6.

Pharmacology
6.1 Pharmacokinetics
6.1.1 Rate and extent of ocular absorption

a. Tear volume will influence ocular absorption.

b. Tear turnover rate will influence ocular absorption.
c. Blink rate will influence ocular absorption.
d. Ratio of conjunctival: corneal surface area will influence ocular absorption.
e. Ocular absorption for topical medications is about 20-40% of the instilled dose.

Many factors have a profound effect on the rate and extent of ocular absorption. The most
important of these are the precorneal factors, such as the tear volume (7—30 pi), tear turnover
time (0.5—2.2 j-ul/min), and the spontaneous blink rate (15 times per min), all of which combine
to limit the time the remains in the conjunctival sac to 3—5 minutes on average. This time will
be reduced further if the medication is irritative, causing increased tear production and blinking.
The corneal thickness and the ratio of conjunctival:corneal surface area (17:1 in humans) will
also influence ocular absorption. The absorption of a medication can be calculated if the total
amount of the drug that has entered the eye is divided by the instilled dose, and the range is 1—
7% for ocular medications.

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6.1.2 Corneal barriers

a. The corneal epithelium is the greatest barrier to ocular drug penetration.

b. Lipophilic drugs penetrate the epithelium via a paracellular route.
c. The stroma has a diffusional rate approximately onequarter that of an aqueous
system.
d. The corneal endothelium is a significant barrier to the penetration of drugs.
e. Transconjunctival and trans-scleral routes contribute to passage of drugs into the
aqueous.

The corneal epithelium is a lipophilic (hydrophobic) layer that is the greatest barrier to ocular
drug penetration. Passage through the epithelium is via an intracellular route in the case of
lipophilic drugs, or via the paracellular route in the case of hydrophilic drugs. The intracellular
route accounts for the most drug transport. The stroma provides relatively little resistance to drug
transport—about one-quarter that of an aqueous system. The single-layered endothelium
provides no significant resistance to the penetration of ophthalmic drugs and is considered to be
in the same pharmacokinetic compartment as the aqueous. Recent studies have demonstrated that
the outer sclera is much less of a barrier to hydrophilic drugs than the corneal epithelium and that
the transconjunctival and trans-scleral routes contribute significantly to ocular penetration of
such drugs. The vascular nature of the episclera and conjunctiva also facilitates the transport of
drugs to deeper ocular tissues.

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6.1.3 Distribution and elimination of ocular medications

a. Binding to melanin can significantly affect the distribution of a drug.

b. Non steroidal anti-inflammatory drugs (NSAIDs) can accumulate in the cornea.
c. Topically applied antibiotics achieve minimal inhibitory concentrations In the vitreous.
d. Eluorescein readily penetrates blood ocular barriers.
e. If the ocular half life of a drug is shorter than the aqueous turnover time, strong tissue
binding of that drug is likely.

The availability of drugs to ocular tissues will be influenced by several factors. Binding of a drug
to melanin in the iris and ciliary body causes a slow release of the drug from this ―reservoir‖,
resulting in a prolonged but reduced effect-—for example atropine in dark irides. Drugs may also
bind to proteins in the aqueous. Rapid turnover of aqueous humour will reduce the availability of
a drug to the intraocular tissues. Drugs tend not to accumulate in ocular tissues such as the iris,
ciliary body and the lens. However NSAIDs and pilocarpine accumulate in the cornea.
Penetration of topical medications into the vitreous is poor, as they must diffuse against an
aqueous humour gradient and diffusion of drugs through the vitreous is slow. This explains why
topical antibiotics do not achieve minimal inhibitory concentrations in the vitreous. The
availability of systemic medications and the elimination of drugs from the eye will be influenced
by the blood ocular barriers. As fluorescein does not cross the intact blood—retinal barrier it can
be used to assess the integrity of the retinal circulation and the retinal pigment epithelium. Once
drugs are absorbed into the anterior chamber they are mostly eliminated by aqueous humour
turnover. The turnover time of the aqueous is about 1.5% per minute of the anterior chamber
volume, which equates to an aqueous half life of 46 minutes. A drug half life of less than 46 min
suggests that metabolism of die drug and uptake by blood vessels is contributing to its ocular
elimination. Conversely, a drug half life of more than 46 min, that is, greater than the aqueous
turnover time, implies there is significant tissue binding of the drug, reducing its elimination
from the eye.

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6.2: Cholinergic agonists
6.2.1 The ocular cholinergic system
a. Cholineacetyl transferase is found in the corneal epithelium and retina.
b. Acetylcholine is found in the corneal sroma and endothelium.
c. Cholinesterase is found in the iris and ciliary body.
d. Cholinesterase is found in the retinal vessels.
e. Muscarinic receptors are found in the epithelium.

Gholineacetyl transferase (the enzyme responsible for acetylcholine production) is found in the
corneal epithelium, the iris, ciliary body, and inner plexiform layer of the retina. Acetylcholine
and cholinesterase are also found in these sites: the latter in particularly high concentrations in
the iris and ciliary body sphincter muscles. However, cholinesterase is not found in the primary
aqueous, the vitreous, or the retinal vessels. Although muscarinic receptors are present in the iris,
ciliary body, and the retina they have not been isolated from the corneal epithelium.

6.2.2 Properties of muscarinic agonists

a. Pilocarpine is a direct muscarinic agonist.
b. Carbachol is both a direct and an indirect muscarinic agonist.
c. These agonists cause miosis and accommodation.
d. They decrease intraocular pressure by decreasing production of aqueous.
e. Muscarinic agonists decrease intraocular pressure by increasing uveoscleral outflow.

Muscarinic agonists may be direct acting (such as pilocarpine) or both direct and indirect acting
(for example, carbachol, which inhibits cholinesterase). They cause the triad of miosis (by
stimulating the iris sphincter muscle), accommodation (by

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stimulating the ciliary muscle), and decreased intraocular pressure. The mechanism of the last
effect is unknown, but the most widely accepted theory is that these agents produce a passive
increase in outflow facility (the scleral spur traction model). Fluorophotometric studies have
shown that pilocarpine reduces the intraocular pressure, despite increasing aqueous production
and decreasing uveoscleral flow.

6.2.3 Uses and side effects of cholinergic agonists

a. Open angle glaucoma.

b. Esotropias.
c. Reversal of an atropine mydriasis.
d. Diagnosis of Adie‘s puplies.
e. These agents commonly cause head and brow ache.

The main clinical use of cholinergic agonists is in treatment of open angle glaucoma and
prophylaxis of closed angle glaucoma, in which treatment halves the incidence of angle closure
in the second eye. By decreasing the accommodative effort, cholinergic agonists have been used
in the treatment of accommodative squints. Pilocarpine, although it will reverse a phenylephrine
mydriasis, will not constrict an atropine mydriasis. Adie‘s pupils : very sensitive to cholinergic
agonists and a solution of Dcarpine of 0.125% will cause a miosis. The most common e effect of
these agents is head or brow aches but these rmally resolve after 2—3 days.

6.2.4 Indirect acting muscarinic agonists

a. Physostigmine acts by phosphorylating cholinesterase.

b. Echothiophate acts by carbamylating cholinesterase.
c. These drugs increase miosis hen used in conjunction with pilocarpine.
d. They cause an initial increase in intraocular pressure.
e. Indirect acting agonists reverse an atropine mydriasis

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Indirect acting muscarinic agonists (IAMAs) inhibit cholinesterase either by phosphorylation (for
example echothiopate), or by carbamylation (for example, physostigmine). Acetylcholine is a
more potent miotic than pilocarpine; therefore caaing pilocarpine to an IAJMA will decrease the
miosis. IAMAs produce an initial rise in intraocular pressure, and the eventual hypotensive effect
is variable. Some IAMAs will reverse an atropine mydriasis.

6.2.5 Uses and side effects of IAMAs

a. These drugs lower intraocular pressure.
b. They are used in the treatment of esotropias.
c. IAMAs are useful to treat lice blepharitis.
d. One of the side effects is cataract.
e. Their use causes iris nodules.

IAMAs such as physostigmine may be used in open angle glaucoma and occasionally as
prophylaxis against angle closure glaucoma. However, they are more likely to cause pupil block
in the second condition than pilocarpine. They cause less accommodative spasm in esotropias
than direct acting agents. Physostigmine will kill Phthirus pubis and Demodex folliculorum. The
risk of cataract with echothiopate is related to dose and duration of treatment and is five times
greater than that of pilocarpine. Hyperplasia of the iris pigment epithelium produced by some
IAMAs can be prevented by concomitant treatment with phenylephrine.

6.2.6 Properties of muscarinic antagonists

a. These drugs compete with acetylcholine for receptor sites.

b. The order of mydriatic potency in vivo is atropine > cyclopentolate > homatropine >
tropicamide.
c. They are susceptible to pigment binding.
d. Muscarinic antagonists may ave a direct χ agonist effect.
e. Their use decreases the convexity and axial width of the lens.

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Muscarinic antagonists, naturally occurring or synthetic, act by competing with acetylcholine for
receptor sites on the post- naptic membrane. Their mydriatic effect, which is produced by
inhibiting the iris sphincter muscle, is also dependent on drug availability. This explains why
tropicamide, which readily penetrates the comeal epithelium, is more effective in vivo than
homatropine. Binding of these drugs by pigment accounts for their decreased efficacy and
latency of action in pigmented eyes. Atropine may supplement its antimuscarinic action by
stimula
ting oc receptors on the dilator muscle. All of these agents will produce cycloplegia by inhibiting
the ciliary muscle. This causes thinning and decreased convexity of the lens, reducing the risk of
posterior synechiae.

6.2.7 Side effects of muscarinic antagonists

These include:
a. Fever.
b. Increase in intraocular pressure.
c. Gatrointestinal disturbances.
d. Ataxic dysarthria.
e. Bradycardia.

Minor side effects associated with muscarinic antagonists are mild fever and skin flushing, which
resolve in 24 hours. The intraocular pressure can be raised in several ways, the most obvious of
which is precipitation of angle closure; however, these drugs may also decrease aqueous outflow.
Pre-testing of patients with open angle glaucoma using 1 % cyclopentolate may predict those
who will be susceptible to a rise in intraocular pressure when taking systemic muscarinic
antagonists (such as antidepressants and some ulcer medications). Gastrointestinal effects
include increased distension and risk of necrotising enterocolitis in neonates. Side effects on the
central nervous system include ataxic dysarthria, cerebellar signs, and an increased risk of
seizures. Cardiovascular side effects, if present, tend to be tachyarrhythmias.

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6.3: The adrenergic system.

6.3.1 Catecholamine receptors in the eye

a. α1 receptors are found in the dilator muscle.

b. α1 receptors are found in the ciliary muscle.
c. β2 receoptors are found in the central epithelium.
d. β2 receptors are found in ciliary processes and trabecular meshwork.
e. Dopamine receptors are found in the retina.

receptors are postjunctional ones and are found on the dilator muscle, ciliary muscle, and the
sphincter muscle (where they have an inhibitory action). There are no βl receptors in the eye but
β2 receptors are found in the ciliary processes and trabecular meshwork. Dopamine has been
isolated from the inner plexiform layer of the retina, where it is thought to be the transmitter in
horizontal cells.

6.3.2 Properties of catecholamines

These drugs:
a. Decrease aqueous production via α2 and β2 receptors.
b. Increase outflow facility.
c. Decrease uveoscleral flow.
d. Inhibit the iris sphincter muscle.
e. produce uveal vasoconstriction.

The influence of catecholamines on intraocular pressure is controversial. Two possible

mechanisms are: (1) a decrease in aqueous production via α2 and β2 receptors is thought to occur
by an effect on the non-pigmented ciliary epithelium or by decreasing ciliary blood flow; (2) an
increase in outflow facility has been postulated, by direct effects on the trabecular meshwork.
XJveoscleral flow is increased indirectly by a decrease in episcleral resistance. Mydriasis occurs
by active stimulation of the dilator muscle and active inhibition of the sphincter via

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α receptors. The vascular tissue of the eye is devoid of β receptors but stimulation of α receptors
will cause vasoconstriction.

6.3.3 Pharmacology of timolol

Timolol:
a. Is a relatively selective β1 antagonist.
b. Has a duration of action of 6-8 hours.
c. Has a greater effect on intraocular pressure than pilocarpine.
d. Causes accommodation.
e. Is metabolized in the eye.

Timolol is a relatively selective β1antagonist, despite the fact that most receptors in the eye are
β2 receptors. This problem is overcome by the aqueous concentrations of timolol, which are
1000 times those required for β2 stimulation. The main effect of the drug is to lower intraocular
pressure (which it does more effectively than pilocarpine). Its duration of action of 12—24 hours
allows for twice daily administration. Timolol has no effect on the pupillary or ciliary muscles
and is metabolised in the liver.

6.3.4 Side effects of ocular p blockers

a. Depression.
b. Bradycardia.
c. Wheeze.
d. Impotence.
e. Decrease in the plasma high density lipoprotein (HDL) cholesterol.

Ocular β blockers, when absorbed into the circulation, can produce a number of ―predictable‖
side effects. They should be used with caution in patients with heart block and heart failure
because of their ability to induce bradyarrhythmias and their negatively inotropic effect. β
blockers will also exacerbate bronchospasm in asthmatics or patients with chronic obstructive

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airways disease. Timolol has been shown to decrease the plasma HDL cholesterol levels by 8%
and to elevate the ratio of total cholesterol:HDL cholesterol by 10%. Lowering of plasma HDL
cholesterol increases the risk of myocardial infarction. Impotence and depression have also been
reported with topical p blockers.

6.3.5 Topical β blockers

a. Levobunolol is relatively β1 selective.

b. Betaxolol is relatively β1 selective.
c. Carteolol has intrinsic sympathomimetic activity.
d. Betaxolol is more efficacious than timolol in lowering the intraocular pressure.
e. Long term drift is a problem associated with topical β blockers.

Betaxolol is the only topical β blocker that is relatively β1 selective (cardioselective). It should in
theory reduce the risk of β2-inhibition, but although it is better tolerated in those patients with
reversible airways disease, it can still induce bronchospasm. Betaxolol is also the least effective
topical β blocker with regard to lowering of the intraocular pressure. Carteolol has intrinsic
sympathomimetic activity (ISA), that is it causes an early transient agonist response. This partial
agonist activity could in theory lower the incidence of systemic side effects such as bradycardia
and bronchospasm; however, this beneficial effect is not evident when carteolol is administered
topically. The ISA of carteolol seems to be effective in minimising the decrease in high density
lipoproteins (HDL) associated with other topical β blockers. Tachyphylaxis is a phenomenon
whereby down- regulation of receptors results in a loss of responsiveness to agonist action; the
β2 adrenergic receptor is prone to such desensitisation. Conversely, prolonged antagonist action
may result in upregulation of β2 adrenergic receptors in the iris and ciliary body, resulting in
reduced ocular hypotensive efficacy of topical β blockers.

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5.3.6 Topical α-agonists
a. Apraclonidine is predominantly an α1-agonist.
b. Apraclonidine reduces intraocular pressure primarily by suppressing aqueous
production.
c. Apraclonidine and brimonidine primarily enter the eye via the cornea.
d. Brimonidine lowers intraocular pressure primarily by increasing uveoscleral outflow.
e. Systemic hypotension is a side effect of brimonidine.

Apraclonidine hydrochloride is a relatively selective α2-agonist. In contrast to clonidine and

brimonidine, it is a highly ionised molecule that penetrates the cornea slowly. The primary route
of delivery to the ciliary body is therefore through the conjunctive and sclera. Apraclonidine
lowers intraocular pressure by suppressing aqueous production without altering tonographic
outflow facility. At peak effect apraclonidine 1% lowers intraocular pressure by 30—40%
compared with the baseline. It is primarily used to prevent spikes in intraocular pressure after
anterior segment laser procedures. Brimonidine is a highly selective α2-agonist that lowers the
intraocular pressure by reducing aqueous production. Although brimonidine 0.2% will produce
an initial 20% reduction in the intraocular pressure, this effect appears to be short lived (less than
6 hours), and the long term efficacy of therapy is doubtful. Topical α-agonists frequently cause
an allergic follicular conjunctivitis, dry mouth and conjunctival blanching. Systemic hypotension
is a well recognised dose-related side effect of topical brimonidine.

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6.4: Ocular hypotensive drugs
6.4.1 Mannitol

This agent:
a. Crosses the blood aqueous barrier.
b. Causes loss of fluid from the eye by diffusion.
c. Should be administered intravenously.
d. Is excreted 90% unchanged by the kidneys.
e. May have an additional effect on intraocular pressure via optic nerve efferents.

Mannitol, like all hyperosmolar agents, does not cross the blood aqueous barrier. It should be
given intravenously over a 20—40 minute period and removes water from the eye by osmosis,
not diffusion. It is excreted 90% unchanged by the kidneys and therefore should be used with
caution in those with compromised renal function because of side effects such as fluid retention
and pulmonary oedema. Experimentally small concentrations of mannitol which do not produce
a measurable rise in plasma osmolarity have been found to decrease intraocular pressure. This
action is thought to be secondary to hypothalamic efferents travelling in the optic nerve.

6.4.2 Glycerol
a. Glycerol is rapidly absorbed from the gastrointestinal tract.
b. It penetrates the inflamed eye better than the non-inflamed eye.
c. HYperosmotic coma is a side effect.
d. Ketoacidosis is a side effect.
e. Hypoglycaemic coma is a side effect.

Glycerol is administered orally and is rapidly absorbed from the gastrointestinal tract. Unlike
mannitol, glycerol penetrates more rapidly into the inflamed eye. The average dose of glycerol
has a calorific load of 330 calories, which in the diabetic may cause hyperglycaemia,
hyperosmotic coma and diabetic ketoacidosis.

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6.4.3 Carbonic anhydrase
a. Carbonic anhydiase catalyses the irrecversible reaction
H+ + HCO3 H2CO3
b. it is found in cells of the proximal renal tubules.
c. Carbonic anhydrase is found in red blood cells.
d. it is found in the pigmented ciliary epithelium.
e. The action of this enzyme lowers intraocular pressure.

Carbonic anhydrase catalyses the reversible reaction H + + HCO3- H2COj. Its bicarbonated
form is the body‘s main buffering agent, playing a vital role in acid-base regulation, and is found
in proximal tubule cells (which produce bicarbonate to buffer pH changes in the urine). Carbonic
anhydrase in red blood cells will catalyse the reaction C02 + H2O H2C03. The bicarbonate
produced dissociates to give H+ ions (buffered by haemoglobin) and HC03- ions (which diffuse
into the plasma). In the non-pigmentary ciliary epithelium, this enzyme stimulates aqueous
production, either by increasing bicarbonate availability for co-transport with sodium, or by
increasing H+ concentrations at the inner membrane for sodium transport.

6.4.4 Uses and side effects of acetazolamide

Acetazolamide:
a. Decreases intraocular pressure.
b. May be administered topically.
C. Causes prasthesiae.
d. Causes depression.
e. Causes gastrointestinal upset

Acetazolamide is a carbonic anhydrase inhibitor. It may be administered orally or intravenously.

It can produce a marked and rapid decrease in the intraocular pressure but has a number of well
documented side effects such as parasthesiae, depression, and gastrointestinal upset. Use of
acetazolamide is contraindicated in patients with severe renal impairment.

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6.1.5 Dorzolamide
a. Is an acetazolamide derivative.
b. Is lipophilic at pH7 and hydrophilic at pH 5.
c. Reduces aqueous formation by inhibiting the carbonic anhydrase isoenzyme II.
d. has an additive IOP lowering effect when used with a β blockier.
e. Does not cause the systemic side effects associated with acetazolamide.

Dorzolamide is a topical carbonic anhydrase inhibitor (CAI). Unfortunately topical

acetazolamide, being very hydrophilic, does not readily penetrate the cornea, and this has led to
the development of thienothiopyran-2-sulphonamides such as dorzolamide hydrochloride. All
thienothiopyran-2-sulphon- amides have an ampholytic character, that is they are relatively water
soluble at pH 5 and pH 9, but are lipid soluble at pH 7. This enables them to pass through the
lipophilic cornea and to reach the ciliary epithelium, where they inhibit carbonic anhydrase
isoenzyme II. Dorzolamide lowers the intraocular pressure by about 20—25% and has an
additive effect when used with a topical β blocker. Despite the small doses absorbed
systemically, side effects such as electrolyte imbalance, renal stones and general malaise have
been reported with dorzolamide.

6.4.6. Latanoprost

a. Is a PGF 2 analogue. Prostaglandin F2α

b. Is activated by enzymic hydrolysis in the cornea.
c. Significantly increases trabecular outflow.
d. Decreases aqueous production.
e. May increase melanogenesis in iris stroma melanocytes.

Latanoprost is a PGF2a derivative that has been modified by addition of an isopropyl ester and a
phenyl substitution. It is a lipophilic prodrug that undergoes enzymic hydrolysis in the cornea to
the biologically active acid of latanoprost. Ocular

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responses are mediated via prostanoid receptors, particularly the FP-receptor. Latanoprost lowers
the intraocular pressure by increasing uveoscieral outflow. It has no effect on aqueous
production, and only minimally increases trabecular outflow. Latanoprost has a short plasma half
life of 17 min and is completely converted to inactive metabolites by the liver, 88% of which are
excreted in the urine. In contrast, the elimination half life in the eye is about .3 hours, as there is
no significant metabolism of latanoprost in the eye. Latanoprost is well tolerated, with no
systemic side effects. The most common ocular side effect is an increase in the brown
pigmentation of lie iris in mixed colour eyes, which is secondary to increased melanogenesis by
iris stromal melanocytes.

6.5 Corticosteroids and non-steroidal anti- fiammatory drugs (NSAIDs)

6.5.1 Glucocorticoid receptors

a. Glucocrticoid receptors are present in all cells.

b. Glucocorticoid receptors are present on cell membranes.
c. Therre is only a single class of glucocorticoid receptor.
d. HSP-90 (heat shock protein) prevents inactive receptors from migrating to the
nucleus.
e. Activated glucocorticoid receptors bind to DNA at promoter regions of steroid –
responsive target genes.

Glucocorticoid receptors are cytosolic receptors that are found to a greater or lesser degree in all
cells. There is only a single class of glucocorticoid receptor, although there are several steroid-
binding domains that are located towards the C-terminal of the molecule. HSP-90 is associated
with the receptor; it acts as a molecular chaperone, preventing the unbound receptor migrating to
the nucleus, and it helps maintain the optimum configuration for corticosteroid binding. Once
corticosteroid binds to the receptor, HSP-90 detaches from the receptor, which then migrates to
the nucleus. There it binds to DNA at promotor regions of steroid-responsive target genes, and
transcription of these genes is then induced or repressed. The Tau 1 sequences

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at the N-terminal of the receptor aid in the transcriptional transactivation of these genes. It is
estimated that the number of steroid-responsive genes per cell is 10—100, which goes some way
to explain the myriad of effects produced by steroids.

6.5.2 Anti-inflammatory effects of steroids

a. Dexamethasone increases synthesis of lipocortin, which inhibits phospholipase A2.

b. Steroids inhibit brandykinin breakdown.
c. Steroids inhibit the transcription of interleukin 1 and interleukin 2.
d. Steroids block the action of cytokines.
e. Steroids inhibit the induction of nitric oxide gene expression by cytokines.

Steroids influence acute and chronic inflammatory processes in a variety of ways.

Dexamethasone increases the synthesis of lipocortin, which inhibits phospholipase A2 and the
subsequent release of arachidonic acid, a substrate for both the prostaglandin and leukotriene
pathways. Steroids may also have an inhibitory effect on other enzymes necessary for eicosanoid
synthesis. Bradykinin is a vasoactive inflammatory mediator that is degraded by angiotensin-
converting enzyme and neural endopeptidases, both of which can be induced by steroids.
Steroids exert an effect on cytokines by inhibiting their transcription, for example that of 11-1, 2,
3, 4, 5, 6 and 8, TNFα and GM-CSF, and by blocking their action, for example that of TNFα.
Nitric oxide is a potent inflammatory mediator and steroids have been shown to inhibit induction
of nitric oxide gene expression by endotoxin and cytokines.

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6.5-3 Effects of corticosteroids on hypersensitivity, humoral and cell mediated
immunity
a. The effect on T cells is greater than that on B cells.
b. B cells are most sensitive to steroids immediately after antigen presentation.
c. Steroids modify type II and III hypersensitivity reactions.
d. Steroids inhibit histidine decarboxylase and multiplication of eosinophils.
e. Steroids decrease graft versus host reactions.

Glucocorticoids modify both humoral and cell mediated immunity by inhibiting B and T
lymphocytes respectively. The B cells are most sensitive to corticosteroids immediately after
their antigen presentation phase, and type II and type III hypersensitivity reactions can be
dampened by decreased antibody production. Type I hypersensitivity reactions are lessened
because corticosteroids reduce histamine production (by inhibiting histidine decarboxylase) and
eosinophil multiplication. Graft versus host reactions are also decreased by administration of
steroids because these drugs inhibit T cell mediated macrophages.

6.5.4 Absorption and metabolism of topical steroids

a. Prednisolone phosphate rapidly penetrates the cornea.
b. Dexamethasone 0.5% (maxidex) is a more potent anti-inflammatory agent than
prednisolone acetate 1% (pred forte).
c. Dexamethasone is excreted unchangted after topical or systemic administration.
d. Fluoromethalone is metabolized in the cornea.
e. The activity of corneal enzymes may enhance the activity of topical corticosteroids

The corneal penetrance of topical steroids depends on the lipophilicity of the formulation and the
integrity of the corneal epithelium. Prednisolone acetate and dexamethasone acetate.

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are lipophilic preparations. They effectively penetrate the cornea and are therefore potent
intraocular anti-inflammatory agents. The anti-inflammatory activity of dexamethasone 0.5%
(maxidex) is approximately 80% that of prednisolone acetate 1% (pred forte). The penetration of
water soluble agents such as dexamethasone phosphate and prednisolone phosphate is increased
threefold when the epithelium is absent. Dexamethasone is not metabolised in the eye or
elsewhere (which explains its relatively long half life) and is excreted unchanged.
Fluoromethalone is metabolised in the cornea and is therefore less likely to cause unwanted
ocular side effects, such as cataract and glaucoma. Topical steroids may be modified by corneal
enzymes—examples of this include the conversion of cortisone and prednisolone to their active
11-hydroxyl components by comeal hydroxylase, and the conversion of phosphate corticosteroid
derivatives to more active alcohol forms by corneal phosphatases.

6.5.5 Actions of NSAIDs

a. Inhibition of lipoxygenase.
b. Inhibition of cyclo-oxygenase.
c. Scavenging free radicals.
d. Analgesic agents.
e. Antipyretic agents.

The specific action of non-steroidal anti-inflammatory drugs is the inhibition of cyclo-

oxygenase, so preventing prostaglandin synthesis. NSAIDs, with the possible exception of
diclofenac,' have no effect on lipoxygenase activity and therefore do not inhibit leukotriene
synthesis. NSAIDs have anti-inflammatory, analgesic and antipyretic properties, not all of which
are initiated solely by the inhibition of cyclo-oxygenase. NSAIDs also have free radical
scavenging activity, and because of their antichemotactic activity they can modulate humoral and
cellular events during inflammatory reactions.

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6-5.6 Ocular effects of prostaglandins
a. Inducing miosis.
b. Breakdown of blood ocular barriers.
c. Changes in intraocular pressure.
d. Coinjunctival hyperaemia.
e. Inflammation.

Prostaglandins have a diverse spectrum of activity on the eye which includes all of the above
effects. The principle indications for topical NSAIDs are the prevention of intraoperative miosis,
the treatment of postsurgical inflammation, adjunctive use with topical steroids in uveitis, and
the treatment of cystoid macular oedema. The most commonly used topical NSAIDs are
flurbiprofen 0.03% and ketorolac 0.5% (phenylalkanoic acid derivatives), diclofenac 0.1% (a
water soluble phenylacetic acid derivative), and indomethacin 0.5—1%. Other classes of NSAID
such as salicylates or fenamates are too unstable in solution or too toxic for ocular applications.

6.6: Ocular anaesthetics

6.6.1 Local anaesthetic agents

a. These are weak acids.

b. They are biphasic.
c. Block changes in the sodium permeability of axonal membranes.
d. The action is more rapid in myelinated nerves.
e. Local anaesthetics are metabolized in the plasma and liver.

Local anaesthetics consist of three major parts: a lipophilic aromatic residue is linked to an
intermediate aliphatic chain by an ester or amide bond, which is joined to a secondary or tertiary
amine. They are weak bases—the charged form binds to the receptor site to prevent sodium
influx across axonal membranes. Local anaesthetics can enter myelinated nerves only at the
nodes of Ranvier so their rate of action here is considerably slower than

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in unmyelinated nerves. Most of these drugs are metabolised in the liver or in the plasma-

6.6.2 Uses and side effects of topical agents

Topical anaesthetics:
a. Produce analgesia for approximately 10-30 minutes.
b. May have antimicrobial effects.
c. Are suitable for systemic use.
d. Inhibit epithelial mitoses and migration.
e. Cause epithelial loosening and erosions.

Commonly used topical anaesthetics include benoxinate, proparicaine, tetracaine and cocaine; all
take effect in seconds and produce analgesia lasting for 10—30 minutes. Tetracaine and
benoxinate have been shown to inhibit growth of some staphylococci, pseudomonas and Candida
species incubated in 24 hour cultures. Topical anaesthetics are extremely toxic and should never
be administered systemically. Side effects are more common with cocaine, and include toxic
effects on the metabolism and ultrastructure of epithelial cells (causing erosions), and inhibition
of mitoses and migration.

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