Factors Influencing Drug Retention Proper placement of the eyedrops

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Accurate and proper placement of an eye drop may considerably improve the efficacy of drug delivery, as the capacity of the conjunctival sac is dependent on the position of the head and technique of instillation. A drop is placed in the inferior cul-de-sac by gently pulling the lower lid away from the globe and creating a pouch to receive the drop. After gently lifting the lid to touch the globe, a small amount liquid is entrapped in the inferior conjunctival sac, where it may be retained up to twice as long as when it is simply dropped over the superior sclera. Drainage from the cul-de-sac may be further reduced by punctual occlusion or simple eyelid closure, which prolongs the contact time of the drug with the external eye. This serves two purposes; first it maximises the contact of drug with the periocular tissues increasing absorption through the cornea and secondly, the systemic absorption is reduced (Figure 11.10).

Figure 11.10 Effect of eyelid closure or nasolacrimal occlusion on systemic absorption of timolol

Figure 11.10 Effect of eyelid closure or nasolacrimal occlusion on systemic absorption of timolol

Influence of instilled volume

When an ophthalmic formulation is instilled into the eye, it is mixed with the precorneal tear film. The osmotic pressure of the mixture depends upon the osmolarity of the tears and of the ophthalmic formulation. If the osmotic pressure obtained is within defined limits, no discomfort is experienced, but if the osmotic pressure is outside these limits the patient experiences irritation eliciting reflex tears and blinking. The original osmolarity of the precorneal tear film is regained two minutes after the non-isotonic solution is administered, mainly due to a rapid flow of water across the cornea. The instillation of a hypotonic drug solution creates an osmotic gradient between the tear film and the surrounding tissues. This induces a flow of water from the eye surface to the cornea, hence the drug concentration on the eye surface is temporarily increased.

The rapid rate of tear turnover and efficient drainage in the eye profoundly affects the bioavailability of topically applied ophthalmic drugs. Increasing the tear volume suddenly, such as following the instillation of an eyedrop, produces rapid reflex blinking which quickly re-establishes the normal tear pool. Typically, the volume of an ophthalmic solution will be 30-50 pl, which is instilled into the lower fornix. The reflex blink can cause as much as 20 pl to spill over the lid margin onto the skin. Most of the remainder is pumped into the nasolacrimal duct until the total tear volume returns to its normal value of 7 pl. As the precorneal volume of fluid (lacrimal and instilled) becomes smaller, the turnover rate of lacrimal fluid will have a greater influence on the residual drug concentration. Therefore, a larger instilled volume will maximize the penetration of ophthalmic drugs, but a larger proportion will be wasted through drainage.

Significant drug absorption can occur through the mucous membrane of the nasolacrimal duct, with as much as 80% of the instilled volume draining into the gastrointestinal tract from where it can be absorbed into the systemic circulation. Severe systemic side-effects can arise which can lead to toxicity problems, particularly in geriatric and paediatric patients. To minimise loss to other absorptive pathways, the volume of the eyedrop should be sufficiently small that the tear film is not significantly perturbed. Volumes of 5-10 pl have been found to minimize side effects due to systemic absorption via the drainage apparatus, and special eyedrop tips which are capable of delivering this volume have been developed8 9. The extent of drug loss due to administration of volumes too large for the eye to retain has been shown in a number of cases. A 10 pl drop of 10% phenylephrine is as potent as the normal 30 pl drop of drug of the same concentration10. Ten and 20 pl drops of tropicamide produce more pupillary dilation compared to 40 and 80 pl drops; moreover, local irritation was seen with the larger drop size11. Unfortunately, although smaller drop sizes may be retained for even longer periods in the conjunctival sac and reduce systemic side effects still further, volumes less than 8 pl require high drug concentrations with consequent problems in formulation.

Preservatives

The vast majority of ophthalmic formulations contain preservatives, most commonly benzalkonium chloride. At high concentrations, preservatives can cause irritation and damage to the ocular surface. In strengths greater than 0.01%, benzalkonium chloride can damage the corneal epithelium by desquamation. Disruption of the corneal barrier increases the non-selective absorption of several compounds of differing water solubility and molecular weight. There is currently considerable interest in developing preservative free formulations to overcome these problems.

Effect of systemically administered drugs

Tear film dynamics can be affected by systemically administered pharmacological agents and locally applied adjuvants. Timolol applied topically reduces tear flow whereas pilocarpine stimulates tear flow. The adjuvant benzalkonium chloride disrupts the tear film whereas methylcellulose increases the stability of the tear film. Certain drugs can influence blink rate as well as tear secretion; for example, general anaesthetics may completely inhibit lid movements.

Drugs that are used to treat common conditions such as hypertension and allergic conditions can also influence tear film dynamics. If a patient presents with a complaint involving the tear film, it is important to rule out whether this is a side effect of other medication. Antihypertensives administered systemically (e.g. reserpine, diazoxide) stimulate tear flow whilst antihistamines reduce tear flow.

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