- ophthalmic drops, ointments,
gels, contact lenses, collagen shields, etc.
indications include:
- treatment and control of
superficial and anterior segment diseases such as conjunctivitis, keratitis,
glaucoma, etc.
- treatment posterior segment
disease such as endophthalmitis or retinitis may be of little value.
- applied directly to the site
of action, reduces the risk of systemic side effects but does not alleviate
them totally.
penetration of drug into the cornea or anterior chamber is dependant
upon a number of factors including:
- molecular size
- pH Many drugs exist in a partially ionized form, with the degree of
ionization depending upon the pH. In
general, increasing the pH of medications or the unionized form, increases the
lipid penetration of the drug.Higher pH values may not be recommended from the
standpoint of stability. Although the eye can tolerate a rather wide range of pH (3.5-10),
reflex tearing will occur, which will wash out the drug effect faster than if
the pH is more
in the physiologic range.
- tonicity - isotonicity not
required. Range is from 0.7%-2.0% (0.9%
sodium chloride is isotonic).
- concentration
- limitations of the eye to hold
ophthalmic drops. normal eye can
momentarily hold 20-30 ul.(normal eyedrop size is approximately 50 ul although
ophthalmic manufacturers have begun to decrease the dropper size so the risk of systemic
side effects and drug waste is reduced).
Blinking and lacrimal drainage then reduce the volume of liquid held by the lid and cul-de-sac
to only 7-10 ul or about 20% of the original drop. Only a small percentage of the topical eyedrop is available for
absorption (some runs down cheek and other drains down the nasolacrimal duct
and may be absorbed by the nasal mucosa or swallowed).
- rapid turnover of tears
depending upon irritation
- loading doses may increase
anterior chamber levels One study found
that using one drop every minute for 5 minutes produced increased
aqueous fluid levels. Loading doses
have routinely been used with fortified antibiotic solutions of
aminoglycosides e.g. gentamicin or tobramycin in bacterial keratitis (AJO1985;99:329-332).
- dilution effect from other
medications. It is probably best to
wait 5 minutes between eye drops to attain the most
beneficialeffects. The systemic absorption of drug down the
nasolacrimal system can be decreased by utilizing punctal
occlusion or gentle eyelid closure for 5 minutes. (Archives Ophthal. Zimmerman
1984;102:551553)
- lipophilic/hydrophilic
properties. cornea has tight epithelial
and endothelial intercellular junctions which slow or prevent the passage of drug through the
cornea. Drug must penetrate the three
layers of the cornea, including the epithelium (lipophilic barrier), stroma (water soluble) and endothelium
(lipid soluble)
Ophthalmic ointments;
- usually consist of a
petrolatum and mineral oil base.
Mineral oil has been added to reduce the temperature at which the
ointment melts.
- some ointments also contain
lanolin as an emulsifier for easier incorporation of water soluble drugs into
the ointment.
- allergies to ophthalmic
ointments may be related to the incorporated lanolin.
- most drugs are very stable in
ointments and do not ionize.
- ointments have longer corneal
contact time and are generally very comfortable. Contact time may not increase bioavailability however, since
only the crystals at the ointment-tear interface will be absorbed.
- ointments also leave a film in
the eye and cause some associated blurry vision. That is why patients acceptance is low, especially during the
day.
B.
Alternate topical delivery systems also have been investigated
including prodrugs such as dipivalyl epinephrine (DPE,
PropineR), sustained
release gels, and ocular inserts or devices.
PropineR (DPE) -
is a prodrug that is a modification of the epinephrine molecule to make it more
lipophilic (17 times). It is cleaved to the active
epinephrine as it is absorbed through the cornea. Therefore, a lower concentration is used and
the drug is less irritating topically and better tolerated by the patient.
Sustained release gels,
such as carbopol gel used in Pilocarpine gel (Pilopine H.S.R)
increase the contact time
of the gel in the eye, reduce side effects
because of bedtime administration, and provide for a sustained release over a
prolonged period of time (once daily
dosing). Also, Betoptic SR
0.25%,VexolR uses a carbopol gel system. Timoptic XER
forms
a gel when the topical drop hits the cations in the tear film.
OcusertR is a membrane-controlled drug delivery system
that is placed in the eye, releasing pilocarpine slowly over a 7 day period. This
product allows a much lower total daily dose to be used than does the topical
solution (Ocusert 40mcg/mlx24
hours=960mcg vs. 4 doses of 2%pilo.=4,000mcg).
LacrisertR is a rod-shaped pellet of preservative-free
hydroxypropylcellulose 5mg. It is used
for dry eye syndrome and is
inserted into the inferior conjunctival sac.
The HPC pellet absorbs ocular fluids and releases the HPC into the tears up to 24 hours.
The Bio-CorR shield is a clear collagen film of flexible
porcine(bovine also made) tissue. It
has been indicated to promote
corneal
epithelial healing
following surgery and trauma. The
shield dissolves slowly over a 12-72 hour period of time. These shields have also been presoaked in antibiotics
and other medications to provide for prolonged drug concentrations in keratitis and
postoperatively in place of subconjunctival injections.
C.
Periocular
administration injections below
the conjunctiva or Tenon's capsule are used to give either prolonged
administration and/or increased penetration of
drug. advantages include:
1.
increased local concentrations of drug, thereby avoiding potential systemic
toxicities.
2.
drugs with poor penetration can achieve higher tissue concentrations.
3.
useful in children or in those who may be poor compliance risks, especially in
corneal ulcer patients.
D. Intraocular
- indications include:
serious
intraocular infections and inflammatory conditions (endophthalmitis, retinal
necrosis, CMV retinitis, etc.) when drug delivery and
therapeutic drug levels are an immediate concern.
- pharmacotherapeutic
considerations include:
1.
dosing/retinal toxicity
2.
half life of the drug in the vitreous/reinjection
3.
volume of drug administered (usually 0.05-0.1ml)
4. injection
technique (stream effect, intraocular structures,etc)
E. Systemic
indications
include:
-
endophthalmitis, panophthalmitis, orbital cellulitis,
pharmacokinetic considerations include:
- drug must penetrate
blood-ocular barrier to achieve effective levels in the eye. The
blood-ocular barrier is divided into:
1. blood-aqueous - will allow more
drug into the anterior segment of the eye during inflammatory conditions
2. blood-retinal barriers.-
prevents significant drug from penetrating the vitreous cavity, even during
most inflammatory
conditions. vascular endothelium of the
retina (nonfenestrated cells) and retinal pigment epithelium provide a substantial
barrier to achieving therapeutic vitreous levels.
- some recent studies with
intravenous cefazolin have shown that repeat doses produced inhibitory levels
in the vitreous cavity
in an inflamed eye (Arch. Ophthalmol. 1990;108:411-414).
II. GLAUCOMA
A. PATHOPHYSIOLOGY OF GLAUCOMA
1.
General
leading cause of blindness,
accounts for 14% of cases visual loss can be prevented
Definition - term for complex disease
characterized by; increased intraocular pressure (“IOP” - normal 10-20 Hg ) AND
the resulting changes in either or both the optic nerve (ON) and visual field
(VF).
Classification
open angle - most common 95% of
all primary glaucomas - associated with increased production or decreased outflow of aqueous
fluid (see figure);usually bilateral; gonioscopy proven open angle, usually
insidious onset
closed angle - closure of
anterior chamber angle; sudden onset-emergency
Risk Factors
-
age - significant increase with age - 0.25% at 20;15% at 70-75
-
family history - 5-13 x's more in close relatives; 6-7 x's greater on maternal
side
-
race - blacks 3-4 x’s higher than whites in open angle glaucoma (OAG)
-
ametropia - myopes greater incidence of OAG
-
sex - angle closure more in females
-
mental set - high stress increased risk
-
systemic disease - greater in diabetics and thyroid disease
-
ocular hypertension - ( IOP with NO
changes observed in ON or VF) - 4% of pts with IOP's < 25 mmHg develop field
loss;
17% with IOP btwn 25-30mmHg;42%>
30mmHg.
Diagnosis
- increased IOP
- tonometry - exponential effect
- cup to disk ratio - first sign, thinning neural rim of
optic nerve head
- visual fields - perimetry - earliest signs are
constriction of peripheral fields & enlargement
of blind spot
2. Treatment Options
Open angle glaucoma may be
treated by different approaches. Clinicians have classicly started most patients on medical
therapy. If medical therapy failed and
the diasease progressed, then laser therapy may be tried. If
laser therapy was unsucessful, then surgical treatment was usually
considered as the last choice.
Patients may commonly be treated with combinations of the above therapies.
1.
Medical treatment
- This will be discussed below
under the pharmacotherapy section.
2.
Laser treatement
- ALT - argon laser
trabeculoplasty (opens TM; stimulates release of factors regulating TM cell
function).
- almost one-half of ALT
group requires medical therapy within two years
- about one-half of ALT eyes do not maintain low IOP's for 5 years
(repeat therapy may cause scarring
and decreased outflow).
3.
Surgical treatment
- trabeculectomy (controls IOP in about 44% controlled ALT
alone;70% with ALT + timolol at 2-5 years -
ALT may defer filtration surgery for 5 years in about 35% of patients with
uncontrolled glaucoma.
- antimetabolite therapy - 5FU and
mitomycin - inhibit wound healing (probably fibroblasts) and the resulting
closing off of
the drainage channel
B. PHARMACOTHERAPY OF GLAUCOMA
In glaucoma therapy, most clinicians try to control the
intraocular pressure with a single topical agent. If that is not effective, combination therapy may be
utillized. Combinations may include a
beta blocker (e.g. timolol or levobunolol), possibly brimonidine (alpha-2
agonist) and/or latanoprost (prostaglandin) or bimatoprost (prostamide), and/or
dorzolamide (topical CAI) and/or even a cholinergic agent (pilocarpine – really
a distant choice).
The autonomic nervous system
innervates the eye through both the sympathetic
and parasympathetic pathways. These systems have often been thought of as
being physiologic antagonists, although that is not always the case. The parasympathetic autonomic system,
referred to as the cholinergic system, has acetylcholine
(Ach) as the neurotransmitter released at the synapse. The sympathetic autonomic system, referred
to as the adrenergic system, has the
transmitter norepinephrine (Nor) released at the effector organ.
A. CHOLINERGIC AGENTS
The parasympathetic, or cholinergic system ocular innervation includes:
1. extraocular muscles and levator
palpebrae
2.
lacrimal and meibomian glands
3. iris sphincter
4. ciliary body.
Cholinergic agents are classified as
- direct-acting (Ach or imitators
of Ach)
- indirect-acting
(agents preventing the breakdown of Ach such as echothiophate).
Cholinergic System
Ciliary ganglion
Effector
cell
CNS -------------------> Ach ---------------------> Ach
Cholinergic
stimulation produces
1. pupillary constriction (miosis)
by causing contraction of the iris sphincter muscle.
2. contraction of the ciliary muscle with a
resulting effect on the scleral spur and on the trabecular meshwork
that
opens up the network and allows drainage of the aqueous fluid.
3. lacrimation similar to other exocrine glands.
1.
Cholinergic Agents
Direct acting (pilocarpine, carbachol [has direct & indirect]) and
indirect acting (acetylcholinesterase
inhibitors such as phospholine iodide) parasympathomimetic agents increase the
outflow of aqueous fluid from the anterior chamber by pulling on the trabecular
meshwork. Generally, one cholinergic
agent may be substituted for another if allergy develops or further IOP
decrease is desired.
Pilocarpine
(Ispoto CarpineR)
-
direct acting, naturally occurring cholinergic agent
-
used primarily in the treatment of primary
open angle glaucoma or acute
angle-closure glaucoma
-
most effective concentrations 1-4%
(range 0.25%-10%)
-
systemic side effects are rare and include vomiting, sweating, diarrhea and
sweating.
-
topical side effects include accommodative spasm, miosis, headache,
follicular conjunctivitis, also rare pupillary block glaucoma,
retinal detachment , allergic dermatitis and
conjunctivitis
-
Ocusert and Pilocarpine gel (Pilopine HSR ) - pilocarpine
semipermeable membrane and sustained action gel, respectively.
- occlude punctum
(technique of putting the finger in the corner of the eye to prevent systemic
drug absorption by the
nasolacrimal system and increase
bioavailability of drug into the eye) may control IOP with pilo 2% every 12
hours. (Zimmerman. AJO 114:1-7;1992)
Carbachol 0.75%-3%
(Ispoto CarbacholR)
-
synthetic molecule combination of acetylcholine and physostigmine. (direct-acting agonist and
anticholinesterase
agent at the same time, and more resistant to
hydrolysis).
-
prolonged duration of effect, dosed every 8 or 12 hours.
-
more potent agent than pilocarpine
- topical side effects similar
to pilocarpine but more severe.
-
may be used in patients allergic to pilocarpine
Echothiophate Ioidide (Phospholine IodideR)
– NOT COMMERCIALLY AVAILABLE AFTER 2001
-
long acting irreversible inhibitor
of cholinesterase.
-
available in concentrations from 0.03%
to 0.25%
- indicated for treatment
of glaucoma and accommodative esotropia.
-
not very stable, must be reconstituted
prior to use and is stable for 1 month at room temperature and 6 months if
refrigerated.
- topical side effects - similar to pilocarpine but more pronounced, including headache, accommodative
spasm, etc.
-
iris cysts, subcapsular
cataracts
-
inhibit the cholinesterase in red blood cells and therefore anesthetic agents such as succinylcholine may be significantly
inhibited.
Stop the medication four-six weeks prior to general anesthesia surgery
(Surv Ophthal., Gerber, 1990; 35
: 205-18).
Others (not used much in
clinical practice); Physostigmine (eserine), Demecarium carbide
(0.125, 0.25%) Humorsol,R Isoflurophate
0.025% oint. (FloroprylR /DFP)
ADRENERGIC AGENTS
Adrenergic
agents used in glaucoma are either direct acting sympathomimetic agent with
both alpha and beta stimulatory effects (epinpehrine), or alpha 2 agonist
(apraclonidine).
Epinephrine is believed to reduce intraocular pressure by causing an increase
in outflow facility (beta) and a very slight increase in aqueous fluid
production and a slight decrease (alpha ) in fluid production through
vasoconstriction and a decrease in ciliary blood flow.
Apraclonidines effects are believed to decrease aqueous
fluid production through a decrease in cAMP, probably similar to beta
blockers. Some further decrease in IOP
when used in combination with beta-blockers.
Apraclonidine is indicated for short term (usually up to 90 days)
adjunctive treatment of glaucoma only. Brimonidine
decreases aqueous fluid formation and increases uveoscelral outflow. Brimonidine is indicated for long term
treatment of glaucoma or ocular hypertension.
Beta blockers decrease aqueous fluid production very
effectively and are the most common first step therapy used in glaucoma
patients.
The
sympathetic nervous system has always been considered the "fight or flight" response system of the body. Acetylcholine is the neurotransmitter at the
preganglionic terminal. Norepinephrine is the postganglionic
neurotransmitter.
Adrenergic System
Superior
Effector
Cervical Ganglion Cell
CNS -------------------> Ach
-------------------> Norepinephrine
There
are no cholinesterases to stop the action of norepinephrine, instead the neurotransmitter is terminated either by;
1. reuptake into the nerve terminal
2. transformation by the enzymes monoamine oxidase (MAO) present in the nerve terminals or
catechol-O-
methyltransferase
(COMT) found in the liver
3. diffusion from the neurotransmitter junctions.
Two types of receptors in the sympathetic system
1.alpha
2.beta
These are further subdivided into:
1. alpha 1 - usually mediate smooth muscle contraction
alpha 2 - usually
mediate feedback inhibition of sympathetic nerve terminals.
2. beta 1 - mediate stimulatory effects on the heart
beta 2 - mediate relaxation of smooth muscle in the
lungs
- stimulation of the alpha receptors;
-
produces increase in blood pressure by arteriolar constriction
- mydriasis in the eye (dilator muscle of the iris) and elevation of the lid (Muller's muscle).
-
alpha 1 agonist - mydriasis, vasoconstriction, etc.;alpha-2 agonist - decrease in aq. formation
- stimulation of the beta receptors;
-
increase in heart rate and relaxation of bronchi.
-
produce a decrease in aqueous fluid
production in the eye by blockade of the beta receptors
2.
Adrenergic agonists
Epinephrine (GlauconR,
EpitrateR)
-
available from 0.25 to 2%. (< 1% not
usually effective)
- 3 salt forms, the hydrochloride, borate
and the bitartrate (free base of 2%
bitartrate salt = 1% conc. of borate & HCl salts.
-
borate salt more comfortable (pH=7.4)
- Systemic toxicity from
topical epinephrine is rare,
but palpitations, tachycardia, hypertensive crisis and headache reported.
- Topical side effects
include, - browache,
lacrimation, stinging, conjunctival hyperemia, allergic blepharoconjunctivitis,
adrenochrome
pigmentation (black conjunctival spots),
stain soft contacts, cystoid macular edema (CME) in aphakes.
-
heat and light degradation (brown
discoloration shows degradation and should not be used).
Dipivefrin
0.1% (PropineR)
- prodrug of
epinephrine (equivalent to approx. epinephrine 2%) converted to epinephrine
as it is absorbed through the cornea.
-
less topical & systemic SE's than with epinephrine
-
potential for CME is NOT reduced.
-
safe in soft contact lens users.
3. Alpha-2 agonists
Apraclonidine 1% and 0.5% (IopidineR)
pharmacologic
properties
- selective alpha 2 agonist causes a
decrease in IOP by inhibiting the
formation of aqueous humor by decreasing cAMP
and thereby decreasing a.f. flow.
- apraclonidine, (some alpha-1 activity
(mydriasis, conjunctival blanching, and eyelid retraction)
indications
-
apraclonidine 1% is indicated to prevent postsurgical
elevations in IOP after argon laser trabeculoplasty or iridotomy.
- apraclonidine 0.5% is short term
adjunctive treatment ( 3 months) in patients on maximally tolerated
medical therapy who require addional
IOP reduction; tried in many acute glaucoma situations because of its potent
effects. Dosed every 8 hours, Effects
may last up to 7-12 hours.
cautions/se's
-
addition of apraclonidine to two aqueous suppressing drugs (like beta blocker
and CAI) is of questionable benefit.
-
less CNS effects than clonidine and previous studies have shown a minimal
effect on mean resting heart rate or arterial BP.
- many alpha-1 relates side effectrs -
conjunctival blanching, mydriasis, eyelid retraction.
- systemic cardiovascular (decrease in
BP) or CNS (drowsiness) - rare
-
dry mouth - most common?
- long term use
is not be feasible because its ocular allergy - (up to 36% with 0.5% within 90
days) - hyperemia, pruritus,
foreign
body sensation, tearing, local edema of lids and conjunctiva), and
tachyphalxis.
- watch
24 hour IOP (43-50 mm Hg) after Nd:YAG capsulotomy (AJO 9/92)
Brimonidine 2% (AlphaganR)
pharmacologic properties
- clonidine lowered IOP
by inhibiting the formation of aqueous fluid (alpha-2 receptor)
(sedation, decreased BP)
- brimonidine
0.2% - alpha 2 agoinst - 23-32 times the alpha-2 selectivity over
apraclonidine
-
produces none or minimal mydriatic/vasoconstrictive effect (alpha 1) that
apraclonidine does.
- brimonidine and clonidine are
oxidatively stable and do not possess hydroquinones. (compounds may cause
allergic reaction
when
metabolized to reactive substance that produces antigens)
-
hydroquinones may trigger allergy (apraclonidine, amodiaquine and epinephrine
all contain)
- reduces IOP by decreasing aqueous
fluid production and by increasing the outflow of A.H. through uveoscleral pathway
(fluorophotometric
studies).
- neuroprotective properties ?
prevent photoreceptor & ganglion cell degeneration
- dosing - indicated -
t.i.d./studies done b.i.d. (timolol exhibited a significant difference at all
trough visits (<0.001) compared
to
brimonidine and as a class of drugs - alpha-2 agonists are t.i.d).
indications
- effective in lowering IOP in
patients with OAG and OHT (4-6 mm Hg vs. 6 mm Hg for timolol 0.5%)
-
approved as primary or adjunctive therapy for patients with OAG or OHT.
- monotherapy or as adjunctive
(additive) therapy
cautions/se’s
ocular: no
tachyphylaxis (IOP drift) was noticed for up to 12 months; according to insert
the IOP lowering effect may
diminish over time in some
patients (variable time of onset).
- ocular allergy rate – 9.6%
- Alphagan-P ( 0.15%
concentration is 25% less than original) - ocular allergy reduced 41% (from 16%
to 10%) and utilizes a new preservative – Purite (oxycholoro complex breaks
down to sodium chloride and water and does not retain in ocular tissues like
benzalkonium chloride).
-
hyperemia; burning and stinging (25%); less in betaxolol study (6.9%)
- lid
edema.
-
mydriasis and eyelid retraction NOT seen
- conjunctival
follicles (7.8%)
systemic: dry mouth (30%),
fatigue/drowsiness, headache,
Alphagan
–P has slightly lower incidence of systemic side effects also.
4. Beta blockers
Timolol (TimopticR Timoptic XER-
gel forming solution) 0.25-0.5%, levobunolol (BetaganR)
0.25%, 0.5% and metipranolol 0.3% (OptipranololR),
carteolol 1% (OcupressR)
pharmacologic
properties
-
nonspecific beta 1 and beta 2 blockers.
-
reduce aqueous fluid production up to 50%.
- recent studies
- suggest beta 2 antagonists have a more significant effect on aqueous
secretion than beta 1 antagonists.
- nonselective
beta blocking agents are more effective in reducing IOP than selective agents
by about 15%
- carteolol also
has partial agonsit activity (ISA or
intrinsic sympathomimetic activity), therefore less pronounced
- decrease in HR
or dyspnea (improved retinal perfusion?); less local discomfort vs timolol,
less dry eye?.
indications
-
used in most forms of glaucoma
- solution dosed
twice daily;maybe once daily (timolol - Ophthal 100:1259-62;1993; levobunolol -
Ophthal 99:424-9;1992).
- Timoptic XE
(gel forming solution) used once daily.
cautions\se's
-
minor topical including stinging, allergic conjunctivitis, ocular myasthenia,
blurred vision, SPK, corneal anesthesia.
- systemic side effects very important
consideration!!
- cardiovascular - bradycardia, heart
block & aggravation of CHF, increase LDL and lower HDL
- pulmonary - bronchospasm in asthma and
COPD patients reported.
- CNS -
hallucinations, insomnia, depression, impotence, mask decrease in blood sugar,
etc.
- punctal occlusion or gentle eyelid
closure while administering the drops may reduce the occurrence of side effects.
- metipranolol
taken off the market in the U.K. because of some reported cases of uveitis
(different formulation in U.S.,
although
a few case reports in U.S. Arch.Ophth.1606,1993;AJO 712,1994)
Betaxolol (Betoptic S 0.25% [suspension]
and Betoptic 0.5%)
pharmacologic
properties
-
beta 1 selective blocker (cardioselective
and pulmonary sparing).
-
use in pts. with asthma or COPD is not strictly contraindicated.
- serum levels of
betaxolol and its protein binding reduce potential for bradycardia more than
the nonselectives
- less effective
lowering IOP but improved blood flow to optic nerve?
-
Betoptic S 0.25% (S=suspension) =
Betoptic 0.5% in lowering IOP (lowers IOP 13- 30%;Drugs 1990p76) similar AC levels obtained.
"S"is in polymer vehicle & bound to ion-exchange resin
(amberlite) for prolonged bsorption;stinging reduced because of the lower
concentration, more comfortable vehicle and prolonged contact time.
5.Carbonic anhydrase inhibitors (CAI's)
pharmacologic
properties (general)
-
effects mainly through the reversible and noncompetitive binding of the enzyme
carbonic anhydrase.
-
carbonic anhydrase catalyzes the first step of the reaction(I), second step(II)
of the reaction occurs very quickly
(not from a specific enzymatic
reaction).
I II
CO2 + H2O <----> H2CO3
<----> H+ + HCO-3
-
Step II occurs rapidly and the net result is that CAI's
prevent the formation of bicarbonate (HCO-3) and H+.
-
The ciliary processes secrete aqueous fluid into the
posterior chamber. Although the exact
MOA is unknown, secretion of aqueous fluid is dependant upon active transport
of sodium by Na+ - K+ -ATPase. The transport of sodium is linked to bicarbonate formation. Therefore,
by decreasing bicarbonate formation, sodium and fluid movement into the
posterior chamber is also reduced with less aqueous fluid formed. Other mechanisms may also contribute to the
effectiveness of CAI's, but their significance is thought to be small.
- because carbonic anhydrase is present in
excessive physiologic quantities in the eye, almost 100% of the activity
must be inhibited for the
aqueous fluid formation to be inhibited.
Acetazolamide (DiamoxR)
pharmacologic
properties
-
used most of all CAI's and therefore more information if available on its
pharmacologic properties
indications
-
only agent available in injectable form and may be used in acute forms of
glaucoma.
-
most common oral dosage is 250mg qid
-
usually reserved for the last step in glaucoma treatment because of undesirable
systemic side effects.
-
improve VA in some retinitis pigmentosa
patients with macular edema. (Arch Ophthal. 107:1445-53, 1989).
cautions/se's
-
paresthesias, metallic taste, nausea and
gastrointestinal irritation.
-
CNS side effects such as confusion,
depression, malaise, fatigue and decreased libido.
- metabolic acidosis
accompanies CAI's and is reflected by a decreased bicarbonate value on the
clinical chemistry
values.
- hypokalemia
usually occurs at the start of treatment but is short term and less of a concern after a week or two.
-
increases in serum uric acid and
precipitated attacks of gout.
-
rare side effects include renal calculi,
blood dyscrasias and dermatitis.
- since these
compounds have a sulfur moiety, the potential for allergies to sulfa is a real concern.
- reduction in
citrate concentration predisposes to calcium carbonate renal stones (the other
2 agents are less of
concern on urine stone
formation).
Methazolamide (NeptazaneR)
pharmacologic
properties
- similar to
acetazolamide in structure but is more lipid soluble.
-
available in a 25mg and 50mg tablet and is given bid or tid.
- acetazolamide
is more highly bound to plasma proteins (95% vs 55%) and therefore the active
or unbound drug,
methazolamide
can be given in smaller doses.
indications
- indications
similar to acetazolamide, not as effective in macular edema in RP.(Ophthalmol
101:687-93,1994). Used
in patients with sickle cell hyphema, less AC acidsosis, therefore less
sickling of RBC’s ??
cautions/se's
- less systemic acidosis
and better tolerated in patients with obstructive pulmonary disease.
- diuresis,
gastrointestinal disorders, and paresthesias are reported to be less of a
problem
- CNS side effects such
as drowsiness, more of a concern.
-
switch from methazolamide to acetazolamide or vice versa, if CAI was effective
but the side effects were not well tolerated.
Dichlorphenamide (DaranideR)
-
least used and tolerated of the CAI's related to its side effect profile.
caution/se's
-
similar to acetazolamide but more exaggerated including confusion and
anorexia.
- diuresis and hypokalemia continue while
the patient is on the medication.
(not as true with acetazolamide or
methazolamide
because of the structural differences between these two compounds and that of
dichlorphenamide).
SYSTEMIC CARBONIC
ANHYDRASE INHIBITORS
Dorzolamide 2% (TrusoptR)
pharmacologic
properties
- only topical ophthalmic formulation of a CAI.
- seven
different isoenzymes of carbonic anhydrase (CA)
- CA II
- found corneal endothelium, ciliary processes, lens & retina; CA IV - c.b.
choriocapillaris, lens, (not sure if present in c.p.’s).
- MOA -
penetrates cornea and good inhibitor of CA II & IV; reduces aqueous humor
inflow since inhibits bicarb and counter ion Na + ; need to inhibit > 99.5% of enzyme for
full pharmacologic effect.
- may
inhibit A.H. secretion by 50%
.
pharmacokinetics/dosing - t.i.d; at 16o
timolol retained 60% of its activity, dorzolamide only 22%
although
some clinicians use b.i.d. as
adjunctive therapy
indications
- for
treatment of open angle glaucoma or ocular hypertension as primary or
adjunctive therapy.
-
others (e.g. macular edema
in uveitis, retinitis pigmentosa ?)
- not
as effective as timolol 0.5% in reducing IOP
cautions/se's
-
systemic side effects rare; Caution in SULFA allergy
- less
common include ocular allergy, blurred vision, dryness, superificial punctate
keratitis.
- no
significant effect on central corneal endothelial cell counts or central
corneal thickness
- ocular; stinging (33%), ocular allergies (10%),allergic
conjunctivitis (4%, resolved after discontinuation)
- SPK -
dorzolamide 10-15% vs. placebo 10.5%
. systemic; bitter
taste (25%; punctal occlusion) digestive system disturbances (7%; e. g.
diarrhea, nausea, gastroenteritis)
- no
acid base or electrolyte disturbances were reported with dorzolamide; minimal/
no effect on heart rate or BP
- sulfonamide - all CAI’s have free sulfonamide group;
caution in sulfa allergy -
idiosyncratic reaction
-
dorzolamide and systemic CAI’s - probably not beneficial.
-
dorzolamide - slightly less effective
than systemic CAI’s (acetazolamide) in reducing IOP (Maus T, et al 1997)
- acetazolamide reduced aqueous
flow 30% vs. 17% for dorzolamide
- 19% for acetazolamide vs. 13%
for dorzolamide reduction in IOP
Brinzolamide suspension 1% (AzoptR) – topical CAI
- carbomer gel
vehicle - less stinging, more blurred vision
- similar IOP
lowering to dorzolamide - dosed tid insert (some studies bid?)
COMBINATION PRODUCTS
Dorzolamide 2% [10mg/ml] + timolol 0.5% [5mg/ml] (CosoptR)
- combination
product dosed bid - close to effectiveness of each agent by themselves
- se’s – taste perversion (bitter,
sour unusual), ocular burning and/or stinging (up to 30%), conj hyperemia,
blurred
vision, SPK,
eye itcing 5-15%
6. Prostaglandins
Prostaglandins are an example of
how basic research/formula modification produced an effective treatment for
OAG.
The naturally occurring prostaglandin’s include PGD, PGE,
PGE2, PGF2alpha , PGI2 . Early studies demonstrated that PGF2 alpha ¯
IOP but too much ocular irritation/conjunctival
hyperemia and did not penetrate after topical administration. (Bito, et al.
1983).
Latanoprost 0.005% (XalatanR)
pharmacologic
properties
-
phenyl substituted analog PhXA 34 - effective in reducing IOP - minimal
conjunctival hyperemia irritation
-
latanoprost - (right-handed epimer PhXA41) analog of PGF 2-alpha - less hyperemia;potent lowering of IOP.
- MOA -outflow
of A.H. thru uveoscleral pathway (A.H. flows thru the connective spaces between
ciliary muscle bundles)
- dosed
once daily - more effective at bedtime
indications
- for
the adjunctive treatment of OAG in
patient intolerant of other IOP meds or nonresponsive to treatment
- used
more often as second or even primary drug of choice
- 1 year follow-up: IOP decrease averaged
from baseline of 25.3 mm Hg to 17.4 mm
Hg (32%) [Camras 1996]
-
adjunctive therapy [ latanoprost + timolol ] - latanoprost provided further
decrease in IOP of 13-14%.
cautions/se's
ocular:
- conjunctival hyperemia (5%) ; thickening of eyelashes ?
- iris discoloration ( 7% - 12%
) [mixed colored irides (green-brown or blue/gray - brown)]
- noticed within
18-26 weeks after initiation of treatment; increase in amount of melanin within
the melanocyte (not
an increase
in # of melanocytes)
- mild punctate
corneal epithelial erosions
- few case reports iritis/cystoid macular edema
(CME) mostly predisposed pts. (prior hx of CME, or lens capsule rupture, etc.
5/98 AJO, 2/98 Ophthalmology ); headache and possibly exacerbation of Herpes
simplex corneal infections
systemic: upper
respiratory signs (7%), muscle or joint pain (4%), non ocular allergy or eczema
(6%)
- combination with pilocarpine
is not established
- refrigerate
until dispensed
- squeeze bottle
gently, when released any remaining medication will go back into the bottle.
Unoprostone isopropyl 0.15% (ResculaR) –
pharmacologic
properties
-
docosanoid (prostaglandin related class).
- may not be active on same
prostaglandin receptor except at higher doses.
- MOA -outflow of A.H. thru
uveoscleral pathway or possibly trabecular meshwork ? unkown MOA
- dosed
twice daily
indications
- for
the adjunctive treatment of OAG in
patient intolerant of other IOP meds or nonresponsive to treatment
- not
sure where this drug fits yet. Not quite as effective as timolol 0.5% bid
cautions/se's
ocular: - (10-25%) burning, stinging, dry eyes,
itching , conjunctival hyperemia; growth & thickening of eyelashes
- iris
discoloration less than with Xalantan
systemic: flu syndrome (6%)
Travoprost
0.0015% (TravoprostR) - prostaglandin F-2 alpha analog, similar to
latanoprost with regards to dosing, side effects, etc.
Ocular
hyperemia is more (up to 50%) but iris pigmentation appears to be less (3%).
Bimatoprost 0.03% (LumiganR)
pharmacologic
properties
-
ocular hypotensive lipid from prostamide class (prostaglandin related
class).
- does not act on F2alpha receptor
(Surv Ophthalmol. May 2001).
- MOA – probalby
outflow
of A.H. thru uveoscleral pathway AND trabecular meshwork
- dosed once daily
- appears to be one of the most
potent agents in lowering IOP
indications
- for
the adjunctive treatment of OAG?
cautions/se's
ocular: - slightly more hyperemia than others ?
- less iris
discoloration less than with Xalantan
7.
Osmotic agents - FYI ONLY !
By increasing serum osmolarity,
an osmotic gradient is formed between the vitreous and aqueous fluids and the
plasma. This osmotic gradient pulls
water from the ocular fluids into the plasma and causes a decrease in
intraocular pressure. Obviously, this
is time dependant effect and is only meant for a short term decrease in
intraocular pressure (approximately 6 hours).
Osmotic agents are used in acute
angle-closure glaucoma and prior to
intraocular surgery to lower IOP.
Mannitol
- intravenous administration requires filtrations because of
crystallization.
- is not metabolized
- watch for fluid overload in
suceptible patients.
- administer over 20-30 minutes
for best effect
Glycerin - an oral product that is
partially metabolized, watch in diabetics
- very sweet taste, may cause
nausea and vomiting
- also available as an eyedrop
for transient corneal edema.
Isosorbide
- not the ANTIANGINAL agent !!! , only the sugar moiety in solution – very
sweet also
- isosorbide is an oral agent,
not metabolized and is therefore safer in diabetics.
REFERENCES:
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