NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

Nonsteroidal anti-inflammatory drugs (NSAIDs),
often referred to as ‘aspirin-like drugs’, are a
heterogeneous group of anti-inflammatory, analgesic
and antipyretic compounds. These are often
chemically unrelated (although most of them are
organic acids), but share certain therapeutic actions
and side-effects.
Mechanisms of action
The NSAIDs largely act by irreversibly blocking the
enzyme cyclo-oxygenase, thus inhibiting the
prostaglandin biosynthesis. They also appear to block
other local mediators of the inflammatory response
such as polypeptides of the kinin system, lysosomal
enzymes, lymphokinase and thromboxane A2; but not
the leukotrienes.
Preparations
A. NSAIDs available for systemic use can be
grouped as follows:
1. Salicylates e.g., aspirin.
2. Pyrazolone derivatives e.g., phenylbutazone,
oxyphenbutazone, aminopyrine and apazone.
3. Para-aminophenol derivatives e.g., phenacetin
and acetaminophen.
4. Indole derivatives e.g., indomethacin and
sulindac.
5. Propionic acid derivatives e.g., ibuprofen,
naproxen and flurbiprofen.
6. Anthranilic acid derivatives e.g., mefenamic
acid and flufenamic acid.
7. Other newer NSAIDs e.g., ketorolac tromethamine,
carprofen and diclofenac.
B. Topical ophthalmic NSAIDs preparations
available include:
1. Indomethacin suspension (0.1%)
2. Flurbiprofen, 0.3% eyedrops
3. Ketorolac tromethamine, 0.5% eyedrops
4. Diclofenac sodium, 0.1% eyedrops
Ophthalmic indications of NSAIDs
1. Episcleritis and scleritis. Recalcitrant cases of
episcleritis may be treated with systemic NSAIDs
such as oxyphenbutazone 100 mg TDS or
indomethacin 25 mg BD.
NSAIDs may also suppress the inflammation in
diffuse and nodular varieties of scleritis, but are
not likely to control the necrotizing form.
2. Uveitis. NSAIDs are usually not used as the
primary agents in therapy of uveitis. They are,
however, useful in the long-term therapy of
recurrent anterior uveitis, initially controlled by
steroid therapy. Phenylbutazone is of use in
uveitis associated with ankylosing spondylitis.
3. Cystoid macular oedema (CME). Topical and/or
systemic antiprostaglandin drugs are effective in
preventing the postoperative CME occurring after
cataract operation. The drug (e.g., 0.03%
flurbiprofen eyedrops) is started 2 days
preoperatively and continued for 6-8 weeks postoperatively.
4. Pre-operatively to maintain dilatation of the
pupil. Flurbiprofen drops used every 5 minutes
for 2 hours preoperatively are very effective in
maintaining the pupillary dilatation during the
operation of extracapsular cataract extraction with
or without intraocular lens implantation.
5. Spring catarrh. Sodium cromoglycate 2 percent
inhibits degranulation of the mast cells and thus
is more useful when used prophylactically in
patients with spring catarrh. Topical
antiprostaglandins are effective in the treatment
of spring catarrh.
6. Topical antihistaminics are helpful in cases of
mild allergic conjunctivitis.

Beta-adrenergic blockers

These are, presently, the most frequently used
antiglaucoma drugs. The commonly used
preparations are timolol and betaxolol. Other available
preparations include levobunolol, carteolol and
metipranolol.
Mechanism of action. Timolol and levobunolol are
non-selective beta-1 (Cardiac) and beta-2 (smooth
muscle, pulmonary) receptor blocking agents.
Betaxolol has 10 times more affinity for beta-1 than
beta-2 receptors.
The drugs timolol and levobunolol lower IOP by
blockade of beta-2 receptors in the ciliary processes,
resulting in decreased aqueous production. The exact
mechanism of action of betaxolol (cardioselective
beta-blocker) is unknown.
Indications. Beta adrenergic blockers are useful in
all types of glaucomas, viz., developmental, primary
and secondary; narrow as well as open angle. Unless
contraindicated due to systemic diseases, betablockers
are frequently used as the first choice drug
in POAG and all secondary glaucomas.
Contraindications. These drugs should be used with
caution or not at all, depending on the severity of the
systemic disease in patients with bronchial asthma,
emphysema, COPD, heart blocks, congestive heart
failure or cardiomyopathy. Betaxolol is the beta
blocker, of choice in patients at risk for pulmonary
diseases. The other contraindication includes known
drug allergies.
Additive effects. Beta-blockers have very good
synergistic effect when combined with miotics; and
are thus often used in combination in patients with
POAG, unresponsive to the single drug.
Side-effects
1. Ocular side-effects are not frequent. These include
burning and conjunctival hyperaemia, superficial
punctate keratopathy and corneal anaesthesia.
2. Systemic side-effects are also unusually low.
However, these are reported more often than ocular
side-effects. These include (i) Cardiovascular effects
which result from blockade of beta-1 receptors. These
are bradycardia, arrhythmias, heart failure and
syncope. (ii) Respiratory reactions: These include
bronchospasm and airway obstruction, especially in
asthmatics. These occur due to blockade of beta-2
receptors; and thus are not known with betaxolol.
(iii) Central nervous system effects. These include
depression, anxiety, confusion, drowsiness,
disorientation, hallucinations, emotional lability,
dysarthria and so on. (iv) Miscellaneous effects are
nausea, diarrhoea, decreased libido, skin rashes,
alopecia and exacerbation of myasthenia gravis.
Preparations
1. Timolol. It is a non-selective beta-1 and beta-2
blocker. It is available as 0.25 per cent and 0.5 percent
eye drops. The salt used is timolol maleate. Its action
starts within 30 minutes, peak reaches in 2 hours and
effects last up to 24 hours. Therefore, it is used once
or twice daily. The drug is very effective, however,
the phenomenon of ‘short-term escape’ and ‘longterm
drift’ are well known. ‘Short-term escape’ implies
marked initial fall in IOP, followed by a transient rise
with continued moderate fall in IOP. The ‘long-term
drift’ implies a slow rise in IOP in patients who were
well controlled with many months of therapy.
2. Betaxolol. It is a cardioselective beta-blocker and
thus can be used safely in patients prone to attack of
bronchial asthma; an advantage over timolol. It is
available as 0.5 percent suspension, and 0.25 percent
suspension, and is used twice daily. Its action starts
within 30 minutes, reaches peak in 2 hours and lasts
for 12 hours. It is slightly less effective than timolol
in lowering the IOP.
3. Levobunolol. It is available as 0.5 percent solution
and its salient features are almost similar to timolol.
4. Carteolol. It is available as 1 percent and 2 per
cent solution and is almost similar to timolol except
that it induces comparatively less bradycardia.
5. Metipranolol. It is available as 0.1 percent, 0.3
percent and 0.6 percent solution and is almost similar
to timolol in all aspects.
Carbonic anhydrase inhibitors (CAIs)
These are potent and most commonly used systemic
antiglaucoma drugs. These include acetazolamide
(most frequently used), methazolamide,
dichlorphenamide and ethoxzolamide.
Mechanism of action. As the name indicates CAIs
inhibit the enzyme carbonic anhydrase which is
related to the process of aqueous humour production.
Thus, CAIs lower the IOP by reducing the aqueous
humour formation.
Indications. These are used as additive therapy for
short term in the management of all types of acute
and chronic glaucomas. Their long-term use is
reserved for patients with high risk of visual loss,
where all other treatments fail.
Side-effects. Unfortunately, 40-50 percent of patients
are unable to tolerate CAIs for long term because of
various disabling side-effects. These include:
1. Paresthesias of the fingers, toes, hands, feet and
around the mouth are experienced by most of the
patients. However, these are transient and of no
consequence.
2. Urinary frequency may also be complained of by
most patients due to the diuretic effect.
3. Serum electrolyte imbalances may occur with
higher doses of CAIs. These may be in the form of (i)
Bicarbonate depletion leading to metabolic acidosis.
This is associated with ‘malaise symptom complex’,
which includes: malaise, fatigue, depression, loss of
libido, anorexia and weight loss. Treatment with
sodium bicarbonate or sodium acetate may help to
minimize this situation in many patients. (ii) Potassium
depletion. It may occur in some patients, especially
those simultaneously getting corticosteroids, aspirin
or thiazide diuretics. Potassium supplement is
indicated only when significant hypokalemia is
documented. (iii) Serum sodium and chloride may be
transiently reduced; more commonly with
dichlorphenamide.
4. Gastrointestinal symptom complex. It is also very
common. It is not related to the malaise symptom
complex caused by biochemical changes in the serum.
Its features include—vague abdominal discomfort,
gastric irritation, nausea, peculiar metallic taste and
diarrhoea.
5. Sulfonamide related side-effects of CAIs, seen
rarely, include renal calculi, blood dyscrasias,
Stevens-Johnson syndrome, transient myopia,
hypertensive nephropathy and teratogenic effects.
Preparations and doses
1. Acetazolamide (diamox). It is available as tablets,
capsules and injection for intravenous use. The
acetazolamide 250 mg tablet is used 6 hourly. Its action
starts within 1 hour, peak is reached in 4 hours and
the effect lasts for 6-8 hours.
2. Dichlorphenamide. It is available as 50 mg tablets.
Its recommended dose is 25 to 100 mg three times a
day. It causes less metabolic acidosis but has a
sustained diuretic effect.
3. Methazolamide. It is also available as 50 mg tablets.
It has a longer duration of action than acetazolamide.
Its dose is 50-100 mg, 2 or 3 times a day.
4. Ethoxzolamide. It is given in a dosage of 125 mg
every 6 hours and is similar to acetazolamide in all
aspects.
5. Dorzolamide (2%). It is a topical carbonic
anhydrase inhibitor. It is water soluble, stable in
solution and has excellent corneal penetration. It
decreases IOP by 22% and has got additive effect
with timolol. It is administered thrice daily. Its side
effects include burning sensation and local allergic
reaction.
6. Brinzolamide (1%). It is also a topical CAI which
decreases IOP by decreasing aqueous production. It
is administered twice daily (BD).

ANTI-GLAUCOMA DRUGS

Classification
A. Parasympathomimetic drugs (Miotics)
B. Sympathomimetic drugs (Adrenergic agonists)
C. β-blockers
D. Carbonic anhydrase inhibitors
E. Hyperosmotic agents
F. Prostaglandins
G. Calcium channel blockers

Sympathomimetic drugs

Sympathomimetics, also known as adrenergic
agonists, act by stimulation of alpha, beta or both
the receptors.
Classification
Depending upon the mode of action, these can be
classified as follows:
1. Both alpha and beta-receptor stimulators e.g.,
epinephrine.
2. Direct alpha-adrenergic stimulators e.g.,
norepinephrine and clonidine hydrochloride.
3. Indirect alpha-adrenergic stimulators e.g.,
pargyline.
4. Beta-adrenergic stimulator e.g., isoproterenol.
Mechanisms of action
1. Increased aqueous outflow results by virtue of
both alpha and beta-receptor stimulation.
2. Decreased aqueous humour production occurs
due to stimulation of alpha-receptors in the ciliary
body.
Side-effects
1. Systemic side-effects include hypertension,
tachycardia, headache, palpitation, tremors,
nervousness and anxiety.
2. Local side-effects are burning sensation, reactive
hyperaemia of conjunctiva, conjunctival
pigmentation, allergic blepharo conjunctivitis,
mydriasis and cystoid macular oedema (in
aphakics).
Preparations
1. Epinephrine. This direct-acting sympathomimetic
drug stimulates both alpha and beta- adrenergic
receptors. Indications: (i) It is one of the standard
drugs used for the management of POAG. (ii) It is also
useful in most of the secondary glaucomas.
Preparations: It is available as 0.5 percent, 1 percent
and 2 percent eyedrops. Dosage: The action starts
within 1 hour and lasts up to 12-24 hours. Therefore,
it is instilled twice daily.
2. Dipivefrine(Propine or dipivalylepinephrine). It is a
prodrug which is converted into epinephrine after its
absorption into the eye. It is more lipophilic than
epinephrine and thus its corneal penetration is
increased by 17 times. Preparations: It is available as
0.1 percent eyedrops. Dosage: Action and efficacy is
similar to 1 percent epinephrine. It is instilled twice daily.
3. Clonidine hydrochloride. It is a centrally-acting
systemic antihypertensive agent, which has been
shown to lower the IOP by decreasing aqueous
humour production by stimulation of alpha-receptors
in the ciliary body. Preparations and dosage. It is
used as 0.125 percent and 0.25 percent eye drops,
twice daily.
4. Brimonidine (0.2%). Mechanism of action. It is a
selective alpha-2 adrenergic agonist and lowers IOP
by decreasing aqueous production and enhancing
uveoscleral outflow. It has an additive effect to betablockers.
Dosage: It has a peak effect of 2 hours and
action lasts for 12 hours; so it is administered twice
daily.
5. Apraclonidine (0.5%, 1%). It is also alpha-2
adrenergic agonist like brimonidine. It is an extremely
potent ocular hypotensive drug and is commonly used
prophylactically for prevention of IOP elevation
following laser trabeculoplasty, YAG laser iridotomy
and posterior capsulotomy. It is of limited use for
long-term administration because of the high rate of
ocular side-effects.

Parasympathomimetic drugs (Miotics)

Parasympathomimetics, also called as cholinergic
drugs, either imitate or potentiate the effects of
acetylcholine.
Classification
Depending upon the mode of action, these can be
classified as follows:
1. Direct-acting or agonists e.g., pilocarpine.
2. Indirect-acting parasympathomimetics or
cholinesterase inhibitors: As the name indicates
these drugs act indirectly by destroying the
enzyme cholinesterase; thereby sparing the
naturallyacting acetylcholine for its actions. These
drugs have been divided into two subgroups,
designated as reversible (e.g., physostigmine)
and irreversible (e.g., echothiophate iodide,
demecarium and diisopropyl-fluoro-phosphate,
DFP3) antic-holinesterases.
3. Dual-action parasympathomimetics, i.e., which
act as both a muscarinic agonist as well as a
weak cholinesterase inhibitor e.g., carbachol.
Mechanism of action
1. In primary open-angle glaucoma the miotics
reduce the intraocular pressure (IOP) by
enhancing the aqueous outflow facility. This is
achieved by changes in the trabecular meshwork
produced by a pull exerted on the scleral spur by
contraction of the longitudinal fibres of ciliary
muscle.
2. In primary angle-closure glaucoma these reduce
the IOP due to their miotic effect by opening the
angle. The mechanical contraction of the pupil
moves the iris away from the trabecular meshwork.
Side-effects
1. Systemic side-effects noted are: bradycardia,
increased sweating, diarrhoea, excessive salivation
and anxiety. The only serious complication noted
with irreversible cholinesterase inhibitors is
‘scoline apnoea’, i.e., inability of the patient to
resume normal respiration after termination of
general anaesthesia.
2. Local side-effects are encountered more frequently
with long-acting miotics (i.e. irreversible
cholinesterase inhibitors). These include problems
due to miosis itself (e.g. reduced visual acuity in
the presence of polar cataracts, impairment of
night vision and generalized contraction of visual
fields), spasm of accommodation which may cause
myopia and frontal headache, retinal detachment,
lenticular opacities, iris cyst formation, mild iritis,
lacrimation and follicular conjunctivitis.
Preparations
1. Pilocarpine. It is a direct-acting parasympathomimetic
drug. It is the most commonly used and
the most extensively studied miotic. Indications: (i)
Primary open-angle glaucoma; (ii) Acute angle-closure
glaucoma; (iii) Chronic synechial angle-closure
glaucoma. Contraindications: inflammatory
glaucoma, malignant glaucoma and known allergy.
Available preparations and dosage are: (a) Eyedrops
are available in 1%, 2% and 4% strengths. Except in
very darkly pigmented irides maximum effect is
obtained with a 4 percent solution. In POAG, therapy
is usually initiated with 1 percent concentration. The
onset of action occurs in 20 minutes, peak in 2 hours
and duration of effect is 4-6 hours. Therefore, the
eyedrops are usually prescribed every 6 or 8 hourly.
(b) Ocuserts are available as pilo-20 and pilo-40. These
are changed once in a week. Pilo-20 is generally used
in patients controlled with 2 percent or less
concentration of eyedrops; and pilo-40 in those
requiring higher concentration of eyedrops.
(c) Pilocarpine gel (4%) is a bedtime adjunct to the
daytime medication.
2. Carbachol. It is a dual-action (agonist as well as
weak cholinesterase inhibitor) miotic. Indications. It
is a very good alternative to pilocarpine in resistant
or intolerant cases. Preparations. It is available as
0.75 percent and 3 percent eyedrops. Dosage: The
action ensues in 40 minutes and lasts for about 12
hours. Therefore, the drops are instilled 2 or 3 times a
day.
3. Echothiophate iodide (Phospholine iodide). It is
a long acting cholinesterase inhibitor. Indications: It
is very effective in POAG. Preparations: Available
as 0.03, 0.06 and 0.125 percent eye- drops. Dosage:
The onset of action occurs within 2 hours and lasts
up to 24 hours. Therefore, it is instilled once or twice
daily.
4. Demecarium bromide. It is similar to ecothiopate
iodide and is used as 0.125 percent or 0.25 per- cent
eyedrops.
5. Physostigmine (eserine). It is a reversible (weak)
cholinesterase inhibitor. It is used as 0.5 percent
ointment twice a day.