Catecholamine-containing nerve fibers are found in their greatest concentrations in the iris dilator muscle and ciliary processes.⁶ Their numbers are much reduced in the rat iris after superior cervical ganglionectomy, but some fibers remain.⁷ A limited number of adrenergic fibers have been found in the iris sphincter muscle.⁸ In chickens and rabbits, the retinal blood vessels have a sympathetic innervation from the superior cervical ganglion.^9,10 This innervation is much more extensive in arterioles than venules and falls off rapidly with increasing distance from the optic nerve head. Some, but not all, investigators have shown catecholamine-containing fibers in the retinal blood vessels of human eyes.^11,12 Electrical stimulation of the superior cervical ganglion causes a 58% to 70% reduction in the blood flow to the choroid of the rabbit,¹³ suggesting that this structure, too, has a sympathetic nervous system innervation.

TRANSMITTER SYNTHESIS, RELEASE, AND INACTIVATION

Norepinephrine is synthesized from tyrosine by the sequential actions of tyrosine hydroxylase, dopa decarboxylase and dopamine-beta-hydroxylase. Tyrosine hydroxylase is the rate limiting enzyme. Norepinephrine is stored in granular vesicles located in varicosities in the terminals of sympathetic neurons. Release of norepinephrine may not occur with each action potential. Rather, release is partially a function of the frequency of action potentials.¹⁴ Increasing this frequency facilitates norepinephrine release. Dopamine-beta-hydroxylase is released along with norepinephrine. Both have been demonstrated in iris neurons¹⁵ and in the aqueous humor.¹⁶ Cervical sympathetic stimulation increases their levels. Rat iris contains phenylethanolamine N-methyltransferase and can, therefore, synthesize epinephrine; this synthesis is reduced but not prevented by superior cervical ganglionectomy or by prior treatment with the sympathetic neurotoxic agent, 6-hydroxydopamine.¹⁷ Rat retina is also capable of synthesizing epinephrine.¹⁸

Released norepinephrine is inactivated primarily by reuptake into the nerve terminals that release it. Reuptake results either in return to a storage vesicle or to degradation by intraneuronal monamine oxidase (MAO). There are at least two forms of MAO, types A and B, both of which have been identified in the iris-ciliary body of rabbits.¹⁹ Neuronal reuptake sites exhibit a feedback mechanism. As more norepinephrine is released, the number of reuptake sites increases and as less norepinephrine is released, the number of reuptake sites decreases.²⁰ Smaller quantities of released norepinephrine are inactivated by being absorbed into the postsynatic neuron or smooth muscle fiber where they are destroyed by MAO or catechol-O-methyl-transferase (COMT). The remainder of released norepinephrine diffuses away into the circulation.

Close synaptic contact with a histologically identifiable area of specialized muscle membrane, as occurs in cholinergic striated muscle fibers, does not occur in the adrenergic system.^21,22 However, the separation between neuron terminal and muscle fiber found in the iris, 15 to 20 nm, is less than that found at most sympathetic innervations. Released norepinephrine stimulates a muscle bundle, rather than a single muscle fiber, not only because it can diffuse over a larger area but also because there are low-resistance interconnections between adjacent muscle fiber membranes, called gap junctions, that are approximately 1 μm in size.²³

RECEPTORS

At pharmacologic doses, drugs may act at nonphysiologic sites as well as at physiologic receptors. Multiple types of adrenergic receptors have been identified. Initially, these were classified as alpha and beta.²⁴ Subsequently, these have been subdivided.²⁵ There are at least two types of alpha-adrenergic receptors, alpha-1 and alpha-2; norepinephrine stimulates both types. Alpha-1 receptors were believed to be purely postjunctional (e.g., on smooth muscle membranes) and alpha-2 receptors were believed to be purely prejunctional (e.g., on norepinephrine-releasing neuron terminals). However, this distinction has not held up. Current terminology refers to receptors by type (e.g., alpha-1 or alpha-2) and does not assume location. Other receptors that may be found on norepinephrine-releasing neurons include beta-adrenergic, dopaminergic, nicotinic, muscarinic, histaminergic, serotinergic, angiotensinergic, opiatergic, prostaglandinergic, GABAergic and adenosinergic. Receptor subtype does not determine function. For example, stimulation of beta-2 adrenergic prejunctional receptors may enhance or inhibit norepinephrine release.²⁶ There is no a priori way of knowing which.²⁷

Adrenergic receptors are polypeptides of molecular weights between 64,000 and 80,000 daltons. They are glycoproteins and have structural similarities to rhodopsin.²⁸ The receptors are coupled to guanine nucleotide regulatory proteins which, in turn, are linked to various cytoplasmic effector enzymes. The guanine nucleotide regulatory protein is a tripeptide, consisting of alpha, beta and gamma subunits, activated when the adrenergic receptor is stimulated by the binding of a GTP molecule. The activated protein then dissociates into subunits of one or two of its peptide chains. One of these subunits activates the effector enzyme while the other subunit(s) activates or inhibits other enzymes,²⁹ resulting in an enhanced or reduced response. Alpha receptors do not seem to elevate adenyl cyclase activity but alter calcium levels and may cause hydrolysis of polyphosphoinositides. Polyphosphoinositides, in turn, may generate one or two secondary messengers, diglycerol and inositol triphosphate. Alpha-2 receptors often reduce adenyl cyclase activity.³⁰ Both alpha-1 and alpha-2 receptors are believed to act primarily through alterations in calcium ion fluxes.³¹ Two subtypes of alpha-1 receptors can be identified pharmacologically, alpha-1A and alpha-1B, and a third and fourth subtype, alpha-1C and alpha-1D, may exist.^32–35 Alpha-1A does not stimulate inositol triphosphate formation but causes influx of extracellular calcium. Alpha-1B stimulates inositol triphosphate and releases intracellular calcium. Thus both subtypes of alpha-1 receptor would raise intracellular levels of calcium but only the alpha-1A subtype would be dependent on extracellular calcium. In contrast to alpha receptors, beta-1 and beta-2 adrenergic receptors activate a guanine nucleotide regulatory protein that, in turn, activates membrane-bound adenyl cyclase. The activated adenyl cyclase catalyzes the formation of the intracellular second messenger, cyclic AMP, from ATP.³⁶

Before prejunctional receptors were identified, norepinephrine release was believed to be dependent only on the rate of axon stimulation. However, when stimulation of prejunctional alpha-2 receptors was found to inhibit norepinephrine release, the importance of this feedback mechanism was quickly appreciated. Alpha-2 receptors were subsequently identified in postjunctional neurons in the central nervous system. In general, drugs do not distinguish between pre- and postjunctional alpha-2 receptors. However, drugs do distinguish between different alpha-2 receptors and a further subdivision has been made (e.g., alpha-2A, alpha-2B,^37,38 alpha-2C and alpha-2D).^39,40 Alpha-2 receptor subtypes have been cloned and sequenced. The alpha-2A receptor resides on human chromosome 10, so an alternative name was given, alpha 2-C10; for similar reasons alpha-2B is also known as alpha 2-C2 and alpha-2C as alpha 2-C4. Alpha-2C receptors have been found in human retinoblastoma cells.⁴¹ Prazosin, imiloxan, and chlorpromazine bind preferentially to alpha-2B receptors rather than to alpha-2A receptors; prazosin and chlorpromazine, but not imiloxan, bind readily with alpha-1 receptors as well. Rauwolscine binds equally well to alpha-2A and -2B receptors, but not to alpha-1 receptors. Oxymetazoline binds preferentially to alpha-2A receptors but not to alpha-2B or alpha-1 receptors.⁴² To further confuse a complex situation, clonidine, which has been considered an alpha-2 agonist, has been found to stimulate another type of receptor as well. This second type of receptor is activated by imidazoline but not by catecholamine.⁴³

SUBSENSITIVITY AND SUPERSENSITIVITY

The number of adrenergic receptor binding sites changes, with time, inversely to the amount of released neurotransmitter.⁴⁴ A prolonged increase in norepinephrine release results in receptor sites becoming desensitized by a number of mechanisms (e.g., by becoming phosphorylated), which changes their structure, or by becoming sequestered (i.e., removed from the cell membrane surface and placed into vesicles).⁴⁵ For example, the agonist-occupied beta-2 receptor can be phosphorylated by an enzyme called beta-adrenergic receptor kinase; phosphorylation results in decreased coupling to the guanine regulatory protein.⁴⁶ Sensitivity to an agonist can also be altered by changes in other receptors. For example, long-term activation of CNS beta receptors will increase the number of alpha-2 receptors.⁴⁷ Different subtypes of alpha-2 receptors undergo different desensitizations to agonists that may explain their evolutionary significance (i.e., to meet differing needs for down-regulation).⁴⁸

Supersensitivity to an adrenergic transmitter can be produced by its absence. Removal of the rat superior cervical ganglion results in decreased levels of released catecholamines.⁴⁹ Simultaneously, the degenerating iris nerve terminals, unable to release norepinephrine, gradually increase their content of catecholamines to a maximum of 25% above baseline at 12 hours, followed by a decline to complete disappearance at 24 hours. Iris supersensitivity to alpha-adrenergic agonists occurs within 2 weeks.⁵⁰ Supersensitivity means that a lower agonist concentration is needed to produce a given submaximal or maximal response, a so-called “shift to the left” of the dose-responsecurve. The magnitude of the maximum response produced may or may not also be increased in the supersensitive state depending on the tissue and the response being measured.

Supersensitivity of skeletal muscle is associated with a marked increase in the number of nicotinic cholinergic receptors. However, supersensitivity in adrenergically innervated smooth muscle is not associated with a dramatic increase in the number of alpha receptors. Several weeks after superior cervical ganglionectomy the rabbit iris exhibits a small decrease in the total number of alpha receptors, presumably due to loss of the prejunctional receptors on the nerve endings.⁵¹ However, there may be small increases in the numbers of postjunctional alpha-2 and beta receptors.⁵² The binding affinities of the alpha and beta receptors remain unchanged. Other mechanisms are needed to explain alpha-adrenergic supersensitivity.⁵³ One is the absence of a neuronal reuptake mechanism that can inactivate the agonist. While this has been claimed to be the primary, or exclusive, cause of iris supersensitivity in rats,⁵⁴ it does not explain the iris supersensitivity that occurs after interruption of the neuronal pathway proximal to the superior cervical ganglion. Such a preganglionic interruption leaves the postganglionic neurons, and their reuptake mechanisms, intact. A second cause of supersensitivity may be an alteration of the muscle fiber's cell membrane not involving the number of receptors. The transmembrane resting potential may be reduced or enzyme kinetics may be enhanced. For example, an increase in norepinephrine-stimulated phosphatidylinositol 4, 5-diphosphate breakdown occurs in the supersensitive rabbit iris dilator muscle.

The most prominent activities of alpha-adrenergic drugs are listed in Table 1.^55,56

TABLE ONE. Most Prominent Activities of Alpha-Adrenergic Drugs

DIRECT AGONISTS

Norepinephrine is approximately equipotent as an alpha-1A, alpha-1B, and alpha-2 agonist. Phenylephrine is primarily an alpha-1 agonist⁵⁷ with both alpha-1A and alpha-1B activity. At eqimolar concentrations phenylephrine has 15% of norepinephrine's alpha-1 potency but less than 1% of norepinephrine's alpha-2 potency.⁵⁸ At high concentrations phenylephrine can stimulate beta receptors and produce a rise in cAMP.⁵⁹ The neuronal reuptake mechanism is less sensitive to phenylephrine than to naturally occurring catecholamines,⁶⁰ but once phenylephrine enters a neuron, it can reduce catecholamine synthesis by up to 50%.⁶¹ Phenylephrine can be converted to epinephrine by hydroxylation in the liver.⁶² Epinephrine is more than 600 times as potent as norepinephrine at alpha-2 receptors and is also a potent alpha-1 agonist.⁵⁸ Methoxamine is a selective alpha-1A agonist not metabolized by monoamine oxidase. Apraclonidine and clonidine are preferential alpha-2A agonists; however, at higher concentrations, alpha-1 effects begin to appear. Clonidine is also an adenosine antagonist.⁶³ Naphazoline is a preferential alpha-2 agonist. Oxymetazoline, like apraclonidine, binds relatively indiscriminately toalpha-2 receptor subtypes but, especially at low concentrations, is a relatively specific alpha-2A agonist.

INDIRECT AGONISTS

Amphetamines act by causing release of stored monoamines (e.g., norepinephrine, dopamine and serotinin) from synaptic vesicles and by inhibiting their reuptake as well.^64,65 They may also be direct alpha-2 antagonists.⁶⁶

Cocaine inhibits the reuptake of monoamines.^67–69 Cocaine is benzoylmethylecgonine, a naturally occurring alkaloid accounting for 0.7% to 1.5% of the total weight of coca leaves. Cocaine is inactivated in many strains of rabbits by the serum enzyme, cocainesterase.⁷⁰ In humans, cocaine is hydrolized by serum cholinesterase⁷¹ and hepatic esterases⁷²; smaller amounts are N-demethylated in the liver.⁷³ Cocaine is not metabolized in the plasma of patients with cholinesterase deficiency who have prolonged apnea to succinylcholine.⁷⁴ When 1.5 mg/kg is applied intranasally in subjects with normal cholinesterase activity, peak plasma levels occur in 15 to 60 minutes and cocaine is cleared from the serum with a half-life of 3.8 hours.⁷⁵ Cocaine is relatively stable at acidic pH's but undergoes spontaneous hydrolysis as the pH is raised.⁷⁶ Solutions below pH 4 appeared relatively stable when stored at 25 °C for 45 days, while increasingly rapid hydrolysis occurred as the pH was raised from 5.5: phosphate buffer accelerates hydrolysis while carbonate buffer does not.^77,78

Cocaine is both a local anesthetic and an indirect adrenergic agonist. The local anesthetic activity correlates well with cocaine's ability to stabilize neuronal cell membranes by inhibiting sodium movement through ion channels.⁷⁹ The indirect adrenergic effect results from cocaine's competing with monoamines (e.g., norepinephrine, dopamine and serotonin) for the reuptake mechanism of peripheral sympathetic neurons.^68,69

Tyramine is actively taken up by nerve endings and causes release of stored norepinephrine.

DIRECT ANTAGONISTS

Dapiprazole, hydralazine, prazosin, and thymoxamine are primarily alpha-1 antagonists. For example, thymoxamine is 100 times as potent at alpha-1 receptors than it is at alpha-2 receptors. Phenoxybenzamine and phentolamine are relatively nonselective alpha antagonists. Rauwolsine and yohimbine are primarily alpha-2 antagonists.

INDIRECT ANTAGONISTS

Guanethidine both produces release of stored norepinephrine into the cytoplasm, where it is destroyed, and prevents norepinephrine reuptake. Reserpine destroys neuronal storage vesicles. 6-Hydroxydopamine destroys the adrenergic nerve endings that take it up.

CORNEA

Alpha-1 receptors have been identified in cell cultures of rabbit, bovine, and human corneal endothelium.⁸⁰ Their physiologic role, and the effects of their pharmacologic stimulation, are not known.

LACRIMAL SECRETION

Alpha-1 agonists, such as phenylephrine and norepinephrine, stimulate protein secretion by lacrimal gland acini in the rat; alpha-1 antagonists inhibit this effect.⁸¹ Drugs that are primarily alpha-2 or beta agonists have no stimulatory effect.

INTRAOCULAR PRESSURE

Unilateral sympathectomy proximal to the cervical ganglion reduces the ipsilateral aqueous humor norepinephrine level and prevents the dark-induced elevation in intraocular pressure found in many mammalian species.^82–85 Melatonin and cAMP levels in the aqueous humor do not appear related to the phenomenon.⁸⁶ The circadian elevation in intraocular pressure can be blocked by an alpha-1 antagonist, prazosin, but not by the alpha-2 antagonist, rauwolscine, or by the nonselective beta blocker, timolol.⁸⁷ Treatment with apraclonidine, an alpha-2 agonist, reduces aqueous humor norepinephrine. This has led to speculation that stimulation of prejunctional alpha-2 receptors might reduce norepinephrine release and blunt the circadian elevation in intraocular pressure.

Oxymetazoline, a relatively selectively alpha-2A agonist is used in low concentrations (e.g., 0.001% to 0.05%) as a conjunctival vasoconstrictor; at these concentrations it does not lower the intraocular pressure in man.⁸⁸ However, at concentrations of 0.1% to 1.5%, it minimumly but significantly lowers the intraocular pressure of normal rabbits and monkeys and, markedly, of glaucomatous monkeys.⁸⁹ This reduction in pressure is associated with a decreased aqueous humor flow rate and an increased uveoscleral outflow.

Topical norepinephrine causes an initial intraocular pressure elevation that is more marked in rabbits with prior superior cervical ganglionectomy.⁹⁰ The intraocular pressure returns to baseline in about 1 hour and then continues to fall, reaching a minimum about 3 to 6 hours after administration.^91,92 The early hypertensive effect appears to be the result of extraocular muscle stimulation and co-contraction, because disinserting the extraocular muscles prevents it.⁹³ This hypertensive response can be prevented by prior administration of the alpha-1 antagonist, phenoxybenzamine. Alpha-2 agonists prolong the rabbit hypotensive phase while alpha-2 antagonists (e.g., yohimbine) prevent it.⁹⁴ The increase in trabecular outflow facility found in monkeys and rabbits after topical, intracameral, or intravitreal injection of norepinephrine or epinephrine appears to be mediated by beta-2 receptors.^95,96 Phenylephrine will not produce increased outflow facility. Pretreatment with timolol prevents the norepinephrine induced increase in outflow facility while pretreatment with the relatively specific beta-1 antagonist, betaxolol, does not. Norepinephrine reduces aqueous humor formation while epinephrine has little effect and phenylephrine has none; none of the three drugs affects episcleral venous pressure.⁹⁷

Clonidine, an alpha-2 agonist and also an adenosine antagonist,⁶³ produces variable transient effects on intraocular pressure in cats, depending on the route of administration.⁹⁸ Unilateral topical application of clonidine produces a slight decrease in blood pressure but a marked bilateral intraocular pressure reduction; clonidine levels in the contralateral eye are insufficient to explain this reduction.⁹⁹ When injected into the external carotid artery, clonidine produces a transient decrease in intraocular pressure followed by an increase associated with contraction of the eyelids and extraocular muscles.¹⁰⁰ This elevation lasts 5 to 10 minutes, followed by a prolonged hypotension. When injected into the vertebral artery or intravenously, the intraocular pressure is reduced. Chronic superior cervical ganglionectomy in cats produces an enhanced bilateral hypotensive response to intravenous clonidine.¹⁰¹ These results demonstrate that clonidine produces ocular hypotension through central nervous system mechanisms as well as ocular mechanisms, such as anterior segment vasocontriction and aqueous humor secretion reduction.¹⁰² In rabbits, ventriculocisternal brain perfusion with clonidine results in reduced intraocular pressure. However, a simultaneous lowering of systemic systolic and diastolic blood pressure occurs, suggesting that, in this circumstance, ocular hypotension is largely a secondary drug effect.¹⁰³

In rabbits, apraclonidine 0.5% given locally reduces intraocular pressure significantly 4 to 24 hours after treatment. When drops are given unilaterally 1 hour before and immediately after bilateral iris laser treatment, an intraocular pressure elevation fails to occur in treated eyes.¹⁰⁴ Aqueous humor protein concentrations, but not prostaglandin E₂ concentrations, are reduced in apraclonidine treated eyes; phenylephrine 5% topically does not reduce aqueous humor protein elevations, which suggests that this apraclonidine effect is alpha-2 receptor mediated.

IRIS

The rabbit iris dilator muscle is stimulated by alpha-1 adrenergic agonists. The result is mydriasis. In vitro, strips of rabbit dilator muscle contract to norepinephrine, an alpha-1A and alpha-1B agonist, but not to methoxamine, a selective alpha-1A agonist.¹⁰⁵ This suggests that alpha-1B receptors predominate. However, in vivo, methoxamine produces mydriasis. Norepinephrine increases the turnover of iris phosphatidic acid and phosphatidylinositol.¹⁰⁶ Inhibition of rabbit monoamine oxidase causes an increased iris dilation from topical norepinephrine. Eight days after a single unilateral injection of pargyline, the two pupils have equal diameters but the treated iris will have a nearly three-fold greater response to a topical 1.5% norepinephrine solution.¹⁰⁷ However, the pupil response to methoxamine, a direct-acting selective alpha-1A agonist not metabolized by monoamine oxidase, remains unchanged. Alpha, but not beta, antagonists prevent mydriasis.¹⁰⁸

Reserpine, a sympatholylic agent that destroys storage vesicles, injected intraperitoneally, 3 mg/kg, is as effective as superior cervical ganglionectomy in producing miosis and markedly reducing rat iris catecholamines.⁵⁰ By 6 hours, all iris catecholamines have completely disappeared.

Amphetamine or cocaine, adminstered systemically, produces pupil dilation. Amphetamine acts both by causing release of stored monoamines from synaptic terminals and by inhibiting their reuptake as well.⁶⁵ Amphetamine, 10 mg/kg, causes a 65% increase in extraneuronal catecholamines within 30 minutes, followed by a gradual reduction in intraneural catecholamines to 30% of baseline levels by 2 hours. Cocaine inhibits the reuptake of a number of monoamines.⁶⁷ Cocaine, 10 mg/kg, causes a significant (100%) increase in extraneuronal iris catecholamines within 30 minutes but has no effect on intraneuronal levels. By 2 hours postinjection, cocaine's effect on extraneuronal catecholamines is gone. Both amphetamine and cocaine induced elevations in extraneuronal catecholamines correlate well with the pupil dilation. Neither cocaine nor amphetamine produces pupil dilation in surgically denervated irides. However, imipramine, a drug that inhibits norepinephrine reuptake, does produce dilation of the denervated rat iris due to its potent anticholinergic (antimuscarinic) sphincter effect.^109,110

Rabbits kept in continuous light for 1 week maintain a miosis that is, presumably, in part due to a sustained reduced sympathetic stimulation of the dilator muscle. There is a resultant supersensitivity to the mydriatic effects of epinephrine and norepinephrine.¹¹¹ Interestingly, however, constant dark, with resultant mydriasis, does not result in subsensitivity to these agonists. The supersensitive surgically denervated rabbit iris responds to norepinephrine with an exaggerated increase in phosphatidic acid and phosphatidylinositol production.¹⁰⁶ Repeated topical application of epinephrine results in reduced dilation and a reduction in induced inositol triphosphate and diacylglycerol formation.¹¹²

Amphibian responses may differ from those of mammals. In frogs, topical application of beta-1 or beta-2 agonists produces prolonged mydriasis. Beta blockers produce miosis. Alpha agonists (e.g., phenylephrine) and alpha antagonists (e.g., phenoxybenzamine) have some effect on pupil diameter but much less so than beta-adrenergic drugs.¹¹³

Alpha-2 agonists inhibit the release of norepinephrine from sympathetic neurons innervating the iris dilator muscle.¹¹⁴ The result should be miosis. In rats and cats, alpha-2 agonists may induce a partial mydriasis by a central nervous system effect.^115–117 Alpha-2 stimulation of the dorsal midbrain area (Edinger-Westphal nucleus) inhibits the parasympathetic innervation of the iris sphincter muscle. In cats, a dose related mydriasis could be achieved by direct injection of small amounts, 0.5 mg, of amphetamine into the third ventricle; this too was associated with inhibition of ciliary nerve activity.¹¹⁸

Iris stromal pigmentation occurs in early life and is dependent on an intact adrenergic innervation. However, melanin formation in the iris pigment epithelium is not dependent on the sympathetic nervous system. The hypopigmentation of iris stromal melanocytes, produced by denervation, can be mimicked pharmacologically in newborn rabbits by topically applying the alpha-adrenergic antagonist, thymoxamine, 0.5%, three times a day for 12 weeks.¹¹⁹ Similar application of the beta blocker, timolol 0.5%, is ineffective.

Phenylephrine oxazolidine is a more lypophilic prodrug of phenylephrine and better penetrates the corneal epithelium.^119a Topical application of phenylephrine oxazolidine to rabbits will produce as much mydriasis as a phenylephrine HCl solution 10 times as concentrated. Unfortunately, the prodrug is unstable in water and must be formulated as to suspension in sesame oil. A pivalic acid prodrug of phenylephrine is more stable and also about 10 times as active as phenylephrine; the unmetabolized prodrug itself may have significant intrinsic adrenergic activity.¹²⁰

CILIARY BODY

Phenylephrine causes an acute localized constriction in the arterioles supplying the ciliary processes^120a and a transient increase in prostaglandin synthesis and release.^121,122 However, after 7 weeks of treatment, rabbit arterioles constrict only 20% compared to that initially. Epinephrine also reduces blood flow to the rabbit iris and ciliary processes, but isoproterenol, a beta agonist without alpha-adrenergic activity has no effect.¹²³ These results suggest that blood flow to the ciliary processes is controlled by alpha-adrenergic receptors. Binding studies show that iris-ciliary body alpha receptors have characteristics typical of alpha-1 receptors (i.e., their order of binding potency is epinephrine < norepinephrine < isoproterenol).¹²⁴ In addition, rabbit ciliary body contains many alpha-2A receptors.¹²⁵ Competitive binding studies with iodoclonidine are consistent with those shown by other alpha-2A receptors (i.e., the sequence of binding affinities is oxymetazoline < chlorpromaÜbk 4Ý Üol 0Ý zine < Ümh- 15Ý< prazosine).

RETINA

Alpha-1 and alpha-2 adrenergic binding sites and norepinephrine have been identified in bovine retinal blood vessels.¹²⁶ The norepinephrine is assumedto be in sympathetic axon terminals because its level becomes almost undetectable following superior cervical ganglionectomy.^127–131 There are norepinephrine accumulating cells in the neuroretina, but these cells do not synthesize the transmitter.¹³² However, the enzyme for epinephrine synthesis, phenylethanolamine-N-methyltransferase, has been identified in a subpopulation of rat amacrine cells.¹³³ Neuroretina contains alpha-2 receptors almost to the exclusion of alpha-1 receptors.^134,135

LIDS

Stimulation of the sympathetically innervated smooth muscle fibers causes lid elevation. Ten normal subjects had unilateral application of 2.5% phenylephrine, 10% cocaine, 1% hydroxyamphetamine and 1% apraclonidine.¹³⁶ At least 24 hours passed between testing each drug. Two drops of each medication were placed in the eye, separated by 10 seconds. Photographs were taken at 1, 3, 5, 10, 15, 30, and 60 minutes. The onset of palpebral fissure widening began soonest with phenylephrine but its duration was the shortest. Hydroxyamphetamine took the longest to reach its maximum effect, 20 to 25 minutes. The mean maximum effect was approximately 1.5 mm and occurred between 10 to 15 minutes after application. The effect began to decline by the 20th minute. By 1 hour, approximately 0.7 mm of widening remained. There was no significant difference in the maximum effect of any of the four drugs.

Naphazoline, 0.1%, a preferential alpha-2 agonist with some alpha-1 activity, given topically, elevates the upper lid, presumably due to the alpha-1 stimulatory effect on Müller's muscle.¹³⁷ However, continued use several times a day for several weeks results in tolerance and a reduced effect. The acute lid effect lasts 2 hours and begins as soon as 5 minutes after instillation. Naphazoline drops also produce conjunctival vasoconstriction and a slight, but statistically significant, pupil dilation (median pupil diameter predrop is 4 mm, and 30 minutes postdrop is 4.5 mm); there is no significant change in intraocular pressure. When a single drop of apraclonidine, 1% is applied, lid retraction is maximum between 1 and 3 hours after instillation.¹³⁸

Thymoxamine, an alpha-1 antagonist, topically¹³⁹ and systemically,¹⁴⁰ can cause paresis of the adrenergically innervated Müller's muscle of the upper lid; this effect could be valuable in treating lid retraction. Guanethidine depletes adrenergic stores and has been used to treat thyroid disease-related lid retraction.¹⁴¹ Unfortunately, chronic use results in conjunctival hyperemia, irritation, and even scarring.¹⁴²

CORNEA

Alpha receptors have been demonstrated in the cultures of epithelium of intact corneas of humans.¹⁴³ The binding of H³-prazosin, an alpha-1 antagonist, was competitively inhibited by the agonists, phenylephrine and norepinephrine; the alpha agonist, methoxamine, stimulated phosphatidylinositol 4, 5-bisphosphate hydrolysis. The physiologic role of these receptors is not known.

LACRIMAL FLUID

Norepinephrine and epinephrine have been detected in human lacrimal fluid.¹⁴⁴ When reflex lacrimal fluid, produced by stimulation with a cut onion, was assayed in 17 subjects, 9 had both detectable norepinephrine, mean ± standard deviation 4.4 ± 3.0 nanomol per liter, and detectable epinephrine,3.7 ± 1.8 nanomol per liter. One subject had only detectable epinephrine and the remaining 7 had neither agonist detectable.¹⁴⁵

CONJUNCTIVA

Phenylephrine, in concentrations of 0.12% and 0.25%, has been used as a conjunctival vasoconstrictor. Loss of efficacy with continued use has been reported.¹⁴⁶ A single drop of phenylephrine 2.5% causes reduction in conjunctival oxygen.¹⁴⁷ In 10 subjects, this effect peaked 10 minutes after instillation and lasted about 80 minutes. Anoxia and sickling may have contributed to the formation of saccular venous dilations in a sickle cell patient treated with phenylephrine 1%.¹⁴⁸ Apraclonidine 1%, one drop to 10 normal subjects significantly reduced conjunctival oxygen tension by 76% at 1 hour and 56% at 3 hours.¹⁴⁹ The following are the concentrations of alpha-2 agonists that one study found produced maximum conjunctival blood vessel constriction (by topical application): 0.02% naphazoline, 0.025% oxymetazoline, and 0.05% tetrahydrozoline. In another study, hyperemia was induced by a 0.0075% histamine solution.¹⁵⁰ Ten minutes later, there was a partial reduction in vasodilation using a drop of 0.001% oxymetazoline; oxymetazoline 0.01% was more effective but virtually no additional improvement was found using 0.05%. This last concentration produced no significant effect on intraocular pressure, pupillary diameter, blood pressure or pulse. Commercial preparations of 0.02% naphazoline and 0.05% tetrahydrozoline have been compared for their blanching effects in normal subject using photographs.¹⁵¹ Single drops produced significant whitening for up to 8 hours; however, the degree of whitening was significantly greater for naphazoline at 1, 3, and 5 hours. After 9 days of treatment, eight times a day, the eyes were reevaluated. Naphazoline-treated eyes, but not tetrahydrozoline-treated eyes, were significantly whiter 5 minutes after the last drop than at pretreatment baseline, and the vasoconstriction from naphazoline remained significant for 4 hours. Neither drug exhibited rebound hyperemia when evaluated at the conclusion of treatment or 24 hours thereafter.

AQUEOUS HUMOR

Norepinephrine is detectable in human aqueous humor.¹⁵² In 6 normotensive patients undergoing cataract surgery, the mean ± standard deviation norepinephrine level was 7.18 ± 4.43 micromoles per liter. In 4 untreated glaucoma patients undergoing trabeculotomy, the level was 3.44 ± 0.97 micromoles per liter and in 4 patients on prior glaucoma medications who were undergoing trabeculectomy, the level was 2.53 ± 0.63 micromoles per liter. When norepinephrine is released by sympathetic nerve endings, so too is the synthesizing enzyme, dopamine-beta-hydroxylase. Dopaminebeta-hydroxylase activity could be detected in the aqueous humor of 8 of 8 patients undergoing cataract surgery.¹⁵³

Norepinephrine 2%, 3%, and 4% eye drops reduces the intraocular pressure in patients with ocular hypertension and glaucoma.^154–156 This effect has been maintained in studies lasting as long as 20 weeks. However, the drug is relatively unstable in solution.

Phenylephrine eye drops usually have no effect on, or slightly reduce, intraocular pressure, whether or not^157–160 open-angle glaucoma is present. Exceptions have been reported.^161,162 One study reported a 20% incidence of phenylephrine-induced intraocular pressure elevations of 6 to 23 mmHg. Transient elevations in intraocular pressure of more than 20 mmHg have been reported despite both open angles and prior administration of muscarinic agonists.¹⁵⁷ The relationship between pigment release from the uveal tissues and these transient elevations is not always clear. Topical application of phenylephrine can result in liberation of pigment into the aqueous humor,^163,164 especially in patients wth pigmentary and pseudoexfoliative glaucoma. It is assumed that the associated transient pressure elevations are due to this pigment blocking the trabecular meshwork.¹⁶⁵ A retrospective study¹⁶⁶ found a 43% incidence of intraocular pressure elevations in normotensive patients with pseudoexfoliation and a 67% incidence of intraocular pressure elevations in ocular hypertensive patients with pseudoexfoliation who received phenylephrine drops. However, there appeared to be no strict correlation between either the use of phenylephrine and the release of pigment or in the release of pigment and an elevation in intraocular pressure. One study¹⁶⁷ consisted of 31 patients with pigmentary dispersion who had chronic ocular hypertension (defined as pigmented open-angles, intraocular pressures of greater than or equal to 24 mmHg and tonographic C values less than or equal to 0.15) and 18 patients with pigmentary dispersion without ocular hypertension. Phenylephrine, 10%, one drop every 5 minutes, was applied three times unilaterally. In 55%of the patients with pigmentary dispersion with chronic ocular hypertension and 78% of those with pigmentary dispersion without ocular hypertension there was moderate to marked pigment liberation. Of the 10 patients with chronic hypertension and marked pigment release from phenylephrine, only two developed a pressure rise of more than 2 mmHg. And there was no intraocular pressure rise, but rather a reduction in intraocular pressure, in the subgroup of normotensive pigmentary dispersion patients who had marked pigment release.

While phenylephrine eye drops usually have no significant effect on the intraocular pressure or the trabecular resistance, there are conflicting reports as to the drug's effect on aqueous humor flow rates. No effect has been claimed.¹⁶⁸ Rapid onset of increased aqueous humor flow of more than 200%¹⁶⁹ has also been reported. Another study¹⁷⁰ found mean ± standard deviation increases in aqueous humor flow of 131% ± 72% and 121% ± 92% at 1 and 2 hours, respectively, after phenylephrine drops without any increase in intraocular pressure. A biphasic response, with an initial increase in aqueous humor flow followed by a reduction below baseline levels at 4 hours, is a third type of pattern reported.

The existence of both central and peripheral effects from clonidine on alpha-2 receptors, and to a lesser degree, alpha-1 receptors, confounds simple interpretations. Topical application of single and multiple drops of clonidine 0.1% to 0.5% to one eye lowers the intraocular pressure in the treated eye and in the contralateral eye. The systemic blood pressure also is reduced.^171–174 In a randomized placebo-controlled study of normotensive human eyes, unilateral topical application of clonidine 0.125% was associated with a bilateral reduction in intraocular pressure, aqueous humor flow and miosis, all of which were more marked in the treated eye; the systolic blood pressure was significantly reduced.¹⁷⁵ Reducing the drop size of clonidine permitted the ocular hypotensive effectwithout a lowering of the blood pressure, but this, too, was only a single drop experiment.¹⁷⁶

Apraclonidine (p-aminoclonidine hydrochloride) has been used clinically instead of clonidine, because the former is less lipophilic and, therefore, less likely to penetrate the brain. This avoids central nervous system-mediated cardiovascular effects. When a single drop of apraclonidine 0.5% was placed unilaterally, there was no contralateral intraocular pressure effect 2, 5, and 8 hours postapplication nor were there significant effects on pupillary diameter and palpebral fissure width¹⁷⁷; single bilateral drops did not significantly affect blood pressure or exercise induced heart rate. A single drop of unilateral apraclonidine 1% did produce a significant contralateral reduction in mean intraocular pressure in normotensive volunteers. This reduction was 40% that of the treated eye. Neither eye showed a tonographic alteration in outflow facility.¹⁷⁸ In addition, the treated eye usually exhibited evidence of alpha-1 adrenergic stimulation such as mydriasis, lid retraction, and conjunctival blanching. Apraclonidine, 1.5%, did not significantly affect the systemic blood pressure of normal volunteers but there was a significant reduction in heart rate after a stress test. The plasma concentrations of apraclonidine, 2, 5 and 8 hours after single or bilateral drops, ranged from undetectable (<0.2 ng/ml) to 3 ng/ml; the mean levels at these three time intervals were 0.45, 0.55, and 0.60 ng/ml after bilateral drops and 0.60, 0.65, and 0.20 ng/ml after unilateral drops.

Apraclonidine, in contradistinction to epinephrine and timolol, reduces fluorometrically measured aqueous humor flow both at night and during the day.¹⁷⁹ Apraclonidine 1%, one drop to one eye, significantly reduces aqueous humor flow, compared to the contralateral control eye, by the second hour after instillation, the effect continuing until at least 8 hours postinstillation.¹³⁸ Maximum comparative decrease in flow, approximately 35%, was achieved 4 hours postinstillation. However, apraclonidine's primary hypotensive effect may be through an increase in outflow facility. A marked increase in outflow facility can be detected by fluorophotometric techniques but not by tonography.

In normotensive volunteers treated with apraclonidine 1% eye drops, bilaterally, two times a day for 1 month, the mean ± standard deviation intraocular pressure fell in 5 hours from 17.5 ± 3.9 mmHg to 10.7 ± 3.4 mmHg and remained at approximately 13 mmHg for the 1 to 4 weeks comprising the test period.¹⁸⁰ There were no significant differences from baseline at any time in mean systolic blood pressure and only on day 15, when there was a 6% change, was there a significant reduction in diastolic blood pressure. The only significant reduction in pulse rate was on day 8, 6 ± 11 beats per minute.

In a masked, crossover dose-response study of 1 week of therapy, subjects with elevated intraocular pressures were treated twice daily with placebo and 0.125%, 0.25%, and 0.5% apraclonidine.¹⁸¹ The 0.25% and 0.5% concentrations were equipotent in lowering the intraocular pressure from a mean baseline of 24.9 mmHg to 16.2 mmHg. The treated eyes demonstrated increased palpebral fissure width and mild pupil dilation; 30% of subjects reported dry nose or dry mouth. The cause of the dry nose and mouth is not clear but it is of interest that clonidine-like imidazolines are alpha-adrenergic antagonists in parotid gland cells of experimental animals.¹⁸² Another study found that raising the apraclonidine concentration to 1% did not improve the ocular hypotensive effect.¹⁸³

Patients who were on chronic bilateral topical timolol treatment for control of elevated intraocular pressures received a single unilateral apraclonidine 1% drop. It produced a significant further reduction in aqueous humor flow to 1.39 ± 0.41 μL/minute, compared to the contralateral eye's flow rate of 1.66 ± 0.38 μL/minute, and lowered intraocular pressure by an additional 1.3 mmHg.¹⁸⁴ Others have reported similar additive hypotensive effects.¹⁸⁵ Perhaps this additivity is possible because of a loss of timolol's activity with prolonged use. Thus, when normal subjects are given a single drop of timolol, there is no further decrease in aqueous humor flow rate produced by a subsequent application of apraclonidine.¹⁷⁹ When subjects with a prior history of elevated intraocular pressure and on treatment with timolol 0.5%, two times a day for a minimum of 4 weeks were treated with an additional drop two times a day of placebo, apraclonidine HCl 1% or dipivefrin HCl 0.1% in arandomized, double-masked crossover study, apraclonidine was more effective than dipivefrin in providing an initial additional hypotensive effect.¹⁸⁶ This difference provided by apraclonidine was significantly greater through the first 8 days of combined treatment but not by the end of the third week. In a retrospective study, apraclonidine 1% eye drops added to the maximum tolerated medications of patients with uncontrolled glaucoma¹⁸⁷ initially provided a variable additive effect, up to 6 mmHg, but this was gradually lost with continued treatment.

Apraclonidine blunts the acute elevation in intraocular pressure that occurs after argon laser iridotomy and trabeculoplasty.^188,189 Other alpha-2 agonists (e.g., brimonidine) are similarly effective.¹⁹⁰ Twenty-eight eyes with chronic narrow-angle glaucoma received one drop of apraclonidine or placebo 1 hour before laser iridotomy and immediately following laser treatment. Six eyes (43%) treated with placebo but none of the eyes treated with apraclonidine had intraocular pressure increases of more than 10 mmHg over baseline during the first 3 hours after laser therapy. The mean intraocular pressures of apraclonidine treated eyes were significantly lower 1, 2, and 3 hours after laser treatment (baseline, 23.6 mmHg; 1 hour, 19.9 mmHg; 2 hours, 19.7 mmHg; and 3 hours, 19.5 mmHg) versus placebo treated eyes (baseline, 20.6 mmHg; 1 hour, 25.6 mmHg; 2 hours, 28.1 mmHg; and 3 hours, 27 mmHg). Mean intraocular pressures thereafter were not significantly different. A single drop of apraclonidine 1% given immediately after laser treatment appears equally effective.¹⁹¹ However, intraocular pressure spikes can be delayed until 24 to 48 hours after laser surgery.^192,193 There is no evidence that the apraclonidine drops given at the time of the procedure have this prolonged a prophylactic effect. When both apraclonidine and pilocarpine are administered, the post-argon laser trabeculoplasty elevation in intraocular pressure is suppressed more effectively than with either agent alone¹⁹⁴; apraclonidine 1% was instilled 1 hour before and immediately after the procedure and/or pilocarpine 4% was instilled immediately after the procedure.

Apraclonidine has been used successfully to limit the intraocular pressure elevations that can occur after cataract surgery. Apraclonidine 1% is effective if two drops are given, the first 30 minutes prior to cataract extraction and the second at the completion of the procedure.^195,196 When a single apraclonidine 1% eye drop is given 1 hour prior to extracapsular cataract extractions utilizing viscoelastic materials and posterior chamber pseudophakes, it produces significantly lower intraocular pressures. Eight hours after application the mean ± standard deviation intraocular pressure is 19.8 ± 4.9 mmHg. Eyes receiving preoperative placebo or apraclonidine only at the completion of surgery, have intraocular pressures, respectively of 27.6 ± 8.3 mmHg and 32 ± 11.4 mmHg.¹⁹⁷ None of the 19 eyes receiving preoperative apraclonidine develop intraocular pressures of 30 mmHg or greater.

Apraclonidine 1% given before, on completion of, and 12 hours after combined cataract extraction and trabeculectomy, significantly lowers the intraocular pressure. Compared to untreated eyes, the mean ± standard deviation intraocular pressure at 24 hours is 23.1 ± 17.4 mmHg in placebo treated eyes and 11.6 ± 11.3 mmHg in apraclonidine treated eyes.¹⁹⁸

Apraclonidine reduces the pressure elevation that occurs in patients with ocular hypertension who are dilated and cyclopleged with muscarinic antagonists (e.g., tropicamide).¹⁹⁹

A single intravenous dose of the alpha-2 agonist, dexmedetomidine, 0.6 μg/kg, given 2 minutes before induction of anesthesia and intubation, significantly lowers intraocular pressure for the next 5 minutes, compared with placebo.²⁰⁰ Eight minutes after the injection (6 minutes postintubation), the effect is no longer significant. The increases in heart rate, systolic blood pressure, and diastolic blood pressure associated with intubation are attenuated significantly. Dexmedetomidine was given intramuscularly prior to cataract surgery performed under regional anesthesia. The intraocular pressures were monitored in the contralateral eye during surgery and in the operated eye after surgery.²⁰¹ Compared to placebo, the 1 μg/kg dose produced a significant reduction in intraocular pressure in the unoperated eye during the first 60 minutes after application and lowered the intraocular pressures of the operated eye until the time of patient discharge that same day. Dexmedetomidine also had a sedative effect which was useful.

Pargyline is a monoamine oxidase inhibitor that increases sympathetic activity by preventing the breakdown of catecholamines such as norepi-neph-rine. It has been given topically as a single 0.5% eye drop.²⁰² It failed to lower the intraocular pressure of normotensive subjects but produced a mean maximum fall in intraocular pressure of 10 chronic open-angle glaucoma subjects of 14 mmHg. This maximum effect occurred 1 hour after instillation. The intraocular pressure had returned to baseline within 5 hours. There was no obvious alteration in pupil diameter.

Guanethidine administered systemically can destroy the sympathetic system permanently, but this effect is species specific.²⁰³ Local application inhibits sympathetic neuron function by preventing catecholamine storage and release. When applied to the human eye, the drug has a mild hypotensive effect, attributed to an initial increase in aqueous humor outflow followed by a presumed reduction in aqueous humor formation.^204,205 With prolonged treatment, these effects are lost. Guanethidine has been used clinically in combination with epinephrine to enhance the latter's hypotensive action by blocking its reuptake.^206,207 In patients receiving a combination of topical guanethidine 3% and epinephrine 0.5%,^208,209 an initial intraocular pressure elevation, of about 3 mmHg, is followed by a prolonged hypotension. Unilateral treatment causes an ipsilateral mydriasis and a bilateral biphasic pressure response; the mydriasis is presumed due to an enhanced epinephrine alpha-adrenergic effect. Unfortunately, guanethidine produces local side effects of conjunctival hyperemia, ptosis, miosis, and corneal irritation.^210,211 Chronic use has resulted in conjunctival scarring.¹⁴²

6-Hydroxydopamine is taken up by adrenergic nerve endings and destroys them, creating a temporary denervation lasting several months. Subconjunctival injections of 6-hydroxydopamine have been used in anatomic studies to determine which neurons are sympathetic.²¹² Similar subconjunctival injections in glaucomatous patients have been used to create a supersensitivity to the hypotensive effects of epinephrine.^213,214

IRIS

The iris dilator muscle constricts in response to stimulation by alpha-1 adrenergic agonists, producing pupil dilation. Stimulation of neuronal prejunctional alpha-2 and muscarinic M-2 receptors inhibits axonal release of norepinephrine.²¹⁵ The maximum effect from topical phenylephrine occurs about 1 hour after application.²¹⁶ A rebound miosis has been claimed.²¹⁷ Irritation of the corneal epithelium promotes drug penetration and enhances the magnitude and rapidity of the response.²¹⁸ Even so, relatively little of the phenylephrine applied penetrates the eye, due to drug loss from spillover and lacrimal drainage. Thus, 50 μg of phenylephrinepowder, which does not produce overflow, placed into the lower fornix, elicits a dilation time-response curve equivalent to that of three drops of phenylephrine HCl 10%.²¹⁹ The reduced reflex and baseline tearing that occurs with aging, as well as increased lid laxity, have been offered as explanations why a single drop of phenylephrine, either 2.5% or 10%, produces a much greater dilation in subjects over 60 years.²¹⁸ The 10% drop produces an increased rate, but not magnitude, of dilation. Unfortunately, the efficacy of these two concentrations on magnitude has not been compared in bright ambient light. This is an important omission because dilating drops are used to facilitate intraocular examinations. The amount of dilation in dim light markedly decreases when the bright light from the slit lamp or ophthalmoscope strikes the retina. It has not been shown that 2.5% phenylephrine is as effective a mydriatic as 10% phenylephrine in this situation.

The effects of two solutions of phenylephrine 2.5% were compared in darkness and in room lighting; one solution was 21 centipoise more viscous than the other.²²⁰ One drop of one solution was applied to one eye and one drop of the other solution to the contralateral eye. There was no significant difference in dilation between the two solutions. The mean millimeter pupil diameters ± standard deviation following the aqueous and viscous solutions, respectively, were: in light, 0.9 ± 1.2 mm versus 0.9 ± 1.1 mm; after a proparacaine drop preceded the phenylephrine drop, 2.3 ± 0.8 mm versus 2.4 ± 0.9 mm; and after a tropicamide drop preceded the phenylephrine drop, 3.8 ± 0.8 mm versus 3.8 ± 1 mm.

Two commercial solutions, 2.5% and 10% phenylephrine, were compared for their efficacy in maintaining intraoperative mydriasis during cataract surgery.²²¹ The more concentrated was also more viscous. Three drops of one of the preparations were given preoperatively, each drop separated by 10 minutes. A drop of cyclopentolate was administered after each one of phenylephrine. The 10% solution provided a significantly larger mean pupil area of 13% prior to making the incision and 57% at the time that aspiration-irrigation was begun. Another approach to keeping the pupil dilated is to use intraocular epinephrine. The alpha-adrenergic effect from an epinephrine 1:1,000,000 irrigation solution will help maintain mydriasis during cataract surgery.²²²

When freshly prepared phenylephrine solutions were compared with commercial ones, a 2.5% fresh solution was found as effective a mydriatic as a 10% commercial solution.²¹⁷ However, no attempt had been made to match the pH's and preservatives of the fresh solutions to those of the commercial ones. The phenylephrine response of the irides of allergic asthmatics was more marked than those of nonallergic nonasthmatic and allergic nonasthmatic controls.²²³ As obtained from their dose-response curves, the concentrations of phenylephrine needed to dilate the pupil 1 mm were: 1.11 ± 0.68% for allergic asthmatics, 1.52 ± 0.67% for nonallergic nonasthmatics, and 1.86 ± 0.81% for allergic nonasthmatics.

Premature infants given either two drops bilaterally of a solution containing both phenylephrine 1% and cyclopentolate 0.2% had significantly more dilation 30 and 60 minutes later than premature infants receiving bilateral cyclopentolate 0.5% eyedrops.²²⁴ The amounts of dilation were the same at both points in time: 2.8 ± 0.6 mm from the combination drops versus 2 ± 0.5 mm from the cyclopentolate drops. Premature infants given one drop to each eye of phenylephrine 2.5% and tropicamide 0.5% had maximum pupil dilation within 20 minutes.²²⁵ Low birthweight children were given phenylephrine 2.5%, one drop every 5 minutes for three doses. One eye received 8 μL drops and the contralateral eye received 30 μL drops. The mean pupil dilations at 1 hour were similar, 4.9 mm versus 4.6 mm, respectively.²²⁶

Phenylephrine 10% has been used, concomitantly with a pilocarpine 2% drop, as a provocative test for angle-closure glaucoma. Presumably the combination of drops increases both pupillary block and angle closure. The test seems insensitive. Testing was performed yearly for 10 years on the fellow eyes of patients who had had acute narrow-angle glaucoma unilaterally. A positive test was defined as an increase in intraocular pressure of 8 mmHg or more and gonioscopic closure of the filtration angle.²²⁷ One hundred and fifteen of 182 eyes had positive tests. Of 67 negative testing eyes, nine (13%) developed spontaneous acute narrowangle glaucoma. However, another study found a 40% incidence of angle-closure glaucoma developing in eyes with negative tests.²²⁸

Phenylephrine, in concentrations of 2.5% to 10%, has been used to minimize iris cyst formation induced by chronic use of phosphorylating anticholinesterases (e.g., echothiophate).²²⁹ Adults do not seem to be at risk for forming the large cysts that occur in children. The mechanism by which phenylephrine is effective is not known. Twenty esotropic children, ages 3 to 14 years, received echo-thiophate bilaterally and phenylephrine unilaterally. Cysts developed in 11 children within 6 weeks and only in those eyes not receiving phenylephrine. Five patients who developed cysts were instructed to change the eye receiving phenylephrine. The cysts regressed in three patients and developed in the eyes no longer receiving phenylephrine. The fourth patient returned with bilateral cysts; his phenylephrine concentration had been reduced from 10% to 2.5%. The fifth patient developed two very small cysts in the eye receiving combination treatment.

Tyramine is an indirect-acting alpha-adrenergic agonist that can produce mydriasis if applied topically²³⁰ and has been used to investigate the pupillary effects of systemically administered tricyclic antidepressants,^231,232 monoamine oxidase inhibitors,²³³ and guanethidine.²³⁴

Cocaine has been used as a diagnostic agent to identify an interruption in the sympathetic pathway to Müller's muscle of the lid and to the dilator muscle of the iris. Such an interruption is referred to as ocular sympathetic paresis, or Horner's syndrome. There is no proven replacement for cocaine in this diagnostic role. Over a century ago, cocaine was suggested as being of value in the diagnosis of ocular sympathetic paresis.²³⁵ A cocaine eye drop dilates the normal iris²³⁶ due to the drug's indirect alpha-adrenergic activity; two drops of 10% cocaine given 5 minutes apart produce maximum dilation at 40 minutes. At 20 minutes 17% of these normal subjects have asymmetric pupil dilation equal to or less than 0.5 mm. A defect in sympathetic innervation, from the hypothalamus to the iris dilator muscle, reveals itself after cocaine is applied because there will be a relative or absolute failure of the pupil to enlarge. Cocaine concentrations of 2% to 10% are applied bilaterally; usually one drop per eye is given at the higher concentrations or two drops per eye at the lower concentrations. The responses of the two irides are compared, the innervation of one of which is presumed to be normal. Anywhere from 20 to 60 minutes after drug instillation, when dilation becomes maximal, the anisocoria is reassessed. If the disparity in the right versus left pupil diameters increases, then the test is considered positive and a diagnosis of ocular sympathetic paresis is given to the eye with the smaller pupil and ptotic lid. If the relative disparity remains the same or decreases, then the test is negative. In a study of 50 normal subjects and 119 patients²³⁷ with unilateral ocular sympathetic paresis cocaine eye drops were applied bilaterally. Fifty to 60 minutes later, normal subjects had up to 0.9 mm anisocoria and Horner's syndrome subjects had as little as 0.3 mm anisocoria. Calculations determined that a postcocaine anisocoria of 0.5 mm gave 77:1 odds that a Horner's syndrome was present. Anisocoria of 1 mm gave odds of 5990:1.

Cocaine stabilizes cell membranes, preventing propagation of action potentials. In sensory neurons, this results in anesthesia. In motor neurons, this results in paralysis. When the cocaine test has not produced the expected result, clinicians have wondered whether the drug has affected the membrane activities of iris dilator muscle fibers, sphincter muscle fibers, parasympathetic sphincter motor neurons, or sympathetic dilator motor neurons. The use of bilateral cocaine drops is of value in minimizing these potentially confounding effects on the interpretation of the test results.

A number of other drugs, for example the heterocyclic antidepressants such as amitriptyline, nortriptyline, imipramine, and desipramine, share cocaine's ability to block monoamine reuptake. These drugs also have potent antimuscarinic properties;²³⁸ therefore, they dilate the pupil in the absence of sympathetic innervation by paralyzing the iris sphincter muscle.

Topical application of cocaine has a toxic effect on the corneal epithelium.²³⁹ This leads to reduced metabolism and disruption of the tight intercellular bonds of the epithelial cells. Reflex tearing is absent, due to corneal anesthesia, for approximately a half hour. The result is a variable but usually mild degree of ocular irritation for several hours after the anesthetic effect of cocaine wears off. Incidences of corneal epithelial ulcers, both infected and sterile, have been reported in association with the use of crack cocaine.²⁴⁰ Eye drops of cocaine, at concentrations similar to those used clinically, can produce a positive urine test for cocaine.²⁴¹

Hydroxyamphetamine 1% dilates the normal pupil. Twenty-six subjects were given two drops bilaterally, each drop separated by 20 to 40 seconds. The pupil diameters were measured 45 to 60 minutes later from photographs taken in “moderately bright light.” There was a mean ± standard deviation increase in pupil diameter of 2 ± 0.6 mm.²⁴² The mean difference between the two eyes of an individual was approximately 0.1 ± 0.3 mm. There was no significant difference found between blue eyed and brown eyed subjects. Hydroxyamphetamine appears to have little or no direct adrenergic activity despite sharing some structural similarities to norepinephrine. In volunteers whose irides were made supersensitive by topical application of guanethidine 5%, a drug that depletes neuronal stores of norepinephrine, subsequent application of hydroxyamphetamine did not produce dilation while application of the direct agonist, phenylephrine 1%, produced a supersensitive mydriasis.²⁴³

Hydroxyamphetamine has been used instead of amphetamine as a mydriatic eye drop because the former is much less likely to cross the blood-brain barrier and produce central nervous system symptoms.²⁴⁴ Hydroxyamphetamine 1% has been found useful in localizing the defect causing ocular sympathetic paresis to either the absence of post-superior cervical ganglion axons or the absence of the innervation proximal to the superior cervical ganglion. Attempts to use epinephrine for this purpose have not been as successful.²⁴⁵ In a Horner's syndrome due to damage to the post-superior cervical ganglion axons, there are few or no adrenergic nerve endings in the iris dilator muscle; an eye drop of hydroxyamphetamine produces little or no pupil dilation. However, in a preganglionic Horner's syndrome, the postganglionic fibers are intact; a drop of hydroxyamphetamine produces significant dilation. The test is performed by placing one drop of hydroxyamphetamine 1% bilaterally. The amount of dilation in an eye with a preganglionic ocular sympathetic paresis is often greater than that in the normal contralateral eye.²⁴⁶ This may be due to dilator muscle supersensitivity or the result of increased accumulation of norepinephrine in the previously unstimulated axon terminals. Hydroxyamphetamine-like drugs cannot replace cocaine in making the diagnosis of ocular sympathetic paresis because they dilate both a normally innervated pupil and a preganglionic Horner's syndrome pupil.²⁴⁷ Tyramine 5% has been used instead of hydroxyamphetamine to test for sympathetic innervational²⁴⁸ defects in Miller-Fisher syndrome and familial amyloidosis.

Hydroxyamphetamine localization may be inaccurate if the lesion occurs very early in life. In the adult superior cervical ganglion, sequential transsynaptic degeneration does not occur when the preganglionic innervation is removed. However, in the very young, it may. This has been demonstrated in lower animals²⁴⁹ and seems to occur in humans.²⁵⁰

Alpha-2 receptors have been identified in high concentration in human cadaver iris epithelium.²⁵¹ While stimulation of brain alpha-2 adrenoreceptors produces mydriasis in mice, rats and cats,^252–254 low doses of intravenous clonidine, 0.1 mg or 0.2 mg, produce miosis in humans.²⁵⁵ These studies failed to control for a direct alpha-2 effect on the iris.

Alpha-adrenergic antagonists have been used clinically as miotic agents to overcome the dilating effects of alpha-1 agonists (e.g., phenylephrine). Thymoxamine is a nonselective alpha antagonist. Topical thymoxamine 0.1%, one drop, completely reversed the mydriasis from a single drop of 2.5% phenylephrine in 63% of subjects within 1 hour.²⁵⁶ Irides with less pigment (i.e., lighter colored) responded more quickly and completely. Thymoxamine is rapidly deacetylated by esterase in the plasma; the metabolite has very similar activity to the parent molecule.²⁵⁷ Whether topical thymoxamine is similarly deacetylated by ocular esterases is not known. Thymoxamine 0.5% applied topically to normotensive and open-angle glaucoma subjects produces miosis without significantly altering intraocular pressure, anterior chamber volume, or tonographically measured outflow facility.^258–260 Thymoxamine 0.01% has been injected into the anterior chamber at the conclusion of cataract surgery to reverse pupil dilation; scopolamine 0.25% and phenylephrine 10% eye drops had produced the mydriasis. Thymoxamine in volumes between 0.4 to 0.6 mL, was effective in constricting the pupil and was additive to the effects of intracameral acetylcholine 0.5%.²⁶¹

In another study of the effect of thymoxamine on the recovery of pupil diameter from phenylephrine mydriasis, subjects were bilaterally dilated with phenylephrine 2.5%, one drop followed 5 minutes later by a second drop.²⁶² Either placebo or thymoxamine 0.1% was administered to each eye 40 minutes after the second phenylephrine drop. There was significantly more pupil constriction in the thymoxamine treated eyes 30, 60, and 120 minutes after application. At 30 minutes after instillation, 26% of thymoxamine treated eyes had returned to baseline diameter compared to 8% of placebo treated eyes; at 2 hours, 55% of thymoxamine treated eyes and 11% of placebo treated eyes had returned to baseline diameters, and at 8 hours 99% of thymoxamine treated eyes and 86% of placebo treated eyes had returned to baseline. When the effects of thymoxamine 0.1% or phenylephrine 2.5% dilation were compared in light and dark irides, thymoxamine was more effective in the lighter irides²⁶³ both in rate and quantity of reversal. Thymoxamine failed to significantly reverse phenylephrine induced mydriasis in the very dark brown irides of a group of 20 black and Hispanic subjects.

In theory, the miosis produced by relaxation of the dilator muscle could be useful in preventing or terminating attacks of acute narrow-angle glaucoma²⁶⁴; further, alpha-adrenergic antagonists, unlike muscarinic agonists, such as pilocarpine, produce miosis without accommodation of the lens. Accommodation can result in pupillary blockade, another cause of acute narrow-angle glaucoma.

A single drop of thymoxamine 0.1%, 0.5%, or 1% produces maximum miosis by 1 hour.²⁶⁵ By 4 hours postdrop, most of the miotic effect of the 0.1% solution is gone but that of the higher concentrations persists. Thymoxamine 0.5% has been used in 26 patients with increased intraocular pressures and narrow angles to determine if the hypertension was due to an open-angle or closed-angle mechanism.²⁶⁶ The intraocular pressure was measured before and 1 hour after two single drops of thymoxamine applied 2 minutes apart. In 8 patients, the angles became wider but the pressure did not drop; these patients were therefore treated as having open-angle glaucoma. In 12 patients, the angles opened and the pressure dropped; 11 of these were treated by surgical iridectomies. Nine responded well to the iridectomies but 2 had plateau iris and did not. Three patients had angles that did not open to thymoxamine nor did their pressures become lower; these were diagnosed ashaving narrow-angle glaucoma and iridectomies were curative. Three patients had a mixed-mechanism; their intraocular pressures were only partially reduced when thymoxamine opened the filtration angle.

Bunazosin is an alpha-1 antagonist with additional pharmacologic actions. When given as a 0.1% drop, it does not produce significant miosis but it does lower intraocular pressure by increasing uveoscleral flow.²⁶⁷ When given as a 0.3% drop, it produces miosis, ptosis, and conjunctival hyperemia as well.²⁶⁸

Dapiprazole HCl is an alpha-1 antagonist. Prior instillation of two single eye drops, 5 minutes apart, of dapiprazole 0.06% markedly limits dilation from phenylephrine 2.5% and 5%; dapiprazole 0.25% is similarly effective against a phenylephrine 10% drop. A 0.5% solution produces a significant miosis within 30 to 60 minutes and a complete reversal of pharmacologic mydriasis in about 2 hours. Dapiprazole produces a more effective and longer-lasting alpha blockade than a similar concentration of thymoxamine.²⁶⁹

CILIARY BODY

Alpha-1 adrenergic receptors have been identified in strips of human ciliary body muscle studied 2 to 3 days after death.²⁷⁰ Receptors are found in both meridionally and circularly oriented smooth muscle fibers. Norepinephrine produces a dose-related relaxation of these strips. This is partially blocked by the selective alpha-1 antagonist, prazosin, and the nonselective antagonist, phentolamine. The selective alpha-2 antagonist, idazoxam, has no effect. Alpha-2 receptors have been identified in the ciliary body epithelium of cadaver eyes.²⁷¹

Two clinical studies have shown that phenylephrine reduces the diopteric power of the eye and lengthens the near point of accommodation.^272,273 In one of these, a potential effect on the near point from pupil dilation was prevented by using an artificial pupil with a 2-mm aperture. In this study,²⁷³ 10 volunteers, ages 19 to 31, had three drops of phenylephrine 10% instilled in one eye. Measurements 40 minutes after those at baseline showed a reduction in accommodation of 0.8 ± 0.3 diopters. The alpha-adrenergic antagonist, thymoxamine 0.5%, by itself, produced an increase in the diopteric power of the near point of accommodation of 0.6 ± 0.2 diopters. Thymoxamine followed 30 minutes later by phenylephrine did not alter the near point. An apparent increase in accommodation in the distance refraction was prevented by the 2-mm artificial pupil. While these results suggest phenylephrine produces a direct alpha-1 adrenergic mediated relaxation of ciliary smooth muscle, the possibility remains of an indirect effect on ciliary muscle strength from constriction of blood vessels.

RETINA

Alpha-2 receptors have been identified in the retina and retina pigment epithelium-choroid.²⁷¹ Chronic glaucoma patients receiving maintenance therapy with pilocarpine and beta-blocker eye drops show a reduction in threshold sensitivity when automated perimetry is performed after a drop of phenylephrine 10%.²⁷⁴ Presumably, this is the result of more light entering the eye rather than a pharmacologic effect on the retina.

The retinal vessels in humans have no adrenergic innervation,²⁷⁵ but this does not preclude the possibility of their having adrenergic receptors. Topical phenylephrine does not affect macular or retinal blood flow, as measured by blue field stimulation, for up to 35 minutes after drop application.²⁷⁶ However, human posterior ciliary artery preparations respond as though alpha-1 but not alpha-2 receptors are present.²⁷⁷ Although it is assumed that insufficient drug reaches these vessels when applied topically, topical epinephrine HCl 2% produces an 8% increase in macular leukocyte velocity 2 hours after application.²⁷⁸ This may be a beta-adrenergic, or combined alpha- and beta-adrenergic effect.

Studies of the systemic levels produced from topical phenylephrine eye drops have been performed in adults under general anesthesia. Blinking and reflex lacrimation do not occur and the head position is horizontal. These factors enhance drug retention by the lids. Anesthetized subjects given two drops, separated by 5 minutes, of either aqueous or viscous phenylephrine 2.5%, have peak mean ± standard deviation venous blood levels 10 minutes after application²⁸⁵ of 3.15 ± 2.12 ng/mL (aqueous preparation) and 2.12 ± 2.52 ng/mL (viscous preparation); these levels are not significantly different. Phenylephrine is not detected in the plasma of any of the subjects 30 minutes after application. When two drops of either aqueous phenylephrine 2.5% or viscous phenylephrine 10% are given to patients under general anesthesia,²⁸⁶ the latter produces significantly higher venous blood levels. The peak plasma levels for all subjects occurs within 20 minutes of application. At 10, 20, and 60 minutes after the second drop the respective blood levels for phenylephrine 2.5% and 10% are 3 ± 1.4 versus 10.2 ± 7.9 ng/mL; 1.1 ± 0.6 versus 6.5 ± 3.3 ng/mL; and 0.2 ± 0.4 versus 1.7 ± 1.1 ng/mL. Infants were given three drops, one every 5 minutes, of phenylephrine 2.5% bilaterally. Mean blood levels 10 minutes after the last drop were 1.9 ng/mL if 30 μL drops are given and 0.9 ng/mL if 8 μL drops are given.²²⁶ Patients under general anesthesia show a poor correlation between the plasma phenylephrine levels and the blood pressure. Presumably, many of the reflexes that would respond are blunted by the anesthetic agent.^285,286 However, even in conscious subjects, it is only when frequent and large doses of phenylephrine drops are given that significant hypertensive changes occur. For example, when 56 patients received three administrations of bilateral phenylephrine 10% eye drops, only two developed elevations of more than 20 mmHg in their systolic or diastolic blood pressures 15 minutes after the last drop.²⁸⁷ In another study, 21 patients receiving six applications of phenylephrine 10% eye drops, one application of two drops every 2 minutes, failed to show any significant elevation in blood pressure.²⁸⁸

Clinically significant side effects may occur after phenylephrine administration if:

1. ÌPhenylephrine is administered as pledgets, as subconjunctival injections, or as lacrimal sac irrigations. These methods expose the patient to unusually large systemic levels of phenylephrine. In one paper of 33 adverse episodes, seven were associated with drug administration by one of these methods.²⁸⁹
   
2. Multiple doses are administered to infants and small children. Phenylephrine, in the usual doses, appears well tolerated. For example, one drop of both phenylephrine 2.5% and tropicamide 0.5% given bilaterally to preterm infants produces a statistically significant increase in the systolic blood pressure but not in the diastolic blood pressure. The systolic increase peaked 8 minutes after drop administration, remained elevated 30 minutes after drop administration, but returned to baseline by 75 minutes after drop application.²²⁵ The mean ± standard deviation baseline blood pressure, 56 ± 10 mmHg systolic/34 ± 7 mmHg diastolic, went to 71 ± 13 mmHg systolic/41 ± 9 mmHg diastolic 8 minutes after eye drop application. There was no change in the pulse rate. Neonates weighing less than 1600 g²²⁴ received a combination solution of phenylephrine 1% with cyclopentolate 0.2%. Two drops were administered to each eye, each drop separated by 5 minutes. There was no significant change in the pulse rate or blood pressure when measured 30 and 60 minutes after administration. However, these measurements were taken long after the expected peak drug level would be expected to occur. There is a case report of multiple drops (approximately 0.5 mL) of 2.5% phenylephrine given topically to an anesthesized 1-year-old child producing systemic hypertension.²⁹⁰
   
3. Preexisting uncontrolled hypertension. Subjects with normal blood pressures and those with controlled systemic hypertension are little affected by phenylephrine. When 1.25 to 6 mg phenylephrine is instilled intranasally, to assure more complete absorption, there is no significant effect on the blood pressure of patients with preexisting systemic hypertension, diabetes, cardiac disease, or thyroid disease.²⁹¹ Nor is the blood pressure altered by intranasal oxymetazoline. In a general population of 120 subjects given phenylephrine 10% eye drops, only 2% developed blood pressure elevations and these were small.²⁹² When 100 patients with systemic hypertension were given phenylephrine 10% eye drops, only 6% developed increases in their blood pressure and these are less than 10 mmHg.²¹⁷ Similar limited effects on blood pressure and pulse rate have been reported in other studies.^293,294
   
4. Adrenergic supersensitivity. Some patients exhibit evidence of relative sympathetic denervation (e.g., orthostatic hypotension). Several case reports exist of myocardial infarction or subarachnoid hemorrhage in patients with orthostatic hypotension given phenylephrine eye drops.^295,296 In a study of four orthostatic hypotensive patients taken off all medications, supersensitivity to phenylephrine was shown by giving the drug intravenously. Compared to eight normal control subjects, less than one fifth the dose of phenylephrine was needed to produce a 25 mmHg elevation in blood pressure. Then the blood pressure and pulse rate were monitored every 3 minutes for 30 minutes before and 2 hours after proparacaine eye drops bilaterally followed by one dose of phenylephrine 2.5% bilaterally. In the control group, there was no significant effect on the blood pressure or pulse rate. All four orthostatic hypotensive patients had a marked blood pressure elevation that occurred within 10 minutes and lasted more than 1 hour. The mean peak systolic/diastolic increase was 44 mmHg/27 mmHg. There were no effects on the pulse rate or rhythm or the intraocular pressure. Diabetic patients often have peripheral neuropathy, which may explain why one study found they had a significant response to topical phenylephrine eye drops. Adrenergic supersensitivity can be created in those taking drugs that prevent storage, uptake, or metabolism of adrenergic drugs. Twenty-seven patients taking reserpine or guanethidine were divided into two groups; one received two eye drops of phenylephrine 10% and the other did not. Only the former had an increase in blood pressure; the mean systolic/diastolic elevation was 30 mmHg/13 mmHg.²⁹⁷
   
5. Systemic administration of beta-adrenergic antagonists. Systemic administration of beta-blockers can alter the response to phenylephrine. Parenteral phenylephrine produces an elevation in systemic and diastolic blood pressure. This stimulates both carotid artery baroreceptors, leading to a reflex slowing of the heart, and beta>2 adrenergic blood vessel receptors, leading to vasodilation.²⁹⁸ This last lowers the blood pressure and brings the heart rate back to baseline. If supine normal males are given intravenous propranolol, a nonselective beta-blocker, followed by intravenous isoproterenol, a nonselective beta agonist, there is no significant effect on pulse rate or blood pressure.²⁹⁹ However, when epinephrine, a nonselective beta agonist, and also an alpha agonist, is infused, there is a sustained increase in arterial blood pressure and a sustained decrease in the pulse rate. Presumably the alpha-adrenergic induced blood pressure increase cannot be compensated for by a beta-mediated vasodilation. Use of a relatively selective systemic beta-1 blocker may reduce the systemic hypertension and bradycardia. Other methods of minimizing these hazards include parenteral use of an alpha adrenergic antagonist (e.g., hydralazine) to prevent hypertension and an antimuscarinic agent (e.g., atropine) to prevent bradycardia. However, there is evidence that atropine potentiates the blood pressure response to phenylephrine, although it does not increase the peripheral vascular resistance.³⁰⁰
   

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