Pharmacology





Pharmacology deals with the basic properties of drugs, their actions, their fate in the human body, and their known side effects. This chapter deals primarily with some of the drugs that act on the eye, either directly by local application or indirectly by systemic absorption.


General principles


Locally applied medication


Ophthalmic preparations placed directly in the eye are available in solution, suspension, or ointment forms. Solutions usually are instilled in the conjunctival sac and do not interfere with vision. There is very little amount of the administered drop that is retained by the eye. When a 50-μL drop is delivered, only 20% is retained (10 μL/50 L). The main disadvantage is that their duration of contact with the eye is short and therefore they require frequent instillation. Polymers often are added to solutions to enhance contact time. Although ointments remain in contact with the eye for prolonged periods, their tendency to reduce vision by creating a greasy film over the surface of the cornea limits their daily usefulness. Ointments frequently are used for bedtime therapy because of their prolonged contact time; in addition, they are less readily washed out with tears. They also are valuable for use in children who are crying ( Table 4.1 ).



Table 4.1

Comparison of characteristics of ophthalmic solutions and ophthalmic ointments












































Characteristics Solutions Ointments
Instillation Easier More difficult
Contact time Shorter Longer (slower movement through nasolacrimal drainage)
Irritation on instillation Frequent Rare
Discharge retention No Yes
Skin allergic reactions Few More frequent
Blurred vision No Yes (film spreads over eye)
Local symptoms (burning, stinging) More frequent Less frequent
Readily contaminated (requires preservatives) Yes No
Stability a problem with storage Yes Less likely


Preparations used in the eye have certain basic requirements regarding tolerance, tonicity, sterility, stability, and penetration.


Tolerance


Eye medications should cause minimal irritation or stinging of the eye. Tolerance of the medication by the eye depends on the solution’s having an ideal acid–base balance. The acid–base balance is denoted in terms of its pH.


Solutions that have a pH greater than 7 are alkaline , whereas agents with a pH less than 7 are acid . The pH of tears is slightly alkaline at 7.4. A large difference between the pH of topical solution and the pH of tears may result in ocular irritation and reflex tearing. Most ophthalmic solutions have a pH that varies from 3.5 to 10.5 ( Fig. 4.1 ).




Fig. 4.1


The eye responds by stinging and irritation when the pH varies from 7.

(Illustration courtesy of J. Krezanowski.)


Tonicity


The tonicity of a solution refers to the concentration of the chemical in that solution. Normal saline solution, or a 0.9% sodium chloride equivalent, has a tonicity approximately that of tears and is therefore well tolerated by the eye. Solutions with a high concentration of a chemical, however, are hypertonic and thus can be quite irritating. However, solutions low in concentration of a chemical (hypotonic solutions), such as water, are equally objectionable in producing irritation of the eye. Ideally, the closer the concentration of the drug to normal tears (0.9% sodium chloride equivalent), the less irritating the drug will be. In some cases in which a high concentration of a locally applied drug is required, this ideal may not be achievable.


Sterility


Solutions must be free from bacterial contamination. This can be achieved either by autoclaving or by passing the solution through bacterial filters. Today most solutions are manufactured in a sterile manner by drug companies. To ensure sterility for long periods, preservatives are usually added. A good preservative should be well tolerated by the eye, nonallergenic, and inhibit the growth of bacteria and fungi. About 95% of all commercially available ophthalmic products are preserved with: (1) benzalkonium chloride, (2) chlorobutanol, or (3) organic mercurials, chiefly thimerosal and phenylmercuric acetate. For eye surgery, however, the preservative drugs are usually eliminated to make the product less irritating to the open tissues. The solutions for eye surgery are available in sterile individual-dose units. For contact lens solutions, these preservatives often are too toxic to the cornea, and less irritating preservatives are incorporated.


Once a sealed bottle is opened, it is no longer considered sterile. Organisms may enter an open bottle with ease. The most notorious organism found in ophthalmic solutions, including antibiotic drops, is Pseudomonas aeruginosa , which can destroy an eye in 48 hours. This organism’s predilection for fluorescein solution has led to the development of dry fluorescein-impregnated paper, because this organism cannot survive in a dry environment.


Stability


Solutions must be reasonably stable and not deteriorate or lose their effectiveness. Drugs such as phenylephrine hydrochloride (Neo-Synephrine) and epinephrine oxidize in the presence of air and bright light and consequently are often packaged in dark or opaque bottles. Some drugs require a special base to provide stability. Eye ointments are prepared in either a petrolatum base or a water-soluble base because these bases have proved to be stable. Drugs such as oxytetracycline (Terramycin), which are relatively unstable for any length of time in solution form, have a long shelf life in ointment form and are generally prepared this way.


Penetration


Eyedrops penetrate the eye directly through the cornea and into the anterior chamber of the eye. They do not, however, penetrate far behind the crystalline lens and therefore cannot reach the back, or posterior portion, of the eye. The cornea acts as a barrier to many drops by virtue of the lipid content of its epithelium, which functions as a barrier to all medications not soluble in fat. Eyedrops also must have water-soluble properties to penetrate the remaining portion of the cornea. Thus agents that penetrate the eye well are those that have both fat- and water-soluble properties. However, when there is mechanical disruption of the epithelial barrier in corneal abrasion or infection, there is an increase in the rate of intraocular drug penetration.


Drugs penetrate the cornea better if they are instilled directly over its surface. When corneal penetration is of utmost importance, the patient should be asked to look down and the drop should be placed above so that it will flow over the cornea.


Alternative routes of medication


Subconjunctival injections


Injections may be administered under the conjunctiva. The subconjunctival medication gains access to the eye by absorption into the bloodstream by the episcleral and conjunctival vessels. Subconjunctival injections are used primarily in the treatment of intraocular infection.


Continuous-release delivery


Discs impregnated with drugs permit continuous delivery of medication 24 hours a day for a full 7 days. A small membrane, sandwiching medication, is inserted into the lower conjunctiva by the patient and it gradually releases its medication. Pilocarpine can be incorporated in the Ocusert and over a period of 7 to 8 days, it is steadily released at a rate of 40 mcg/h. Lacrisert provides a continuous release of hydroxypropyl cellulose for lubrication in patients with dry eyes.


Retrobulbar injections


Drugs may be administered by injecting medication through the skin of the lower lid, the point of the needle emerging behind the eyeball . Retrobulbar injections of a local anesthetic are often used to paralyze the extraocular and eyelid muscles and anesthetize the eye before commencement of intraocular surgery. Retrobulbar injections are less commonly used for cataract surgery but are used before vitreoretinal surgeries.


Intracameral injection


An injection may be given into the anterior chamber at the start of cataract surgery to enhance patient comfort under topical anesthesia. The injection of 0.5 mL of preservative-free 1% lidocaine (Xylocaine) has resulted in a dramatic improvement in patient comfort, with a decrease in light sensitivity. This advance has led to essentially painless cataract surgery without the use of retrobulbar or peribulbar injections. Vancomycin and other antibiotics may be used.


Systemic medication


The term systemic drugs refers to those drugs that are taken orally or by injection subcutaneously (under the skin), intramuscularly (in the muscle), or intravenously (into the vein). These routes of administration are usually chosen because of some disease in the posterior part of the eye or orbit that cannot be reached by locally applied medication. In particular, conditions such as cellulitis, uveitis, and acute allergic reactions often require systemic medication.


Complications of locally administered drugs


Allergic reactions


Many ophthalmic preparations can cause contact allergic reactions involving primarily the skin of the lids and the conjunctiva. Because hypersensitivity develops as a result of the patient’s exposure to the agent, allergic reactions usually follow repeated application of the medication. Thus a delay in time occurs between the reaction to the use of a particular drug and the development of a state of hypersensitivity. This delay in time can be weeks, months, or years and is referred to as the induction period .


Once the hypersensitivity state is established, further instillation of the agent serves only to aggravate the allergic response. In the skin, allergic reactions may consist of edema, redness, vesiculation, scaling, and oozing, depending on the patient’s sensitivity. In the conjunctiva, the most common reaction is either marked chemosis or swelling or low-grade congestion and redness of the conjunctival tissues. Differentiation should be made between an allergic response and an ocular irritation caused by the drug. Some patients with allergies complain of itchiness. In many cases, however, differentiation between the two can be made only by a smear of the discharge of the conjunctiva that reveals the typical cell of an allergic response: the eosinophil.


One of the most common ophthalmic preparations to cause allergic reactions of the skin of the eyelid is atropine. Of the antibiotics, neomycin is most likely to create a hypersensitivity state and induce an allergic response ( Fig. 4.2 ).




Fig. 4.2


Allergic conjunctivitis with swelling of the bulbar conjunctiva.

(Reproduced from Spalton D, Hitchings R, Hunter P. Atlas of Clinical Ophthalmology . 3rd ed. St Louis: Mosby; 2004, with permission.)


Toxic reactions


Some drugs can produce irreversible damage within the eye or cause systemic disturbances within the human body. Echothiophate iodide (Phospholine Iodide), used in glaucoma, can cause cataracts, iris cysts, and retinal detachments. If this drug is absorbed systemically in sufficient quantities, it may cause nausea, vomiting, diarrhea, bladder cramps, and cardiac irregularities. One can reduce systemic absorption of eye medication by applying gentle finger pressure to the inner corner of the eyelids, over the lacrimal sac, for 1 minute when instilling drops. This will prevent drops from passing through the nasolacrimal duct to the back of the throat, where they are absorbed.


Discoloration of the eye


Pigmentation of the conjunctiva may occur after the prolonged use of epinephrine, silver nitrate, or silver–protein compound (Argyrol). Epinephrine (Adrenalin) causes black spots in the lower conjunctival sac. Silver–protein produces a slate-silver discoloration of the conjunctiva.


Undesirable side effects


Some undesirable side effects may occur. For example, topically applied steroids can:




  • Raise the intraocular pressure and cause glaucoma



  • Potentiate the growth of viruses, which in herpes simplex infection can cause widespread corneal damage



  • Potentiate the growth of bacteria



  • Cause delay in wound healing



Pigmentary changes in the macula with loss of vision may occur in patients using chloroquine (antimalarial also used in treating rheumatoid arthritis and systemic lupus erythematosus), phenothiazines (antipsychotic) or indometacin (a nonsteroidal antiinflammatory drug [NSAID]). Oral contraceptive agents may cause migraine-like syndromes, as well as retinal vascular occlusions. Cataracts can occur after the use of antiglaucoma medication such as echothiophate iodide.


Idiosyncrasy


An idiosyncrasy is a constitutional peculiarity in which an individual reacts in a bizarre fashion to a drug. For example, an unexpected reaction to cocaine may occur and the person may develop tremors, motor excitability, or convulsions and may even collapse.


Loss of effect by inactivation


Some ophthalmic solutions may lose their potency if not stored properly. For example, if exposed to light and heat, epinephrine turns brown and loses its effect. Patients receiving epinephrine derivatives should be warned of this contingency and told to keep their eyedrops in a cool, dark place, such as the refrigerator. Prostaglandins are heat sanative.


Spread of infection


In some offices, hospitals, or clinics, where a single bottle is used for a group of patients, the dropper easily can become contaminated. Consequently, infection may spread from patient to patient. This hazard can be eliminated by using small sterile disposable bottles of medication or by limiting the use of the eyedrops or ointment to one individual. When eyedrops are used, care must be exercised that the tip of the eyedropper does not touch the lashes or the eye, so that contamination of the dropper and the eye solution is avoided ( Fig. 4.3 ). Some regulatory commissions recommend that bottles of ocular medications be discarded after being opened for 28 days.




Fig. 4.3


Instillation of eyedrops. (A) Incorrect method. Note contamination of tip of bottle by lashes. (B) Correct method. Note tip of bottle is held free of globe and lashes.


Prescription writing


In some U.S. states, the pharmacy boards require that all prescriptions be written as printed or typed (but not as cursive) on special approved prescription paper that protects against altering. Other regulatory regulations may require that prescriptions be electronically written/transmitted. Ophthalmic assistants should be knowledgeable on their state’s requirements.


Physicians use many symbols for writing prescriptions. These symbols provide a direct communication from the physician to the pharmacist. The use of Latin symbols today is an anachronism, yet several Latin symbols are retained because of tradition and for brevity ( Table 4.2 ). The following is the format for prescription writing; the setup is shown in Fig. 4.4 .



  • 1.

    The patient’s name, address, and date of prescription


  • 2.

    The name of the drug and the percentage of concentration or the dosage of each unit (the drug usually is written out in full to avoid any confusion)


  • 3.

    The amount of the drug to be supplied, headed by the symbol M or Mitte, which signifies the quantity


  • 4.

    Sig or S, from the Latin signa , “to mark,” or in English, “label,” which indicates to the pharmacist what directions to label on the medicine


  • 5.

    The signature of the physician with notation “substitution permitted” or “dispense as written”


  • 6.

    Possibly some notation at the bottom of the prescription, for example, “may be repeated 2 times,” “refill prn for 1 year,” or “no refill.”



Table 4.2

Abbreviations and symbols used in prescription writing




































































































Abbreviation or symbol Meaning
RX take thou
g gram
h hour (hora)
q every
hs bedtime (hora somni)
qs quantity sufficient
od right eye (oculus dexter)
os left eye (oculus sinister)
ou both eyes (oculi uterque)
mg milligram
< less than
> more than
aa equal parts (ana)
Sol solution
Ung ointment
Ʒ dram
oz ounce
tsp teaspoon
gt, gtt drop, drops (gutta, guttae)
M mix (misce)
bid twice a day (bis in die)
tid three times a day (ter in die)
qid four times a day (quater in die)
q4h every 4 hours
ac before meals (ante cibum)
pc after meals (post cibum)
non rep do not repeat (non repetatur)
ad lib as much as wanted (ad libitum)
ss half (semis)
aq water
prn as the situation demands (pro re nata)



Fig. 4.4


Example of a prescription form.


Autonomic drugs


The body contains an involuntary nervous system, which is not under our direct control. This system acts to protect the body, provide nutrition and elimination, and carry on daily regulatory activity. The autonomic nervous system is affected by our emotional behavior. The typical “fear” reaction causes our pupils to dilate, our skin to sweat, and even our hair to stand on end.


The autonomic nervous system is subdivided into the sympathetic and parasympatheti c nervous systems. Drugs that mimic the action of these two opposing types of involuntary nervous systems are said to be sympathomimetic and parasympathomimetic , respectively. Sympathomimetic drugs such as epinephrine and phenylephrine act directly on the end organ; they are sometimes called adrenergic agents . Parasympathomimetic drugs either act on the end organ in a manner similar to that of acetylcholine or interfere with the action of the enzyme cholinesterase , which destroys the acetylcholine normally produced in the tissues. Pilocarpine acts directly on the end organ, whereas eserine, dipivefrin (DP), and echothiophate iodide represent inhibitors of cholinesterase. Some drugs act on the end organ to block the action of the parasympathetic system; they are called parasympatholytic (cholinergic blocking) agents . Atropine, homatropine, and cyclopentolate are representative of this group.


Autonomic drugs that affect the eyes are divided into mydriatic, cycloplegic, and miotic agents, which comprise most of the commonly used eye medications.


Mydriatic and cycloplegic agents


Mydriatic drops act on the iris musculature and serve to dilate the pupils. Cycloplegic drops act not only on the iris by dilating the pupil but also on the ciliary body, paralyzing the fine focusing muscles so that the eye is no longer able to accommodate for near vision ( Fig. 4.5 ). Cycloplegic drops are essential in the refraction of children’s eyes and for iritis therapy. Mydriatic agents are primarily used to dilate the pupil for intraocular examinations.




Fig. 4.5


Sites of action of mydriatic, cycloplegic, and miotic agents. Mydriatic drugs act on the dilator muscle of the iris. Cycloplegic drugs act by inhibiting the sphincter muscle of the iris and by paralyzing the ciliary muscle. Miotic drugs act by stimulating the sphincter muscle of the iris, causing the pupil to constrict.


Mydriatic agents


Mydriatic agents with little or no cycloplegic effect are phenylephrine, hydroxyamphetamine, eucatropine hydrochloride, epinephrine, and cocaine.


Phenylephrine hydrochloride (Neo-Synephrine) is available in strengths of 2.5% and 10%. The latter exerts a rapid dilating effect in about 15 minutes and wears off in 1 to 2 hours. Adverse responses with 10% topical phenylephrine have occurred within 20 minutes of the last application of this drug. Some of these patients were treated with application of a cotton pledget of the drug, some by subconjunctival injection, and others by irrigation of the lacrimal sac. A number of deaths have resulted from myocardial infarction and some patients have required cardiac and pulmonary resuscitation for treatment of cardiac arrest. Another group of patients had a marked rise in blood pressure, tachycardia (fast heartbeat), or reflex bradycardia (slowing of the heart). The local ocular reaction reported was massive subconjunctival hemorrhage.


This drug should be used very cautiously or not at all in patients with heart disease, hypertension, aneurysm, or advanced atherosclerosis. Only the 2.5% solution should be used in older adults and in infants. Phenylephrine hydrochloride dilating drops are not recommended for use in low-birthweight infants. The 10% solution should not be used for irrigation. When the drug is used, a cotton pledget should be held over the lacrimal sac for 1 to 2 minutes. Patients who are taking antidepressants or monoamine oxidase (MAO) inhibitors should be treated with caution. These patients may exhibit a significant increase in heart rate.


Phenylephrine is used most commonly as an adjunct to the parasympatholytic drugs (e.g., tropicamide [Mydriacyl] and cyclopentolate [Cyclogyl]) to dilate the pupil for ophthalmoscopy. Despite these serious complications with 10% phenylephrine, no serious adverse effects have been reported with the ophthalmic use of 2.5%, although dizziness, fast, irregular or pounding heartbeats, increased blood pressure, and trembling have been reported.


Epinephrine (Adrenalin) exerts a mild mydriatic effect.


Cocaine is primarily a strong anesthetic agent but also exerts a mild mydriatic effect. It can be used to establish the diagnosis of Horner syndrome. It allows one to determine whether a small pupil is part of this syndrome or whether it is caused by other causes, such as a congenital asymmetry of pupil size (physiologic anisocoria).


The drugs that act as pure mydriatic agents exert their effect by stimulating the dilator muscle of the iris.


Cycloplegic agents


Cycloplegic agents act by paralyzing the sphincter muscle of the iris, and thereby producing iris dilation, and by paralyzing the ciliary muscle, which inactivates accommodation. Examples of cycloplegic agents are atropine, homatropine, scopolamine, cyclopentolate, and tropicamide.


Atropine (Isopto Atropine, Atropine-Care, generic), available as 0.5% and 1% solutions and ointment, is one of the most powerful cycloplegic and mydriatic agents. After atropine has been instilled in an adult eye, it requires 10 to 14 days for accommodation to return and the pupil to return to its normal size. With children, the local effects on the eye are similar but systemic complications are more common. The side effects of systemic absorption in children consist of rapid pulse, fever, flushing, and mouth dryness. Systemic absorption of atropine can be reduced by applying pressure over the lacrimal sac. Atropine may cause allergic manifestations in the form of an eczematoid rash around the eye and conjunctival injection. Parents should be instructed in the method of giving the drops and in observing for signs of local or systemic toxicity. Adverse reactions should be reported immediately to the ophthalmologist’s office so that proper steps can be taken.


Homatropine (Isopto Homatropine, generic) is a weaker cycloplegic than atropine and is available in strengths of 2% and 5%. Its effect wears off faster than atropine and accommodation returns in 1 to 3 days.


Scopolamine (Isopto Hyoscine) is midway between atropine and homatropine in duration of action. Scopolamine produces fewer allergic responses than atropine and thus is used as a substitute for it.


Cyclopentolate (Cyclogyl, Cylate, AK-Pentolate, generic) is available in strengths of 0.5%, 1%, and 2%. It has a rapid onset of effect (30 minutes) and a duration of action of 6 to 24 hours, which makes it an ideal agent for office use. Occasionally, children can show signs of systemic toxicity not unlike that seen with atropine.


Tropicamide (Mydriacyl, Tropicacyl, generic), 0.5% and 1%, exerts its effects in 20 to 40 minutes and wears off in 4 to 6 hours. It is a relatively weak agent for paralyzing accommodation and is used primarily for its dilating ability when ophthalmoscopic examination is required.


Cycloplegics are used in the treatment of iritis to relieve ciliary muscle spasm and produce pupillary dilation. The latter is important in preventing the iris from binding down to the lens to form posterior synechiae. These agents are commonly used to inactivate the ciliary muscle for the purpose of objective refraction ( Table 4.3 ). The eyes of darkly pigmented persons dilate with difficulty and hence require stronger concentrations and repeated instillations to obtain an adequate effect. Drugs, such as atropine and homatropine, are not used routinely in adult eye refraction because of the prolonged delay in accommodation and pupillary function.



Table 4.3

Routines for common cycloplegic agents
























Drug Strength Frequency
Atropine


  • Younger than 2 years, 0.5%



  • Older than 2 years, 1%

Under 5 years, 3 times daily for 3 days before examination
Homatropine 2%, 5% One drop every 15 min for four applications 1 hour before examination
Cyclopentolate 0.5%, 1%, 2% One drop every 5 min for two applications 30 min before examination
Tropicamide 0.5%, 1% One drop every 5 min for two applications 20 min before examination

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Jun 26, 2022 | Posted by in OPHTHALMOLOGY | Comments Off on Pharmacology
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