Apraclonidine hydrochloride is the generic drug in the commonly-known brand Iopidine (Medicines.org.uk, 2019). A derivative of clonidine, it is a sympathomimetic licensed for use in glaucoma therapy and lowers intraocular pressure by reducing aqueous humour formation. Available commercially in two strengths in a sterile isotonic solution for topical application to the eye (Medicines.org.uk, 2019), apraclonidine 0.5% is licensed for the lowering of intraocular pressure in patients with ocular hypertension or glaucoma, whereas apraclonidine 1% is intended for the prevention and control of post-operative spikes in intraocular pressure (Committee, 2019).
Mechanism of action
Apraclonidine is an a2 adrenergic receptor agonist and a weak a1 adrenergic receptor agonist (Committee, 2019).
Side effects
It should be noted that the side-effects that are recorded under the use of apraclonidine are related to its licensed use for Glaucoma, rather than is use in the treatment of eyelid ptosis. This may mean that they are only present following long-term use, rather than the short-term use associated with the treatment of ptosis. However, it is always important to make patients aware that the product is unlicensed for use in eyelid ptosis.
Common or very common side effects that have been documented include conjunctivitis, dry eye, contact dermatitis, ocular intolerance, rhinitis and taste disturbances (Committee, 2019).
Uncommon side effects that may be experienced include asthma, blepharitis, chest pain, conjunctival vascular disorders, corneal erosion and infiltrates, dyspnoea, eyelid ptosis or retraction, impaired co-ordination, irritability, keratitis, keratopathy, myalgia, mydriasis, nervousness, parosmia, photophobia, rhinorrhoea, throat irritation and visual impairment (Committee, 2019; Medicines.org.uk, 2019).
Cautions and contraindications
The use of apraclonidine is contraindicated where there is a history of severe or unstable and uncontrolled cardiovascular disease (Medicines.org.uk, 2019).
There is no information available on the use of apraclonidine in either pregnancy or breast feeding, and the manufacturer therefore advises to avoid use in these instances (Committee, 2019). The manufacturer also advises to use with caution in both hepatic impairment and chronic renal failure (Committee, 2019).
Eyelid ptosis with toxins
Ptosis is the medical term to describe drooping or abnormal lowering. The word ptosis is derived from the Greek for ‘falling’ and, when used in relation to the eyelid, can more accurately be described as blepharoptosis (King, 2019).
Botulinum toxin-induced ptosis is a well-documented complication following treatment, and in many cases can be avoided with experience, caution and good technique (Omoigui and Irene, 2005). Three separate clinical studies were assessed for the incidence of ptosis, and incidence was found to be 5.37% (ClinicalTrials. gov, 2018), 5.02% (ClinicalTrials.gov, 2016) and 6.06% (ClinicalTrials.gov, 2015). Further studies have suggested that this percentage is influenced by the expertise of the injector; therefore, incidence would be much lower in an experienced injector (King, 2019).
This is significant because there are far fewer experienced injectors than those with less experience. Some reports suggest that experienced injectors are likely to account for less than 1% of all injectors (Redaelli and Forte, 2003). A systematic review of 31 clinical studies, with a total of 1678 participants, found the incidence of eyelid ptosis to be 2.5% (Brin et al, 2009).
Eyelid ptosis can be unilateral or bilateral and generally presents within 3–7 days of treatment. The droop may be severe to the point that it leads to restriction of vision or it may be subtle, with just the feeling of a heavy lid or, more typically, difficulty in being able to apply eye make-up (King, 2019).
Risk factors for eyelid ptosis
There are several factors that may make eyelid ptosis a higher risk in some people, which in turn means that there are ways in which to minimise its occurrence. When a patient presents to clinic for botulinum toxin A injections, a full medical history must always be taken (King, 2019), and all relevant history should be gathered. Previous facial surgery should be discussed, as well as pre-existing medical conditions and neurological conditions, such as myasthenia gravis, multiple sclerosis and previous history of Bell's palsy or ptosis (King, 2019). Following a full consultation, comprehensive advice regarding potential side effects and complications, symptoms to look out for and be aware of, and who to contact should any problems or concerns arise should be given before gaining informed consent. As part of the consultation, pre-treatment photographs should be taken (Klein, 2001), and patients should be advised that post-treatment they should avoid sunbathing, saunas, drinking alcohol, massage or anything that causes excessive sweating, as this could cause the toxin to spread further than required (Redaelli and Forte, 2003).
The patient should be thoroughly assessed before treatment. In addition to the patient's age and lifestyle, which could play a role in the current condition of the patient's skin, factors such as smoking or regular sun bed usage, the anatomy and musculature of the patient's face should be taken into consideration (King, 2019). Of particular relevance is the position of the brow; a heavy brow or short brow may increase risk of ptosis. Any pre-treatment asymmetry of the brows should be recorded, and the patient should be made aware of this before any treatment commences (Klein 2001).
The condition of the frontalis is very important and factors that affect this should be taken into consideration, for example, sun exposure and damage, the thickness of skin, its elasticity and therefore the reliance on the action of the frontalis muscle to hold the brow in place. The muscle can be tested to see if it is holding the brow at rest by asking the patient to sit upright, look forward and then close their eyes. If the brow lowers during this check, then the lines of the forehead should not be treated, as the risk of ptosis would be too high (King, 2019). Care should always be taken to ensure that the product is genuine and is diluted correctly.
A significant risk for eyelid ptosis is the experience and technique of the practitioner, as is injection placement, technique and choice of dosage (King, 2019). There are specific rules to follow when injecting that reduce the risk of eyelid ptosis. First, caution should be taken in any patient who has previously had facial surgery. This may have led to scar tissue and alteration to either nerve or muscle activity in the facial region.
Injections should remain 1 cm above the brow, and never lateral to the mid-pupillary line when treating the glabellar (Klein, 2001). Care should always be taken to ensure that this distance is measured from the natural brow position, rather than the apparent position of brows, which may be tattooed, micro-bladed or drawn on. Risk of diffusion of toxin can be minimised by applying pressure with a finger from the non-injecting hand to the supraorbital rim while injecting the corrugator supercilii muscles (Klein, 2001). Care should be taken to simply apply pressure to the rim, rather than physically lift the muscle up manually, as this may change the position of injection. To prevent misplacement of toxin, needles should point superiorly away from the orbit when injecting the glabellar (Omoigui and Irene, 2005).
When the area is cleaned following injection, it is also wise to wipe any debris gently in the direction away from the eye, rather than accidentally physically pushing the toxin towards a risk zone. When treating under the eye during treatment of crows feet, injections should remain 1 cm away from the margin of the orbit, and never medial to the mid-pupillary line (King, 2019). Injections should never be placed directly below the eye if there has been a negative eyelid extraction test (snap test), with a delay in the skin below the eye returning to its original position following being manually pulled down, if there has been previous eye surgery or if there is a significant amount of pre-treatment scleral show.
Apraclonidine in ptosis
Duration of ptosis may be limited by stimulating the affected muscles via either exercise or electrical stimulation. Some practitioners recommend placing the back of an electric toothbrush over the muscle for several minutes a day (King, 2016). There is currently no licensed treatment for botulinum-induced ptosis, which is commonly managed conservatively. Ptosis can also occur in Horner's syndrome and, although not caused by botulinum toxin, has been effectively treated with apraclonidine. Studies do suggest that the use of apraclonidine can provide a reversal option (Omoigui and Irene, 2005).
Although the use of apraclonidine is unlicensed for the treatment of ptosis, its use is widespread and the commonly accepted dosage used is 1–2 drops of apraclonidine 0.5% three times a day (King, 2019). As mentioned previously, despite its widespread use in aesthetic practice, it is difficult to locate any up-to-date information or formal evaluation of its use. However, on searching the reputable studies of its use, it seems the most common practice is to use apraclonidine regularly until the problem resolves. In many cases, this within a matter of weeks, as the effects of the toxin and therefore the ptosis wear off naturally. However, some practitioners may recommend to their patients that if the ptosis does not affect day-to-day tasks, such as driving, to only use the apraclonidine on a ‘when required’ basis, such as special occasions, to minimise side effects.
The levator palpebrae superioris and superior tarsal muscle elevate the eyelid. The superior tarsal muscle is a smooth muscle innervated by sympathetic nerves that have preganglionic cell bodies in the upper thoracic levels of the spinal cord and postsynaptic cell bodies in the superior cervical ganglion. The superior tarsal muscle has origins beneath the levator superioris, a voluntary muscle innervated by the oculomotor nerve, and at approximately 12 mm in length, it inserts superiorly on the tarsal border and can lift the lid up to 2 mm (Omoigui and Irene, 2005).
Apraclonidine, being an alpha-adrenergic receptor agonist and a mydriatic agent, causes the contraction of the superior tarsal muscle, the adrenergic muscle also known as Muller's muscle, and the resulting eyelid lift.
It should be noted that although commonly used for the treatment of eyelid ptosis, there is relatively little literature on its usage and no formal dosage has been established. It is therefore used off license and the patient should always be made fully aware of this.
Conclusion
It is clear that there are significant risk factors for eyelid ptosis. It is essential that thorough consultation occurs pre-treatment and that the patient's anatomy and musculature are intricately examined. Patients should be fully informed of the risk of complications following treatment and should be given information on what to do should questions or symptoms arise. Informed consent should always be obtained before treatment and photographs and identification of pre-treatment asymmetry should always be noted and disclosed.
It is of the utmost importance that practitioners have in-depth knowledge of facial anatomy and musculature and are aware of the changes that take place to these as we age. Care should be taken to always use correct technique to minimise the occurrence of any complications, not just ptosis. With regards to the use of apraclonidine in the treatment of eyelid ptosis, despite the widespread recommendation of its use, more research needs to be conducted to formally assess its role in these situations. Its optimal dosage also needs to be fully established.