Box 22-3  Factors affecting bioavailability of topical ocular medication

    I. Tear factors

A.Rate of tearing

B.Punctal occlusion

C.Nasolacrimal drainage

D.Orbicularis function (eyelid squeezing)

E.Dilution with a second drug

  II. Corneal factors

III.Drug and formulation factors

A.Concentration and volume instilled

B.Solubility characteristics

C.Dissociation constant

D.Molecular weight

E.pH

F.Tonicity

G.Electrolyte composition

H.Wetting agents/preservatives

I.Viscosity

J.Buffers

K.Vehicle or delivery system

IV. Drug elimination

A.Tear flow

B.Diffusion into the vascular system

C.Diffusion from the cornea to the tear layer

D.Bulk flow of aqueous humor

E.Metabolism

F.Active transport

G.Binding to melanin

H.Binding to protein V. Miscellaneous

A.Genetic variation in ocular structure and function

B.General metabolic factors

1.Blood flow

2.Hormonal regulation

3.Neural regulation

4.Availability of nutrients

5.Age

C.Drug-related factors

1.Local and systemic side effects

2.Drug–drug interaction

3.Tolerance

4.Compliance

VI. Disease factors

A.Inflammation

B.Intactness of epithelium

C.State of blood–aqueous barrier and blood–retinal barrier

D.Aqueous humor and tear protein concentrations

Modified from Bergamini MVW. In: Drance SM, Neufeld AH, editors: Glaucoma: applied pharmacology in medical treatment, New York, Grune Stratton, 1984.

chemotherapy for cancer than they do when choosing eyedrops for minor ocular irritation.32

Bioavailability refers to the rate and extent of absorption across a surface or tissue. The bioavailability of topical medication is considered in the following pages under the headings of tear film, corneal barriers, drug formulation, and drug elimination (Box 22-3). It is important to emphasize that the most important factors limiting the bioavailability of many common topical ocular medications are compliance and efficiency of instillation.33 Discussion of these issues follows.

Bioavailability of topical ocular medication

The penetration of topically applied medication into the eye is proportional to the concentration of the drug that comes in contact with the cornea over time. For many drugs this relationship holds

true over a wide range of concentrations (e.g., 10 6 to 10 1 M for pilocarpine).34,35 The drug concentration in contact with the cor-

nea is diluted by tears and washed out into the lacrimal drainage system. The half-life of various drugs in the tear layer is estimated to be 2–20 minutes. Alteration of the molecule or vehicle in a way that increases the half-life, such as increasing the viscosity, will increase the efficacy and duration.

The normal volume of the conjunctival cul-de-sac is 7  l. After instillation of an eyedrop, the volume temporarily increases to 30  l.36 Most commercial eyedrops have a volume of 30–75  l.37 Thus even a single drop exceeds the capacity of the cul-de-sac, so that the excess drains onto the skin and into the lacrimal system. Some investigators have postulated that the relative bioavailability

of many topical medications could be increased by decreasing the volume of the eyedrops to 5–20  l.38–40

Tear film

Under normal circumstances the turnover rate of the tear film is 15% per minute41; this depends on the rate of tearing rather than the capacity of the lacrimal drainage system.The instillation of eyedrops stimulates tearing and increases the turnover rate to 30% per minute. Eyedrop instillation also causes contraction of the orbicularis muscle (e.g., blinking, squeezing), which propels tears toward the lacrimal drainage system. It is possible to reduce the flow of tears and medication into the lacrimal system and prolong drug– cornea contact time by placing pressure over the canaliculi and closing the eyelids gently after administering eyedrops.42,43

Drugs that pass into the nasolacrimal system can be absorbed rapidly by the heavily vascularized mucosa of the nasopharynx and oropharynx. Drugs absorbed in this manner do not pass through the gastrointestinal tract and the liver and are not metabolized by these tissues (i.e., there is no first-pass effect).43 Thus drugs absorbed from the nasolacrimal passages can act as if they have been given by intravenous injection rather than oral administration. For this reason the instillation of multiple eyedrops over a short interval is more likely to produce increased systemic absorption and side effects than increased therapeutic benefit.

If saline solution is instilled in rabbits within 30 seconds of pilocarpine administration, the effect of pilocarpine on pupil diameter is reduced by 45% (Fig. 22-1). If saline solution is administered within 2 minutes, pilocarpine’s effect is diminished by 17%. If saline solution is added after 5 minutes, there is little loss of response to pilocarpine.44 Patients should be warned about this washout effect.

Corneal barriers

Most topically administered drugs enter the eye by passing through the cornea. (The movement of drugs across the conjunctiva and sclera accounts for less than 2% of the intraocular concentration.)45 This process usually occurs by passive diffusion and follows firstorder kinetics (i.e., the absorption depends on the drug concentration gradient, the solubility characteristics of the substance, and

Fig. 22-1  Change in pupillary diameter after instillation of 25  l of 2.5 10 2 M pilocarpine in rabbits ( ), when 25  l of saline solution is instilled 2 minutes later ( ), and 30 seconds later ( ). (Modified from Chrai SS, and others: J Pharm Sci 63:333, 1974.

Reproduced with permission of the copyright owner, the American Pharmaceutical Association.)

the dissociation constant for ionizable substances).Thus the rate of entry is initially high but declines rapidly.

To understand drug absorption, it is useful to think of the cornea as a lipid–water–lipid sandwich. The lipid content of the epithelium and endothelium is approximately 100 times greater than that of the stroma, and thus these former layers are more permeable to lipophilic than to hydrophilic substances.46–48 The corneal epithelium is the major barrier to drug penetration except for the most lipid-soluble substances.When the epithelium is disrupted (e.g., by irritation, ulcer, or abrasion), drug penetration is often increased. The corneal stroma is more permeable to hydrophilic than to lipophilic substances. Because of the dual nature of the corneal barriers, drugs possessing both lipid and water solubility penetrate the cornea more readily.

Many topical ophthalmic medications are weak acids or bases.The non-ionized drug molecule traverses the epithelium and then dissociates.The ionized form of the drug passes through the stroma more readily and then associates for passage through the endothelium.

Many topically administered medications accumulate in the cornea, which then becomes a temporary drug reservoir. When the medication concentration in the tears falls to low levels, there is a net movement of drug from the cornea to the tear layer. After absorption, many medications distribute rapidly and reach similar

concentrations in the aqueous, iris, and ciliary body. Drug concentrations are usually lower in the lens and vitreous.49,50 Although

there is controversy, most studies indicate that medications do not

pass against aqueous flow from the anterior chamber through the pupil into the posterior chamber.51–54 Under some circumstances,

however, certain agents such as topically applied epinephrine may get into the vitreous.55 Drugs may reach the ciliary body by following the uveoscleral flow of aqueous humor.56

Drug formulation

A number of properties of a drug and its formulation (e.g., molecular weight, pH, tonicity, electrolyte composition, wetting effect, stability, viscosity) influence ocular penetration. Most topical ocular drugs have a low molecular weight (i.e., less than 500 Da), which favors corneal passage.57 As mentioned previously, many topical medications are weak acids or bases. These drugs are often more

stable at non-physiologic pH levels (e.g., pilocarpine is more stable at pH 6.5 than at pH 7.4).58,59 Eyedrop solutions are adjusted

to this pH but are not buffered so that the tear layer can return rapidly to physiologic pH levels. This ensures drug stability and prevents excessive irritation, which leads to tearing on instillation, diluting and washing away the drug.

Ocular penetration increases with increasing concentration of the drug in the eyedrop. However, if the drug concentration in the eyedrop is too great, the resulting increase in osmolality pulls fluid across the conjunctiva, diluting the medication in the tear film.60 The ocular penetration of many topical medications is aided more by prolonging drug–cornea contact time than by increasing the concentration of the eyedrop.61–63 A number of systems have been used to prolong drug–cornea contact time and to enhance pulsed

entry of medication into the eye. These include presoaked contact lenses,42,43 the addition of soluble polymers to eyedrop solu-

tions,64–66 soluble gels,67,68 aqueous suspensions,69 ointments,70 solid hydrophilic inserts,71 binding to polymers,72 and binding to

liposomes.73,74 A viscous vehicle can increase ocular drug penetration by 50–100%.75,76 The increased viscosity produces more rapid

drug saturation and slower washout of medication by the tears. Water-soluble polymers are commonly used to increase drug–

cornea contact time. Currently used polymers have been assessed

with respect to corneal retention time or delivery of a marker compound and are listed in order of decreasing effectiveness: hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, and polyvinyl alcohol.77–79 However, the effect of water-soluble polymers on drug penetration appears to be greater in rabbit eyes than in human eyes because rabbits have a lower blink rate and a slower tear turnover.80

Aqueous suspensions contain a drug dispersed as fine particles. The vehicle, often combined with a dispersion agent, is a saturated solution of the sparingly soluble drug. Tissue absorption occurs from the solution. As tearing dilutes the medication, the suspended drug particles go into the solution.The particles are retained longer in the cul-de-sac than are standard solutions and thus provide greater drug bioavailability.81 Ointments increase drug bioavailability by increasing drug–cornea contact time, decreasing dilution by tears, and slowing nasolacrimal drainage.82–84 Ointments are not used frequently, however, because they are difficult to instill and interfere with vision.

It is also possible to prolong drug–cornea contact time with systems that produce a controlled (i.e., steady) release of medication. Eyedrops produce a pulsed or biphasic pattern of drug delivery consisting of a transient overdose followed by a prolonged underdose. The initial overdose can be associated with systemic side effects. Controlled release requires a system that delivers medication with zero-order kinetics (i.e., drug delivery is independent of the amount of drug remaining). Therefore the rate of medication delivered remains constant until the supply is exhausted. Controlled-release systems have several potential advantages, including achieving a therapeutic effect with less medication, reducing side effects, and placing less reliance on patient compliance. The Ocusert system, the best example of this approach in ophthalmic therapy, uses a membrane that allows continuous diffusion of pilocarpine from a central reservoir.85

Preservatives added to eyedrop solutions often increase drug penetration. For example, the therapeutic effect of carbachol is enhanced greatly by the presence of benzalkonium chloride, which acts both as a preservative and a wetting agent.86,87 However, evidence exists that the effect of preservatives may be mediated by structural changes in the cornea and conjunctiva that are not necessarily favorable.21–23,66

Drug elimination

The bioavailability of a drug at its active site within the eye depends on many processes besides the rate of transcorneal penetration.These include drug metabolism, active transport out of the eye, binding to melanin and protein, diffusion into the vascular system, and bulk flow with aqueous humor.88 Most of the drug loss

occurs soon after instillation in the cul-de-sac because of overflow onto the face and drainage into the nasolacrimal system.89,90 Once

in the anterior chamber, the drug is eliminated with the bulk flow of aqueous humor via both the trabecular and uveoscleral outflow pathways.91 Some portion of the drug also diffuses into the vascular system of the anterior uvea, conjunctiva, and episclera. The diffusional loss to the vascular system is greater in inflamed eyes with dilated, more permeable vessels. As mentioned previously, the corneal epithelium serves as a drug reservoir for many medications.

Drug from the cornea is also lost to the limbal blood vessels and the tear film.92,93

The eye contains a variety of enzyme systems capable of metabolizing drugs.94,95 Some drugs (e.g., pilocarpine and dipivefrin)

are even metabolized during corneal passage.96 This  metabolic capability is used by the prodrug dipivefrin, which is converted to its active agent, epinephrine, by esterase enzymes located in the cornea and aqueous humor.97–99 In addition to metabolism, active transport

systems in the ciliary body and retina remove drugs from the eye (e.g., penicillin, indomethacin).100–102 These transport systems are

similar to those found in the renal tubule and liver.103

Many drugs (e.g., pilocarpine, timolol) bind to melanin pigment in the anterior uveal tract.104–106 This binding has a complex

effect on drug bioavailability. On one hand, the melanin binding competes with the active site for the drug. Conversely, the melanin binding also creates a type of drug reservoir in the eye. The net effect of the binding process is to require higher concentrations

of some drugs in pigmented eyes to produce the same therapeutic effect.107–109 It has been suggested that the difference in bioavail-

ability of some drugs in pigmented eyes is not totally explained by melanin binding.The difference in bioavailability of some drugs also involves greater metabolism in pigmented eyes (e.g., the metabolic conversion of pilocarpine to pilocarpic acid is greater in pigmented rabbits).110 Drugs also bind to protein in the tears, cornea, and aqueous humor, thereby reducing bioavailability.111 Protein binding increases when the eye is inflamed and the blood–aqueous and blood–retinal barriers are compromised.

Compliance

No discussion of general pharmacologic principles would be complete without examining the issue of compliance or adherence which is the newer preferred term. Adherence refers to the patient’s behavior in following the prescribed regimen, including medications, follow-up visits, and lifestyle changes.

Most forms of open-angle glaucoma are chronic, slowly progressive, and asymptomatic; in fact, the only symptoms may arise

from the therapy. Thus open-angle glaucoma is a fertile situation for patient defaulting.112–114 The physician should be very aware of

the possibility that failure of medical treatment to meet the therapeutic goals may be caused, at least in part, by defaulting rather than by lack of efficacy of the drug regimen. Studies using eyedrop medication monitors have confirmed the longstanding suspicion

that some glaucoma patients do not take their medication(s) as pre- scribed.115–119 In one study, 6% of patients administered less than

one-quarter of prescribed pilocarpine doses, 15% less than one half of prescribed doses, and 35% less than three-quarters of prescribed doses.117 The corresponding figures for timolol are somewhat better but still indicate considerable room for improvement (i.e., 8% administered less than half of the prescribed doses, and 27% administered less than three-quarters of prescribed doses).118 Furthermore, patients sometimes compress doses during the day and skip entire days (i.e., take drug holidays); 24% of patients have at least 1 day per month in which they take no doses of pilocarpine, and 47% have at least 1 day per month in which they take no doses of timolol. It is likely that defaulting also occurs with epinephrine or dipivefrin

treatment and is even more common with the systemic carbonic anhydrase inhibitors.120,121 Poor compliance may account for as

much as 10% of the vision loss seen in glaucoma.122

Patients usually remember to take their medication on the day they return to the office or clinic.117 This leads to IOP readings that may be misleading and not truly reflective of the patient’s status over the past several weeks or months.This observation may explain some of the cases of progressive glaucomatous damage despite what appears to be good IOP control. Patients will often