SYSTEMIC ANTI-GLAUCOMA THERAPY

Guest author

LOVELY SINGH

Ajmal Khan Tibbiya College

Aligarh, India

HYPEROSMOTIC AGENTS

Administered systemically to lower intra-ocular pressure (IOP) acutely.

MECHANISM OF ACTION

• Reduce vitreous volume and thus IOP, by creating an osmotic gradient between blood and vitreous.
• Larger the dose and more rapid the administration, greater the reduction in IOP.
• Limited effectiveness and duration of action when blood-aqueous barrier is disrupted.
• Serum osmolality rises by the hyperosmotic agents, causing a net movement of intra-ocular water, primarily from the vitreous, into the retinal and uveal vessels.
• Gradually, when the osmolality gradient between the serum and vitreous decreases, the flow of water out of the eye diminishes. Once the hyperosmotic agent is cleared from systemic circulation, there is relative reversal of osmotic gradient due to the dehydrated vitreous and a subsequent rebound rise in IOP.
• An alternative theory suggests hyperosmotic agents may act through receptors in the central nervous system. Hyperosmotic agents were found to be active only in eyes with intact optic nerves.

• The induced blood-ocular osmotic gradient is influenced by the following factors:

1. Size: Smaller molecules increase osmolality greater than larger molecules per unit of weight.
2. Rate of administration: A larger osmotic gradient can be achieved with rapid administration of the hyperosmotic agents.
3. Rate of ocular penetrance: The lesser the ocular penetrance the larger the blood ocular gradient is allowed to persist. This increases the IOP-lowering effect.
4. Drugs and inflammation: May alter the blood-ocular barrier and affect the hyperosmotic agents’ action.
5. Systemic clearance: A drug with faster metabolism and clearance allows shorter duration of IOP control.
6. Oral ingestion of fluids: Concomitant ingestion of fluids decreases serum osmolality, causing decreased IOP control.
7. Distribution of drug in body fluids: A drug contained primarily in extracellular space (e.g. mannitol) allow a greater osmotic effect than a substance which passes intracellularly and distributed in total body water (e.g. urea).

INDICATIONS

Short-term or emergency treatment of elevate IOP.

Useful in acute conditions of elevated IOP (e.g. acute angle closure).

Effective when elevated IOP renders iris non-reactive to agents which combat pupillary block such as parasympathomimetic agents (e.g. pilocarpine).

Used to lower IOP or reduce vitreous volume prior to initiation of surgical procedures.

CONTRAINDICATIONS

• Should not be used for long-term therapy.
• May cause rebound elevation in IOP if the agent penetrates the eye and reverses osmotic gradient.
• Diabetes mellitus.
• Congestive heart failure.
• Renal failure.

ORAL AGENTS

AGENT	DOSE	ONSET OF ACTION	PEAK EFFECT	DURATION OF ACTION	NOTES
GLYCEROL (50% or 75%) solution	1-1.5gm/Kg BW (2-3cc/Kg BW)	10 min. after ingestion.	30-60 minutes	5 hours	100% solution also available.
ISOSORBIDE (45% solution)	1-1.5gm/Kg BW		1-3 hours	3-5 hours	Fewer side-effects than glycerol
ETHYL ALCOHOL (40-50% solution)				Brief action, since alcohol rapidly enters the eye.	Can cause nausea, vomiting.

INTRAVENOUS AGENTS

(1) Mannitol

10-20% solution is given in a dose of 1-1.5g/kg BW, at a delivery rate of 3-5 ml/minute.

Onset of action: 10-30 minutes

Peak effect: 40-60 minutes

Duration of action: 2-6 hours

It is excreted in urine.

Mannitol penetrates the eye poorly and so it is especially effective in the presence of ocular inflammation.

Mannitol does not cause tissue necrosis if it extravasates during administration.

(2) Urea

30% solution is used in the dose of 2-7 ml/kg BW.

Onset of action: 15-30 minutes.

Maximum effect in: 60 minutes

Duration of action: 4-6 hours

Urea diffuses throughout the body fluids and has relatively greater ocular penetrance so it's less effective than mannitol.

Ocular inflammation may make Urea ineffective and cause a rebound rise in IOP.

It is excreted in urine.

It does not have a long shelf-life and decomposes to ammonia.

May cause local thrombophlebitis and skin necrosis.

ORAL CARBONIC ANHYDRASE INHIBITORS

(1) Acetazolamide

Synthetic sulfonamide.

Decreases IOP by reducing aqueous production.

It acts locally at the ciliary processes to inhibit isozyme II of carbonic anhydrase.

Concomitant administration of bicarbonates does not affect the IOP lowering efficacy of Acetazolamide.

There is complete absorption following oral administration of Acetazolamide.

Peak plasma levels are attained 1 hour after ingestion.

Maximum IOP reduction occurs 2-6 hours after an oral dose and persists beyond 7 hours.

Sustained release capsule produces peak levels in 3-4 hours and the effect is seen upto 6-18 hours.

Principle route of excretion is via active secretion of the unaltered drug by the renal tubules.

Pharmaceutics:

Acetazolamide is available in following forms=

(1) 125mg and 250mg tablets.

(2) 500mg sustained release capsules.

(3) Intravenous (each vial has equivalent to 500mg Acetazolamide).

Indications:

It is reserved for patients in whom topical drugs are ineffective or the patient is intolerant to them.

Contraindications:

It produces metabolic acidosis. Therefore, may potentiate acid-base imbalance in patients with pre-existing acidosis.

Urinary citrate excretion is reduced leading to renal stone formation.

Renal potassium excretion is increased.

High dose aspirin increases the risk of salicylate toxicity.

Sulpha-type allergic reactions may also occur.

The induced acidosis and hemoconcentration may predispose patients with hemoglobinopathies to sickling of red blood cells.

Adverse reactions:

Life-threatening reactions= marrow suppression, aplastic anemia.

Sulpha-type reactions= including anaphylactic shock

Potassium depletion

Renal stones

Metabolic acidosis

Malaise

Weight loss

Depression

Anorexia

Paresthesia

Transient myopia due to ciliary body swelling.

Dose: 250-1000mg/day in four divided doses.

Pediatric dose: 5-10mg/kg BW 4-6 times per day.

Known to produce forelimb abnormalities in rodent offspring and so should be avoided in pregnancy or lactation.

Elderly individuals have higher incidence of side effects and tolerate carbonic anhydrase inhibitors poorly. Therefore, the initial dose should be reduced.

(2) Dichlorphenamide (Daranide)

The concentration of drug required to inhibit 50% of carbonic anhydrase activity is 30 times higher for Acetazolamide than for Dichlorphenamide.

It has been reported to be more efficacious than Acetazolamide.

IOP reduction starts in 30 minutes after a 200mg dose.

Maximum pressure reduction occurs in 2 hours and persists for 6 hours.

An initial priming dose of 100-200mg is followed with 25-50mg, one to four times a day.

Confusion and anorexia are more common with Dichlorphenamide.

(3) Methazolamide

Better tolerated and carbonic anhydrase inhibitors.

Produces less metabolic disturbance.

Well tolerated in elderly and young patients.

Available in 25 and 50mg tablets; for twice or thrice daily dosage.

Severe hematologic reactions including aplastic anemia have been reported.

Complications of hyperosmotic agents

1. Headache
2. Backache
3. Nausea and vomiting
4. Increased Urination frequency and retention
5. Cardiac complications (chest pain, pulmonary edema and congestive heart failure).
6. Renal impairment
7. Neurologic status (lethargy, seizures and obtundation.
8. Subdural and subarachnoid hemorrhage
9. Hypersensitivity reactions
10. Hyperkalemia or ketoacidosis (especially on glycerol administration to diabetic patients).