Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

Acute pain with no previous treatment?

Acetaminophen

Inadequate analgesia with 1,000 mg of acetaminophen four times per day?

NSAIDs contraindicated?

Start ibuprofen, 400 mg every four to six hours, advancing to higher dosage if needed.

Inadequate analgesia?

Use hydrocodone-acetaminophen combination.

Inadequate analgesia with hydrocodoneacetaminophen ± ibuprofen?

Consider other NSAIDs or COX-2 inhibitors (if not contraindicated) or oral oxycodone (Roxicodone), morphine (Duramorph), or advance to higher level of care (parenteral

analgesia and/or pain-management specialist).

Figure 7-2 Algorithm for the treatment of most patients with acute pain. (NSAIDs = nonsteroidal anti-inflammatory drugs; COX = cyclooxygenase) (Adapted from Sacks CJ. Oral analgesics for acute nonspecfic pain. Am Fam Physician 2005;71:913–918.)

opioid agents. In ophthalmic practice the treatment of acute trauma may involve pressure patching, bandage (or disposable) contact lenses, cold compresses, cycloplegics, or various combinations of these modalities as required for treatment of large corneal abrasions, external ocular foreign bodies, or anterior uveitis. These ancillary strategies can have analgesic-like qualities and may be extremely useful in enhancing the pain-relieving effects of the analgesics. Furthermore, orally administered caffeine can be effective not only in enhancing analgesia but also in overcoming the drowsiness and sedation associated with the opioid analgesics. Continuous or long-term topical anesthetics should never be used to augment orally administered analgesics. The risks of local complications far outweigh the benefits from the unsupervised administration of topical anesthetics (see Chapter 6).

Although many analgesics are available for clinical use,few opioid and nonopioid analgesics have widely accepted pediatric dosage guidelines. The drugs listed in Table 7-9 are the most commonly prescribed for children, and it is recommended that those dosage schedules approved by the U.S. Food and Drug Administration be used.

Treatment of Mild to Moderate Pain

As in adults, mild pain in children is initially treated with nonopioids. Because of its association with Reye’s syndrome, aspirin has been abandoned in pediatric practice in favor of safer agents,such as acetaminophen and the nonsalicylate NSAIDs. Acetaminophen is as effective as aspirin for treatment of pain in children and produces very few serious side effects when given in therapeutic doses. The recommended dosage is approximately 10 mg/kg orally every 4 hours or 10 to 15 mg/kg rectally every 4 hours, with a maximum of five doses in a 24-hour period. Rectal absorption may be inconsistent, and a larger dose of acetaminophen is sometimes required to achieve effective plasma levels. Because of its favorable safety profile, acetaminophen is often the first agent used for most children with mild to moderate pain, but it can also be of benefit in more severe pain as an adjunct to opioid analgesia.

The nonsalicylate NSAIDs are especially useful for pain of inflammatory origin.These analgesics are relatively safe, are well tolerated, have few serious side effects, can decrease or even eliminate the need for opioids, and are nonaddictive. NSAIDs that have been used effectively and are approved for use in children include ibuprofen, naproxen, and tolmetin. Because all these drugs can cause gastritis, they should be taken with meals. If GI side effects persist with one NSAID, an alternative agent should be selected.

Treatment of Moderate to Severe Pain

Treatment of moderate to severe pain requires use of opioid analgesics combined with nonopioids such as acetaminophen. An elixir containing 120 mg acetaminophen and 12 mg codeine per 5 ml is generally effective.

Table 7-9

Analgesics Commonly Used in Children

PO = oral; PR = rectal.

The oral route of administration should be used whenever possible.

Codeine is the most commonly prescribed opioid analgesic for treatment of moderate to severe pain in ambulatory children older than 3 years of age. Several preparations are available (i.e., liquids or tablets), and use is determined by the patient’s age and preference. The recommended initial pediatric dosage for codeine is 0.5 to 1.0 mg/kg orally along with 10 mg/kg acetaminophen, every 4 to 6 hours, administered concurrently. Although dosing is based on the codeine component, the amount of acetaminophen should not exceed the recommended dosage of 15 mg/kg every 4 hours.

Management of Side Effects

Stool softeners and cathartics can be used in children, as in adults, to relieve symptoms of constipation. Nausea and vomiting generally diminish as opioid therapy is continued, but antihistamines with antiemetic effects, such as hydroxyzine or promethazine, may be helpful as adjuvants to diminish unpleasant GI symptoms. Reducing the opioid dose to minimal analgesic levels may help to limit sedation or drowsiness. Mild respiratory depression, an uncommon side effect in children, may require only that the opioid dose be reduced.

ANALGESIC USE IN ELDERLY PATIENTS

Prescribing analgesics for elderly patients can be difficult. Older patients are much more likely than younger ones to experience GI and other side effects of drug use. In addition, they are generally taking more medications that may interact with the prescribed analgesic. Other factors, such as reduced renal and hepatic function, can also affect the efficacy and accumulation of the analgesic,thus increasing the risk of drug toxicity.

Practitioners must therefore take a careful medical and drug history to determine potential contraindications to analgesics. Prior analgesic use should be reviewed to determine, if possible, what analgesics were effective and what side effects, if any, occurred. This review is a very practical process in selecting the proper analgesic for all patients, especially the elderly. Acute renal failure induced by the NSAIDs is more common in older patients, especially in those who are taking diuretics or who have congestive heart failure, liver disease, or kidney disease. Safer analgesics for these patients include sulindac (Clinoril) or a nonacetylated salicylate. Ibuprofen and diclofenac are potential alternatives because they do not tend to accumulate in patients with renal impairment. Acetaminophen is another option, because it rarely causes acute renal failure when used on a short-term basis.

One of the major problems with use of NSAIDs in elderly patients, especially women, is the increased incidence of gastric mucosal damage (NSAID gastropathy). This condition can lead to significant GI bleeding and

even death. Options for preventing or treating this problem include the following: (1) use of drugs that may produce less gastric irritation, such as ibuprofen, fenoprofen, diclofenac, COX-2 inhibitors, choline–magnesium salicylate, enteric-coated aspirin, or acetaminophen; (2) use of an H2 blocker, such as ranitidine or famotidine prophylactically; (3) use of misoprostol (Cytotec), a synthetic prostaglandin E1 analogue, which inhibits gastric acid secretion while possessing mucosal protective properties; and (4) use of omeprazole (Prilosec), a proton pump inhibitor, which significantly reduces gastric acid secretion and may have fewer side effects than misoprostol.

Most patients having cataract extraction are elderly, and some may have bleeding disorders. Because acetaminophen and the nonacetylated salicylates affect platelet aggregation only minimally, these analgesics are preferred for preoperative or postoperative use.

Treatment of Mild to Moderate Pain

The most useful nonopioid analgesics for treatment of pain in the elderly are listed in Box 7-3. For treatment of mild to moderate acute pain, a practical approach is to initiate therapy with acetaminophen, 650 to 1,000 mg to a maximum of 4,000 mg/day. If pain continues, an NSAID should be substituted. If pain still persists, an alternative NSAID, preferably from a different therapeutic class, should be selected. If the alternative NSAID is ineffective, full-dose acetaminophen combined with an NSAID should be considered. Combinations of several NSAIDs, however, should not be used. This approach is often effective without resorting to the use of opioid analgesics.

Treatment of Moderate to Severe Pain

Elderly patients in moderate to severe pain may require narcotic analgesics, but the use of opioids can be associated with significant toxicity because of the unique metabolic and physiologic alterations in aging patients.

Box 7-3 Preferred Analgesics for Use in

Elderly Patients

Nonopioids

Acetaminophen

Ibuprofen

Diclofenac

Diflunisal

Fenoprofen

Naproxen sodium

COX-2 inhibitors

Opioids

Codeine with acetaminophen

Oxycodone with acetaminophen

Opioids are detoxified in the liver.The metabolic capacity of the liver declines with age, thus reducing drug clearance and enhancing the cumulative effects of narcotics. This is of special concern in elderly patients with heart failure or liver disease. In addition, the degree of analgesia and CNS depression produced by opioids is enhanced by normal aging, especially in patients with preexisting CNS dysfunction such as stroke or dementia. Furthermore, opioid-induced respiratory depression is enhanced in the elderly and in persons with depressed CO2 drives associated with obesity or chronic obstructive pulmonary disease. Urinary retention can also be a problem in elderly men with benign prostatic hypertrophy.

The opioid analgesics of choice for use in the elderly are listed in Box 7-3. For treatment of moderate to severe pain, an effective opioid regimen consists of a combination of acetaminophen with 15 to 60 mg codeine or acetaminophen with 5 to 30 mg oxycodone.Acetaminophen combinations with hydrocodone are also frequently used. If pain persists, an alternative opioid analgesic should be selected. Adjuvants such as caffeine may enhance the analgesic activity of the opioid.

Management of Side Effects

Opioid-induced constipation is more troublesome in older patients, and it should be anticipated by instituting laxative therapy along with the narcotic.A typical laxative regimen consists of psyllium and a stool softener. A mild stimulant laxative such as bisacodyl (Dulcolax) can be added if constipation becomes problematic.

Nausea and vomiting are other opioid-induced effects that are more significant in elderly patients. Nausea can result from vestibular stimulation, so limiting physical activity may be useful to reduce symptoms.If drug therapy is needed, hydroxyzine is preferable to a phenothiazine. Because the antihistamines have significant anticholinergic effects that can be troublesome in elderly individuals, these drugs should not be routinely given with the opioid unless absolutely needed.

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Drugs that stimulate the adrenergic division of the autonomic nervous system, referred to as “sympathomimetics” or “adrenergic agonists,” can affect various ocular functions, including pupil size, width of the palpebral fissure, diameter of ocular blood vessels, and aqueous flow and accommodation. In clinical practice these agents are used for pupillary dilation (see Chapter 20), pharmacologic testing for oculosympathetic lesions (Horner’s syndrome) (see Chapter 22), vasoconstriction of conjunctival vessels and relief of minor allergic reactions (see Chapters 13 and 27), and, on occasion, treatment of ptosis (see Chapter 23). When used for dilating the pupil they are usually referred to clinically as mydriatics.

Drugs that block action of the sympathetic nervous system are known as adrenergic receptor antagonists, antiadrenergics, or adrenergic-blocking agents. Drugs that block β receptors are used clinically to control intraocular pressure (IOP) (see Chapters 10 and 34).The α-receptor–blocking agents, referred to clinically as mydriolytics, can be useful to reverse the effects of mydriatic drugs.This chapter presents an overview of the adrenergic innervation to the eye and considers the pharmacologic actions,uses,side effects,and contraindications of mydriatics and mydriolytics in current clinical use.

ADRENERGIC INNERVATION

TO THE EYE

The sympathetic innervation to the eye, as previously described, originates from the posterior and lateral nuclei of the hypothalamus. Fibers descend through the lateral aspects of the brainstem to the intermediolateral columns in the cervical cord. Myelinated preganglionic neurons emerge from the thoracic section (C8-T2) of the spinal cord through the anterior roots. They then ascend over the apex of the lung through the stellate ganglion and the cervical sympathetic chain to synapse in the superior cervical ganglion (Figure 8-1). This part of the pathway comprises the preganglionic portion.

Unmyelinated fibers emerge from the superior cervical ganglion and course toward the cavernous sinus by

following the carotid plexus adjacent to the carotid artery. There, the fibers cross over the sixth cranial nerve and join the ophthalmic division of the fifth nerve. The fibers then bypass the ciliary ganglion and accompany the long ciliary nerves to the iris dilator muscle and Müller’s muscle of the eyelid, thus completing the postganglionic portion of the oculosympathetic pathway (see Figure 8-1).

Previous studies have shown that accommodation mediated via ciliary smooth muscle activity also receives sympathetic innervation. Sympathetic nerves reach the ciliary muscle through the uveal blood vessels in close association with arteries and terminal arterioles. The distribution of the adrenergic fibers in the ciliary muscle appears to vary across species. In primates sympathetic nerve terminals, mainly β receptors, can generally be found in the anterior portion of the ciliary muscle. The accommodative amplitude significantly decreased in human subjects after instillation of phenylephrine (an α agonist) or hydroxyamphetamine (an α and β agonist). Such observations provide evidence that both sympathetic and parasympathetic divisions of the autonomic nervous system can affect accommodation but not equally. Furthermore, the nature of sympathetic innervation can be summarized as follows:

1.The sympathetic input is inhibitory in nature and mediated via β-adrenergic receptors, predominantly of the β2 subgroup.

2.The input is relatively small with respect to the prominent parasympathetic output and has a maximum dioptric value of around –1.50 D.

3.The time course of sympathetic activity is significantly slower than that of parasympathetic activity, taking 10 to 40 seconds to reach its maximum effect. In contrast, parasympathetically mediated responses are completed in approximately 1 to 2 seconds for normal visual environments.

4.Sympathetic activity appears to be augmented by

concurrent parasympathetic activity.

The posterior half of the trabecular meshwork and the inner wall of Schlemm’s canal also contain adrenergic

nerve terminals. Certain orbital muscles also receive adrenergic innervation. The tonic contraction of the tarsal smooth muscle of the upper lid (Müller’s muscle) is under adrenergic control. The convergence mechanism through the lateral rectus muscle is also at least partially controlled by adrenergic innervation. In addition, there is adrenergic control of intraocular and orbital muscles, cornea, lens, and retina.

MYDRIATICS

Phenylephrine

Pharmacology

Phenylephrine is a synthetic sympathomimetic amine structurally similar to epinephrine. It acts primarily on α1 receptors and has little or no effect on β receptors. A minor part of its pharmacologic effects may be attributed to release of norepinephrine from adrenergic nerve terminals.

After topical application phenylephrine contracts the iris dilator muscle and smooth muscle of the conjunctival arterioles, causing pupillary dilation and blanching of the

conjunctiva, respectively. Müller’s muscle of the upper lid is stimulated, which widens the palpebral fissure. IOP may decrease in normal eyes and in eyes with open-angle glaucoma.

Preparations of phenylephrine used for mydriasis are available in 2.5% and 10% solutions (Table 8-1). The designated Pregnancy Category for phenylephrine hydrochloride is C. In solution, phenylephrine is clear and is colorless to slightly yellow. Like all adrenergic agonists, it is subject to oxidation on exposure to air, light, or heat. To prolong its shelf life, an antioxidant, sodium bisulfite, is frequently added to the vehicle.

Clinical Uses

For mydriasis, instillation of 2.5% or 10% solution results in maximum dilation within 45 to 60 minutes depending on the concentration instilled (Figure 8-2). Recovery from mydriasis occurs in 6 to 7 hours.

Accommodative amplitude measurements after instillation of 2.5% or 10% phenylephrine generally indicate that the effect is far less than the decrease observed with cycloplegic agents such as tropicamide (see Chapter 9). A loss of approximately 2.00 D (7.93 D from 9.95 D) at

Contains inactive ingredients of the following: aBenzalkonium chloride.

bBenzalkonium chloride 0.01%, EDTA, sodium bisulfite. cBenzalkonium chloride 1:7,500.

dBenzalkonium chloride 1:10,000.

eBenzalkonium chloride 1:10,000, methylcellulose. fAlso contains 0.25% tropicamide.

1 hour with 2.5% phenylephrine was reported. Before drug instillation the average accommodation was 9.31 D, and with 10% phenylephrine residual accommodation was 7.64 D. Two hours after instillation, an average loss of 1.52 D was reported for both concentrations of drug.

Dilation of the pupil with 2.5% and 10% commercial preparations has been studied in patients selected at random and not controlled for age or iris color. The results indicate that the higher concentration does not necessarily produce a significantly greater mydriasis. The data also appear to indicate that the 10% concentration may be a more effective mydriatic in blue irides than is the 2.5% concentration, although no statistically significant

Figure 8-2 Mydriasis induced by 2.5% and 10% phenylephrine (n = 112 eyes). (Reprinted with permission from Paggiarino DA, Brancato LJ, Newton RE. The effect on pupil size and accommodation of sympathetic and parasympatholytic agents. Ann Ophthalmol 1993;25:244–253.)

difference was observed. In general, dark irides have a greater frequency of poorer dilation than do light irides with adrenergic mydriatics.

Dose–response curves for phenylephrine indicate, as previously shown, an increasing mydriatic effect with concentrations up to 5%. Between 5% and 10% the curve begins to plateau, and little additional effect is observed by increasing the concentration to 10%.

In certain instances phenylephrine may also dilate the pupil at concentrations much lower than 2.5%. The mydriatic effect of 0.125% phenylephrine has been compared in unabraded and posttonography eyes. Three of 10 patients with unabraded corneas showed significant pupillary dilation of 1.0 to 1.5 mm after instillation of two drops of 0.125% phenylephrine compared with the control eye receiving saline. In posttonography patients, however, the test eye was dilated in all instances compared with the control eye.

Mechanical procedures that alter corneal epithelial integrity, thereby enhancing corneal drug penetration, can affect the response to certain ophthalmic drugs, including phenylephrine. Corneal trauma from procedures such as tonometry or gonioscopy can compromise corneal epithelial integrity and facilitate the pharmacologic effects. The mydriatic response of phenylephrine can also be enhanced by the prior instillation of a topical anesthetic.

Phenylephrine and tropicamide have been mixed together into a single combination solution for routine pupillary dilation. In one study commercially available preparations of 1% tropicamide and 2.5% phenylephrine were mixed together in equal amounts, thus producing a combination solution containing 0.5% tropicamide and 1.25% phenylephrine. This combination solution

116 CHAPTER 8 Mydriatics and Mydriolytics

was shown to have the same mydriatic effect as the standard commercially available preparations administered separately. This combination solution allows the patient’s pupil to be dilated with only one single drop and is said to be more convenient for the practitioner and better accepted by the patient. Furthermore, the single-drop combination may be better tolerated by young children.

In addition to its usual mydriatic effect for diagnostic purposes, phenylephrine has several other clinical uses. The drug can be a valuable aid in breaking posterior synechiae. Application of the 10% solution to the cornea preceded by a topical anesthetic is usually recommended to help break the adhesion. Furthermore, the effectiveness of topical 10% phenylephrine solution is used for peripheral corneal vessel vasoconstriction during LASIK refractive surgery.

The drug can also be used concomitantly with echothiophate to prevent the formation of miotic cysts during treatment of open-angle glaucoma or accommodative esotropia. Addition of the 2.5% concentration to the echothiophate regimen is recommended. The mechanism whereby phenylephrine prevents cyst formation is not known. However, inhibition of the intense miosis may account, at least in part, for the beneficial effect.

Ptosis resulting from sympathetic denervation, as in Horner’s syndrome,may respond to topical phenylephrine. Dramatic effects on the uneven palpebral apertures are sometimes observed (see Figure 23-15).

Phenylephrine can also be used as a diagnostic test for Horner’s syndrome (see Chapter 22). Phenylephrine in the 1% concentration can markedly dilate the pupil with postganglionic sympathetic denervation. It causes minimal or no dilation in the normal eye. If the lesion is central or preganglionic, the affected pupil responds in a manner similar to the normal eye because denervation hypersensitivity is minimal or absent.

Side Effects

Unintended local and systemic consequences can be caused by the topical instillation of phenylephrine (Table 8-2).

Table 8-2

Side Effects of Topical Phenylephrine

Ocular Effects. Local adverse events can include transient pain, lacrimation, and keratitis (see Table 8-2). Phenylephrine eyedrops have also been reported to cause allergic dermatoconjunctivitis, resulting in a “scalded” appearance around the eye.

Studies have demonstrated that phenylephrine can cause the release of pigmented granules from the iris. The pigment appears in the aqueous (aqueous floaters) 30 to 40 minutes after instillation of the 2.5% or 10% concentration. These floaters usually disappear within 12 to 24 hours. The release of pigment appears to be related to age and iris color, occurring more frequently in older individuals with brown irides. The pigmented granules have the same characteristics as melanin derived from the pigmented epithelium of the iris. It has therefore been suggested that phenylephrine may cause rupture of the pigmented epithelial cells of the iris. Because this phenomenon has been observed primarily in older patients, it may be due to aging changes in the neuroepithelium.

In patients over age 50 years phenylephrine has been observed to cause a rebound miosis the day after drug administration. Moreover, the instillation of phenylephrine at that time causes a diminished mydriatic response.Similarly,with long-term use of the drug reduced dilation can occur, which makes long-term frequent use clinically unsatisfactory. In addition, long-term use of phenylephrine at low concentrations for ocular vasoconstriction can result in rebound congestion of the conjunctiva.

Systemic Effects. Ocular administration of phenylephrine has been reported to induce acute hypertension (see Table 8-2). Sixty patients were studied after three applications of the 10% solution in each eye at 10-minute intervals.Thirty minutes after the last drop, systolic elevations of 10 to 40 mm Hg and diastolic elevations of 10 to 30 mm Hg occurred in all subjects. In each case pulse rate decreased 10 to 20 beats per minute. In contrast to these observations, however, other investigators reported a lack of systemic vasopressor response with the 10% concentration.

Data collected by the National Registry of DrugInduced Ocular Side Effects suggest that, in the general population, a group of patients may have certain risk factors for side effects from topical ocular 10% phenylephrine. Of 15 patients with myocardial infarcts, 11 died after topical application of 10% phenylephrine. The average age of these patients was 71 years, and nine individuals had a history of cardiovascular disease.

The effects of 2.5% phenylephrine on systemic blood pressure and pulse have also been investigated. No significant change was observed in systolic and diastolic blood pressures in 252 patients ranging in age from 3 to 92 years. In another study, two cases of acute systemic hypertension were reported after instillation of 2.5% phenylephrine. Both patients, who were 69 and 71 years of age, were scheduled for surgery, and each received multiple

drops of the phenylephrine. The medical history of one patient included diabetes and cardiac disease.

It is likely that age and physical status determine patients’ responses to topical ocular phenylephrine. Neonates respond to 10% phenylephrine with significant increases in blood pressure.Patients with insulin-dependent diabetes may demonstrate increased systolic and diastolic blood pressure in response to topical 10% phenylephrine. Similarly, individuals with idiopathic orthostatic hypotension respond to low concentrations of phenylephrine with marked blood pressure elevations. Other systemic reactions reported with topical ocular 10% phenylephrine include severe occipital headache, subarachnoid hemorrhage, ventricular arrhythmias, tachycardia, reflex bradycardia, ruptured aneurysm, and blanching of the skin.

Patients taking certain systemic medications are also more sensitive to the pressor effects of phenylephrine. In individuals taking atropine, the pressor effect of phenylephrine is augmented, and tachycardia can occur. Tricyclic antidepressants and monoamine oxidase (MAO) inhibitors also potentiate the cardiovascular effects of topical phenylephrine. The concomitant use of phenylephrine is contraindicated with these agents, even up to 21 days after cessation of MAO inhibitor therapy. Similarly, patients taking reserpine, guanethidine, or methyldopa are at increased risk for adverse pressor effects from topical phenylephrine because of denervation hypersensitivity accompanying the chemical sympathectomy.

Systemic reactions to 2.5% phenylephrine after topical ocular application to an intact eye have rarely been reported in adults. However, an acute rise in systolic blood pressure occurred in a 1-year-old child after the instillation of 0.5 ml of 2.5% phenylephrine during nasolacrimal duct probing.

The threshold dosage of phenylephrine in the average adult has been estimated to be 0.4 mg intravenously, 2 mg subcutaneously, and 50 mg orally. The upper limit for safe dosage in normal adults is approximately 1.5 mg intravenously and 300 mg subcutaneously. Because a 50-ml drop of 10% phenylephrine contains 5 mg of drug, multiple applications can result in overdosage, especially if absorption from the site of administration is enhanced or if the patient is compromised by age, body size, use of concomitant medications, or trauma. Furthermore, the extent of the absorption into the systemic circulation of topically applied phenylephrine is unknown because absorption has been shown to be possibly diminished due to local vasoconstriction.

Contraindications

Based on data submitted to the National Registry of DrugInduced Ocular Side Effects and those acquired by other investigators, the following guidelines for the clinical use of 10% phenylephrine are suggested:

•Use phenylephrine 10% with caution in patients with cardiac disease, idiopathic orthostatic hypotension, hypertension, aneurysms, insulin-dependent diabetes, and advanced arteriosclerosis.

•Give only one application of the 10% concentration per hour to each eye.

•The drug is contraindicated in patients taking MAO inhibitors, tricyclic antidepressants, reserpine, guanethidine, or methyldopa.

•Concomitant use of topical phenylephrine is discouraged in atropinized patients, because tachycardia and hypertension can occur.

•Prolonged irrigation, application with a conjunctival pledget,or subconjunctival injection of the 10% solution is not recommended.

•Only the 2.5% solution is recommended for infants and the elderly.

Phenyephrine10% concentration appears to be associated with an increased risk of significant adverse ocular and systemic events; therefore the 2.5% solution, with appropriate precautions, is recommended for routine use. Phenylephrine in solution can lose its pharmacologic activity over time or with improper use or storage; consequently, the manufacturer’s instructions should be followed concerning expiration date and proper handling of the drug. Loss of drug effect can occur even without visible color change.

Hydroxyamphetamine

Pharmacology

Hydroxyamphetamine (β-4-hydroxyphenylisopropylamine) is similar in chemical structure to norepinephrine. It is classified as an indirect-acting adrenergic agonist, its primary pharmacologic action is believed to be due to release of norepinephrine from adrenergic nerve terminals. It may also directly stimulate α-receptor and possibly β-receptor sites, although this effect has been considered minimal and probably clinically insignificant.

Hydroxyamphetamine has little if any effect on accommodation or on the refractive state. It also does not raise IOP in eyes with open anterior chamber angles.

Clinical Uses

Topical instillation of a 1% solution in eyes with normal adrenergic innervation causes mydriasis and also some vasoconstriction. However, hydroxyamphetamine is used only as a mydriatic agent. After topical application onset occurs within 15 minutes, maximum dilation occurs within 60 minutes,and the duration of mydriasis is approximately 6 hours. The U.S.Food and Drug Administration has labeled this drug as a Pregnancy Category C.

Studies have compared the mydriatic effects of phenylephrine and hydroxyamphetamine. One study compared 10% phenylephrine with several drugs, including 1% hydroxyamphetamine.The time to maximum dilation was similar (70.2 minutes for phenylephrine and 64.8 minutes for hydroxyamphetamine). The amount of mydriasis produced was somewhat greater with 10% phenylephrine: 2.42 mm compared with 1.93 mm with 1% hydroxyamphetamine.

118 CHAPTER 8 Mydriatics and Mydriolytics

TIME (min)

Figure 8-3 Comparison of mydriatic effect of 2.5% phenylephrine and 1% hydroxyamphetamine in young adult subjects. (Reprinted with permission from Semes LP, Bartlett JD. Mydriatic effectiveness of hydroxyamphetamine. J Am Optom Assoc 1982;53:899–904.)

Another study compared the mydriatic effect of 2.5% phenylephrine to 1% hydroxyamphetamine in a group of 28 young adult subjects without ocular disease. The two agents produced a nearly equal pupillary dilation (Figure 8-3). The maximum effect with both drugs occurred at approximately 45 minutes.

To achieve greater pupillary dilation and overcome the constrictor effect of cholinergic stimulation, particularly on exposure to bright illumination, both phenylephrine and hydroxyamphetamine can be used in conjunction with a cholinergic antagonist, such as tropicamide or cyclopentolate. Additionally, phenylephrine 1% combined with a low concentration of 0.2% cyclopentolate (Cyclomydril) is recommended for neonates for funduscopic examinations.

Hydroxyamphetamine 1% is combined with tropicamide 0.25% as a combination formulation commercially available as Paremyd. A single drop of Paremyd produces a mydriatic effect significantly greater than that of a single drop of either an adrenergic agonist alone or tropicamide 0.5% or 1%. Furthermore, Paremyd has a mydriatic efficacy equivalent to that of phenylephrine 2.5% followed by tropicamide 0.5%, instilled separately, for the first 45 minutes to an hour (Figure 8-4). In addition, statistically significant differences were demonstrated in the cycloplegic effect within the first hour after drug instillation of Paremyd and after instillation of 2.5% phenylephrine followed by 0.5% tropicamide.

Error Bars: 1 SE

7

Tropic+Phenyleph Paremyd

3

Figure 8-4 Mean pupil size changes as a function of time after the instillation of either Paremyd or a combined dose of phenylephrine 2.5% and tropicamide 0.5%. (SE = standard error.) (Reprinted with permission from Zeise MM, McDougall BWJ, Bartlett JD, et al. J Am Optom Assoc 1996;67:681.)

The use of Paremyd results in pupil size sufficient for binocular indirect ophthalmoscopy and, as with 0.5% or 1.0% tropicamide, the effect is independent of age, iris color, or skin color. No significant differences were observed in overall pupil diameter after instillation of either Paremyd alone or separate instillations of phenylephrine (2.5%) and tropicamide (0.5%). A difference in the recovery phase was observed. Pupil size decreased more rapidly as a function of time after instillation of Paremyd than after the use of 2.5% phenylephrine combined with 0.5% tropicamide when the two were administered separately.

Some investigators also showed that two drops of Paremyd instilled 5 minutes apart in contrast to the use of one drop only produced no additional mydriatic effect, irrespective of iris color or skin pigmentation.Furthermore,the use of a topical anesthetic does not appear to increase the efficacy of Paremyd.

Hydroxyamphetamine is clinically useful for differentiating between central or preganglionic and postganglionic sympathetic denervation. Because the drug stimulates release of endogenous norepinephrine from its stores in adrenergic nerve terminals, it fails to dilate a pupil with postganglionic sympathetic denervation,depending on the extent of damage. If the lesion causing Horner’s syndrome is central or preganglionic, however, hydroxyamphetamine should cause normal mydriasis, because the nerve endings of the postganglionic fibers should contain normal amounts of norepinephrine and thus respond normally.

Side Effects

When used for routine mydriasis, hydroxyamphetamine appears to be effective while causing little, if any, ocular irritation. It has been suggested that, due to the indirect action of this drug, it may be a safe mydriatic to use in eyes with shallow anterior chambers, and it may be more readily counteracted with miotics. In patients with openangle glaucoma, hydroxyamphetamine elevates IOP minimally, if at all. Reductions of IOP have also been reported.

The actions of hydroxyamphetamine on the cardiovascular system differ in certain respects from those of phenylephrine. The drug can raise blood pressure, but unlike with phenylephrine the pressor response is characterized by tachyphylaxis. The drug can also produce sinoauricular tachycardia and ventricular arrhythmia after systemic administration.

Contraindications

Contraindications to the topical use of hydroxyamphetamine for routine mydriasis are similar to those to phenylephrine. Because of its tachyphylaxis and ineffectiveness in postganglionic denervation, however, hydroxyamphetamine may be a safer mydriatic for use in patients with insulin-dependent diabetes, idiopathic orthostatic hypotension, or chemical sympathectomy produced by therapy with systemic guanethidine, reserpine, or methyldopa. Thus hydroxyamphetamine seems to be less strongly contraindicated than phenylephrine for certain high-risk patients.

Cocaine

Pharmacology

Cocaine is a naturally occurring alkaloid present in the leaves of the shrub Erythroxylon coca and other species of trees indigenous to Peru and Bolivia. Chemically it is an ester of benzoic acid with a nitrogen-containing base.

Cocaine exhibits several pharmacologic effects. After local application it acts as an anesthetic by blocking the initiation and conduction of nerve impulses. In addition, it has been shown to block neuronal reuptake of norepinephrine, thus potentiating adrenergic activity. Moderate doses increase heart rate and cause vasoconstriction. The most striking systemic effect of cocaine is central nervous system stimulation.

The ocular effects of cocaine include anesthesia (see Chapter 6), mydriasis, and vasoconstriction. The mydriatic effect of cocaine depends on the presence of a functioning adrenergic innervation. After topical application to the eye,the pupil begins to dilate within 15 to 20 minutes. The maximum effect, which is typically less than 2 mm of dilation, occurs within 40 to 60 minutes, and the pupil may remain dilated for 6 or more hours. The mydriasis is accompanied by vasoconstriction that causes blanching of the conjunctiva. Cocaine is also readily absorbed through the mucous membranes into the systemic circulation.

Clinical Uses

Topical ocular application of cocaine can result in serious corneal epithelial damage; therefore clinical uses of this drug are limited. Although it is no longer used for such routine ophthalmic procedures as tonometry, the drug is useful in the diagnosis of Horner’s syndrome (see Chapter 22). However, when administering hydroxyamphetamine, 48 hours must elapse before the subsequent test because cocaine inhibits the uptake of hydroxyamphetamine into the presynaptic vesticles. In addition, due to its ability to loosen the corneal epithelium, it can be helpful in the debridement of herpetic corneal ulcers.

Side Effects

The most striking effect of systemic absorption of cocaine is central nervous system stimulation. Signs and symptoms can include excitement, restlessness, rapid and irregular pulse, dilated pupils, headache, gastrointestinal upset, delirium, and convulsions. Death usually results from respiratory failure. Moderate doses of cocaine can also raise body temperature. Systemic absorption through mucous membranes is rapid and has been compared in speed with that of intravenous administration.

The most significant effect of topical ocular cocaine administration is damage to the ocular tissue. Grossly visible grayish pits and corneal epithelial irregularities can occur, especially with repeated application. The corneal epithelium may loosen, leading to large areas of erosion. Single applications, however, as in the diagnosis of Horner’s syndrome, rarely lead to corneal abnormalities. Although cocaine hydrochloride is designated as Pregnancy Category C, it should be administered to a pregnant woman only if needed.Also, after topical use of cocaine for Horner’s testing, patients should be cautioned that urine tests may be positive for up to 2 days.

Contraindications

Because of its peripheral adrenergic and central nervous system stimulatory effects, cocaine should be used with caution in patients with cardiac disease or hyperthyroidism.

MYDRIOLYTICS

Attention has focused on developing noncholinergic miotic agents that safely and effectively reverse the effects of mydriatics. Theoretical evidence was presented that the use of a cholinergic antagonist, such as pilocarpine, to induce miosis after the use of an adrenergic mydriatic, such as phenylephrine, produced spasm of accommodation and increased the risk of angle-closure glaucoma and pupillary block. In addition, stimulation of the dilator and sphincter muscles simultaneously is most likely to produce shallowing of the anterior chamber and to result in pupillary block. Therefore two agents, thymoxamine and dapiprazole, were developed. Thymoxamine is not commercially available in the United States,and dapiprazole is in clinical use to reverse diagnostic mydriasis.