PHARMACOLOGY-I (BP404TP)

DR. SUBHASH UNIVERSITY, JUNAGADH

Lecture 30 – Drugs used in myasthenia gravis and glaucoma

Myasthenia Gravis
Myasthenia gravis is an autoimmune disorder affecting about 1 in 10,000
population, due to development of antibodies directed to the nicotinic receptors
(NR) at the muscle endplate  reduction in number of free NM cholinoceptors
to 1/3 of normal or less (Fig. 7.3) and structural damage to the neuromuscular
junction. This results in weakness and easy fatigability on repeated activity, with
recovery after rest.
The eyelid, external ocular, facial and pharyngeal muscles are generally involved
first. Later, limb and respiratory muscles get affected. Neostigmine and its
congeners improve muscle contraction by allowing ACh released from
prejunctional endings to accumulate and act on the receptors over a larger area,
as well as by directly depolarizing the endplate.

Prof. Morvi M. Raval Dr. Subhash University, Junagadh

Treatment is usually started with neostigmine 15 mg orally 6 hourly; dose and
frequency is then adjusted to obtain optimum relief from weakness. However, the
dosage requirement may fluctuate from time to time and there are often
unpredictable periods of remission and exacerbation. Pyridostigmine is an
alternative which needs less frequent dosing.
If intolerable muscarinic side effects are produced, atropine can be added to block
them. These drugs have no effect on the basic disorder which often progresses;
ultimately it may not be possible to restore muscle strength adequately with anti-
ChEs alone.
Corticosteroids afford considerable improvement in such cases by their
immunosuppressant action. They inhibit production of NR-antibodies and may
increase synthesis of NRs. However, their long term use has problems of its own.
Prednisolone 30–60 mg/day induces remission in about 80% of the advanced
cases; 10 mg daily or on alternate days can be used for maintenance therapy.
Other immunosuppressants have also been used with benefit in advanced cases.
Both azathioprine and cyclosporine also inhibit NR-antibody synthesis by
affecting T-cells, but response to the former is slow in onset (takes upto 1 year),
while that to the latter is relatively quick (in 1–2 months).
Thymectomy is effective in a majority of the cases. It produces gradual
improvement and even complete remission has been obtained. Thymus may
contain modified muscle cells with NRs on their surface, which may be the source
of the antigen for production of anti-NR antibodies in myasthenic patients.

Diagnostic Tests
(a) Ameliorative test: Initially edrophonium 2 mg is injected i.v. as a test dose.
If nothing untoward happens, the remaining 8 mg is injected after 30–60
sec. Reversal of weakness and short-lasting improvement in the strength
of affected muscles occurs only in myasthenia gravis and not in other
muscular dystrophies.
(b) Provocative test: myasthenics are highly sensitive to d-tubocurarine; 0.5
mg i.v. causes marked weakness in them but is ineffective in non-
myasthenics. This test is hazardous: facilities for positive pressure
respiration must be at hand before performing it. This test is better not
performed.
(c) Demonstration of anti-NR antibodies in plasma or muscle biopsy specimen
is a more reliable test.

Prof. Morvi M. Raval Dr. Subhash University, Junagadh

 Glaucoma
Glaucoma is a group of diseases characterized by a progressive form of optic
nerve damage. This is generally but not necessarily associated with raised (> 21
mmHg) intraocular tension (i.o.t), but the etiology is unknown and there are many
risk factors.
The chief therapeutic measure is to lower i.o.t., either by reducing secretion of
aqueous humor or by promoting its drainage. Lowering of i.o.t. retards
progression of optic nerve damage even in normal/low i.o.t. glaucoma.
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). Glaucoma is
seen in two principal clinical forms:

(1) Site of action of miotics in angle closure glaucoma: contraction of sphincter

pupillae removes pupillary block and reverses obliteration of iridocorneal angle
(2) Site of action of miotics in open angle glaucoma: contraction of ciliary muscle
pulls on scleral spur and improves trabecular patency
(3) Site of action of (a) β blockers (b) α1 agonists (c) α2 agonists (d) carbonic
anhydrase inhibitors: all reduce aqueous secretion by ciliary body

Prof. Morvi M. Raval Dr. Subhash University, Junagadh

(4) Site of action of prostaglandins and adrenaline (α agonist action): increase
uveoscleral outflow by altering permeability and/or pressure gradients
(5) Site of action of adrenaline (β2 agonist action): possibly increases aqueous
conductivity of trabecular filtering cells

A. Open angle (wide angle, chronic simple) glaucoma

It is probably a genetically predisposed degenerative disease affecting patency of
the trabecular meshwork which is gradually lost past middle age. 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.

1. β Adrenergic blockers
Topical β blockers have been the first line drugs till recently, but PG F2α
analogues are the preferred drugs now. In contrast to miotics, the β blockers donot
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
adenylylcyclase due to β2 receptor blockade in the ciliary epithelium (see Fig.
10.2) and a secondary effect due to reduction in ocular blood flow. They are as
effective as miotics and produce less ocular side effects.
Ocular β blockers are lipophilic with high ocular capture (to reduce systemic
effects) and have no/weak local anaesthetic activity (to avoid corneal
hypoesthesia and damage).
Ocular side effects of β blockers These are generally mild and infrequent—
stinging, redness and dryness of eye, corneal hypoesthesia, allergic
blepharoconjunctivitis and blurred vision.

Timolol
It is the prototype of ocular β blockers; is nonselective (β1 + β2) and has no local
anaesthetic or intrinsic sympathomimetic activity.
The ocular hypotensive action (20–35% fall in i.o.t.) becomes evident within 1
hour and lasts for ~12 hours. After chronic dosing, the action is smooth and well
sustained. Some effect on i.o.t. persists for 1–2 weeks following discontinuation.

Prof. Morvi M. Raval Dr. Subhash University, Junagadh

This feature, in contrast to pilocarpine drops, gives a high level of clinical safety,
i.e. 1 or 2 missed doses will not affect i.o.t. control. However, ~30% cases of open
angle glaucoma fail to achieve the desired level of i.o.t. with timolol alone, and
may need additional medication.

2. α Adrenergic agonists
Dipivefrine It is a prodrug of Adr; penetrates cornea and is hydrolysed by the
esterases present there into Adr, which itself has poor corneal penetration and
causes ocular smarting, reactive hyperemia. The released Adr (from dipivefrine)
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).
Though better tolerated and longer acting than Adr, dipivefrine still produces
significant ocular burning and other side effects. It is infrequently used for add
on therapy.

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. Allergic conjunctivitis and other ocular
side effects are similar to but less frequent than with apraclonidine. Because of
weaker α1 action, side effects like mydriasis, eyelid retraction, conjunctival
blanching followed by hyperemia are less prominent, but dry mouth, sedation and
a small fall in BP have been noted.
Brimonidine is indicated both for short-term (prophylaxis of i.o.t. spikes post
laser/post surgery) as well as long-term use in glaucoma. It is generally used for
add on therapy only.

3. Prostaglandin analogues
Low concentration of PGF2α was found to lower i.o.t without inducing ocular
inflammation. It acts by increasing uveoscleral outflow, possibly by increasing
permeability of tissues in ciliary muscle or by an action on episcleral vessels. An
effect on trabecular outflow has also been demonstrated, but is less marked.

Prof. Morvi M. Raval Dr. Subhash University, Junagadh

Latanoprost Instilled in the eye, this PGF2α derivative has shown efficacy similar
to 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. Though ocular irritation
and pain are relatively frequent, no systemic side effects are reported.
Blurring of vision, increased iris pigmentation, thickening and darkening of
eyelashes have occurred in some cases. Macular edema can develop during
treatment with any PGF2α analogue, especially in aphakic patients; a watch
should be kept to detect it early.
Because of good efficacy, once daily application and absence of systemic
complications, PG analogues have become the first choice drugs for open angle
glaucoma.

4. Carbonic anhydrase inhibitors

Acetazolamide Oral treatment with acetazolamide (0.25 g 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—paresthesia, anorexia, hypokalaemia, acidosis, malaise
and depression restrict long-term use to few cases in which target i.o.t. is not
achieved even by concurrent use of 2–3 topical drugs.

5. Miotics: Till the 1970s topical pilocarpine and/or antiChEs were the standard
antiglaucoma drugs. However, because of several drawbacks, they are now used
only as the last option. In open angle glaucoma, they 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 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. Brimonidine/dorzolamide (occasionally dipivefrine) are used only
when there are contraindications to PG analogues and/or β blockers, or to
supplement their action.

B. Angle closure (narrow angle, acute congestive) glaucoma

Prof. Morvi M. Raval Dr. Subhash University, Junagadh

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 (Fig. 10.3A,B). 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.
Failure to lower i.o.t. quickly may result in loss of sight. Vigorous therapy
employing various measures to reduce i.o.t. is instituted.
1. 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.
2. Acetazolamide: 0.5 g i.v. followed by oral twice daily is started concurrently.

3. 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.

Prof. Morvi M. Raval Dr. Subhash University, Junagadh