BRIMONIDINE WITHOUT PRESERVATIVES (ALPHA VISION SINE)

DR JOSEF FLAMMER

ENGLISH VERSION

For the drug therapy of glaucoma, the physicians have various antiglaucomatous drugs with

different mechanisms of action at their disposal. The range of glaucoma therapies is now

being expanded with the market launch of the preservative-free brimonidine (Alpha-Vision®

sine).

Brimonidine is a highly selective α2- adrenoreceptor agonist. Adrenoreceptors are receptors

that are stimulated with epinephrine and norepinephrine and thus transfer information from

the sympathetic nervous system and the adrenal cortex to terminal organs. They play a diverse role, including in the regulation of blood pressure and eye pressure.

Accordingly, pharmacological attempts have been made for a long time to influence these

receptors. Unfortunately, this pharmacology is not so easy to understand. Because there are

different adrenoreceptors (α, β etc.) and even more subtypes (e.g. α1, α2, α3 etc.) and

finally, sub-subtypes (e.g. α2A, α2B, α2C, etc.). These receptors are expressed in different

organs to different degrees and their density is not constant. They are permanently

degraded and newly synthesized. This activity depends on the current demand of the

respective cell and is therefore variable in time [1].

To distinguish: Mode of action of the α2-agonists at pre- and postsynaptic α2-receptors,

α2 receptors occur both presynaptically and postsynaptically. The same agonist acts

inhibiting via the presynaptic receptors and stimulating via the postsynaptic receptors.

In the central nervous system, the presynaptic α2 receptors predominate. Here agonists have

an inhibitory effect, i.e. the release of neurotransmitters is reduced. Therefore, they lead to

analgesia, sedation, blood pressure reduction and hyperthermia.

In the periphery, however, the post-synaptic α2 receptors predominate. Here the agonists

lead to stimulation and thus, among other things, to vasoconstriction [2].

α2-receptor agonists in ophthalmology:

Already in the 1960s, a α2 receptor agonist, namely clonidine, was used for the treatment of

arterial hypertension [2]. In the 1970s, clonidine was also marketed as eye drops for

lowering eye pressure [3, 4]. Because of the side effects, the application remained limited.

Clonidine was particularly popular as premedication before retrobulbar anesthesia because

it also reduced anxiety, pain and blood pressure [5].

In 1988, apraclonidine, an amino derivative of clonidine that is less lipophilic and therefore

crosses the blood-brain barrier less frequently, was introduced to the market. Apraclonidine

thus has fewer central effects such as lowering blood pressure. Unfortunately, however,

allergies are relatively common [4].

Brimonidine followed in 1997, an imidazoline which has less central effects than clonidine

and causes fewer allergies than apraclonidine. It lowers the intraocular pressure by reducing

the production of aqueous humor and improving uveoscleral outflow. In contrast to betablockers, it also lowers intraocular pressure at night [4, 6].

Now there is this new brimonidine free of preservatives with similarly good effects, but

considerably less side effects [7]. The extension of the spectrum of preservative-free

antiglaucomatous agents is positive, because preservatives - especially benzalkonium

chloride - can cause chronic irritation, trigger allergies and aggravate a sicca syndrome [8].

Neuroprotection and vasoconstriction by Brimonidine

α2 agonists have a neuroprotective effect in vitro. Whether this is also the case in vivo in

glaucoma patients are difficult to prove. Visual field studies indicate that this is the case [9]. In

order to have this effect, however, the molecule must pass through the blood-brain or

blood-retina barrier. For this reason, a slightly central sedative and rarely a blood pressure

lowering effect must be accepted for brimonidine [4].

Brimonidine also has a slight vasoconstrictive effect, both in the periphery and the eye. This

is why caution is advised in patients with Raynaud's syndrome [10]. This effect is exploited in

a local application on the skin for the treatment of rosacea [11].

Dr. K. Konieczka in Basel investigated the effect of glaucoma drugs on corneal temperature.

After brimonidine (but not placebo) the temperature decreased slightly (due to

vasoconstriction in the anterior segment of the eye) for about 90 minutes. Interestingly, this

effect was significantly stronger in patients with Flammer syndrome (FS) than in patients

without FS [12]. This also corresponds to our clinical experience: Patients without FS tolerate

brimonidine significantly better than patients with FS.

In summary, we can say that Alpha-Vision® sine1 twice a day has a good lowering of

intraocular pressure and a possibly neuroprotective effect and can be combined with other

drugs. It has significantly fewer side effects than its predecessor molecules. The central

effects and vasoconstrictions are weak but still present. Therefore, Alpha-Vision® sine1 is

more suitable for glaucoma patients without FS than for glaucoma patients with FS.

Prof. Dr. Med. Josef Flammer

Former head of the eye clinic, University Hospital Basel, Switzerland