Ординатура / Офтальмология / Английские материалы / Basic Sciences in Ophthalmology_Velayutham_2009
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29 Medical Management
of Glaucoma
There is a tremendous change and introduction of newer drugs in the management of glaucoma in the recent past.
The treatment is aimed at lowering the IOP, which is the major factor in the disease process.
The reduction of pressure could be achieved either by reducing the aqueous production or by facilitating the aqueous outflow. The pressure is brought down to the required levelcalled as Target pressure at which there is no progression of the symptom complex.
The newer concept in management is Neuroprotection. These are various drugs, which are being tried to protect the nerve damage and are still in the experimental stage.
Gene therapy is also gaining popularity in the recent past.
CLASSIFICATION OF ANTI-GLAUCOMA DRUGS
Older Classification
Based on the site of action :
Cholinergic drugs.
Adrenergic drugs dopaminergic drugs.
Carbonic anhydrase inhibitors.
Hyperosmotic agents.
Neuro protective drugs.
Alternative group of drugs.
Newer Classification
Based on the Mode of action of the drugs:
A)Drugs increasing the aqueous outflow.
B)Drugs reducing the aqueous production.
OCULAR CHOLINERGICS
Ocular cholinergics have been the main stay in medical management of Glaucoma, both primary or secondary.
They can be classified as direct acting and indirect acting depending on the site of action.
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DIRECT ACTING CHOLINERGICS
These are the group of Cholinergics, which directly stimulate the effector muscle (Sphincter Pupillae) by acting on the parasympathetic neuromuscular junction.
They are—
Pilocarpine.
Carbachol.
Among these Pilocarpine is the most commonly used directly acting anticholinergic drug and has been time tested.
INDIRECT ACTING ANTICHOLINERGIC DRUGS
These drugs are also known as anticholinesterases. Main action of these drugs is to prevent destruction of acetylcholine at neuromuscular junction by acetylcholine esterase, and thus making available more of neurotransmitter at neuromuscular junction and stimulating parasympathetic system.
These group of drugs can be divided into
•Reversible cholinesterase inhibitors.
•Irreversible cholinesterase inhibitors.
Reversible Cholinesterase Inhibitors
The Carbamate Inhibitors
i)Physiostigmine.
ii)Neostigmine.
iii)Pyridostigmine.
iv)Demecarium Bromide.
Irreversible Cholinesterase Inhibitors
i)Ecothiophate.
ii)Di Isopropyl Pyrophosphate (DPP)
PILOCARPINE
It is a directly acting anticholinesterase drug mainly acting on sphincter muscle directly.
Derived from the plant Pilocarpus microphyllus, dispensed in hydrochloride or nitrate salt. Pilocarpine stimulates only muscarinic receptors.
Mechanism of Action
It is a parasympathomimetic drug acting on muscarinic receptors causing
•Constriction of Pupillary sphincter.
•Contraction of ciliary muscle.
Due to constriction of ciliary sphincter, there is no crowding of peripheral iris in narrow angle patients, thus facilitating the outflow.
Due to contraction of ciliary muscle it produces a pull over the scleral spur, by contraction of longitudinal muscle, thus opening the trabecular meshwork beams and facilitating the outflow.
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Uses
1)Primary open angle glaucoma.
2)Primary angle closure glaucoma.
Dosage and Concentration
Available in 1%, 2%, and 4% concentrations. Dosage is 4 - 6 times per day
Pilocarpine is less effective in higher-pressure ranges, due to ischemia of sphincter pupillae. Therefore, always used with other pressure lowering agents if the IOP is in the higher range.
Various Forms of Pilocarpine Available
1)Pilocarpine Solution Eye drops: Concentrations available are 1%, 2%, and 4% dissolved in water-soluble base preservative.
2)Ocusert: (Membrane Controlled Devices): This is a controlled release of pilocarpine system with concentration of 20 and 40 micrograms of drug released per hour.
Advantage is improved compliance due to decreased frequency of application.
Applied once a week
3)Pilocarpine Gel: This is also a controlled release system of pilocarpine with ease of once daily once administration.
4)Soluble Insert Devices: Impregnated with pilocarpine provides IOP control for 24 hrs.
It is inserted in the cul-de-sac. Another advantage is that it can be removed when desired effect is achieved.
5)Soft Contact Lenses: Soft contact lenses soaked in pilocarpine increase the corneal contact time. Therefore greater aqueous levels and longer IOP control are attained.
6)Subconjunctival injections of pilocarpine can be tried, but are not used commonly because of corneal edema.
Adverse Effects
1.Decreased vision in low illumination.
2.Induced myopia.
3.Headache, supraorbital pain, browache.
4.Conjunctival congestion.
5.Lens opacities.
6.Retinal detachment.
7.Iris cyst.
8.Increased inflammation due to break in blood retinal barrier. Hence, not used in inflammatory glaucomas.
9.Cicatrical pemphigoid—rare.
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Systemic Side Effects
Nausea, vomiting, diarrhoea, diaphoresis, lacrimation, salivation, smooth muscle contraction, bronchospasm.
Indirect Parasympathomimetics
Physiostigmine, ecothiopate iodide, rarely used now-a-days.
ADRENERGIC STIMULATORS
Epinephrine, Dipivefrine,Apraclonidine, Brimonidine.
Epinephrine
This direct acting sympathomimetic stimulates both Alpha and Beta Adrenergic receptors.
Mechanism of action can be divided into three phases:
Phase -I Decrease in aqueous production, due to initial vasoconstrictive effect thus slowing the ultrafiltration procedure.
Phase - II Increase in aqueous outflow. This forms the major bulk, which is responsible for decrease in IOP.
Phase - III Late increase in aqueous outflow facility.
Administration: It is available in concentrations of 0.5%, 1%, and 2%. Administered twice daily.
Available with various bases like hydrochloride, borate and bitartarate.
Dipivefrine
This is a prodrug of epinephrine, which undergoes pharmacological conversion into epinephrine into the body when administered.
Mechanism of action is same as that of Epinephrine.
Drug Interaction
Has got additive effect when used along with miotics.
Has additive effect when used with or pretreatment with Beta-blockers. Betoxolol > Timolol.
Adverse Effects
Local
1)Itching and burning sensation.
2)Reactive hyperaemia. Less with Dipivefrine.
2)Adrenochrome deposits on the lower palpebral conjunctiva, In case of bullous keratopathy deposits are seen on the cornea leading to Black Cornea. Deposits may be either in Stag Horn shape or in a branching pattern.
3)Tearing.
4)Photophobia.
5)Punctal epidermalisation and occlusion.
6)Madarosis.
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7)Mydriasis.
8)Epinephrine maculopathy.
9)Corneal epithelial damage.
Clinical Therapeutic Uses
Useful as second line of drugs in combination with Miotics or Carbonic anhydrase inhibitors in POAG.
Apraclonidine
Apraclonidine is α2 Adrenergic agonist
Mechanism of action
Apraclonidine reduces the IOP by reducing the aqueous production.
Added advantage of Apraclonidine is that, it does not penetrate the blood brain barrier like its parent compound clonidine, which causes systemic hypotension.
Side Effects
Transient dry nose and dry mouth, follicular conjunctivitis, contact dermatitis. Eyelid retraction in rare cases.
Therapeutic Uses
Apraclonidine is mainly used in the treatment of transient rise of IOP. As in—
1.Post laser procedures of anterior segment, where there is a transient spike in the IOP, as in Post-Iridotomy, Post Laser iridoplasty, and Post Laser Yag capsulotomy etc.
2.It is also used in chronic maintenance treatment of open angle glaucoma.
For transient rise of IOP, apraclonidine is given before and after the procedure.
For long term use Apraclonidine is used twice daily. Available in 1% and 0.5% concentrations.
Brimonidine (0.2%)
Brimonidine tartarate has selectiveAlpha 2 agonist mechanism of action lowering of the IOP is by
i)Decrease in aqueous production.
ii)Increase in uveoscleral outflow without affecting conventional outflow
and episcleral venous pressure.
Recently it has been found that Brimonidine also increases the optic nerve blood flow thus assuming a role in neuroprotection.
Adverse Reaction: Conjunctival hyperemia and burning sensation are the major side effects of this drug, which may force the patient to discontinue the drug.
Uses: Used as second line drug in treatment of POAG.
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ADRENERGIC INHIBITORS
Beta Adrenergic Blockers
Nonselective adrenergic inhibitors:
Timolol, Levobunolol, Carteolol, Metipranolol, Metaprolol, Pindolol, Nadolol, Befunolol, Penbutolol.
Selective beta adrenergic blockers:
Betoxolol is the only selective Beta adrenergic blocker in clinical use.
Timolol
It is a non-selective adrenergic beta 1 and beta 2 antagonist
Mechanism of Action
Timolol reduces the IOP by reduction in aqueous production with its direct action on the ciliary processes and ciliary perfusion thus affecting the ultrafiltration.
It is available in 0.25% and 0.5% concentrations.
Administered as twice daily dosage for effective and sustained lowering of IOP.
Efficacy
Short-term Escape: In the initial phase of treatment, patients respond very well with good control of IOP which continues for 3-4 weeks and then a plateau is reached. This short term escape from high IOP is due to initial increase in the receptors.
Long-term Drift: In some patients after long term therapy with timolol, the patient stops responding to the drug and IOP starts raising slowly. This phenomenon is explained by tachyphylaxis and down regulation of receptors.
This can be prevented by changing the drug for 60 days in a year and then restarting the drug. This is known as Timolol holiday.
Adverse Reactions
Ocular
Itching, burning sensation, superficial punctate keratitis, corneal anesthesia, reduced tear production; Timolol is usually well tolerated.
Systemic
Timolol being a nonselective β blocker, it is contraindicated in patients with Cardiovascular system disorders - Bradycardia, ↑ heart block, heart failure, decreased nocturnal blood flow, decreased exercise tolerance. Respiratory: - COPD, Induces bronchospasm
Diabetes Mellitus: - It masks hypoglycemia in Insulin dependent diabetes mellitus.
CNS - causes depression, anxiety, confusion, hallucinations, aggravation of myasthenia gravis, nausea, diarrhea, abdominal cramps.
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Uses
It can be used in control of IOP in all forms of Glaucoma.
1)Primary open angle glaucoma.
2)Acute attack of angle closure glaucoma.
3)Postoperative -Glaucoma in Aphakia /Pseudophakia.
4)Initial management of pediatric glaucomas.
5)It is also useful in Ocular Hypertensives to prevent progression to frank glaucoma and prevent damage.
Levobunolol
It is an analog of propranolol. It is a non-selective β- blocker.
Advantage of Levobunolol over Timolol is its ease of administration as once daily doses, which effectively controls the IOP comparable to Timolol.
Adverse effects - similar to that of Timolol.
Clinical usessimilar to that of Timolol. In addition, it has shown effective control of IOP in postoperative spikes.
Carteolol - similar to other β - blockers.
MetipranololSimilar to other β - Blockers, Granulomatous anterior uveitis is commonly encountered following use of this drug.
Betaxolol
It is a cardioselective Beta 1 antagonist but it has some action on beta 2 receptors which produces the lowering of IOP by decrease in aqueous production without affecting the outflow.
Therefore reduction in IOP is less compared to Timolol. Available in: 0.25% and 0.5% concentration.
Indications:
Treatment of ocular hypertension. Treatment of POAG.
Used in combination therapy along with other drugs.
Side Effects
Reduced corneal sensitivity, itching.
Systemic side effects are similar to Timolol except for respiratory side effects, which are minimal or nil.
Alpha Adrenergic Inhibitors
Thymoxamine
Dapiprazol
Bunazosin
Prazosin
Thymoxamine
It is an alpha antagonist, which competes with norepinephrine for alphareceptors.
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Mechanism of action: It produces miosis by inhibiting the dilator muscle without affecting the ciliary muscle.
Clinical Applications
1)Reversal of mydriasis in case of phenylephrine induced mydriasis.
2)Management of angle closure glaucomait causes miosis, inspite of ischemia.
3)Differentiating between angle closure glaucoma with open angle glaucoma with narrow angles (Thymoxamine breaks the angle closure attack, but it has no effect on the open angle glaucoma).
4)Management of Pigmentary glaucoma.
5)Management of Eyelid retraction.
CARBONIC ANHYDRASE INHIBITORS
Carbonic anhydrase inhibitors belong to sulphonamide group of drugs.
This group of drugs, reduces IOP by reducing the aqueous humor formation.
Mechanism of Action
Sodium movement into the posterior chamber is directly linked to bicarbonate synthesis, which in turn results in movement of isotonic fluid into posterior chamber, thus aqueous humor is formed by active secretion.
If bicarbonate synthesis is obstructed then there is reduced aqueous production. Carbonic anhydrase inhibitors contain free sulphonamide, which competes with the bicarbonate ion in binding to enzyme carbonic anhydrase. Thus it blocks the bicarbonate synthesis and aqueous humor formation.
CO2 + H2O → H2CO3 + H+
Various carbonic anhydrase inhibitors available are: Acetazolamide.
Acetazolamide sustained release capsules.
Methazolamide - Metabolised by liver hence contraindicated in liver disease. Ethoxazolamide.
Dichlorphenamide.
Dorzolamide.
Acetazolamide induces metabolic acidosis and reduces the IOP and also increases the visual function in glaucomatous eyes by increasing the blood flow to the optic nerve.
Hypotensive effect of CA inhibitors starts 2 hrs after administration and lasts for 6 hrs.
Dosage and Administration
Acetazolamide:
Dosage 250 mg every 6 hrs orally. 500mg sustained release tablets bid orally.
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Dichlorphenamide
25 - 50 mg 1 - 3 times daily orally.
Methazolamide
50 - 100 mg 2-3 times daily orally.
Other uses of acetazolamide
1.Increases the absorption of subretinal fluid.
2.Increases the adhesion between RPE and neurosensory retina.
3.Used in macular oedema in patients with retinal pigment epithelial disease.
Clinical uses
1)Acute angle closure glaucoma.
2)Secondary glaucomas.
Routes of administration
Intravenous/oral/topical - Oral is the most common route used.
Side Effects
Ocular
Transient myopia, noted in few persons.
Systemic
Metabolic acidosis, hypokalemia, malaise, fatigue, weight loss, metallic taste, abdominal discomfort, nausea, taste alteration, epigastric burning, renal calculi, blood dyscrasias, thrombocytopenia, agranulocytosis, aplastic anemia, exfoliative dermatitis, hypersensitive nephropathy.
Contraindications
1)Adrenal Insufficiency.
2)Severe Liver or Renal impairment.
3)Hyperchloremic metabolic acidosis, renal calculi.
4)Sulphonamide hypersensitivity.
Topical CA Inhibitors
(a)Dorzolomide: 2%. It is a topical carbonic anhydrase inhibitor.
(b)Brinzolamide 1%.
(c)Sezolamide.
(d)Acetazolamide.
They are effective topical CA Inhibitors, administered two - three times daily dosage.
Mechanism of action is similar to other CA inhibitors. They cause reduction in IOP by reducing the aqueous production.
Maximum IOP reduction is within 2 hours after the instillation of drops.
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Side effects
Topical CA inhibitors are well tolerated than systemic CA inhibitors. Frequent side effects noted are - Burning and stinging sensation in the eyes. Brinzolamide has got less ocular discomfort as compared to Dorzolamide.
Superficial punctate keratitis has been noted in some patients.
Patients allergic to sulphonamides may have anaphylaxis, erythema multiforme, Steven Johnsons syndrome, bone marrow depression, hemolytic anaemia, thrombocytopenic purpura, leucopenia etc.
HYPEROSMOTIC AGENTS
Systemic hyperosmotic agents are used for the immediate control of IOP.
Hyperosmotic agents available are:
1)Glycerine.
2)Isosorbide.
3)Mannitol.
Mechanism of Action
These agents increase the plasma osmolarity, thus causing the water from the eye mainly vitreous to be drawn into the systemic circulation, thereby reducing the intraocular volume and thus decreasing the IOP.
Indications
These agents are used as adjunctive therapy to lower the IOP rapidly :
i)Acute attack of glaucoma.
ii)Prior to ocular surgery.
iii)In Phacomorphic glaucoma.
Contraindications
•Anuria.
•Severe dehydration.
•Acute pulmonary edema.
•Cardiac failure or decompensation.
Glycerine
Glycerine is available as 50% and 75% lime flavoured oral solution. Dosage - 1.0 to 1.5g /Kg body weight.
Has got high caloric value therefore should be avoided in patients with diabetes.
Isosorbid
Isosorbide is available as 45% mint flavoured solution
Dosage 1-2 g/Kg of body weight.
Mannitol
Available in 5 - 25 % solution.
Dosage 1-2 g / kg of body weight, given over a short period of time, i.e., 30 minutes.