbinoxamine maleate
ARBINOXA, PALGIC (tabs, solution)
Diphenhydramine HCI
BENADRYL Injection
Hydroxyzine HCI
HYDROXYZINE HCL (tabs, syrup)
Desloratadine
CLARINEX (tabs, ODT, syrup)
Fexofenadine HCl
ALLEGRA (tabs, ODT, suspension)
Levocetirizine dihydrochloride
XYZAL (tabs, solution)
Montelukast
SINGULAIR (tabs, chew tabs, granules)
Cromolyn sodium
GASTROCROM (oral solution)
Ocular Allergy Medication Options
Tetrahydrazoline HCI
VISINE*, MURINE* Plus
Naphazoline HCI
NAPHCON® eye drops,
VASOCON*
Phenylephrine HCI
PREFRIN*
Oxymetazoline HCI
VISINE L.R.*
Naphazoline/Antazoline
VASOCON*-A
Naphazoline/Pheniramine
NAPHCON-A® eye drops
Ketorolac
ACULAR*
Suprofen
PROFENAL® solution
Diclofenac
VOLTAREN*
* Trademarks are the property of their respective owners
**Vexol is a trademark of N.V. Organon
Levocabastine LIVOSTIN*
Emedastine EMADINE® solution
Loteprednol
Rimexolone
ALREX*
VEXOL** suspension
Cromolyn
CROLOM*, MAXICROM™ solution
Lodoxamide
ALOMIDE® solution
Nedocromil
ALOCRIL*, TILAVIST*
Pemirolast
ALAMAST*
Azelastine
OPTIVAR*, LASTIN*
Ketotifen
ZADITOR*, ALAWAY*,
ZYRTEC, CLARITIN
Epinastine
ELESTAT*
Olopatadine PATANOL® PATADAY
Bepotastine
BEPREVE
Alcaftadine
LASTACAFT
Thank You!!!