Mechanism Of Action

Osmotic drugs lower IOP by increasing the osmotic gradient between the blood and the ocular fluids. Following administration of osmotic drugs, the blood osmolality is increased by up to 20 to 30mOsm/L, which results in loss of water from the eye to the hyperosmotic plasma. This movement of water from the eye to the circulation is associated with a lowering of IOP.

The mechanism of reduction of IOP is likely due to reduction of vitreous volume, which probably results from the water transfer caused by the osmotic gradient

Table 8.1 Factors Affecting Osmotic Gradient

1. Ocular penetration

2. Distribution in body fluids

3. Molecular weight and concentration

4. Dosage

5. Rate and route of administration

6. Rate of systemic clearance

7. Type of diuresis between the retina-choroid and the vitreous.9'10 Water absorption by the iris appears to play an insignificant role in the hypotony induced by osmotic agents.11 Although aqueous formation rates were not measured, conventional outflow facility does not change after administration of an osmotic agent.12 A mechanism mediated by the central nervous system has been proposed,13 perhaps via central osmoreceptors; however, this possibility has been disputed.14

The degree of IOP lowering is determined by the osmotic gradient caused by these drugs. The following factors influence degree and duration of the osmotic gradient (table 8.1)15:

1. Ocular penetration. Drugs that enter the eye rapidly produce less of an osmotic gradient compared with drugs that penetrate slowly or not at all. Ocular permeability to some drugs is greatly increased when the eye is inflamed and congested. This reduction of the osmotic gradient in inflamed eyes has been demonstrated after administration of urea, which is of relatively low molecular weight, and was less pronounced following treatment with glycerol and mannitol.16'17 Although certain drugs (e.g., ethyl alcohol) enter the aqueous rapidly, part of their ocular hypoten-sive effect is due to relatively slow penetration in the avascular vitreous.

2. Distribution in body fluids. Drugs confined to the extracellular fluid space (e.g., mannitol) produce a greater effect on blood osmolality at the same dosage compared with drugs distributed in total body water (e.g., urea). For this reason, a larger dose in milliosmoles is required of urea compared with mannitol to produce the same osmotic gradient.

3. Molecular weight and concentration. Because the blood osmolality depends on the number of milliosmoles of substance administered, drugs with low molecular weight have potentially greater effect compared with compounds of high molecular weight at the same dosage in grams per kilogram. Thus, the lower molecular weight of urea compared with mannitol compensates for the greater distribution in body water of urea compared with mannitol. Also, osmotic drugs are administered as solutions, with osmolality directly proportional to the concentration. Drugs with low solubility require larger volumes of solution, with subsequently less effect on blood osmolality. Also, ingestion of fluids after osmotic drug use decreases blood osmolality, which decreases the osmotic gradient between the blood and the eye. This may occur following intake of fluids intended to make oral osmotic drugs more palatable.

4. Dosage. The change in blood osmolality depends on the total dose administered and the weight of the patient. With other factors being equal, a heavier patient has more body water and requires more drug compared with a lighter patient to achieve an equivalent osmotic gradient.

5. Rate and route of administration. Drugs administered intravenously bypass absorption from the gastrointestinal tract, generally producing a more rapid and greater osmotic gradient compared with orally administered drugs. When drugs are infused intravenously, a rate of 60 to 100 drops per minute is recommended.

6. Rate of systemic clearance. The rate of drug clearance from the systemic circulation influences the duration of action. Most osmotic drugs are excreted rapidly in the urine. Glycerol and ethyl alcohol, for example, are also metabolized.

7. Type of diuresis. Most osmotic drugs induce a diuresis, which may be hyper-, iso-, or hypoosmotic. After administration of ethyl alcohol, for example, the excreted urine is hypoosmotic, which can further increase the effect of the drug on blood osmolality.

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