Pharmacology 4th semester

1. DRUGS USED IN GLAUCOMA AND MYASTHENIA GRAVIS
SATYAJIT GHOSH
B. PHARM 4TH
SEMESTER

2.  Drugs used in glaucoma: -
i. Glaucoma is a group of eye diseases which result in damage to the optic nerve and cause vision loss. The most common type is open-angle (wide angle,
chronic simple) glaucoma, in which the drainage angle for fluid within the eye remains open, with less common types including closed-angle (narrow
angle, acute congestive) glaucoma.
ii. The chief therapeutic measure is to lower intraocular tension (i.o.t.), either by reducing secretion of aqueous humour or by promoting its drainage.
iii. Major amount of aqueous (90%) drains through the trabecular route, while 10% fluid passes into the connective tissue spaces within the ciliary muscle
then via suprachoroid into episcleral vessels (uveoscleral outflow).
iv. Glaucoma is seen in two principal clinical forms; viz. 'open angle' and 'angle closure' glaucoma.
 Open angle (wide angle, chronic simple) glaucoma: -
It is a genetically predisposed degenerative disease affecting patency of the trabecular meshwork. The i.o.t. rises insidiously and progressively. Ocular
hypotensive drugs are used on a long-term basis and constitute the definitive treatment in majority of cases.
Topically drugs for glaucoma
β-Adrenergoc blockers
Timolol
Betaxolol
Levobunolol
Carteolol
α-Adrenergic agonists
Dipivefrine
Apraclonidine
Brimonidine
Prostaglandins analogues
Latanoprost
Travoprost
Bimatoprost
Carbonic anhydrase inhibitors
Acetazolamide
Dorzolamide
Brinzolamide
Miotics
Pilocarpine
Physostigmine
Echothiophate

3. A- 𝛃 Adrenergic blockers: -
The β blockers do not affect pupil size, tone of ciliary muscle or outflow facility, but lower i.o.t. by reducing aqueous formation.
This probably results from down regulation of adenylyl cyclase due to β2 receptor blockade in the ciliary epithelium and a secondary effect due to
reduction in ocular blood flow.
Ocular side effects of 𝛽 blockers: -
These include stinging, redness and dryness of eye, corneal hypoesthesia, allergic blepharon, conjunctivitis and blurred vision.
Systemic adverse effects: -
These occur due to absorption through nasolacrimal duct. Life-threatening bronchospasm has been reported in asthmatic and COPD patients.
Bradycardia, accentuation of heart block and CHF are common side effect. Systemic adverse effects can be minimized by applying mild pressure on
the inner canthus of the eye for about 5min after instilling the eye drop to prevent entry of the drug into nasolacrimal duct from where it is mainly
absorbed.
DRUGS NOTE PREPARATIONS
Timolol
 It is nonselective β and has no local anaesthetic or intrinsic
sympathomimetic activity.
 The ocular hypotensive action (20-35% fall in i.o.t.) becomes
within 1 hour and lasts for 12 hours.
 30% cases of open angle glaucoma fail to achieve the desired
level of i.o.t. with timolol alone and may need additional
medication.
GLUCOMOL, OCUPRES, IOTIM, LOPRES = 0.25 % and 0.5%
eye drops
TIMOI.AST = 0.5% as gel forming eyedrop for OD use.
Betaxolol
 It is a β1 selective blocker has less bronchopulmonary and
less cardiac, central and metabolic side effects.
 It exerts a protective effect on retinal neurones, by blocking
some Ca2+ channels and reducing Na+/Ca2+ influx.
 Betaxolol is less efficacious in lowering i.o.t. than timolol,
because ocular preceptors are predominantly of the β2
subtype.
 Transient stinging and burning in the eye are common side
effects.
OPTIPRESS, IOBET, OCUBETA = 0.5% eye drops

4. Levobunolol
 It has been introduced as a once daily alternative to timolol.
 The ocular and systemic effects are very similar to timolol
except for longer duration of action.
BETAGAN = 0.5% ophthalmic soln
B- Adrenergic agonists: -
DRUGS NOTE PREPARATIONS
Dipivefrine
 It is a prodrug of adrenaline; penetrates cornea and is hydrolysed
by the esterases present there into adrenaline.
 The released adrenaline lowers i.o.t. by augmenting uveoscleral
outflow, β2 receptor mediated increase in hydraulic conductivity
of trabecular filtering cells, as well as by reducing aqueous
formation (α1 + α2 receptor mediated).
PROPINE = 0.1 % eye drop
Apraclonidine
 It is a polar clonidine congener which does not cross blood-brain
barrier, but applied topically (0.5- 1%) it lowers i.o.t. by 25%.
 It decreases aqueous production by primary α2 and subsidiary α1
action in the ciliary body.
 Itching. lid dermatitis, follicular conjunctivitis, mydriasis, eyelid
retraction, dryness of mouth and nose are common side effects.
ALFADROPS DS = 1% eye drops.
Brimonidine
 This clonidine congener is more α2 selective and more lipophilic
than apraclonidine.
 It lowers i.o.t. by 20- 27% by reducing aqueous production and by
increasing uveoscleral flow.
 Peak effect on i.o.t. occurs after 2 hours of instillation. Allergic
conjunctivitis and other ocular side effects are similar to but less
frequent than with apraclonidine.
 Brimonidine is indicated both for short-term as well as long-term
use in glaucoma. It is generally used for add-on therapy only.
ALPHAGAN-P, BRIMODIN-P = 0.15 % eye drops,
IOBRIM = 0.2 % eye drops.
C- Prostaglandin analogues: -
It acts by increasing uveoscleral outflow, increasing permeability of tissues in ciliary muscle or by an action on episcleral vessels.
DRUGS NOTE PREPARATIONS
Latanoprost
 It has efficacy similar lo timolol (i.o.t. reduction by 25-35%) and
the effect is well sustained over long-term.
 It reduces i.o.t. in normal pressure glaucoma also.
LACOMA, XALATAN, LATOPROST = 0.005% eye drops.
LACOMA-T, LAPROST PLUS, LATOCHECK-T eye drops
with timolol 0.5% eye drops.

5.  It has no systemic side effects. Blurring of vision, increased iris
pigmentation, thickening and darkening of eyelashes have
occurred in some cases.
 Macular edema can develop during treatment with any PGF20
analogue, especially in aphakic patients.
Travoprost
 Another selective FP-prostanoid receptor agonist which lowers
i.o.t. mainly by increasing uveoscleral outflow and a minor effect
on trabecular outflow.
 The effect starts within 2 hours, peaks at 12 hours and lasts for 24
hours or more.
TRAVATAN = 0.004% eye drops.
TRAVACOM = 0.004% with timolol 0.5% eye drop.
Bimatoprost
 A synthetic prostamide derivative found to be equally or more
effective than latanoprost in lowering i.o.t.
LUMIGAN, CAREPROST 0.03% eye drops
D- Carbonic anhydrase inhibitors: -
DRUGS NOTE PREPARATIONS
Acetazolamide
 Oral treatment with acetazolamide (0.25g 6-12 hourly) reduces aqueous
formation by limiting generation of bicarbonate ion in the ciliary
epithelium.
 It is used to supplement ocular hypotensive drugs for short-term
indications like angle closure, before and after ocular surgery/laser therapy.
 Systemic side effects include paraesthesia, anorexia, hypokalaemia, acidosis,
malaise
Dorzolamide
 (2% eye drops BD-TDS) It is a topically useful carbonic anhydrase inhibitor
developed to circumvent systemic side effects of acetazolamide.
 It lowers i.o.t. by 20%; less efficacious than timolol. Ocular stinging, burning,
itching, corneal edema and bitter taste are the usual side effects.
 Dorzolamide is used only as add on drug to topical β blockers/PG analogues,
or when these drugs are contraindicated.
DORTAS, DORZOX = 2% eye drops.
E- Miotics:
 In open angle glaucoma, pilocarpine combined with anti ChEs lower i.o.t. by increasing ciliary muscle tone thereby improving patency of
trabeculae.
 The current approach to treatment of open angle glaucoma can be summarized as- start monotherapy with latanoprost/another PG analogue, or a
topical β blocker; if target i.o.t. is not attained, either change over to the alternative drug or use both the above concurrently.

6.  Brimonidine/dorzolamide (occasionally dipivefrine) are used only when there are contraindications to PG analogues and/or β blockers, or to
supplement their action. Topical miotics and oral acetazolamide are added only as the last resort.
 Angle closure (narrow angle, acute congestive) glaucoma: -
i. It occurs in individuals with a narrow iridocorneal angle and shallow anterior chamber. The i.o.t. remains normal until an attack is precipitated,
usually by mydriasis.
ii. The i.o.t. rises rapidly to very high values (40- 60 mmHg). It is an emergent condition with marked congestion of eyes and severe headache.
iii. Following drugs are used: -
a- Hypertonic mannitol (20%) 1.5- 2 g/kg or glycerol (10%):
infused i.v. decongest the eye by osmotic action. A retention enema of 50% glycerine is also sometimes used.
b- Acetazolamide:
0.5 g i.v. followed by oral twice daily is started concurrently.
c- Miotic:
Once the i.o.t. starts falling due to the above i.v. therapy, pilocarpine 1-4% is instilled every 10 min initially and then at longer intervals.
Contraction of sphincter pupillae changes the direction of forces in the iris to lessen its contact with the lens and spreads the iris mass centrally →
pupillary block is removed and iridocorneal angle is freed.
d- Topical β blocker:
Timolol 0.5% is instilled 12 hourly in addition.
 Drugs used in myasthenia gravis: -
i. Myasthenia gravis (MG) is a long-term neuromuscular disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected
muscles are those of the eyes, face, and swallowing. It can result in double vision, drooping eyelids, trouble talking, and trouble walking.

7. ii. Myasthenia gravis is an autoimmune disease which results from antibodies that destroy nicotinic acetylcholine receptors at the junction between the nerve
and muscle. This prevents nerve impulses from triggering muscle contractions.
A- Diagnosis: -
a- Physical examination: -
During a physical examination to check for MG, a doctor might ask the person to perform repetitive movements. For instance, the doctor may ask one
to look at a fixed point for 30 seconds and to relax the muscles of the forehead, because a person with MG and ptosis of the eyes might be involuntarily
using the forehead muscles to compensate for the weakness in the eyelids.
b- Blood tests: -
If the diagnosis is suspected, serology can be performed:
 One test is for antibodies against the acetylcholine receptor; the test has a reasonable sensitivity of 80–96%, but in ocular myasthenia, the
sensitivity falls to 50%.
 A proportion of the people without antibodies against the acetylcholine receptor have antibodies against the MuSK protein.
 In specific situations, testing is performed for Lambert-Eaton syndrome.
c- Electrodiagnostic: -
Muscle fibers of people with MG are easily fatigued, which the repetitive nerve stimulation test can help diagnose. In single-fiber electromyography,
which is considered to be the most sensitive test for MG, a thin needle electrode is inserted into different areas of a particular muscle to record the
action potentials from several samplings of different individual muscle fibers.
Two muscle fibers belonging to the same motor unit are identified, and the temporal variability in their firing patterns is measured. Frequency and
proportion of particular abnormal action potential patterns, called "jitter" and "blocking", are diagnostic.

8. Jitter refers to the abnormal variation in the time interval between action potentials of adjacent muscle fibers in the same motor unit. Blocking refers
to the failure of nerve impulses to elicit action potentials in adjacent muscle fibers of the same motor unit.
d- Edrophonium test: -
This test requires the intravenous administration of edrophonium chloride or neostigmine, drugs that block the breakdown of acetylcholine by
cholinesterase (acetylcholinesterase inhibitors).
The edrophonium test is performed by rapid intravenous injection of 2 mg of edrophonium chloride, followed 45 sec later by an additional 8 mg if the
first dose is without effect.
A positive response consists of brief improvement in strength, unaccompanied by lingual fasciculation (which generally occurs in nonmyasthenic
patients).
B- Management: -
a- Acetylcholinesterase inhibitors: -
i. Acetylcholinesterase inhibitors can provide symptomatic benefit and may not fully remove a person's weakness from MG.
ii. While they might not fully remove all symptoms of MG, they still may allow a person the ability to perform normal daily activities.
iii. Usually, acetylcholinesterase inhibitors are started at a low dose and increased until the desired result is achieved. If taken 30 minutes before a
meal, symptoms will be mild during eating, which is helpful for those who have difficulty swallowing due to their illness.
iv. Another medication used for MG, atropine, can reduce the muscarinic side effects of acetylcholinesterase inhibitors. Pyridostigmine is a relatively
long-acting drug (when compared to other cholinergic agonists), with a half-life around four hours with relatively few side effects.
b- Immune suppressants: -
The steroid prednisone might also be used to achieve a better result, but it can lead to the worsening of symptoms for 14 days and takes 6–8 weeks to
achieve its maximal effectiveness.

9. Other immune suppressing medications may also be used including rituximab.
c- Plasmapheresis and IVIG: -
If the myasthenia is serious (myasthenic crisis), plasmapheresis can be used to remove the putative antibodies from the circulation.
Also, intravenous immunoglobulins (IVIGs) can be used to bind the circulating antibodies. Both of these treatments have relatively short-lived
benefits.
d- Surgery: -
As thymomas are seen in 10% of all people with the MG, they are often given a chest X-ray and CT scan to evaluate their need for surgical removal of
their thymus glands and any cancerous tissue that may be present.