Ocular pharmacology 3

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• Parasympathomimetic drugs (Miotics)
• Sympathomimetic drugs (Adrenergic drugs)
• Beta-blockers
• Carbonic anhydrase inhibitors
• Hyperosmotic agents
• Prostaglandins analogue

Parasympathomimetic also called cholinergic drugs.
They can be classified according to the mode of action:
or agonists (Pilocarpine)
parasympathomimetic or
cholinesterase inhibitors:
Parasympathomimetic: It is muscarinic
agonist as well as a weak cholinesterase inhibitor
(Carbacol)

The miotics reduce the 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 fibers of ciliary muscles

MECHANISM OF ACTION: PILOCARPINE
• 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

 Local side effects include:
a) miosis,
b) brow ache,
c) myopic shift and
d) exacerbation of the symptoms of cataract.

 Systemic side effects are rare but include
• confusion,
• bradycardia,
• bronchospasm,
• gastrointestinal symptoms and
• urinary frequency.

Sympathomimetic drugs: (also known as adrenergic
drugs and adrenergic amines) are stimulant
compounds which mimic the effects of endogenous
agonists of the sympathetic nervous system. It acts
by stimulation alpha, beta or both the receptors.

Depending upon the mode of action, these can be
classified as follows:
i. Both alpha and beta receptor stimulator, e.g.
epinephrine.
ii. Direct alpha-adrenergic stimulators e.g.
norepinephrine,
iii. Indirect alpha-adrenergic stimulator, e.g. pargyline
iv. Beta-adrenergic stimulator, i.e. isoproterenol
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results by virtue of
both alpha and beta receptors stimulation
production occurs
due to stimulation of alpha receptors in the ciliary
body.

 This direct acting Sympathomimetic drugs
stimulates both alpha and beta- adrenergic
receptors.
 Indications: It is one of the standard drug used
for the management of POAG. It is also useful in
most of the secondary Glaucomas.

 Preparations: It is available as 0.5%, 1% and 2%
eye-drops.
 Dosage: The action starts within one hour and
last up to 12 – 24 hours. Therefore, it is installed
twice daily.

Propine or dipivalylepinephrine: It is a strong
prodrug which is converted into epinephrine after
it’s absorption into the eye.
It is more lipophilic than epinephrine and thus its
corneal penetration is increased by 17 times.
Preparation: It is available as 0.1% eye drops.
Dosage: Action and efficacy is similar to 1%
epinephrine. It is installed twice in a day.

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 beta-blockers.
Dosage: It has a peak effect of two hours and action
lasts for 12 hours; so it is administered twice daily.

It is a selective alpha-2 adrenergic agonist like
Brimonidine. Apraclonidine 1% (or 0.5%) is used
principally to prevent or treat an acute rise in IOP
following laser surgery on the anterior segment. It
is generally not suitable for long-term use

 Beta-adrenergic antagonists (beta 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.

Timolol and levobunolol are nonselective 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.
Beta-blockers reduce IOP by decreasing aqueous
production, mediated by an effect on the ciliary
epithelium.

• There may be limited supplementary effect if a
topical beta-blocker is added when a patient
already takes a systemic beta-blocker; the
combination may also involve a relatively high
risk of systemic side effects.

 Beta-blockers should not be instilled at bedtime as
they may cause a profound drop in blood pressure
while the individual is asleep, thus reducing optic
disc perfusion and potentially causing visual field
deterioration;
 Beta-blockers are also preferred in conditions such as
ocular inflammation and cystoid macular oedema, or
where there is a history of herpes simplex keratitis.

 Non-selective
• Timolol maleate
• Levobunolol HCL
• Metipranolol
 Selective:
• Betaxolol

Betaxolol twice daily has a lower hypotensive
effect than timolol. However, optic nerve blood
flow may be increased so that visual field
preservation may be superior. Betaxolol is
relatively cardio selective (beta-1 receptors), so
causes less bronchoconstriction.

Levobunolol once or twice daily has a broadly
similar profile to timolol.
Carteolol twice daily is similar to timolol. It has
a more selective action on the eye than on the
cardiopulmonary system
Metipranolol twice daily is similar to timolol
but has been linked with granulomatous
anterior uveitis

 Ocular side effects are minimum
 Systemic:
• Bronchospasm
• Cardiovascular. Effects include heart block,
bradycardia, worsening of heart failure and
hypotension, the pulse should be assessed before
prescription.
• Due to peripheral vasoconstrictive effects should
be cautious in patients with peripheral vascular
disease, including Raynaud phenomenon.

 Unpleasant but less severe side effects include
• sleep disorders,
• reduced exercise tolerance,
• hallucinations, confusion, & depression,
• fatigue, headache, nausea, dizziness, decreased
libido and dyslipidemia.

 They are chemically related to sulfonamide
antibiotics and are relatively contraindicated in
patients allergic to sulfonamide antibiotics
 They lower IOP by inhibiting aqueous secretion,
and via the topical route are used three times
daily as monotherapy or twice daily as
adjunctive treatment.

• Dorzolamide: The main adverse effects are
stinging and a transient bitter taste following
administration; allergic blepharoconjunctivitis is
not uncommon.
• Brinzolamide: is similar to dorzolamide, but with
a lower incidence of stinging and local allergy. It
is a suspension

 Usually used for short-term treatment,
particularly in patients with acute glaucoma.
Because of their systemic side effects, long-term
use is reserved for patients at high risk of visual
loss. Sulfonamide (‘sulfa’) allergy is a relative
contraindication.
 Acetazolamide is available as 250 mg tablets
(250–1000 mg daily in divided doses)

• Paranesthesia: pins & needles’ sensation in the
extreme
• Hypokalemia
• malaise and lowered mood,
• gastrointestinal symptoms,
• renal stones,
• Stevens–Johnson syndrome (very rare)
• dose-related bone marrow suppression,
idiosyncratic aplastic anemia (exceptionally rare
but with 50% mortality).

Osmotic agents lower IOP by creating an osmotic
gradient so that water is ‘drawn out’ from the
vitreous into the blood.
They are employed when a short-term reduction in
IOP is required that cannot be achieved by other
means, such as in resistant acute angle-closure
glaucoma or when the IOP is very high prior to
intraocular surgery.

• They are of limited value in inflammatory
glaucoma, in which the integrity of the
blood–aqueous barrier is compromised.

 cardiovascular overload as a result of increased
extracellular volume (caution in patients with
cardiac or renal disease),
 urinary retention (especially elderly men)
 headache,
 backache,
 nausea and confusion.

is given intravenously (1 g/kg body
weight or 5 ml/ kg body weight of a 20%
solution in water) over 30–60 minutes; peak
action occurs within 30 minutes
is a metabolically inert oral agent
with a minty taste; the dose is the same as for
glycerol. It may be safer for diabetic patients.

is an oral agent (1 g/kg body weight
or 2 ml/kg body weight of a 50% solution) with a
sweet and sickly taste, and can be given with
lemon (not orange) juice to avoid nausea.

 Peak action occurs within 1 hour.
 Glycerol is metabolized to glucose, and careful
monitoring with insulin cover may be required if
administered to a (well-controlled only) diabetic
patient.

 Increase uveoscleral outflow;
 Increase trabecular outflow
Dose: one drop before bed.

 Conjunctival hyperaemia is very common.
 Eyelash lengthening, thickening,
hyperpigmentation and occasionally increase in
number.
 Irreversible iris hyperpigmentation occurs in up
to a quarter of patients after 6 months.

• It is caused by an increase in the number of
pigmented granules within the superficial stroma
rather than an increase in the number of
melanocytes. Iris naevi and freckles are not
affected.

 Hyperpigmentation of periocular skin is common
but reversible.
 Preoperative use of PG agents may increase the
likelihood of cystoid macular oedema following
cataract surgery.
 Anterior uveitis is rare, but prostaglandins
should be used with caution in inflamed eyes.

 occasional headache,
 precipitation of migraine in susceptible
individuals, malaise, myalgia,
 skin rash and
 mild upper respiratory tract symptoms.

Latanaprost may cause fewer ocular
adverse events than other PG agents and
so is often used first line,

Travaprost is similar to Latanaprost,
though it may lower IOP to a slightly
greater extent, particularly in black
patient

Bimataprost has been shown to have a
greater IOP-lowering effect than the other
PG agents in several studies, but may
cause more conjunctival hyperaemia

• Tafluprost is a newer prostaglandin
derivative, and was the first available in
preservative-free form. Its IOP-lowering
efficacy may be slightly less than that of
other PG agents, but it is well tolerated

 Miotics
 Epinephrine
 Bimatoprost

 Prostaglandin (latanoprost)
 Epinephrine, Dipiverfrine
 Brimonidine
 Apraclonidine

 Carbonic anhydrase inhibitors (acetazolamide,
dorzolamide)
 Alpha receptor stimulators in ciliary process
(epinephrine, dipivefrine, clonidine, brimodin,
Apraclonidine
 Beta blockers (timolol, betaxolol, levobunolol)
 Hyperosmotic agents (glycerol, Mannitol, urea)

Inhibitors of VEGF block its interaction with
receptors on the endothelial cell surface and so
retard or reverse vessel growth. They have become
the predominant means of treatment for CNV.

Monoclonal antibody Bevacizumab (Avastin)
Antibody derivative Ranibizumab (Lucentis)
Aptamer Pegaptanib (Macugen)
Fusion protein Aflibercept (Eylea)
Aptamers are synthetic molecules that can be
raised against any kind of target, including toxic
or non immunogenic ones. They bind their target
with affinity similar or higher than antibodies.
They are 10 fold smaller than antibodies and can
be chemically-modified at will in a defined and
precise way.

 Recombinant humanized monoclonal antibody
that blocks angiogenesis by inhibiting VEGF-A
 It received its first approval in 2004, for
combination use with standard chemotherapy for
metastatic colon cancer

It has since been approved for use in
 Certain lung cancers,
 Renal cancers,
 Ovarian cancers
 Glioblastoma multiforme of the brain

Clinical trial results suggest that it is
approximately comparable to ranibizumab in
efficacy and safety, though some assessments have
suggested that the risk of serious systemic adverse
events is marginally higher with bevacizumab than
ranibizumab.
By seeing the difference you will understand why
“off level”? (next slide)

148 Kilodaltons 48 Kilodaltons
Half Life 20 days. Half Life 3 days.
Clearance is slow 100 folds faster.140
times higher affinity
Less costly Costly

• Ranibizumab (Lucentis®). Ranibizumab is a
humanized monoclonal antibody fragment
developed specifically for use in the eye. It non-
selectively binds and inhibits all isoforms of
VEGF-A.

It is a recombinant fusion protein that binds to
VEGF-A, VEGF-B and placental growth factor
(PlGF). After becoming commercially available, it
was adopted rapidly into clinical practice,
principally because the recommended maintenance
regimen consists of one injection every 2 months in
contrast to the monthly injections recommended
with ranibizumab and bevacizumab

Ocular pharmacology 3

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