The adrenergic system and adrenergic agonists

Adrenergic agonists have been used as ocular hypotensive agents since 1900 when Darier treated glaucoma patients with subconjunctival injections of epinephrine. Two decades later, Hamburger applied epinephrine topically to reduce intraocular pressure (IOP). Then epinephrine drugs fell into disrepute for years because the agents were unstable in solution and were capable of precipitating or aggravating angle-closure glaucoma. With the development of gonioscopy, which allowed more correct classification of the glaucomas, and with the availability of antioxidants to stabilize solutions, the epinephrine agents again assumed a major role in the treatment of glaucoma until the advent of the β-blocking agents.

Despite the fact that epinephrine has been used as a treatment for glaucoma since the beginning of the twentieth century, we still lack a complete understanding of the mechanism(s) by which, at least some, adrenergic agents reduce IOP (see section on mechanism(s) of action, pp. 377-8, for a more detailed discussion).

A brief review of the anatomy and physiology of the sympathetic nervous system may be helpful in understanding what is known about the action of adrenergic agents. The first-order sympathetic fibers arise in the hypothalamus and descend to the intermediolateral horn of the lower cervical and upper thoracic spinal cord. The second-order neurons pass through the white rami communicantes into the sympathetic chain and synapse in the superior cervical ganglion. The third-order neurons travel to the eye with the branches of the carotid artery, where they innervate a variety of tissues, including smooth muscle of the uveal vessels and iris dilator, as well as the ciliary processes.

Three main endogenous transmitters – norepinephrine, epinephrine, and dopamine – mediate the effects of the adrenergic system. Most adrenergic agents act directly or indirectly as either agonists or antagonists at neuroeffector junctions by binding to receptors located on the cell. Through the pioneering work of Ahlquist and Lands and co-workers, we now know that there are a variety of adrenergic receptors that are classified by their location and relative affinity for different agonists and antagonists. Currently five major types are recognized: α 1 , α 2 , β 1 , β 2 , and β 3 . Subtypes of both α 1 and α 2 have been identified throughout the body and in the eyes of both rabbits and humans. In the eye, stimulation of α 1 -receptors causes mydriasis, vasoconstriction, elevation of IOP, and eyelid retraction, whereas stimulation of α 2 -receptors causes decreased aqueous humor formation and, probably, increased outflow of aqueous. Obviously, inhibition of a particular receptor type will cause the opposite effect. Many agents have effects on more than one receptor type, causing a complicated and occasionally paradoxical response. Adrenergic agents in clinical use or of interest clinically include combined α and β agonists (e.g., epinephrine), α 2 agonists (e.g., brimonidine), α 1 and α 2 agonists (e.g., apraclonidine), β agonists (e.g., isoproterenol), α antagonists (e.g., bunazosin), and β antagonists (e.g., timolol). A summary of the adrenergic receptors is given in Table 24-1.

Table 24-1

Systemic adrenergic receptors

Receptor Location Function Agonist Specific antagonist Response to agonist
α 1 Postsynaptic, blood vessel, smooth muscle Vasoconstriction Methoxamine, Phenylephrine,Clonidine, Apraclonidine Prazosin, Phenoxybenzamine,Bunazosin E≥NE>I
α 2 Presynaptic/ postsynaptic Inhibit neurotransmitter release (e.g., norepinephrine) Clonidine, Brimonidine,Apraclonidine Yohimbine E≥NE>I
β 1 Cardiac muscle Cardiac excitability and contraction CGP 7760B Atenolol, Practolol, Metaprolol, Betaxolol I>E=NE
β 2 Blood vessel, smooth muscle, bronchi, gastrointestinal tract Vasodilation, relax bronchial and gastrointestinal smooth muscle Salbutamol Butoxamine I≥E>NE

E, Epinephrine; NE, norepinephrine; I, isoproterenol.

Norepinephrine is the neurotransmitter at most sympathetic neuroeffector junctions. Norepinephrine is stored in synaptic vesicles in the cytoplasm of axon terminals, is released in response to nerve impulses, and diffuses across the junction to the effector organ. Norepinephrine is removed from active sites by a variety of mechanisms. Generally, norepinephrine is removed by active reuptake into axon terminals, where it either is metabolized or re-enters storage granules. Other pathways for norepinephrine removal include uptake into non-neuronal tissue, diffusion away from the active site, and metabolism by the enzymes monoamine oxidase and catechol O -methyltransferase.

Epinephrine is a circulating neurohumoral factor synthesized and released by the adrenal medulla. It is carried to local effector sites by the circulation. Epinephrine is mostly metabolized by the enzymes monoamine oxidase and catechol O -methyltransferase; a small portion of the circulating epinephrine is removed by active uptake into tissue.

When an agonist binds to a β-adrenergic receptor, the target cell goes from its normal state to an activated state. Coupling proteins are then released that activate the enzyme adenyl cyclase, causing one of several known ‘second’ messengers to be synthesized and released into the cell. These second messengers – including Ca ++ , cyclic adenosine monophosphate (cAMP), inositol triphosphate, and cyclic guanosine monophosphate – regulate protein phosphorylation, which, in turn, can cause changes in the cell metabolism, sensitivity, membrane permeability, or ion transport.

The mechanism by which α-receptors alter cellular metabolism is not as clear. It is postulated that the α 2 -adrenergic receptor is coupled in an inhibitory fashion to adenylate cyclase. Activation of α 1 -adrenergic receptors stimulates turnover of membrane phosphoinositol and mobilizes intracellular calcium.

A number of substances called antagonists bind competitively to adrenergic receptors without triggering receptor action. These compounds inhibit neurotransmitters or agonists from stimulating adrenergic function. However, some antagonist agents also possess some capacity to stimulate adrenergic receptor sites; these agents are said to have intrinsic sympathomimetic activity (see Ch. 25 ).

When adrenergic receptors are stimulated by an agonist for some time, subsensitivity may develop; this phenomenon might be related to internalization of the cell surface receptors (i.e., downregulation of receptors). Conversely, when receptors are exposed to an antagonist or receive defective neurotransmission over time, supersensitivity develops. Denervation supersensitivity develops rapidly and is related to the loss of the neural tissue that ordinarily removes agonists from the receptor sites. Non-denervation supersensitivity develops more slowly and consists of an increased response to ordinary concentrations of agonists at the receptors. In some cases, this may be related to an increased number of cell surface receptors (i.e., upregulation of receptors).



For many years it was generally thought that epinephrine lowered IOP by means of an early β-adrenergic-mediated effect decreasing aqueous humor production and a late α-adrenergic-mediated effect increasing outflow facility. However, recent studies have cast doubt on this theory. Unfortunately, some of the recent studies have yielded conflicting results rather than a new consensus concerning the mechanism by which epinephrine reduces IOP. Other important considerations in attempting to interpret the literature on this subject include species differences, an undue emphasis on short-term rather than long-term studies, and the difficulty in explaining the response of aged, human eyes with glaucoma by extrapolating results from experiments performed in young, healthy animal eyes.

The most widely accepted hypothesis regarding the ocular hypotensive effect of epinephrine is that it increases both conventional and unconventional outflow from the eye. Some investigators ascribe the effect of epinephrine on trabecular outflow to α-adrenergic receptors, to β-adrenergic receptors. The latter theory is supported by experiments in primates, which find that analogs of cAMP increase outflow facility and that the improved outflow of aqueous produced by epinephrine is blocked by pretreatment with timolol. On the other hand, approximately half of the increased outflow facility induced by epinephrine can be inhibited by indomethacin. Whether this means that the prostaglandin system is involved in the epinephrine effect is not clear. A recent study confirms that prostaglandins may play some role in the effectiveness of epinephrine at least in rabbits. Evidence in rabbits also suggests that topical epinephrine causes adenosine release into the anterior chamber which may play an important role in its ocular hypotensive effect.

The influence of epinephrine on aqueous humor outflow is not abolished by detaching the ciliary muscle, suggesting a direct effect on the outflow channels. Alvarado and co-workers showed that epinephrine in tissue culture opens the extracellular spaces of human Schlemm’s canal endothelium and trabecular meshwork cells in tissue culture through a β-adrenergic-mediated mechanism. Some authorities believe that the effect on uveoscleral outflow is greater than the effect on conventional outflow. This theory is supported by experiments in lower primates. Some tonographic studies in humans suggest that the full effect of epinephrine on aqueous outflow may not develop for several months.

Studies using fluorophotometry indicate that short-term epinephrine treatment produces a small increase rather than a decrease in aqueous humor formation. An increase in aqueous flow is also seen after administration of other β-adrenergic agonists such as salbutamol and metaproterenol; this effect is blocked by the β-adrenergic antagonist timolol but not the α-adrenergic antagonist thymoxamine. There is a small α-adrenergic effect, decreasing aqueous humor production, but this is only recognized after inhibition of β-adrenergic stimulation. Thus the effect of epinephrine on IOP is a summation of several processes. The major therapeutic effect seems to be an increase in the outflow of aqueous via both conventional and unconventional pathways. Stimulation of cAMP is associated with at least some of this effect. Epinephrine seems to have little long-term effect on aqueous humor formation.

It is important to stress that the mechanism just outlined is controversial and disputed by many investigators. Some studies show that epinephrine treatment actually decreases aqueous humor formation. The findings of these studies are based on tonography, which does not measure aqueous production directly. However, a few studies using fluorophotometry also find an epinephrine-induced decrease in aqueous flow. This apparent contradiction cannot be explained at present.

Pretreatment of rabbits with small doses of dexamethasone seems to facilitate the effect of even small doses of epinephrine. What the mechanism of this effect might be, whether this effect holds for humans, and whether it can be used clinically remain conjectural.

A number of other theories have been proposed to explain the reduction in IOP after epinephrine treatment, including those that follow:

  • 1.

    Decreased episcleral venous pressure. Epinephrine produces vasoconstriction and decreased episcleral venous pressure, but these effects are generally short-lived and do not explain the long duration of ocular hypotension. Furthermore, drugs such as phenylephrine that produce vasoconstriction have little effect on IOP, whereas adrenergic drugs such as isoproterenol that do not produce vasoconstriction reduce IOP.

  • 2.

    Alteration of pressure relationships in the intrascleral vascular plexus.

  • 3.

    Destruction of adrenergic nerve terminals.

  • 4.

    Reduction in the effective number of β-adrenergic receptors.

  • 5.

    Induction of adrenergic supersensitivity. It is possible that numbers 3,4, and 5 are related.

  • 6.

    Increase in prostaglandin synthesis.

  • 7.

    Activation of lysosomal hyaluronidase, leading to an alteration in the components of the trabecular meshwork.

  • 8.

    Movement of fluid into the ciliary channel. Because the optic vesicle invaginates during embryologic development, the polarity of the non-pigmented epithelial cells of the ciliary body is reversed (i.e., fluid moves from the apex of the non-pigmented epithelial cells across the basal–lateral membranes into the posterior chamber). It is postulated that β-adrenergic stimulation increases fluid movement into the space between the pigmented and non-pigmented epithelial layers. This accumulation decreases net fluid flow into the posterior chamber.

None of these alternative theories has sufficient proof at present to warrant acceptance.


Dipivefrin is a prodrug, which means that it must undergo biotransformation before exhibiting its pharmacologic effect. Dipivefrin itself has limited sympathomimetic activity until it is converted to epinephrine by esterase enzymes in the cornea and other tissues. Dipivefrin, a synthetic analog of epinephrine, is created by adding two pivalic acid side chains to the parent molecule ( Fig. 24.1 ). This increases the lipid solubility of the compound by 600 times and the ocular penetration by 17 times when compared with epinephrine. Thus administering dipivefrin in a low concentration produces a substantial intraocular concentration of epinephrine.

Fig. 24-1

Clinical adrenergic agonists.

The assumption that dipivefrin functions strictly by conversion to epinephrine is questioned by at least one investigator. It is known that dipivefrin is converted to a number of metabolites other than epinephrine, including 3-monopivalic acid, 4-monopivalic acid, and dipivalyl mandelic acid. The activity of these metabolites is unknown. Dipivefrin in its unmetabolized form also binds to β-adrenergic receptors in one animal model. The significance of this observation is unclear at the present time.


Because norepinephrine is the normal postganglionic mediator of the adrenergic nervous system, the drug might be expected to have a profound effect on aqueous humor dynamics. Intracameral norepinephrine produces a significant decrease in IOP by increasing the trabecular outflow facility; this is the case even when the ciliary muscle is disinserted, suggesting a direct effect on the trabecular meshwork. Norepinephrine administered topically as a 2–4% solution does decrease IOP, perhaps through an α-adrenergic-mediated effect on outflow facility. However, the IOP-lowering effect of topical norepinephrine in humans is too modest for clinical effectiveness, perhaps because of limited ocular penetration or substantial neuronal reuptake.

When administered to rabbits, norepinephrine causes a biphasic alteration in IOP. The effect in animals is potentiated by bilateral cervical ganglionectomy and a variety of drugs, including monoamine oxidase inhibitors, tetracaine, cocaine, and corticosteroids. In most cases, the apparent potentiation is caused by decreased neuronal uptake and by increased ocular penetration of norepinephrine as a result of altered corneal permeability.



Phenylephrine hydrochloride is a potent synthetic sympathomimetic agent that differs from epinephrine in that it lacks a hydroxyl group on the 4 position of the benzene ring (see Fig. 24-1 ). The drug acts predominantly on α 1 -adrenergic receptors and is used topically in concentrations of 0.125–10% to induce vasoconstriction or mydriasis or to break posterior synechiae. Following instillation of topical phenylephrine, mydriasis reaches a maximum in 60–90 minutes with recovery by 6 hours. Phenylephrine can produce mydriasis even in patients treated with strong miotics. The drug is often used in combination with, or as a diluent for, echothiophate to prevent the development of cysts of the iris pigment epithelium. Phenylephrine produces a slight fall in IOP but is of little use in the chronic therapy of glaucoma. Occasionally topical phenylephrine administration produces an increase in IOP from the release of iris pigment particles. This phenomenon may be more common in patients with the pigment dispersion syndrome or pigmentary glaucoma. Phenylephrine also has the capability of triggering an attack of acute angle closure in susceptible eyes.


The α 2 -adrenergic agonists reduce IOP largely by decreasing aqueous formation. Topical α 2 agonists have been studied and used for their ability to lower IOP for over a quarter of a century.


The first such α 2 -adrenergic agonist, clonidine, an imidazole derivative, is used as an antihypertensive agent. The drug acts principally as a central and peripheral α 2 agonist, thereby inhibiting norepinephrine release and suppressing sympathetic outflow to the cardiovascular system. The drug also acts as an α 1 agonist and α 1 and α 2 antagonist in some situations.

Applied topically to normal and glaucomatous eyes in concentrations of 0.125% and 0.05%, clonidine lowers IOP for 6–8 hours. The 0.15% concentration of clonidine is slightly less effective in reducing IOP than 2% pilocarpine. There is controversy concerning the mechanism by which clonidine lowers IOP; most investigators believe clonidine acts through central and peripheral adrenergic mechanisms to reduce aqueous humor formation by means of vasoconstriction in the uveal tract. A few investigators note a small increase in outflow facility, but most detect little or no change. Clonidine also produces a transient reduction of episcleral venous pressure. The drug apparently requires an intact central nervous system to lower IOP. Clonidine is known to bind to α-receptors in rabbit ciliary body–iris preparations. When the α 2 -receptors in the rabbit ciliary body are stimulated, they appear to couple with adenylate cyclase in the cell membrane to inhibit the synthesis of cAMP and thus inhibit aqueous production. Therefore both α 2 -adrenergic stimulation and β-adrenergic blockade will decrease aqueous humor formation. The effects are synergistic as documented by several clinical studies.


A derivative of clonidine, apraclonidine was found to act similarly to clonidine without the systemic side effects. The basic clonidine molecule is altered by having an amino group in the paraposition of the benzene ring. This alteration reduces the ability of the drug to penetrate the blood–brain barrier and thus reduces the risk of systemic hypotension. The agent was originally called para-aminoclonidine but was subsequently renamed apraclonidine. Its mechanism of action for lowering IOP is presumably the same as that of clonidine. Apraclonidine, like clonidine, may reduce episcleral venous pressure and, unlike clonidine, may increase trabecular outflow. Both clonidine and apraclonidine have some α 1 – and α 2 -adrenergic agonist activity. Therefore some of the effect of the agents may be due to anterior segment vasoconstriction, which causes decreased blood flow to the ciliary body and consequent decreased aqueous formation.


More recently, another α 2 -adrenergic agonist, brimonidine, has been identified as a potent ocular hypotensive agent. Brimonidine is much more selective than clonidine and apraclonidine for α 2 -receptors. Like its pharmacologic cousins, it decreases IOP by reducing aqueous formation; in addition, it acts by increasing uveoscleral outflow. Furthermore, brimonidine seems to have the additional property of neuroprotection, at least in some animal models and in some small human studies. Because of its effectiveness and relatively low side effect profile compared to other adrenergic agonists, brimonidine has become the most commonly used antiglaucoma medication of this group of agents. Brimonidine’s effectiveness may be reduced by concomitant administration of non-steroidal anti-inflammatory agents; this has implications both for its mechanism of action as well as in clinical use.

Brimonidine was first marketed in a 0.2% solution. However, more recently it has been produced in a 0.15% and even 0.1% solution. These latter solutions seem to be equally effective as the 0.2% solution with possibly reduced systemic and topical side effects. In addition, the use of preservatives other than benzalkonium chloride (e.g., polyquaternarium, Purite™) seems to reduce some of the topical side effects of brimonidine. Brimonidine has been combined with timolol in a fixed combination with comparable results to the separate, concomitant medications. Brimonidine can produce cardiovascular instability in infants and is therefore contraindicated in the first 5 years of life. Sleepiness and lethargy are relatively common side effects in children and thus these agents should be avoided in those under 15 years of age if possible. Topical brimonidine (as well as some β-blocking agents and prostaglandin derivatives) alters the expression of matrix metalloproteinases and their inhibitors in corneal cells and thus may contribute to ocular surface disease. Whether this is an effect of the agent directly or is caused by or affected by the preservative remains to be demonstrated.



Isoproterenol is a non-selective β-adrenergic agonist having essentially equal activity at β 1 – and β 2 -receptors. Applied topically in concentrations of 1–5%, isoproterenol lowers IOP with little effect on pupillary diameter or accommodation. The usefulness of the drug is limited by systemic side effects such as tachycardia, dysrhythmias, and palpitations. The d -isomer of isoproterenol lowers IOP in rabbits without producing cardiovascular changes but is inactive in primate and human eyes.


Salbutamol (albuterol) is a selective β 2 -adrenergic agonist. Topical application of a 4% solution lowers aqueous humor production and IOP for up to 48 hours. Clinical usefulness of the drug is limited by rapid tachyphylaxis and symptoms of conjunctival hyperemia and pain.


Other selective β 2 -adrenergic agonists such as terbutaline, soterenol, and reproterol lower IOP in laboratory animals and man.


Dopaminergic agents stimulate dopamine receptors (either type 1 or type 2 or both). In addition, most of these agents also stimulate α-adrenergic receptors (both α 1 and α 2 ). Stimulation of some dopamine receptors and α-adrenergic receptors shares the inhibition of cAMP release. Dopamine lowers IOP by reducing aqueous humor formation. Agonists having selective dopamine 2 receptor activity such as lergotrile and pergolide appear to be better ocular hypotensive agents than dopamine itself. However, some of the same dopamine agonists can raise IOP in eyes with glaucoma. Furthermore, some dopamine antagonists can lower IOP perhaps by inhibiting dopamine 1 receptors. Likely, several subtypes of dopamine receptors with different actions exist; which ones are active in the eye, what they do, and how they interact with the α- and β-adrenergic receptors remain to be elucidated.

The dopamine receptor agonist bromocriptine lowers IOP in human eyes when administered orally or topically. This effect is blocked by intravenous metoclopramide, a dopamine 2 antagonist, suggesting that this agonist is truly acting through dopamine receptors. A selective dopamine 1 agonist, fenoldapam, has actually been shown to raise IOP in humans possibly by activation of adenyl cyclase. None of the dopaminergic agents have found their way into active clinical use.



There have been a number of attempts to potentiate the effects of endogenous epinephrine and norepinephrine or exogenously administered catecholamines with drugs that inhibit either monoamine oxidase or catechol O -methyltransferase. The monoamine oxidase inhibitors clorgyline, deprenyl, and pargyline lower IOP in rabbit eyes when administered topically. There is one report that topical clorgyline lowers IOP in glaucomatous human eyes. A catechol O- methyltransferase inhibitor has been shown to potentiate the effects of topical epinephrine on the pupil and IOP (i.e., the dose–response curve is shifted to the left so that the same response can be obtained with a lower dose of epinephrine in the presence of the inhibitor). Up to now these drugs have been of limited clinical use for the treatment of glaucoma.


6-Hydroxydopamine has been used to enhance the IOP response to topical epinephrine treatment. The drug is taken up into peripheral nerves and causes a temporary degeneration of axon terminals. This produces a transient chemical sympathectomy and a supersensitivity to both α- and β-adrenergic agonists. 6-Hydroxydopamine is administered to the eye by iontophoresis or more commonly by subconjunctival injection. The 6-hydroxydopamine injection causes release of endogenous norepinephrine, which increases outflow facility and decreases IOP for a few days to 2 weeks. The purpose of the 6-hydroxydopamine injection, however, is not the transient ocular hypotensive response but rather the development of supersensitivity to α- and β-adrenergic agonists. The supersensitivity phase lasts a few weeks to 6 months and can be re-established by repeating the injection. It appears that 6-hydroxydopamine shifts the dose–response curve for epinephrine to the left (i.e., the same maximal response to epinephrine is obtained with a smaller dose of the drug) but probably does not increase the maximum effect. Similar hypersensitivity can be produced in rabbit eyes with the drug α-methyl-para-tyrosine, an inhibitor of norepinephrine synthesis.

Although early investigators believed that the combination of 6-hydroxydopamine and topical epinephrine was capable of aiding a high percentage of uncontrolled glaucoma patients, later investigators found this was not to be true. The drug is rarely used today, but even during the time of maximal popularity, it was reserved for those patients whose conditions were uncontrolled with more conventional therapy. Injections of 6-hydroxydopamine can produce conjunctival hyperemia, subconjunctival hemorrhage, transient mydriasis, chemosis, lid edema, and ptosis, which persist for a few days to a few weeks. Systemic side effects were rare.


Protriptyline, a tricyclic antidepressant drug, blocks neuronal reuptake of norepinephrine. There is one report that protriptyline prolongs the ocular hypotensive response to norepinephrine. Other investigators failed to confirm this finding.


Guanethidine is a sympatholytic drug that acts by displacing norepinephrine from postganglionic sympathetic nerve endings. The drug depletes tissue stores of norepinephrine, decreases reuptake of norepinephrine by the nerve terminals, and lowers sympathetic tone. Topical application of 5–10% guanethidine releases norepinephrine from nerve endings, leading to mydriasis, increased outflow facility, and decreased IOP. However, guanethidine alone is of little benefit in the long-term treatment of glaucoma. The drug is administered to produce a chemical sympathectomy and a supersensitivity to topical epinephrine. Combinations of guanethidine (1–5%) and epinephrine (0.05–1%) are capable of lowering IOP in a wide variety of glaucoma conditions. Some investigators believe the combination of guanethidine and epinephrine is more effective than either agent alone, whereas other investigators believe the combination merely displaces the dose–response curve to the left. Topical guanethidine can produce discomfort, soreness, conjunctival hyperemia, superficial punctate keratitis, lid edema, and ptosis. Side effects are common. Although it was popular for a while in Europe, the drug never gained much headway as part of the antiglaucoma regimen in the United States, either alone or in combination.


A number of agents that bypass the β-adrenergic receptor and stimulate the adenylate cyclase system by nonadrenergic mechanisms also lower IOP. For example, cholera toxin administered intravitreally or by close arterial injection reduces IOP in animals. Similarly, organic fluorides and a number of gonadotropic hormones – including luteinizing hormone, thyroid-stimulating hormone, and follicle-stimulating hormone – act as ocular hypotensive agents. The best studied drug in this class is the plant derivative forskolin (non-proprietary name colforsin). Forskolin administered topically or intravitreally lowers IOP in rabbit and monkey eyes. Its proposed mechanism of action is to decrease aqueous formation by increasing cAMP formation; exactly how this would work has not been satisfactorily explained. This appears to be its mechanism of action in rabbits; however, forskolin seems to have little effect on the formation of aqueous humor in man. In early experiments in human eyes, topical 1% forskolin reduced IOP for at least 5 hours. Forskolin also potentiates the effect of epinephrine in reducing both aqueous formation and IOP, possibly by increasing the permeability of the blood–aqueous barrier. However, multiple dosing in glaucomatous monkey eyes showed development of tachyphylaxis within 24 hours. This, plus a poor corneal penetration rate, have limited its use as an antiglaucoma drug. Because some forskolin analogs also reduce IOP, perhaps one or more will be found that penetrates the cornea better and produces little or no tachyphylaxis.

Clearly, the adrenergic system is complex; the mechanisms involved are elusive, and no single theory is fully able to explain why combined α- and β-adrenergic agonists such as epinephrine and dipivefrin, β-adrenergic agonists such as isoproterenol, α 2 agonists such as apraclonidine and brimonidine, α 1 antagonists such as bunazosin, and β antagonists such as timolol all are effective at lowering IOP – even in combination. Perhaps many of these mechanisms are active, and which one(s) predominate may be determined by dose, timing, and individual sensitivity, as well as other unidentified physiologic and pharmacologic factors.


The agents currently in clinical use, likely to be so in the near future, or of interest to this discussion include the combined α and β agonists (non-selective), the β agonists, the α 2 agonists, the α 1 antagonists, and the β antagonists ( Table 24-2 ). However, of all these agents, brimonidine is the one that has the most use. See Chapter 25 for a discussion of the α- and β-blocking agents.

Table 24-2

Adrenergic agents

Drug type Effect on intraocular pressure Mechanism Site and action
α 1 (e.g., phenylephrine) Mixed Vasoconstriction
α 2 (e.g., clonidine, brimonidine, apraclonidine) Decreases Decreases aqueous formation, increases trabecular outflow (apraclonidine), increases uveoscleral outflow (brimonidine) Inhibits ciliary epithelial adenyl cyclase
β 2 (e.g., isoproterenol) Decreases Increases trabecular outflow, decreases aqueous formation (?) Trabecular cell β receptor, ciliary body epithelium β receptor
Dopamine 1 Increases Unknown Stimulates adenyl cyclase
Dopamine 2 Decreases Decreases aqueous formation Inhibits ciliary epithelial adenyl cyclase
α 1 Decreases Decreases aqueous formation (?), increases uveoscleral outflow (?) Unknown
α 2 Decreases Unknown Unknown
β 1 and β 2 Decreases Decreases aqueous formation Ciliary epithelium β receptor, inhibits ciliary body adenyl cyclase
β 2 (e.g., betaxolol) Decreases Decreases aqueous formation Ciliary epithelium β receptor, inhibits ciliary body adenyl cyclase
Dopamine Decreases Unknown Unknown


Epinephrine (Eppy, Epinal, Epifrin, and generics)

Epinephrine stimulates both α- and β-adrenergic receptors. It is manufactured for topical ophthalmic use in three different salt forms – hydrochloride, bitartrate, and borate (see Fig. 24.1 ). Commercial preparations are usually described as the concentration of epinephrine salt rather than the concentration of available free epinephrine. This is important in the case of epinephrine bitartrate because a 2% solution contains approximately 1.1% epinephrine. When administered in equivalent doses, the hydrochloride, borate, and bitartrate salts appear to be equally effective in reducing IOP.

Hydrochloride solutions are stable and have been available in 0.5%, 1%, and 2% concentrations. However, hydrochloride solutions are rather irritating because they have a pH of approximately 3.5. Borate solutions have been available in 0.5% and 1% concentrations and are less irritating because they have a pH of 7.4. Bitartrate solutions are stable but are also irritating because of low pH.

The commercial epinephrine preparations contain preservatives and antioxidants. The latter are particularly important because oxidized epinephrine solutions are less effective and more irritating. Patients should be warned to discard epinephrine preparations that are discolored or muddy in appearance. Because of their relative chemical instability and relatively high rate of side effects, epinephrine compounds have been largely replaced by the prodrug dipivefrin and by the α 2 agonist brimonidine.

The effect of epinephrine on IOP is proportional to the concentration of the drug, reaching a maximum in most patients with the 1% or 2% solution.

After topical administration of epinephrine, IOP begins to fall in 1 hour, reaches a minimum in 2–6 hours, and returns to baseline in 12–24 hours. The effect of epinephrine on IOP appears to be additive with that of the miotics and the carbonic anhydrase inhibitors. However, combined treatment of epinephrine and non-selective topical β-adrenergic antagonists is often disappointing. It appears that only a minority of patients obtain a clinically useful additional long-term reduction of IOP when epinephrine is added to a topical β-adrenergic antagonist or vice versa. (See Ch. 25 for a detailed discussion.)

Dipivefrin (Propine and generics)

Dipivefrin, 0.1%, is roughly equivalent in its ocular hypotensive effect to 1–2% epinephrine. Dipivefrin is supplied as a 0.1% solution that is administered every 12–24 hours. Following topical administration, IOP begins to fall in 30–60 minutes, reaches a minimum in 1–4 hours, and returns to baseline in 12–24 hours. Because dipivefrin produces its ocular hypotensive effect by biotransformation to epinephrine, there is no reason to administer epinephrine and dipivefrin concurrently. Dipivefrin has the same additive effect to β-antagonist medications that epinephrine does. On average, one can expect an additional reduction in IOP of about 2 mmHg when adding dipivefrin to timolol. However, individual responses vary greatly, and a trial may be worthwhile.

Dipivefrin produces less external irritation, burning, and systemic side effects than does epinephrine (see the section on side effects, p. 383). Although the advent of dipivefrin caused the epinephrine salts to fall into disuse, the introduction of the α 2 agonists has reduced the usefulness of dipivefrin because of their improved additivity to β-blocking agents.

Suggestions for use

In the recent past, epinephrine and dipivefrin were used widely for the treatment of open-angle glaucoma. In addition, the drugs were helpful in patients with secondary glaucoma and in patients with angle-closure glaucoma following an iridectomy. Because administration of dipivefrin produces lower blood levels of epinephrine, it is the non-selective adrenergic agent of first choice; this is especially true in those patients in whom systemic conditions might be exacerbated by increased levels of circulating epinephrine. Dipivefrin has largely replaced epinephrine, and in the discussion that follows, they are treated as the same unless otherwise noted.

Patients and family physicians should be warned that topical epinephrine/dipivefrin treatment can induce systemic side effects. Patients should be instructed to instill only one drop of medication in each eye and to use punctal occlusion and simple eyelid closure to reduce systemic absorption. If epinephrine treatment is used, it should be initiated with a low concentration of the drug and increased as needed. The common practice of initiating therapy in all patients with 1% or 2% epinephrine should be discouraged because many patients receive maximum benefit from lower concentrations of the drug and because most of the side effects are dose related. Old, discolored solutions should be discarded because they are less effective and more irritating. Aphakic and, perhaps, pseudophakic patients should be warned of potential visual loss from macular edema and should test their vision weekly at home.

It is helpful to initiate epinephrine treatment with a unilateral trial because only 70% of glaucoma patients respond with a significant fall in IOP. Epinephrine has a slight contralateral effect on IOP, but this is unlikely to confuse the results of a one-eye trial.

It is well known that topical epinephrine/dipivefrin may produce mydriasis, potentially precipitating or aggravating angle-closure glaucoma. Mydriasis is more marked with concomitant β-adrenergic antagonists and may occur despite concomitant miotic treatment. Thus all patients require careful gonioscopy before and soon after initiating epinephrine treatment. Pupillary dilation may improve vision in some patients receiving miotic treatment, especially those with opacities of the media. Other patients may complain of decreased vision, perhaps from the loss of the pinhole effect or as a direct effect on the retina.

Side effects

More than 50% of patients started on long-term epinephrine treatment become intolerant to the drug. This figure is considerably less with dipivefrin. Most of the intolerance reactions are external in nature, including hyperemia, irritation, tearing, and blepharoconjunctivitis ( Box 24-1 ). A minority of the intolerance reactions are systemic in nature, including palpitations, hypertension, and premature ventricular contractions. These are even less frequent with dipivefrin. It is important to emphasize that one drop of a 2% epinephrine solution contains 0.1 mg of the drug; this amount, if completely absorbed, is within the range of the usual systemic dose used for the treatment of an acute asthma attack (i.e., 0.1–0.5 mg).

Box 24-1

Lid and conjunctiva

  • Hyperemia

  • Burning/stinging

  • Tearing

  • Blepharoconjunctivitis

  • Skin blanching

  • Adrenochrome deposits

  • Madarosis

  • Ocular pemphigoid

Lacrimal system

  • Lacrimal stones


  • Epithelial edema

  • Endothelial toxicity

  • Epithelial erosion from tarsal adrenochrome deposits

  • Adrenochrome deposits

  • Soft contact lens staining

Iris and uveal tract

  • Mydriasis and angle closure

  • Visual distortion/blurred vision

  • Photophobia

  • Iridocyclitis


  • Cystoid macular edema


  • Headache/browache

  • Tachycardia/dysrhythmia

  • Premature ventricular contractions

  • Palpitations

  • Anxiety/nervousness/pallor/faintness

  • Tremor

  • Increased blood pressure

  • Cerebrovascular accident

  • Myocardial infarction

  • Death

Epinephrine/dipivefrin side effects

Epinephrine treatment is contraindicated in a number of conditions, including severe hypertension, cardiac disease, and thyrotoxicosis. Patients treated with drugs that block uptake of epinephrine and norepinephrine (e.g., reserpine) or that inhibit monoamine oxidase (e.g., phenylzine, tranylcypromine) or catechol O -methyltransferase are at greater risk of developing systemic side effects with epinephrine treatment. The safety of topical epinephrine treatment in children and pregnant women has not been fully tested.

Patients with primary open-angle glaucoma (POAG) may be more susceptible to the effects of epinephrine in the eye and in the body in general, which may make them more likely to develop systemic side effects. In one study, 69% of the patients with POAG treated with epinephrine developed premature ventricular contractions as noted on tonography, as opposed to 19% of patients with secondary glaucoma. This kind of study has not been repeated with dipivefrin.

Epinephrine causes an initial vasoconstriction followed by a rebound vasodilation. Many patients receiving epinephrine eyedrops complain of conjunctival hyperemia either because of the cosmetic appearance or because of the implication of alcohol consumption. Some individuals, believing that topical epinephrine relieves the hyperemia, begin a pattern of overuse. This same scenario has been seen with the apraclonidine. Tearing and burning on drug instillation are also common symptoms. Switching to dipivefrin or an epinephrine borate preparation can often relieve these symptoms.

Instilled epinephrine undergoes oxidation and polymerization to form adrenochrome, a pigment of the melanin family. Adrenochrome deposits are often found in the lower conjunctival cul-de-sac, where they may be mistaken for foreign bodies ( Fig. 24-2 ). These deposits generally produce no symptoms because they are encapsulated by squamous epithelium. On the other hand, adrenochrome deposits in the upper tarsal conjunctiva have a branching or stag-horn appearance and can cause corneal epithelial abrasions. Adrenochrome material can also be deposited in the corneal epithelium, especially in the presence of increased IOP and bullous keratopathy. A diffuse plaque of adrenochrome covering the cornea can resemble a malignant melanoma. Adrenochrome deposits in the conjunctiva may last for years even after discontinuation of the drug.

Fig. 24-2

Adrenochrome deposits in conjunctiva from epinephrine.

Adrenochrome material is frequently deposited in the lacrimal sac and nasolacrimal ducts; this can be responsible for nasolacrimal system obstruction and epiphora, especially after long-term use. Actual adrenochrome calculi may be found or felt in the lacrimal drainage system. Stopping the epinephrine product may help, but resolution may take years or may require removal or dacryocystorhinostomy. Adrenochrome deposits occur more commonly when patients use old, discolored epinephrine solutions and when they have been applying the medication for prolonged periods of time.

Epinephrine drugs can produce a hypersensitivity blepharoconjunctivitis, including lid erythema, lichenification, and conjunctival chemosis, vascular engorgement, and follicular hypertrophy ( Fig. 24-3 ). Occasionally this is accompanied by mild iridocyclitis and subepithelial infiltration of the cornea. Some patients who develop hypersensitivity blepharoconjunctivitis with epinephrine treatment can tolerate dipivefrin indefinitely. Some have cross-reactivity. Other patients can continue epinephrine treatment if a weak topical corticosteroid such as 1% medrysone is administered concurrently. Medrysone is unlikely to elevate IOP, even with long-term administration.

Feb 12, 2019 | Posted by in OPHTHALMOLOGY | Comments Off on The adrenergic system and adrenergic agonists

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