Selectivity of site of action and systemic effects of topical
`alpha agonists
`Alan L. Robin, MD*t, and Yochanan Burnstein, MD*
`
`Clonidine hydrochloride, apraclonidine hydrochloride, and bri·
`monidine tartrate constitute the three topical o: agonists that are
`used in the treatment of elevated intraocular pressure. All the o:
`agonists have prejunctional (o: 2) as well as postjunctional (o: 1)
`effects. Within the past year, questions have arisen about their
`local and systemic effects, and their effects upon the optic
`nerve. We will, therefore, attempt to clarify these points, to pro·
`vide a greater understanding of the role of o: agonists in glau·
`coma therapy.
`
`Mechanism of action
`The ocular hypotensive effects of clonidine hydrochlo(cid:173)
`ride, apraclonidine hydrochloride, and brimonidine tar(cid:173)
`trate are mediated via a 2 receptors in a number of ways.
`There are at least three different types of a 2 receptors.
`There is a difference in species specificity of these re(cid:173)
`ceptors: that is, one compound may be more selective for
`a particular a 2 receptor in one animal model, while less
`selective in a second animal model.
`
`'Department of Ophthalmology, University of Maryland School of Medicine,
`6115 Falls Road, Baltimore, MD 21209, and Johns Hopkins University School of
`Medicine; and ' School of Hygiene and Public Health, Johns Hopkins University,
`Baltimore, MD 21209, USA.
`
`Current Opinion in Ophthalmology 1998, 9;11:30-33
`
`Abbreviation
`
`lOP
`
`intraocular pressure
`
`© 1998 Lippincott·Raven Publishers
`ISSN 1040-8738
`
`30
`
`When a 2 adrenoreceptors in the ciliary body are acted
`upon, intracellular cyclic AMP levels diminish and subse(cid:173)
`quently, aqueous production decreases [1]. Outflow facil(cid:173)
`ity as well as episcleral venous pressure may be affected
`by all three compounds [2-4). In one report, brimonidine
`was found to increase uveoscleral flow [4]. Central ner(cid:173)
`vous system penetration, while contributing to adverse
`effects, may play a role in the reduction of intraocular
`pressure (lOP) by both clonidine and brimonidine [5].
`lOP is a well-known risk factor for the progression of
`glaucomatous damage. To date, it has been the only risk
`factor that we have attacked in the therapy of most forms
`of open-angle glaucoma. An ideal therapeutic modality
`would protect axons from both primary and secondary
`nonapoptotic axoplasmic death in addition to lowering
`lOP. It has been suggested, but in no way proven, that a
`agonises may also provide neuroprotection [6).
`
`Neuroprotection
`The definition of glaucoma has gradually changed over
`the past few decades to include a set of diseases sharing a
`particular pattern of optic nerve damage. Most, but not
`all, have elevated lOP as a major risk factor. Many glau(cid:173)
`coma medications, notwithstanding a agonises, have
`proven efficacious in reducing lOP. What would be per(cid:173)
`haps more desirable, however, is a medication aimed at
`protecting the optic nerve in addition to decreasing a risk
`factor.
`
`Burke and Schwartz [6] have suggested that brimonidine
`might be able to accomplish this goal. Verbal communica(cid:173)
`tion with Schwartz has confirmed that they have seen this
`neuroprotective capability with clonidine, although it has
`not yet been evaluated for apraclonidine.
`
`Burke and Schwartz used a rat model in which the rat op(cid:173)
`tic nerve was crushed and intraperitoneal brimonidine was
`then administered. After 2 weeks, axonal excitability was
`increased 2.5-fold and axonal survivability was increased
`
`Downloaded from http://journals.lww.com/co-ophthalmology by TcGgJMX2ueX7fc3LT8H0jna7zBBHdt/fNNv3v2UbmyyoGkZB/fCz+8Nm1f5+6s9ZvehbFtpc/VFY2BHbrqMrLMbCAGvBYTo0hcIjhNuEDN/wvb7TKrLyOkB0zNQGU/15Th5LmRAwVOrC8K5KRgWutdk7ZkgN9P85Q3GNK4PqSjI= on 08/30/2021
`
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`Selectivity of site of action and systemic effects of topical alpha agonists Robin and Burnstein 31
`
`fourfold. Whether or not this acute crush model is analo(cid:173)
`gous to what happens in humans with chronic glaucoma
`is uncertain. Many problems such as drug formulation
`and delivery, species specificity, and toxicity must be ad(cid:173)
`dressed before any claims or realistic suggestions can be
`made. Additionally, even without regard to species dif(cid:173)
`ferences, it is important to determine whether this model
`is at all applicable to human glaucoma. It is likely that
`crush damage which is produced acutely is not related to
`the chronic slow damage seen in humans. It could be
`that apoptosis is much more critical than this type of cell
`death. Brimonidine may not get to axons in adequate
`concentrations when given locally to the eye, and not by
`intraperitoneal injection. Also, adverse reactions such as
`sedation and systemic hypotension might override any
`local optic nerve benefits if an adequate amount of the
`drug was administered.
`
`Burke and Schwartz found similar results with clonidine,
`but not timolol maleate (personal communication). Prior
`studies with dexmedetomidine (another o: 2 agonist) used
`in 14 rabbits found that it also protected against ischemic
`brain damage [7]. It is possible that many o: agonists have
`some type of neuroprotective ability, but it is far too
`early to suggest that this class of medications has any
`clinical applicability for humans with glaucoma.
`
`Efficacy and dosing
`Apraclonidine shows a peak hypotensive effect of 30% to
`40% 3 to 5 hours after administration and a trough level
`reduction of 20% to 30% [8]. Brimonidine has a maxi(cid:173)
`mum effect at 2 hours with a 20% to 30% pressure lower(cid:173)
`ing [9]. It has been claimed that tachyphylaxis occurs
`with chronic use of apraclonidine, but this has not been
`shown with brimonidine [I 0]. However, there is no well(cid:173)
`documented evidence that tachyphylaxis truly occurs
`with apraclonidine. Reports of tachyphylaxis have been
`from uncontrolled studies of eyes with glaucoma on
`maximal-tolerated medical therapy. It could be that if
`these studies had either active or placebo controls, there
`would not be any clinically significant tachyphylaxis.
`The absence of a control group makes it difficult to truly
`monitor response to a medication. Additionally, eyes re(cid:173)
`quiring surgery may respond differently to medications
`than those eyes that are well controlled on either one or
`two eye-pressure-lowering medications.
`
`A concentration of 0.5% proved most efficacious for apra(cid:173)
`clonidine [11]. For brimonidine, a dose-response effect
`was observed during the first week of treatment, with a
`greater response with the use of 0.5% brimonidine. By
`the second week, a similar effect was achieved with 0.2%
`solution [9].
`
`Apraclonidine probably requires three times a day dosing
`for maximal effect. Claims to the effectiveness of bri-
`
`monidine administered twice daily are based on the fact
`that the morning lOP levels, approximately 2 hours after
`administration, were the same whether the drug was ad(cid:173)
`ministered twice or three times a day [12]. The afternoon
`trough level, however, showed a difference of 3.5 mm
`Hg between the two groups, rendering twice a day ad(cid:173)
`ministration far inferior to three times a day dosing. Sim(cid:173)
`ilarly, in a comparison of brimonidine twice daily to timo(cid:173)
`lol during a 12-month period, mean peak lOP decreases
`were comparable to timolol, whereas mean decrease
`from baseline was significantly less for trough values of
`brimonidine than for timolol [13]. Brimonidine, like apr(cid:173)
`aclonidine, should be administered thrice daily for a con(cid:173)
`stant, around the clock hypotensive effect.
`
`Side effects related to localized o:2 effects
`There are several points to keep in mind when discussing
`the side-effect potential of o:2 agonists such as clonidine,
`brimonidine, and apraclonidine. The degree to which a
`centrally mediated side effect occurs depends upon the
`concentration of the drug within central nervous system
`tissues, which in turn is related to its ability to cross the
`blood-brain barrier. Drug penetration into the brain is de(cid:173)
`pendent upon the lipophilicity of the drug. Both brimoni(cid:173)
`dine and clonidine are more highly lipophilic than apra(cid:173)
`clonidine [14]. This increased lipophilicity suggests that
`they can be absorbed much more easily into both the
`blood stream and the central nervous system through the
`blood-brain barrier.
`
`The degree to which a peripherally mediated side effect
`occurs depends upon the concentration of the drug
`within the systemic circulation in relation to the drug's
`potency. Apraclonidine is less likely than brimonidine to
`be absorbed systemically from topical ocular administra(cid:173)
`tion because it is less lipophilic (ie, it is more hydrophilic
`and charged at physiologic pH).
`
`All three medications are relatively selective o: 2 agonists.
`The degree of selectivity is only important if tissue con(cid:173)
`centrations are within the range required for o: 1 activity. If
`tissue or circulating levels of drug are insufficient to pro(cid:173)
`duce o:2 effects, then o:1 effects are highly improbable.
`
`The degree of selectivity reported depends on whether
`it is based upon receptor affinity or functional potency,
`as well as the experimental conditions of the assay.
`Functional potency seems more appropriate for agonists,
`whereas receptor affinity is more relevant to antagonists.
`Binding affinity data has been used to characterize the
`selectivity of all three medications [15-17]. The func(cid:173)
`tional data has been ignored and it shows apraclonidine's
`selectivity to be higher [18]. Moreover, other published
`binding affinity data, using cells with cloned human re(cid:173)
`ceptors that showed the o:2 to o:1 selectivity of apracloni(cid:173)
`dine to be 528-fold and that of brimonidine to be 759-fold,
`
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`

`32 Glaucoma
`
`is largely ignored [19]. a 2 Selectivity is sufficient for both
`drugs to consider their primary ocular effect to be related
`to a 2 activation.
`
`It is questionable whether a 1 activation, either locally or
`systemically, occurs at usual ophthalmic doses. For ex(cid:173)
`ample, Allergan's (Irvine, CA) published data shows the
`EC 50 of apraclonidine to be 216 nmoi/L for causing in
`vitro contraction of the rabbit iris dilator muscle (mydria(cid:173)
`sis), with this response considered to be mediated by a 1
`receptors [18]. Moreover, they reported an EC50 of 1.9
`nmoi/L for apraclonidine in activating a 2 receptors. Ad(cid:173)
`ditional data show that iris concentrations of brimonidine
`are about 10 times higher than those of apraclonidine,
`which tends to nullify the difference between the drugs
`with regard to functional potency and affinity.
`
`Side effects of selective a 2 agonists
`Central nervous system effects
`Sedation is mediated by postsynaptic receptors located
`in the locus coeruleus, which lies behind the blood-brain
`barrier. This pharmacologic effect is potentiated by ben(cid:173)
`zodiazepines and can be used advantageously to reduce
`anesthetic requirements. Clonidine is used in certain cir(cid:173)
`cumstances as a sedative to reduce the amount of anes(cid:173)
`thesia required for humans. Xylazine, another a 2 agonist,
`is used by veterinarians in large nonhuman animals to in(cid:173)
`duce sedation. A limitation of xylazine is the variability
`of the sedation.
`
`This could result in a possible overdose situation if bri(cid:173)
`monidine is used in a patient who has received either
`clonidine for anesthesia or is on benzodiazepines. It
`might be unusual for an anesthesiologist who is about to
`use clonidine for induction to ask a patient requiring
`surgery, especially urgent surgery, whether he or she is
`on brimonidine eye drops. Likewise, many physicians
`prescribing benzodiazepines would probably not know a
`patient is taking brimonidine.
`
`Sedation related to brimonidine could interfere with a
`patient's ability to operate machinery, drive a car, or re(cid:173)
`main alert and awake, particularly after alcohol consump(cid:173)
`tion. It is unlikely that a patient would associate this
`complication with brimonidine. Additionally, a patient
`might not associate fatigue with the use of an eye drop.
`Apraclonidine is far less likely to produce sedation, be(cid:173)
`cause it does not enter the central nervous system to the
`degree that brimonidine does, nor is it absorbed into the
`system circulation as effectively.
`
`in patients with little counteracting sympathetic stimula(cid:173)
`tion (ie, those at rest) and is related to both central and
`peripheral actions of these agents. Recently, it has been
`postulated that the hypotensive effect of imidazoline(cid:173)
`like compounds is mediated by imidazoline-preferring
`receptors located in the rostal ventrolateral medulla that
`mediate peripheral sympathoinhibition [20]. The central
`nervous system side effects are believed to be mediated
`via a 2 receptors.
`
`Clonidine can produce systemic hypotension and brady(cid:173)
`cardia via a site in the central nervous system. The mech(cid:173)
`anisms may involve inhibition of sympathetic outflow
`and enhancement of parasympathetic nervous activity.
`
`It is reasonable to assume that a 2 agonists that reach
`higher concentrations within the central nervous system
`are more likely to produce systemic hypotension and se(cid:173)
`dation. The production of hypotension and sedation by
`a 2 agonists has been shown to correlate well with their
`partition coefficient (their ability to penetrate the central
`nervous system) [21].
`
`a 2 Agonists inhibit norepinephrine release from periph(cid:173)
`eral prejunctional nerve endings. This action contributes
`to their bradycardic effect. Presumably, the greater the
`lipophilicity of the compound, the more likely It IS to
`reach the systemic circulation and, depending on the
`dose, produce this effect.
`
`Hypertension and vasoconstriction
`a 2 Agonists produce vasoconstriction by their activation
`of vascular extra junctional a 2 receptors. If the concentra(cid:173)
`tion of a relatively selective a 2 agonist is sufficiently high
`to enable stimulation of vascular a 1 receptors, this too
`will result in vasoconstriction. Nevertheless, even with(cid:173)
`out a 1 activation, a 2 receptor activation can produce
`vasoconstriction. Locally in the eye, both brimonidine
`and apraclonidine produce anterior segment (ie, conjunc(cid:173)
`tiva, iris, ciliary body) vasoconstriction [22].
`
`Under certain clinical situations, this added stimulation
`of vasoconstrictive receptors can produce systemic hy(cid:173)
`pertension. This is particularly true if there is excessive
`sympathetic tone present (ie, if the patient is under stress
`or is taking a monoamine oxidase inhibitor or a tricyclic
`antidepressant [norepinephrine reuptake blocker]). Be(cid:173)
`cause this is a peripheral action, it too depends upon the
`circulating drug level and potency of the particular agent
`whether or not vasoconstriction occurs.
`
`Cardiovascular system
`Hypotension and bradycardia
`The cardiovascular actions of a 2 agonists are classified as
`peripheral or central and include systemic hypotension
`and bradycardia. Bradycardia is especially likely to occur
`
`Respiratory system
`Clonidine itself does not produce any marked effects
`upon respiration. Brimonidine and apraclonidine, in nor(cid:173)
`mal human volunteers, have not been found to produce
`adverse effects on respiration [23].
`
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`Selectivity of site of action and systemic effects of topical alpha agonists Robin and Burnstein 33
`
`Endocrine system
`cx 2 Agonists can potentiate the secretion of growth hor(cid:173)
`mone and inhibit the release of insulin by a direct action
`on pancreatic 13 cells [24]. Neither of these is considered
`important in normal clinical situations.
`
`Hematologic system
`cx2 Agonists induce platelet aggregation. A concurrent re(cid:173)
`duction in circulating catecholamines may clinically off(cid:173)
`set this effect.
`
`Gastrointestinal system
`ex Agonists inhibit salivation and produce dry mouth via
`activation of peripheral postsynaptic cx2 receptors. This
`peripherally mediated inhibition of salivary secretion can
`be augmented by the centrally mediated sympathetic in(cid:173)
`hibition. Activation of peripheral postsynaptic cx 1 recep(cid:173)
`tors has been shown to enhance parasympathetic-medi(cid:173)
`ated salivation [24]. Thus, any cx 1 activity occurring would
`produce less dry mouth compared with the absence of cx 1•
`
`Conclusions
`The ex agonists have proven to be a powerful addition to
`the armamentarium of pressure-reducing agents. A solid
`understanding of their actual and potential strengths and
`limitations is crucial so that they may be used in a safe
`and efficacious manner.
`
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