Chapter 29
Alpha-Adrenergic Drugs
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The eye is innervated by catecholamine-containing axons originating from the superior cervical ganglion, a sympathetic nervous system structure. These postganglionic axons innervate multiple tissues including the smooth muscle fibers in the iris dilator muscle, conjunctival blood vessels, and lids. The axon terminals release the transmitter, norepinephrine1 resulting in dilation of the pupil, blanching of the conjunctiva, and widening of the palpebral fissure. Catecholamine-containing nerve endings have also been demonstrated in human cornea.2 In the fetus, these are subepithelial; in the adult, they are found only in the stroma. The physiologic role of these corneal fibers is not known but they may mediate epithelial chloride transport; this theory is based on experiments demonstrating that exogenous catecholamines stimulate rabbit corneal epithelium transport by a cAMP related mechanism.3 Catecholamine-containing nerve endings have been demonstrated in the areas of the trabecular meshwork and corneal limbus of mammals, including humans.4,5

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.


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


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


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.

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The discovery of multiple subclasses of alpha-adrenergic receptors has altered the classification of drugs. A given drug may be an agonist at one type of alpha receptor but not at another. Binding does not necessarily correlate with agonist activity. For example, clonidine and apraclonidine bind relatively indiscriminately to the various alpha-2 subtypes but both preferentially activate alpha-2A receptors. Structurally, alpha-adrenergic agonists tend to be either catecholamine derivatives or imidazoline derivatives. Catecholamine contains a 6-carbon unsaturated (benzene) ring. Imidazolines have a 5-membered ring consisting of 3 carbon and 2 nitrogen atoms. Imidazolines usually have a longer duration of action. Examples of catecholamine derivatives are norepinephrine, epinephrine, phenylephrine, tyramine, hydroxyamphetamine, and ephedrine. Examples of imidazoline derivatives are clonidine, phentolamine, naphazoline, tetrahydrozoline, antazoline, tolazoline, yohimbine, oxymetazoline, and xylometazolone.

The most prominent activities of alpha-adrenergic drugs are listed in Table 1.55,56


TABLE ONE. Most Prominent Activities of Alpha-Adrenergic Drugs




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.


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.


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.


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.

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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.


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.


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.


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


Phenylephrine causes an acute localized constriction in the arterioles supplying the ciliary processes120a 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).


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

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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


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.


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


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.


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 not157–160 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


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


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.


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.

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There are many case reports of systemic side effects after topical phenylephrine use.279–284 However, when prospective controlled studies, usually of normal populations, are performed, there is little evidence of any significant systemic effect. It appears that there is no intrinsically safe or dangerous concentration of topical phenylephrine eye drops, but rather there are certain patients who may be susceptible to developing side effects no matter what concentration is applied.

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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Allergic blepharoconjunctivitis has been produced by phenylephrine eye drops.301 The reaction usually begins 4 to 6 hours after exposure and becomes maximum within 24 hours; this suggests a delayed-type cellular hypersensitivity.
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1. Gillis CN, Schneider FH, Van Orden LS, Giarman NJ: Biochemical and microfluorometric studies of norepinephrine redistribution accompanying sympathetic nerve stimulation. J Pharmacol Exp Ther 151:46, 1966

2. Toivanen M, Tervo T, Partanen M et al: Histochemical demonstration of adrenergic nerves in the stroma of human cornea. Invest Ophthalmol Vis Sci 28:398, 1987

3. Klyce SD, Neufeld AH, Zadunaisky JA: The activation of chloride transport by epinephrine and Db cyclic-AMP in the cornea of the rabbit. Invest Ophthalmol 12:127, 1973

4. Holland MG, von Sallmann L, Collins EM: A study of the innervation of the chamber angle. Am J Ophthalmol 44 (II):206, 1957

5. Ehinger B: Connections between adrenergic nerves and other tissue components in the eye. Acta Physiol Scand 67:57, 1966

6. Laties A, Jacobowitz D: A histochemical study of the adrenergic and cholinergic innervation of the anterior segment of the rabbit eye. Invest Ophthalmol 3:592, 1964

7. Olson L, Seiger A: A system of atypical catecholamine-containing nerve fibers in the rat iris present after total superior cervical ganglionectomy. Med Biol 58:94, 1980

8. Nomura T, Smelser GK: The identification of adrenergic and cholinergic nerve endings in the trabecular meshwork. Invest Ophthalmol 13:525, 1974

9. Furukawa H: Autonomic innervation of preretinal blood vessels of the rabbit. Invest Ophthalmol Vis Sci 28:1752, 1987

10. Guglielmone R, Cantino D: Autonomic innervation of the ocular choroid membrane in the chicken. Cell Tissue Res 222:417, 1982

11. Rushkell GL: Dual innervation of the central artery of the retina in monkeys. In Kant JS (ed): The Optic Nerve, pp 48–58. London, Kimpton, 1972

12. Ehinger B: Adrenergic nerves to the eye and to related structures in man and in the cynomolgus monkey (Macaca irus). Invest Ophthalmol 5:42, 1966

13. Beausang-Linder M: Effects of sympathetic stimulation on cerebral and ocular blood flow. Acta Physiol Scand 114:217, 1982

14. Brock JA, Cunnane TC: Relationship between the nerve action potential and transmitter release from sympathetic postganglionic nerve terminals. Nature 326:605, 1987

15. DePotter WP, DeSmet F, Cambie E: Subcellular distribution of noradrenaline and dopamine ß-hydroxylase in sympathetic nerves innervating the rabbit iris. Arch Int Pharmacodyn 227:157, 1977

16. Gual A, Garcia AG, Belmonte C: Dopamine ß-hydroxylase activity in the aqueous humor: Effects of cervial sympathetic stimulation and reserpine. Exp Eye Res 34:789, 1982

17. Elayan H, Kennedy B, Ziegler MG: Epinephrine synthesis in the rat iris. Invest Ophthalmol Vis Sci 31:677, 1990

18. Cohen J, Hadjiconstantinou M: Identification of epinephrine and phenylethanolamine N-methyltransferase activity in rat retina. 43:2725, 1984

19. Bauscher LP: Identification of A and B forms of monoamine oxidase in the iris-ciliary body, superior cervical ganglion and pineal gland of albino rabbits. Invest Ophthalmol 15:529, 1976

20. Lee C-M, Javitch JA, Snyder SH: Recognition sites for norepinephrine uptake: Regulation by neurotransmitter. Science 220:626, 1983

21. Ehinger B, Falck B, Sporrong B: Possible axo-axonal synapses between peripheral adrenergic and cholinergic nerve terminals. Z Zellforsch Mikrosk Anat 107:308, 1970

22. Katzman R, Broida R, Raine CS: Reinnervation, myelination and organization of iris tissue implanted into the rat midbrain--An ultrastructural study. Brain Res 138:423, 1977

23. Burnstock G: Cholinergic, adrenergic and purinergic neuromuscular transmission. Fed Proc 36:2434, 1977

24. Ahliquist RP: Study of adrenotropic receptors. Am J Physiol 153:586, 1948

25. Lands AM, Arnold A, McArliff JP et al: Differentiation of receptor systems activated by sympathomimetic amines. Nature 214:597, 1967

26. Stein M, Deegan R, He H, Wood AJJ: ß-Adrenergic receptor-mediated release of norepinephrine in the human forearm. Clin Pharmacol Ther 54:58, 1993

27. Patel S, Patel U, Vithalani D, Verma SC: Regulation of catecholamine release by presynaptic receptor system. Gen Pharmacol 12:405, 1981

28. Dixon RAF, Kobilka BK, Strader DJ et al: Cloning of the gene and cDNA for mammalian ß-adrenergic receptor and homology with rhodopsin. Nature 321:75, 1986

29. Tant W-J, Gilman AG: Type-specific regulation of adenyl cyclase by G protein Bγ subunits. Science 254:1500, 1991

30. Hoffman BB, Lefkowitz RJ: Agonist interactions with alpha-adrenergic receptors. J Cardiovasc Pharmacol 4:514, 1982

31. Lipscombe D, Kongsamut S, Tsien RW: α-Adrenergic inhibition of sympathetic neurotransmitter release mediated by modulation of N-type calcium-channel gating. Nature 340:639, 1989

32. Schwinn DA, Lomasney JW, Lorenz W et al: Molecular cloning and expression of the cDNA for a novel alpha 1-adrenergic receptor subtype. J Biol Chem 265:8183, 1990

33. Ford APDW, Williams TJ, Blue DR, Clarke DE: α1-Adrenoceptor classification: Sharpening Occam's razor. Trends Pharmacol Sci 15:167, 1994

34. Minneman KP, Esbenshade TE: α1-Adrenergic receptor subtypes. Annu Rev Pharmacol Toxicol 34:117, 1994

35. Han C, Abel PW, Mineman KP: α1-Adrenoceptor subtypes linked to different mechanions for increasing intracellular Ca2+ in smooth muscle. Nature 329:333, 1987

36. O'Dowd BF, Lefkowitz RJ, Caron MG: Structure of the adrenergic and related receptors. Annu Rev Neurosci 12:67, 1989

37. Daly RN, Sulpizio AC, Levitt B et al: Evidence for heterogeneity between pre- and postjunctional alpha-2 receptors using 9-substituted 3-benzazepines. J Pharmacol Exp Ther 247:122, 1988

38. Bylund DB, Ray-Prenger C, Murphy TJ: Alpha-2A and alpha-2B adrenergic receptor subtypes: Antagonist binding in tissues and cell lines containing only one subtype. J Pharmacol Exp Ther 245:600, 1988

39. Ruffolo RR Jr, Nichols AJ, Stadel JM, Hieble JP: Pharmacologic and therapeutic applications of α2-adrenoceptor subtypes. Annu Rev Pharmacol Toxicol 32:243, 1993

40. Bylund DB, Blaxall HS, Iversen LJ et al: Pharmacological characteristics of α2-adrenergic receptors: Comparison of pharmacologically defined subtypes with subtypes identified by molecular cloning. Mol Pharmacol 42:1, 1992

41. Gleason MM, Hieble JP: The α2-adrenoceptors of the human retinoblastomas cell line (Y79) may represent an additional example of the α2C adrenoceptor. Br J Pharmacol 102:222, 1992

42. Young P, Berge J, Chapman H, Cawthorne MA: Novel α2-adrenoceptor antagonists show selectivity for α2A and α2B adrenoceptor subtypes. Eur J Pharmacol 168:381, 1989

43. Lehmann J, Koenig-Berard E, Vitou P: The imidazoline preferring receptor. Life Sci 14:1690, 1989

44. Creese I, Sibley DR: Receptor adaptations to centrally acting drugs. Annu Rev Pharmacol Toxicol 21:357, 1981

45. Lefkowitz RJ, Stadel JM, Caron MG: Adenylate cyclase-coupled beta-adrenergic receptors: Structure and mechanisms of activation and desensitization. Annu Rev Biochem 52:159, 1983

46. Benovic JL, Mayor F Jr, Somers RL et al: Light-dependent phosphorylation of rhodopsin by ß-adrenergic receptor kinase. Nature 321:869, 1986

47. Maggi A, U'Prichard DC, Enna SJ: ß-Adrenergic regulation of α2-adrenergic receptors in the central nervous system. Science 207:645, 1980

48. Eason MG, Liggett SB: Subtype selective desensitization of α2-adrenergic receptors. J Biol Chem 267:25473, 1992

49. Schipper J, Tilders FJH, Ploem JS: Extraneuronal catecholamine as an index for sympathetic activity: A scanning microfluorometric study of the iris of the rat. J Pharmacol Exp Ther 211:265, 1979

50. Kramer SG, Potts AM: Iris uptake of catecholamines in experimental Horner's syndrome. Am J Ophthalmol 67:705, 1969

51. Page ED, Neufeld AH: Characterization of α- and ß-adrenergic receptors in membranes prepared from the rabbit iris before and after development of supersensitivity. Biochem Pharmacol 27:953, 1978

52. Watanabe Y, Lai R-T, Maeda H, Yoshida H: Reserpine and sympathetic denervation cause an increase of post-synaptic α2-adrenoceptors. Eur J Pharmacol 80:105, 1982

53. Akhtar RA, Abdel-Latif AA: Surgical sympathetic denervation increases α1-adrenoreceptor-mediated accumulation of myoinositol triphosphate and muscle contraction in rabbit iris dilator smooth muscle. J Neurochem 46:96, 1986

54. Shibata K, Takei S, Kawai T et al: Decrease in neuronal uptake of noradrenaline simply explains the supersensitivity after sympathectomy in the rat iris dilator. Jpn J Pharmacol 50:19, 1989

55. Lomasney JW, Cotecchie S, Lefkowitz RJ, Caron MG: Molecular biology of α-adrenergic receptors: Implications for receptor classification and for structure-function relationships. Biochem Biophys Acta 1095:127, 1991

56. Berridge TL, Gadie B, Roach AG, Tulloch IF: α2-Adrenoceptor agonists induce mydriasis in the rat by an action within the central nervous system. Br J Pharmacol 78:507, 1983

57. Drew GM: Effects of α-adrenoceptor agonists and antagonists on pre- and postsynaptically located α-adrenoceptors. Eur J Pharmacol 36:313, 1976

58. Berthelsen S, Pettinger WA: A functional basis for classification of α-adrenergic receptors. Life Sci 21:595, 1977

59. Tahiliani AG, Verma SC, McNeill JH: Cyclic AMP-dependent and independent positive inotropic effects of phenylephrine. Gen Pharmacol 13:369, 1982

60. Matheny JL, Carrier GO, Ahlquist RP: Role of neuronal and extraneuronal uptake in responses of rabbit iris dilator muscle to levarterenol and phenylephrine. J Pharm Sci 66:93, 1977

61. Manukhin BN, Volina EV: Reverse trans-synaptic regulation of catecholamine synthesis in adrenergic neurones. Biochem Pharmacol 31:653, 1982

62. Crowley JR, Williams CM, Fregly MJ: In vivo catecholamine formation from phenylephrine. J Pharm Pharmacol 35:264, 1983

63. Stone TW, Taylor DA: Clonidine as an adenosine antagonist. J Pharm Pharmacol 30:792, 1978

64. Azzaro AJ, Ziance RT, Rutledge CO: The importance of neuronal uptake of amines for amphetamine-induced release of [3H] norepinephrine from isolated brain tissue. J Pharmacol Exp Ther 189:110, 1974

65. Knepper SM, Grunewald GL, Rutledge CO: Inhibition of norepinephrine-transport into synaptic vesicles by amphetamine analogs. J Pharmacol Exp Ther 247:487, 1988

66. Fiszman ML, Luchelli-Fortis MA, Stefano FJE: Amphetamine antagonizes the presynaptic inhibitory effect of clonidine through an interaction at the level of the alpha 2-adrenoceptors. Gen Pharmacol 20:351, 1989

67. Koe BK: Molecular geometry of inhibitors of the uptake of catecholamines and serotonin in synaptosomal preparations of rat brain. J Pharmacol Exp Ther 199:649, 1976

68. Whitby LG, Hertting G, Alexrod J: Effect of cocaine on the disposition of noradrenaline labeled with tritium. Nature 187:604, 1960

69. Trendelenburg U, Graefe KH, Eckert E: The prejunctional effect of cocaine on the isolated nictitating membrane of the cat. Naunyn Schmiedebergs Arch Pharmacol 275:69, 1972

70. Cauthen SE, Ellis RD, Larrison SB, Kidd MR: Resolution, purification and characterization of rabbit serum atropinesterase and cocainesterase. Biochem Pharmacol 25:181, 1976

71. Stewart DJ, Inaba T, Tang BK, Kalow W: Hydrolysis of cocaine in human serum by cholinesterase. Life Sci 20:1557, 1977

72. Stewart DJ, Inaba T, Lucassen M, Kalow W: Cocaine metabolism: Cocaine and norcocaine hydrolysis by liver and serum esterases. Clin Pharmacol Ther 25:464, 1979

73. Inaba T, Stewart DJ, Kalow W: Metabolism of cocaine in man. Clin Pharmacol Ther 23:547, 1978

74. Jatlow P, Barash PG, Van Dyke C et al: Cocaine and succinylcholine sensitivity: A new caution. Anesth Analg 58:235, 1979

75. Van Dyke C, Barash PG, Jatlow P, Byck R: Cocaine: Plasma concentration after intranasal application in man. Science 191:859, 1976

76. Baselt RC: Stability of cocaine in biological fluids. J Chromatogr 268:502, 1983

77. Gupta VD: Stability of cocaine hydrochloride solutions at various pH values as determined by high-pressure liquid chromatography. Int J Pharmaceut 10:249, 1982

78. Murray JB, Al-Shoura H: Stability of cocaine hydrochloride in aqueous solution. J Pharm Pharmacol 28(suppl 1):24P, 1976

79. Matthews JC, Collins A: Interactions of cocaine and cocaine congeners with sodium channels. Biochem Pharmacol 32:455, 1983

80. Walkenbach RJ, Ye G-S, Reinach PS, Boney F: Alpha-1 adrenoceptors in the corneal endothelium. Exp Eye Res 55:443, 1992

81. Dartt DA, Rose PE, Dicker DM et al: α1-Adrenergic agonist-stimulated protein secretion in rat exorbital lacrimal gland acini. Exp Eye Res 58:423, 1994

82. Braslow RA, Gregory DS: Adrenergic decentralization modifies the circadian rhythm of intraocular pressure. Invest Ophthalmol Vis Sci 28:1730, 1987

83. Liu JHK, Dacus AC: Endogenous hormonal changes and circadian elevation of intraocular pressure. Invest Ophthalmol Vis Sci 32:496, 1991

84. Yoshitomi T, Gregory DS: Ocular adrenergic nerves contribute to control of the circadian rhythm of aqueous flow in rabbits. Invest Ophthalmol Vis Sci 32:523, 1991

85. Kiuchi Y, Yosnitomi T, Gregory DS: Do α-adrenergic receptors participate in control of the circadian rhythm of IOP? Invest Ophthalmol Vis Sci 33:3186, 1992

86. Liu JHK, Dacus AC: Aqueous humor cyclic AMP and circadian elevation of intraocular pressure in rabbits. Curr Eye Res 10:1175, 1991

87. Liu JHK, Dacus AC, Bartels SP: Adrenergic mechanism in circadian elevation of intraocular pressure in rabbits. Invest Ophthalmol Vis Sci 32:2178, 1991

88. Duzman E, Anderson J, Vita JB et al: Topically applied oxymetazoline: Ocular vasoconstrictive activity, pharmacokinetics, and metabolism. Arch Ophthalmol 101:1122, 1983

89. Wang RF, Lee PY, Taniguchi T et al: Effect of oxymetazoline on aqueous humor dynamics and ocular blood flow in monkeys and rabbits. Arch Ophthalmol 111:535, 1993

90. Waitzman MB, Woods WD, Cheek WV: Effects of prostaglandins and norepinephrine on ocular pressure and pupil size in rabbits following bilateral cervical ganglionectomy. Invest Ophthalmol Vis Sci 18:52, 1979

91. Langham ME, Diggs EM: Quantitative studies of the ocular response to norepinephrine. Exp Eye Res 13:161, 1972

92. Langham ME, Krieglstein GK: The biphasic intraocular pressure response of rabbits to epinephrine. Invest Ophthalmol 15:119, 1976

93. Rowland JM, Potter DE: Adrenergic drugs and intraocular pressure: The hypertensive effect of epinephrine. Ophthalmol Res 12:221, 1980

94. Innemee HC, DeJenge A, Van Meel JCA et al: Differential effects of selective α1 and α2 adrenoreceptor agonists on intraocular pressure in the conscious rabbit. Documenta Ophthalmol 52:287, 1982

95. Eakins KE: The effect of intravitreous injections of norepinephrine, epinephrine and isoproterenol on the intraocular pressure and aqueous humor dynamics of rabbit eyes. J Pharmacol Exp Ther 140:79, 1963

96. Robinson JC, Kaufman PL: Effects and interactions of epinephrine, norepinephrine, timolol and betaxolol on outflow facility in the cynomolgus monkey. Am J Ophthalmol 109:189, 1990

97. Green K, Padgett D: Effects of various drugs on pseudofacility and aqueous humor formation in the rabbit eye. Exp Eye Res 28:239, 1979

98. Innemee HC, Van Zwieten PA: The influence of clonidine on intraocular pressure. Doc Ophthalmol 46:309, 1979

99. Innemee HC, Hermans AJM, van Zwieten PA: The influence of clonidine on intraocular pressure after topical application to the eyes of anesthetized cats. Albrecht von Graefes Arch Klin Exp Ophthalmol 212:19, 1979

100. Innemee HC, van Zwieten PA: An increase in intraocular pressure due to clonidine. Albrecht von Graefes Arch Klin Exp Ophthalmol 207:149, 1978

101. Innemee HC, van Ommeren JD, van Zwieten PA: The influence of acute and chronic cervical sympathectomy on the ocular hypotensive effect of clonidine. Albrecht von Graefes Arch Klin Exp Ophthalmol 212:11, 1979

102. Macri FJ, Cevario SJ: Clonidine effects on aqueous humor formation and intraocular pressure. Arch Ophthalmol 96:2111, 1978

103. Liu JHK, Neufeld AH: Study of central regulation of intraocular pressure using ventriculocisternal perfusion. Invest Ophthalmol Vis Sci 26:136, 1985

104. Sugiyama K, Kitazawa Y, Kawai K: Apraclonidine effects on ocular responses to YAG laser irradiation to the rabbit iris. Invest Ophthalmol Vis Sci 31:708, 1990

105. Takayanagi I, Shiraishi K, Kokubu N: α1ß-adrenoceptor mechanisms in rabbit iris dilator. Jpn J Pharmacol 59:301, 1992

106. Abdel-Latif AA, Greek K, Smith JP et al: Norepinephrine stimulated breakdown of triphosphoinositide of rabbit iris smooth muscle: Effects of surgical sympathetic denervation and in vivo electrical stimulation of the sympathetic nerve of the eye. J Neurochem 30:517, 1978

107. Colasanti BK, Barany EH: Potentiation of the mydriatic effect of norepinephrine in the rabbit after monoamine oxidase inhibition. Invest Ophthalmol Vis Sci 18:200, 1979

108. Langham ME, Simjee A, Josephs S: The alpha and beta adrenergic responses to epinephrine in the rabbit eye. Exp Eye Res 15:75, 1973

109. Rehavi M, Maayani S, Sokolovsky M: Tricyclic antidepressants as antimuscarinic drugs: In vivo and in vitro studies. Biochem Pharmacol 26:1559, 1977

110. Ishikawa S, Oono S, Hikita H: Drugs affecting iris muscle. In Dikstein S (ed): Drugs and Ocular Tissues. Basel, S. Karger, 1977

111. Colasanti BK, Trotter RR: Alterations in adrenergic sensitivity of the rabbit iris after variation of environmental lighting conditions. Invest Ophthalmol 15:44, 1976

112. Yousufzai SYK, Abdel-Latif AA: Alpha1-adrenergic receptor induced subsensitivity and supersensitivity in rabbit iris-ciliary body. Invest Ophthalmol Vis Sci 28:409, 1987

113. Srivastava YP, Jaju BP: Characterization of adrenoceptors of frog iris. Indian Exp Biol 20:612, 1982

114. Crosson CE, Heath AR, DeVries GW, Potter DE: Pharmacological evidence for heterogeneity of ocular α2-adrenoceptors. Curr Eye Res 11:963, 1992

115. Koss MC: Pupillary dilation as an index of central nervous system α2-adrenergic stimulation. J Pharmacol Methods 15:1, 1986

116. Pitts DK, Marwah J: Cocaine-elicited mydriasis in the rat: Pharmacologic comparison to clonidine, d-amphetamine and desipramine. J Pharmacol Exp Ther 247:815, 1988

117. Berridge TL, Gradie B, Roach AG, Tulloch IF: α2-Adrenoceptor agonists induce mydriasis in the rat by an action within the central nervous system. Br J Pharmacol 78:507, 1983

118. Koss MC: Studies on the mechanism of amphetamine mydriasis in the cat. J Pharmacol Exp Ther 213:49, 1980

119. Odin L, O'Donnell FE Jr: Adrenergic influence on iris stromal pigmentation: Evidence for alpha-adrenergic receptors. Invest Ophthalmol Vis Sci 23:528, 1982

119a. Chien DS, Schoenwald RD: Improving the ocular absorption of phenylephrine. Biopharm Drug Dispos 7:453, 1989

120. Mindel JS, Shaikewitz ST, Podos SM: Is phenylephrine pivalate a prodrug? Arch Ophthalmol 98:2220, 1980

120a. Van Buskirk EM, Bacon DR, Fahrenbach WH: Ciliary vasoconstriction after topical adrenergic drugs. Am J Ophthalmol 109:511, 1990

121. Engstrom P, Dunham EW: Alpha-adrenergic stimulation of prostaglandin release from rabbit iris-ciliary body in vivo. Invest Ophthalmol Vis Sci 22:757, 1982

122. Yohai D, Ganon A: Effect of adrenergic agonists on eicosanoid output from isolated rabbit choroid plexus and iris-ciliary body. Prostaglandins Leukotrienes Med 28:227, 1987

123. Morgan TR, Green K, Bowman K: Effects of adrenergic agonists upon regional ocular blood flow in normal and ganglionectomized rabbits. Exp Eye Res 32:691, 1981

124. Neufeld AH, Page ED: In vitro determination of the ability of drugs to bind to adrenergic receptors. Invest Ophthalmol Vis Sci 16:1118, 1977

125. Jin Y, Verstappen A, Yorio T: Characterization of α2-adrenoceptor binding sites in rabbit ciliary body membranes. Invest Ophthalmol Vis Sci 35:2500, 1994

126. Forster BA, Ferrari-Dileo G, Anderson DR: Adrenergic alpha1 and alpha2 binding sites are present in bovine retinal blood vessels. Invest Ophthalmol Vis Sci 28:1741, 1987

127. Haggendal J, Malmfors T: Identification and cellular localization of the catecholamines in the retina and the choroid of the rabbit. Acta Physiol Scand 64:58, 1965

128. Laties AM, Jacobowitz D: A comparative study of the autonomic innervation of the eye in monkey, cat and rabbit. Anat Rec 156:383, 1966

129. Wyse JPH, Lorscheider FL: Low retinal dopamine and serum prolactin levels indicate an inherited dopaminergic abnormality in BW rats. Exp Eye Res 32:541, 1981

130. Nesselhut T, Osborne NN: Is noradrenaline a major catecholamine in the bovine retina? Neurosci Lett 28:41, 1982

131. Hadjiconstantinou M, Cohen J, Neff NW: Epinephrine: A potential neurotransmitter in retina. J Neurochem 41:1440, 1983

132. Fukuda M, Ishimoto I, Kuwayama Y et al: Monamine accumulating neuron system in the rat retina with special reference to noradrenaline accumulating neurons. Exp Eye Res 43:487, 1982

133. Hadjiconstantinou M, Mariani AP, Panula P et al: Immunohistochemical evidence for epinephrine containing retinal amacrine cells. Neuroscience 13:547, 1984

134. Bittiger H, Heid J, Wigger N: Are only alpha-2 adrenergic receptors present in bovine retina? Nature 287:645, 1980

135. Osborne NN: Binding of (-)(3H) noradrenaline to bovine membrane of the retina: Evidence for the existence of alpha 2-receptors. Vis Res 22:1401, 1982

136. Munden PM, Kardon RH, Denison CE, Carter KD: Palpebral fissure responses to topical adrenergic drops. Am J Ophthalmol 111:706, 1991

137. Uncini A, DeNicola G, DiMuzio A et al: Topical naphazoline in treatment of myopathic ptosis. Acta Neurol Scand 87:322, 1993

138. Gharagozloo NZ, Relf SJ, Brubaker RF: Aqueous flow is reduced by the alpha-adrenergic agonist, apraclonidine hydrochloride (ALO2145). Ophthalmology 95:1217, 1988

139. Dixon RS, Anderson RL, Hatt MU: The use of thymoxamine in lid retraction. Arch Ophthalmol 97:2147, 1979

140. Chitkara DK, Hudson JM: Blepharoptosis caused by systemic thymoxamine. Am J Ophthalmol 111:524, 1991

141. Sneddon JM, Turner P: The effect of local guanethidine on the palpebral fissure and the pupil in thyrotoxicosis and its interaction with sympathomimetic amines. J Physiol (Lond) 189:20, 1967

142. Wright P: Adverse reactions to guanethidine eye drops. Br J Ophthalmol 71:323, 1987

143. Walkenbach RJ, Ye G-S, Reinach PS, Boney F: Alpha-adrenoceptors in human corneal epithelium. Invest Ophthalmol Vis Sci 32:3067, 1991

144. Zubareva TV, Kiseleva ZM: Catecholamine content of the lacrimal fluid of healthy people and glaucoma patients. Ophthalmologica 175:329, 1977

145. Trope GE, Rumley AG: Catecholamine concentrations in tears. Exp Eye Res 39:247, 1984

146. Meyer SM, Fraunfelter FT: Phenylephrine hydrochloride. Ophthalmology 87:1177, 1980

147. Isenberg SJ, Green BF: Effect of phenylephrine hydrochloride on conjunctival PO2. Arch Ophthalmol 102:1185, 1984

148. Fink AI, Funahashi T, Robinson M, Watson RJ: Conjunctival blood flow in sickle-cell disease: Preliminary report. Arch Ophthalmol 66:824, 1961

149. Serdahl CL, Galustian J, Lewis RA: The effects of apraclonidine on conjunctival oxygen tension. Arch Ophthalmol 107:1777, 1989

150. Fox SL, Samson CR, Danzig MR: Oxymetazoline in the treatment of allergic and non-infectious conjunctivitis. J Int Med Res 7:528, 1979

151. Abelson MB, Butrus SI, Weston JH, Rosner B: Tolerance and absence of rebound vasodilation following topical ocular decongestant usage. Ophthalmology 91:1364, 1984

152. Trope GE, Rumley AG: Catecholamines in human aqueous humor. Invest Ophthalmol Vis Sci 26:399, 1985

153. Gual A: Dopamine ß-hydroxylase activity in human aqueous humor. Exp Eye Res 37:99, 1983

154. Pollack IP, Rossi H: Norepinephrine in treatment of ocular hypertension and glaucoma. Arch Ophthalmol 93:173, 1975

155. Bigger JF: Norephrine therapy in patients allergic to or intolerant of epinephrine. Ann Ophthalmol 11:183, 1979

156. Pollack I: Effect of 1-norepinephrine and adrenergic potentiators on the aqueous dynamics of man. Am J Ophthalmol 76:641, 1973

157. Becker B, Gage T, Kolker AE, Gay AJ: The effect of phenylephrine hydrochloride on the miotic treated eye. Am J Ophthalmol 48:313, 1959

158. Harris LS: Cycloplegic-induced intraocular pressure elevations: A study of normal and open-angle glaucomatous eyes. Arch Ophthalmol 79:242, 1968

159. Posner A: Neo-Synephrine in glaucoma simplex. Am J Ophthalmol 31:222, 1948

160. Schimek RA, Liberman WJ: The influence of Cyclogyl and Neo-Synephrine on tonographic studies of miotic control in open-angle glaucoma. Am J Ophthalmol 51:781, 1951

161. Hill K: What's the angle on mydriasis? Arch Ophthalmol 79:804, 1968

162. Lee PF: The influence of epinephrine and phenylephrine in intraocular pressure. Arch Ophthalmol 60:863, 1958

163. Aggarwal JL, Beveridge B: Liberation of iris pigment in the anterior chamber after instillation of 10% phenylephrine hydrochloride solution. Br J Ophthalmol 55:544, 1971

164. Mitsui Y, Takagi Y: Nature of aqueous floaters due to sympathetic mydriatics. Arch Ophthalmol 65:626, 1961

165. Kristensen P: Mydriasis-induced pigment liberation in the anterior chamber associated with acute rise in intraocular pressure in open-angle glaucoma. Acta Ophthalmol 43:714, 1965

166. Mikelberg FS, Pinkerton RMH: The effect of topical phenylephrine on intraocular pressure in pseudoexfoliation. Glaucoma 4:114, 1982

167. Epstein DL, Boger WP III, Grant WM: Phenylephrine provocative testing in the pigmentary dispersion syndrome. Am J Ophthalmol 85:43, 1978

168. Lee DA, Brubaker RF: Effect of phenylephrine on aqueous humor flow. Curr Eye Res 2:89, 1982

169. Van Genderen MM, van Best JA, Oostoerhuis JA: The immediate effect on phenylephrine on aqueous flow in man. Invest Ophthalmol Vis Sci 29:1469, 1988

170. Araie M, Mori M, Oshika T: Effect of topical phenylephrine on the permeability of the blood-aqueous barrier in man. Graefes Arch Clin Exp Ophthalmol 230:171, 1992

171. Hasslinger C: Catapresan [2-(2,6-dichlorophenylamino)-2 imidazolhydrochlorid]--ein neues augendruchksenkindes medikament. Klin Monatsbl Augenheilkd 154:95, 1969

172. Edelhauser E, Nemetz U: Zur intrackularen Drucksenkung mit Clonidin. Klin Monatsbl Augenheilkd 160:188, 1969

173. Krieglstein GK, Langham ME, Leydhecker W: The peripheral and central neural actions of clonidine in normal and glaucomatous eyes. Invest Ophthalmol 17:149, 1978

174. Hodapp E, Kolker AE, Kass MA et al: The effect of topical clonidine on intraocular pressure. Arch Ophthalmol 99:1208, 1981

175. Lee DA, Topper JE, Brubaker RF: Effect of clonidine on aqueous humor flow in normal human eyes. Exp Eye Res 38:239, 1984

176. Petursson G, Cole R, Hanna C: Treatment of glaucoma using minidrops of clonidine. Arch Ophthalmol 102:1180, 1984

177. Coleman AL, Robin AL, Pollack IP et al: Cardiovascular and intraocular pressure effects and plasma concentrations of apraclonidine. Arch Ophthalmol 108:1264, 1990

178. Robin AL: Short-term effects of unilateral 1% apraclonidine therapy. Arch Ophthalmol 106:912, 1988

179. Koskela T, Brubaker R: Apraclonidine and timolol: Combined effects in previously untreated normal eyes. Arch Ophthalmol 109:804, 1991

180. Abrams DA, Robin LA, Pollack IP et al: The safety and efficacy of topical 1% ALO 2145 (p-aminoclonidine hydrochloride) in normal volunteers. Arch Ophthalmol 105:1205, 1987

181. Jampel HD, Robin AL, Quigley HA, Pollack IP: Apraclonidine--a one-week dose-response study. Arch Ophthalmol 106:1069, 1988

182. Davis JN, Maury W: Clonidine and related imidazolines are postsynaptic alpha adrenergic antagonists in dispersed rat parotid cells. J Pharmacol Exp Ther 207:425, 1978

183. Abrams DA, Robin AL, Crandall AS et al: A limited comparison of apraclonidine's dose response in subjects with normal or increased intraocular pressure. Am J Ophthalmol 108:230, 1989

184. Gharagozloo NZ, Brubaker RF: Effect of apraclonidine in long-term timolol users. Ophthalmology 98:1543, 1991

185. Yaldo MK, Shin DH, Parrow KA et al: Additive effective of 1% apraclonidine hydrochloride to non-selective ß-blockers. Ophthalmology 98:1075, 1991

186. Morrison JC, Robin AL: Adjunctive glaucoma therapy: A comparison of apraclonidine to dipivefrin when added to timolol maleate. Ophthalmology 96:3, 1989

187. Lish AJ, Camras CB, Podos SM: Effect of apraclonidine on intraocular pressure in glaucoma patients receiving maximally tolerated medications. J Glaucoma 1:19, 1992

188. Robin L, Pollack IP, de Faller JM: Effects of topical ALO 2145 (p-aminoclonidine hydrochloride) on the acute intraocular pressure rise after argon laser therapy. Arch Ophthalmol 105:1208, 1987

189. Brown RH, Stewart RH, Lynch MG et al: ALO2145 reduces the intraocular pressure elevation after anterior segment laser surgery. Ophthalmology 95:378, 1988

190. Barknebey HS, Robin AL, Zimmerman TJ et al: The efficacy of brimonidine in decreasing elevations in intraocular pressure after laser trabeculoplasty. Ophthalmology 100:1083, 1993

191. Holmwood PC, Chase RD, Krupin T et al: Apraclonidine and argon laser trabeculoplasty. Am J Ophthalmol 114:19, 1992

192. Nesher R, Kolker AE: Delayed increased intraocular pressure after Nd:YAG laser posterior capsulotomy in a patient treated with apraclonidine. Am J Ophthalmol 110:94, 1990

193. Romanowski A: Prophylactic use of apraclonidine for intraocular pressure increase after Nd:YAG capsulotomies. Am J Ophthalmol 114:377, 1992

194. Dapling RB, Cunliffe IA, Longstaff S: Influence of apraclonidine and pilocarpine alone and in combination on post laser trabeculoplasty pressure rise. Br J Ophthalmol 78:30, 1994

195. Araie M, Ishi K: Effects of apraclonidine on intraocular pressure and blood-aqueous barrier permeability after phacoemulsification and intraocular lens implantation. Am J Ophthalmol 116:67, 1993

196. Prata JA, Rehder CL Jr, Mello PAA: Apraclonidine and early postoperative intraocular hypertension after cataract extraction. Acta Ophthalmol 70:434, 1992

197. Wiles SB, MacKenzie D, Ide CH: Control of intraocular pressure with apraclonidine hydrochloride after cataract extraction. Am J Ophthalmol 111:184, 1991

198. Robin AL: Effect of topical apraclonidine on the frequency of intraocular pressure elevations after combined extracapsular cataract extraction and trabeculectomy. Ophthalmology 100:628, 1993

199. Hill RA, Minckler DS, Lee M et al: Apraclonidine prophylaxis for postcycloplegic intraocular pressure spikes. Ophthalmology 98:1083, 1991

200. Jaakola ML, Ali-Melkkila T, Kanto J et al: Dexmedetomidine reduces intraocular pressure, intubation responses and anesthetic requirements in patients undergoing ophthalmologic surgery. Br J Anaesth 68:570, 1992

201. Virkkila M, Ali-Melkkila T, Kanto J et al: Dexmedetomidine as intramuscular premedication in outpatient cataract surgery. Anaesthesia 48:482, 1993

202. Mehra KS, Roy PN, Singh R: Pargyline drops in glaucoma. Arch Ophthalmol 92:453, 1974

203. Johnson EM, Marcia RA, Yellin TO: Marked difference in the susceptibility of several species to guanethidine induced chemical sympathectomy. Life Sci 20:107, 1977

204. Hendley ED, Eakins KE: The mechanism of action of guanethidine on aqueous humor dynamics. J Pharmacol Exp Ther 150:393, 1965

205. Bonomi L, DiComite P: Outflow facility after guanethidine sulphate administration. Arch Ophthalmol 78:337, 1967

206. Paterson GD, Paterson G: Drug therapy of glaucoma. Br J Ophthalmol 56:288, 1972

207. Nagasubramanias S, Tripathi RC, Poinoosawmy D, Gloster J: Low concentration guanethidine and adrenaline therapy of glaucoma. Trans Ophthalmol Soc UK 96:179, 1976

208. Hoyng PFJ, Dake CL: The combination of guanethidine 3% and adrenaline 0.5% in one eye drop (GA) in glaucoma treatment. Br J Ophthalmol 63:56, 1979

209. Hoyng PFJ: Verification of the biphasic response in intraocular pressure during treatment of glaucoma patients with 3% guanethidine and 0.5% adrenaline. Doc Ophthalmol 51:161, 1981

210. Riley RC, Moyer NJ: Experimental Horner's syndrome--a pupillographic evaluation of guanethidine-induced adrenergic blockade in humans. Am J Ophthalmol 69:442, 1970

211. Murray A, Glover D, Hitchings R: Low-dose combined guanethidine 1% and adrenaline 0.5% in the treatment of chronic simple glaucoma: A prospective study. Br J Ophthalmol 65:533, 1981

212. Akagi Y, Ibata Y, Sano Y: The sympathetic innervation of the ciliary body and trabecular meshwork of the cat. Cell Tissue Res 173:261, 1976

213. Schwartz AL, Alper MG, Helfgott M: 6-Hydroxydopamine in the treatment of open-angle glaucoma. Am J Ophthalmol 92:792, 1981

214. Diamond JG: 6-Hydroxydopamine in treatment of open-angle glaucoma. Arch Ophthalmol 94:41, 1976

215. Jumblatt JE, Hackmiller RC: M2-type muscarinic receptors mediate prejunctional inhibition of norepinephrine release in the human iris-ciliary body. Exp Eye Res 58:175, 1994

216. Davanger M: The pupillary dilation curve after mydriatics. Acta Ophthalmol 49:565, 1971

217. Haddad NJ, Moyer NJ, Riley FC: Mydriatic effect of phenylephrine hydrochloride. Am J Ophthalmol 70:729, 1970

218. Weiss DL, Shaffer RN: Mydriatic effects of one-eighth per cent phenylephrine. Arch Ophthalmol 68:727, 1962

219. Thornton CN, Hanna C: Mydriasis from topically administered phenylephrine HCl powder. Am J Ophthalmol 89:809, 1980

220. Folk JC, Kumar V, Piper JG et al: Aqueous vs viscous phenylephrine. II. Mydriatic effects. Arch Ophthalmol 104:1192, 1986

221. Duffin RM, Pettit TH, Straatsma BR: 2.5% vs 10% phenylephrine in maintaining mydriasis during cataract surgery. Arch Ophthalmol 101:1903, 1983

222. Corbett MC, Richards AB: Intraocular adrenaline maintains mydriasis during cataract surgery. Br J Ophthalmol 718:95, 1994

223. Davis PB: Pupillary responses and airway reactivity in asthma. J Allergy Clin Immunol 77:667, 1986

224. Isenburg S, Everett S, Paralhoff E: A comparison of mydriatic eyedrops in low-weight infants. Ophthalmology 91:278, 1984

225. Lees BL, Cabal LA: Increased blood pressure following pupillary dilation with 2.5% phenylephrine hydrochloride in pre-term infants. Pediatrics 68:231, 1981

226. Lynch MG, Brown RH, Goode SM et al: Reduction of phenylephrine drop size in infants achieves axial dilation with decreased absorption. Arch Ophthalmol 105:1364, 1987

227. Mapstone R: The fellow eye. Br J Ophthalmol 65:410, 1981

228. Wishart PK: Does the pilocarpine phenylephrine provocative test help in the management of acute and subacute angle closure glaucoma. Br J Ophthalmol 75:284, 1991

229. Chin NB, Gold A, Breinin GM: Iris cysts and miotics. Arch Ophthalmol 71:611, 1964

230. Peet M, Yates RA, Shields AG: Dose-response relationship for mydriasis produced by topical ocular tyramine in man. Br J Clin Pharmacol 9:96, 1980

231. Ghose K: Correlation of pupil reactivity to tyramine or hydroxyamphetamine and tyramine pressor responses in patients treated with amitryptyline or mianserin. Br J Clin Pharmacol 3:666, 1976

232. Szabadi E, Besson J, Bradshaw CM: Pupil responsiveness to tyramine in depressed patients treated with amitryptyline. Br J Clin Pharmacol 2:362, 1975

233. Bevan-Jones B, Lind NA: Interactions of monamine oxidase inhibition and sympathomimetic amines on the iris. Br J Pharmacol 41:428p, 1971

234. Sneddon JM, Turner P: The interactions of local guanethidine and sympathomimetic amines in human eye. Arch Ophthalmol 81:622, 1969

235. Utnoff W: Zur diagnostischen Bedeutung der reflectorischen Pupillerstarre. Berl Klin Wochenschr 23:54, 1886

236. Friedman JR, Whiting DW, Kosmorsky GS, Burde RM: The cocaine test in normal patients. Am J Ophthalmol 98:808, 1984

237. Kardon RH, Denison CE, Brown CK, Thompson HS: Critical evaluation of the cocaine test in the diagnosis of Horner's syndrome. Arch Ophthalmol 108:384, 1990

238. Arnold SE, Kahn RJ, Faldetta LL et al: Tricyclic antidepressants and peripheral anticholinergic activity. Psychopharmacology 74:325, 1981

239. Gundersen T, Liebman SD: Effect of local anesthetics on regeneration of corneal epithelium. Arch Ophthalmol 31:29, 1944

240. Sachs R, Zagelbaum BM, Hersh PS: Corneal complications associated with the use of crack cocaine. Ophthalmology 100:187, 1993

241. Bralliar BB, Skarf B, Owens JB: Ophthalmic use of cocaine and the urine test for benzoylecgonine. N Engl J Med 320:1757, 1989

242. Cremer SA, Thompson HS, Digre KB, Kardon RH: Hydroxyamphetamine mydriasis in normal subjects. Am J Ophthalmol 110:66, 1990

243. Thompson HS, Mensher JH: Adrenergic mydriasis in Horner's syndrome. Am J Ophthalmol 72:472, 1971

244. Trendelenburg U, Muskus A, Fleming WW, Gomez Alonso de la Sierra B: Modification by reserpine of the action of sympathomimetic amines. J Pharmacol Exp Ther 138:170, 1962

245. Maloney WF, Younge BR, Moyer NJ: Evaluation of the causes and accuracy of pharmacologic localization in Horner's syndrome. Am J Ophthalmol 90:394, 1980

246. Cremer SA, Thompson HS, Digre KB, Kardon RH: Hydroxyamphetamine mydriasis in Horner's syndrome. Am J Ophthalmol 110:71, 1990

247. Thompson HS: Diagnosing Horner's syndrome. Trans Am Acad Ophthalmol Otol 83:840, 1977

248. Okajiima T, Imamura S, Kawasaki S et al: Fisher's syndrome: A pharmacologic study of the pupils. Ann Neurol 2:63, 1977

249. Mytilineou C, Black IB: Regeneration of sympathetic neurons: Effect of decentralization. Brain Res 109:382, 1976

250. Weinstein JW, Zweifel TJ, Thompson HS: Congenital Horner's syndrome. Arch Ophthalmol 98:1074, 1980

251. Matsuo T, Cynader MS: Localization of alpha-2 adrenergic receptors in the human eye. Ophthalmic Res 245:213, 1992

252. Heal DJ, Prow MR, Buckett WR: Clonidine-induced hypoactivity and mydriasis in mice are respectively mediated via pre- and postsynaptic α2-adrenoceptors in the brain. Eur J Pharmacol 170:19, 1989

253. Hey JA, Ito T, Koss MC: α-Methyldopa produces mydriasis in the rat by stimulation of CNS α2 adrenoceptors. Br J Pharmacol 94:834, 1988

254. Gherezghiher T, Christensen HD, Koss MC: Studies on the mechanism of methyl-dopa-induced mydriasis in the cat. Naunyn Schmiedebergs Arch Pharmacol 320:58, 1982

255. Clifford JM, Day MD, Orwin JM: Reversal of clonidine induced miosis by the α2-adrenoceptor antagonist RX781094. Br J Clin Pharmacol 14:99, 1982

256. Relf SJ, Gharagozloo NZ, Skuta GL et al: Thyroxamine reverses phenylephrine-induced mydriasis. Am J Ophthalmol 106:251, 1988

257. Creuzet MH, Prat G, Malek A et al: In vitro and in vivo α-blocking activity of thymoxamine and its two metabolites. J Pharm Pharmacol 32:209, 1980

258. Wand M, Grant WM: Thymoxamine hydrochloride: Effects on the facility of outflow and intraocular pressure. Invest Ophthalmol 15:400, 1976

259. Lee DA, Brubaker RF, Nagataki S: Effect of thymoxamine on aqueous humor formation in the normal human eye as measured by fluorophotometry. Invest Ophthalmol Vis Sci 21:805, 1981

260. Susanna R, Drance SM, Schulzer M, Douglas GR: The effects of thymoxamine on anterior chamber depth in human eyes. Can J Ophthalmol 13:250, 1978

261. Grehn F: Intraocular thymoxamine for miosis during surgery. Am J Ophthalmol 103:709, 1987

262. Wright MM, Skuta GL, Drake MV et al: Time course of thymoxamine reversal of phenylephrine-induced mydriasis. Arch Ophthalmol 108:1729, 1990

263. Diehl DLC, Robin AL, Wand M: The influence of iris pigmentation on the miotic effect of thymoxamine. Am J Ophthalmol 111:351, 1991

264. Ruthowski PC, Fernandez JL, Galin MA, Halasa H: Alpha-adrenergic receptor blockade in the treatment of angle-closure glaucoma. Trans Am Acad Ophthalmol Otol 77:137, 1973

265. Mapstone R: Safe mydriasis. Br J Ophthalmol 54:690, 1970

266. Wand M, Grant WM: Thymoxamine test. Arch Ophthalmol 96:1009, 1978

267. Oshika T, Araie M, Sugiyama et al: Effect of bunazosin hydrochloride on intraocular pressure and aqueous humor dynamics in normotensive human eyes. Arch Ophthalmol 109:1569, 1991

268. Trew DR, Wright LA, Smith SE: Ocular responses in healthy subjects to topical bunazosin 0.3% an α1-adrenoceptor antagonist. Br J Ophthalmol 75:411, 1991

269. Bonomi L, Michieletto S, Marchini G et al: Effects of ocular instillations of dapiprazole on pupil motility. Clin Ther Res 34:469, 1983

270. Zeterstrom C, Hahnenberger R: Pharmacological characterization of human ciliary muscle adrenoceptors in vitro. Exp Eye Res 46:421, 1988

271. Matsuo T, Cynader MS: Localization of alpha-2 adrenergic receptors in the human eye. Ophthalmic Res 24:213, 1992

272. Garner LF, Brown B, Barker R, Colgan M: The effect of phenylephrine hydrochloride on the resting point of accommodation. Invest Ophthalmol Vis Sci 24:393, 1983

273. Zetterstrom C: Effects of adrenergic drugs on accommodation and distant refraction in daylight and darkness. Acta Ophthalmol 66:58, 1988

274. Rebolleda F, Munoz FJ, Victoria MF et al: Effects of pupillary dilation on automated perimetry in glaucoma patients receiving pilocarpine. Ophthalmology 99:418, 1992

275. Laties AM: Central retinal artery innervation: Absence of adrenergic innervation to the intraocular branches. Arch Ophthalmol 77:405, 1967

276. Robinson F, Petrig BL, Sinclair SH et al: Does topical phenylephrine tropicamide or proparacaine affect macular blood flow? Ophthalmology 92:1130, 1985

277. Yu D-Y, Alder VA, Su E-N et al: Agonist response of human isolated posterior ciliary artery. Invest Ophthalmol Vis Sci 33:48, 1992

278. Robinson F, Chen S, Petrig BL et al: The acute effect of topical epinephrine on macular blood flow in humans. Invest Ophthalmol Vis Sci 33:18, 1992

279. McReynolds WU, Havener WH, Henderson JW: Hazards of sympathomimetic drugs in ophthalmology. Arch Ophthalmol 56:176, 1956

280. Vaughan RW: Ventricular arrhythmias after topical vasoconstrictors. Anesth Analg 52:161, 1973

281. Solosko D, Smith RB: Hypertension following 10% phenylephrine ophthalmic. Anesthesiology 36:187, 1972

282. Wilensky JT, Woodward H: Acute systemic hypertension after conjunctival instillation of phenylephrine hydrochloride. Am J Ophthalmol 76:156, 1973

283. Matthews TG, Wilczek AM, Shennan AT: Eyedrop induced hypertension. Lancet 2:827, 1977

284. Borromeo-McGrail V, Bordiuk JM, Keitel H: Systemic hypertension following ocular administration of 10% phenylephrine in the neonate. Pediatrics 51:1032, 1973

285. Kumar V, Schoenwald RD, Barcellos WA et al: Aqueous vs viscous phenylephrine. I. Systemic absorption and cardiovascular effects. Arch Ophthalmol 104:1189, 1986

286. Kumar V, Schoenwald RD, Chien DS et al: Systemic absorption and cardiovascular effects of phenylephrine eyedrops. Am J Ophthalmol 99:180, 1985

287. Epstein DL, Murphy E: Effect of combined 1% cyclopentolate-10% phenylephrine eye drops in systemic blood pressure of glaucoma patients. Ann Ophthalmol 13:735, 1981

288. Smith RB, Read S, Oczypok PM: Mydriatic effect of phenylephrine. Eye Ear Nose Throat Monthly 55:36, 1976

289. Fraunfelder FT, Scafidi AF: Possible adverse effects from topical ocular 10% phenylephrine. Am J Ophthalmol 85:447, 1978

290. Wellwood M, Goresky GV: Systemic hypertension associated with topical administration of 2.5% phenylephrine HCl. Am J Ophthalmol 93:369, 1982

291. Van Alyea OE, Donnelly WA: Systemic effects of intranasal medication. Eye Ear Nose Throat Monthly 31:476, 1952

292. Heath P, Geiter CW: Use of phenylephrine hydrochloride (Neo-Synephrine hydrochloride) in ophthalmology. Arch Ophthalmol 41:172, 1940

293. Brown MM, Brown GC, Spaeth GL: Lack of systemic effects of topical ocular 10% phenylephrine. Invest Ophthalmol Vis Sci 18 (suppl):276, 1979

294. Brown MM, Brown GC, Spaeth GL: Lack of side effects from topically administered 10% phenylephrine eyedrops: A controlled study. Arch Ophthalmol 98:487, 1980

295. Robertson D: Contraindication to the use of ocular phenylephrine in idiopathic orthostatic hypotension. Am J Ophthalmol 87:819, 1979

296. Fraunfelder FT, Meyer SM: Possible cardiovascular effects secondary to topical ophthalmic 2.5% phenylephrine. Am J Ophthalmol 99:362, 1985

297. Kim JM, Stevenson CE, Mathewson HS: Hypertensive reactions to phenylephrine eyedrops in patients with sympathetic denervation. Am J Ophthalmol 85:862, 1978

298. Reeves RA, Boer WH, DeLeve L, Leenen FHH: Non-selective beta-blockade enhances pressor responsiveness to epinephrine, norepinephrine and angiotensin II in normal man. Clin Pharmacol Ther 35:461, 1984

299. Harris WS, Schoenfeld CD, Brooks RH, Wessler AM: Effect of beta-adrenergic blockade on the hemodynamic responses to epinephrine in man. Am J Cardiol 17:484, 1966

300. Levine MAH, Leenen FHH: Role of vagal activity in the cardiovascular responses to phenylephrine in man. Br J Clin Pharmacol 33:333, 1992

301. Geyer O, Neudorfer M, Lazar M et al: Cellular sensitivity in allergic blepharoconjunctivitis due to phenylephrine eyedrops. Graefes Arch Clin Exp Ophthalmol 231:748, 1993

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