Ординатура / Офтальмология / Английские материалы / Ophthalmic Drugs Diagnostic and Therapeutic Uses 5th edition_Hopkins, Pearson_2007
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238 OPHTHALMIC DRUGS
with timolol. Furthermore, unoprostone was not significantly different from brimonidine and dorzolamide as adjunctive therapy to timolol (Hommer et al 2003). It has also been shown to improve the diurnal curve characteristics in patients who continue to have an elevated pressure on latanoprost 0.005% alone (Stewart et al 2001).
Combined preparations Because of their different modes of action, it is possible to mix drugs from different groups to achieve an enhanced effect. This is necessary when control is not achieved with a single medication or when the effect of the original therapy wears off with time. It is possible to combine a drug from one group with another from one of the other two groups:
•beta-blockers and miotics
•beta-blockers and carbonic anhydrase inhibitors
•beta-blockers and prostaglandin analogues.
A common combination used to be pilocarpine and timolol but this mixture has been to a large extent superseded by the other combinations listed. Timolol is normally applied twice daily whereas pilocarpine requires administration four times a day. Airaksinen et al (1987) compared timolol and pilocarpine with pilocarpine alone. Not only was a greater effect found with the combination, but the duration of effect was sufficient to allow twice daily administration. Leroy & Collignon-Brach (1990) found that a combination of timolol 0.5% and pilocarpine 2% was more effective in lowering intraocular pressure than timolol alone. Maclure et al (1989) found similar results in patients who could not be controlled on timolol alone. Patients reported systemic effects consistent with those of betablockers while the local ocular side-effects were due to the miotic. No commercial preparation of a beta-blocker and miotic is available.
Studies of beta-blockers with adrenaline (Allen & Epstein 1986) and with dipivefrin (Ober & Scharrer 1980, Parrow et al 1989) have also been undertaken and demonstrated advantages of these combinations. Drance et al (1991) found that a mixture of timolol and adrenaline (epinephrine) was more effective than either agent on its own. Now that adrenaline is rarely employed in any form of glaucoma treatment, such combinations are only of academic interest.
Combining two compounds from the same group, e.g. two miotics or two beta-blockers, cannot be justified pharmacologically and sometimes leads to antagonism rather than additive benefits.
Timolol is combined with two preparations commercially: the carbonic anhydrase inhibitor dorzolamide and the prostaglandin analogue latanoprost. The trouble with the latter combination is the timing of doses. Latanoprost is normally administered once a day – at night – whereas timolol is normally given in the morning and evening. The combination drop used at night, compromises the normal dose schedule for timolol.
DRUGS FOR THE TREATMENT OF GLAUCOMA 239
Preparations
Products |
Presentation |
Concentrations |
Preservative |
Cosopt |
Eyedrops |
Dorzolamide 2.0 |
BAK |
|
|
Timolol 0.5 |
|
|
|
|
|
Xalacom |
Eyedrops |
Latanoprost 0.005 |
BAK |
|
|
Timolol 0.5 |
|
|
|
|
|
BAK, benzalkonium chloride
Clinical note
Guidelines published by the Royal College of Ophthalmologists in 2004 indicate that the drugs of first choice in the treatment of primary open-angle glaucoma are prostaglandin analogues or beta-blockers, with
carbonic anhydrase inhibitors and alpha agonists representing second choice. Combination drops are becoming increasingly popular (if for no other reason than saving patients prescription charges!)
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243
Chapter 15
Artificial tears and ocular lubricants
THE TEAR FILM
THE PRECORNEAL TEAR FILM
The classic model of the tear film describes it as a trilaminar structure comprising an anterior lipid layer about 0.1 μm thick, a central aqueous layer about 71 μm thick and an inner mucin layer 0.02–0.05 μm thick. A more complex six-layer model of the tear film has been proposed in which there is uncertainty about the thickness of the tear film, invasive methods suggesting a value between 4 and 8 μm whereas interferometric measurement suggests a value of 40 μm. Similarly, a histological study has suggested that the mucous layer is 0.8–1.0 μm thick.
LIPID LAYER
Lipid is secreted by the tarsal meibomian glands and the accessory sebaceous glands of Zeis. It serves to:
•inhibit evaporation of the underlying aqueous layer
•lower the surface tension of the tear film
•provide a barrier along the eyelid margins to prevent overflow of the marginal tear strip onto the skin.
The lipid layer is adversely affected by meibomian gland dysfunction with the result that the tear film might become destabilized.
AQUEOUS LAYER
Aqueous is secreted by the lacrimal gland and the accessory glands of
Krause and Wolfring. Its functions are to:
•allow access of atmospheric oxygen to the avascular corneal epithelium
•provide some antibacterial protection for the eye
•provide a regular surface to allow optimal visual function
•flush away debris from the cornea and conjunctival sac.
244 OPHTHALMIC DRUGS
Inadequate production by the lacrimal gland or excessive evaporation of the tears gives rise to an aqueous deficiency. The normal rate of evaporation is about 0.1 μL/min but it might be twice this rate in dry eyes (Rolando et al 1983).
MUCIN LAYER
Mucin is secreted by the conjunctival goblet cells, the crypts of Henle and the glands of Manz. Its role is to:
•allow the tear film to be attached to the underlying microvillae and microplicae of the corneal epithelial cells
•act as a lubricant for eyelid movement over the ocular surface.
Conjunctival scarring as a consequence of conditions such as a chemical burn or ocular cicatricial pemphigoid can lead to the destruction of goblet cells resulting in a mucin deficiency.
The corneal surface is continually re-surfaced with tears. For this to occur, it is essential that:
•the blink reflex is normal
•there is congruity between the ocular surface and the eyelid
•the corneal epithelium is intact.
If any one of these three requirements is not fulfilled, the tear film will be abnormal. For example:
•the blink reflex can be reduced in Alzheimer’s disease
•the congruity between the ocular surface and eyelid is reduced by a pingueculum or pterygium
•integrity of the corneal epithelium is impaired by a variety of conditions, e.g. persistent epithelial defect.
KERATOCONJUNCTIVITIS SICCA
A minor decrease in the aqueous layer is relatively common in postmenopausal women and a significant decrease can result in keratoconjunctivitis sicca (KCS), in which damage to the interpalpebral ocular surface (i.e. ocular surface disease) can occur, together with symptoms of ocular discomfort.
A population-based prevalence study conducted on 2482 individuals aged 65 years or more revealed that 14.6% reported symptoms that were suggestive of dry eye (Schein et al 1997). Extrapolated to the US population aged 65–84 years, this study yielded an estimate that 4.3 million people experience symptoms of ocular irritation either often or all the time.
ARTIFICIAL TEARS AND OCULAR LUBRICANTS 245
In Sjögren’s syndrome, an autoimmune disease, a chronic inflammatory process damages both those glands that produce tears and those that produce saliva, causing symptoms of dry eye and dry mouth. Women are nine times more likely to be affected than men and the onset is usually after the age of 40 years. In primary Sjögren’s syndrome, a dry mouth is associated with KCS and, in its secondary form, there is a coexisting disease such as rheumatoid arthritis, systemic lupus, systemic sclerosis or polymyositis.
When the dry eye is secondary to some primary cause then this must receive attention as well as the provision of symptomatic relief. The initial approach to tear augmentation and conservation is to provide tear supplements, commonly in the form of aqueous eyedrops and, when necessary, guidance on ocular hygiene. In more severe cases, punctal occlusion or tarsorraphy might be required. Other modes of treatment have included bandage hydrogel contact lenses, moisture chamber goggles, oestrogen replacement and salivary gland transplant in which the parotid duct is transposed to the conjunctival sac.
EXAMINATION OF THE TEAR FILM
Procedures commonly used by primary eye care practitioners to evaluate the tear film include:
•Tear break-up time (TBUT): following the instillation of a small quantity of fluorescein, the patient blinks a few times and then keeps the eye open while looking slightly upwards and inwards. The time taken for a break to appear in the tear film is measured. This is repeated twice more. The average TBUT ranges from 10 to 40 seconds and a value of less than 10 seconds is regarded as abnormal.
•Non-invasive break-up time (NIBUT): the patient keeps the eye open while fixating the target of a one-position keratometer. The time taken for any distortion of the mire image to occur is noted. The normal value for the mean of three consecutive measurements is greater than 10 seconds and less than this is considered abnormal.
TEAR VOLUME
SCHIRMER I TEST
The end of a dry, sterile, filter strip is folded over the eyelid margin between the middle and outer third of the lid. The patient looks directly ahead and blinks normally. After 5 min, a length of 10–30 mm of the strip should be wet. A value of less than 5 mm indicates inadequate tear production. This test, which measures both basal and reflex secretion, has poor sensitivity and specificity.
246 OPHTHALMIC DRUGS
PHENOL RED THREAD TEST
A sterile, yellow-coloured cotton thread impregnated with phenol red is hooked over the lower eyelid margin in a similar manner to the Schirmer I test. After 15 seconds, 14 ± 4 mm of the thread should appear wet and red in colour. The shorter duration of this test should induce much less reflex tearing than the Schirmer I test and should be a better indicator of aqueous production. A wetted length of less than 9 mm is indicative of a dry eye.
TEAR CLEARANCE TEST
Fluorescein is instilled into the lower fornix and, after 5 min, a Schirmer filter strip is positioned (as previously described) for a further 5 min. The length of strip that has been wetted is recorded. Delayed clearance has been reported to show better correlation with the severity of symptoms of ocular irritation in KCS than the Schirmer I test (Alfonso et al 1999, Macri & Pflugfelder 2000).
TEAR MENISCUS HEIGHT
The height of the tear meniscus or prism at the lower lid margin is assessed using the slit-lamp microscope, preferably equipped with a graticule eyepiece. The normal height is between 0.2 and 0.5 mm and a value of less than 0.1 mm suggests an aqueous deficiency. It should be noted that the prior instillation of fluorescein can result in an overestimation of tear meniscus height (Oguz et al 2000). When performing this test, the appearance of the meibomian glands and their orifices should be noted. At the same time, it is also important to note any abnormality of the position of the eyelid or the pattern of blinking.
STAINING
ROSE BENGAL
A drop of sterile rose Bengal (see Chapter 10) is instilled in the eye, which is examined with the slit-lamp microscope. Rosy red staining of the bulbar conjunctiva and inferior cornea is indicative of KCS. A disadvantage of this stain is that it causes significant stinging in dry eyes (Manning et al 1995).
LISSAMINE GREEN
This supravital stain (see Chapter 10) is used in a similar manner to rose Bengal and has the advantage that it causes much less stinging. It is not available for use in the UK.
ARTIFICIAL TEARS AND OCULAR LUBRICANTS 247
QUESTIONNAIRE
In less severe cases of dry eye, identification can be facilitated by the use of a questionnaire, the scope of which elicits information about diseases (e.g. rheumatoid arthritis) and drugs (e.g. antihistamines, oral contraceptives) that are known to be associated with the condition (McMonnies 1986). Information is also elicited about environmental factors that might lead to an increased rate of tear evaporation. It has been claimed that the questionnaire can discriminate between normals and sicca syndrome patients with a sensitivity of 98% and a specificity of 87% (McMonnies 1987).
Numerous other procedures, including flurophotometry, impression cytology of the conjunctival epithelium, measurement of osmolarity and analysis of protein levels in the tears, are generally confined to a research setting.
FORMULATION OF TEAR SUPPLEMENTS
Marquardt (1986) sets down four requirements for artificial tears: They must:
•not irritate the eye
•have a good lubricating effect
•have a long retention time
•not disturb the optics of the eye.
These ideals relate only to the short-term benefits to the patient. Obviously, the ultimate aim is to prevent damage to the cornea as well as giving the patient symptomatic relief. Much attention has been given to the measure of corneal permeability as an assessment of the degree of corneal epithelial damage. The normal intact healthy cornea provides a barrier to the passage of drugs and other solutes into the corneal stroma. If the epithelium is damaged then this barrier is disrupted and permeability is increased. Gobbels & Spitznas (1989) found that patients with dry eye had corneal permeabilities 2.8 times greater than normal patients. Subsequently, they chose this parameter in a comparison of different formulations (Gobbels & Spitznas 1991).
As artificial tears are by their indication utilized in an environment that has been compromised by a lack of normal tears, all components of formulation are important. A drop that would be well tolerated by a normal eye may cause problems to a patient with dry eyes. Formulation can be considered under the following headings:
•osmolarity
•pH
•preservatives
•viscolizers.