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The Effect Of Lidocaine And Proparacaine On Tear Production




This study determined the effect of Lidocaine and Proparacaine on tear production. The tear production of  forty young and healthy subjects within the age range of 18-35 years who were qualified to participate in this study were evaluated before and after instillation of Lidocaine 2% and Proparacaine 0.5% over a period of 25 minutes using Schirmer′s test. The results obtained showed mean changes of 18.40mm, 26.43mm, 30.38mm at 5mins, 15mins and 25mins respectively from the baseline of 25.85mm in OD and 20.82mm, 22.55mm and 23.48mm at 5mins, 15mins and 25mins respectively from the baseline of 25.70mm in OS. The effects of the Lidocaine and proparacaine on tear production showed that Proparacaine had a statistically significant decrease in tear quantity than Lidocaine after instillation of the drugs using Z-test and ANOVA. The general peak of its decreasing effects on tear production was evident at 5 minutes after instillation of lidocaine and proparacaine. Statistically F-value was greater than P-value, this implies that lidocaine and proparacaine have much effect on the mean tear production and are not the same on the various time lags.



1.1     Background to the study

“Anesthetic” comes from the Greek word “anesthesia” meaning the absence or loss of sensation. Anesthetic act by temporally blocking the sensation of pain during diagnostic and therapeutic procedures; this is by inhibiting the influx of sodium ionsinto the nerve cytoplasm. It binds to the specific receptor site within the sodium ions movement through this pore. This property blocks the pain sensation locally hence the name local anesthetic (George et al., 2010).

Local anesthetics are made mostly from amino-esters and amino-amides. Examples of Local anesthetic include Amethocaine, Lidocaine, Bupivacaine, Tetracaine, Novesine, Proparacaine etc.

As ophthalmic surgeries are performed with increasing frequency in outpatient’ facilities, local anesthesia is a reasonable alternative to general anesthesia for selected patients with open globe injuries.

Human eye and the accessibility of its nerve supply permit most adult ocular surgery to be done with the use of both topical and local anesthetic. The Conjunctiva and Cornea are readily anesthetized by the means of topical instilled anesthetic agent.

Daily routine optometric/ophthalmologic and other medical and paramedical practices use anesthetics for in and out patients (for both children and adults), to anesthetize either the entire body or part of the body. Anesthesia is loss of feeling or sensation in a part or all parts of the body (Millodot, 2004).

Basically, two types of anesthetics exist:

  1. General anesthetic and
  2. Local anesthetic

General anesthetic could be further classified into intravenous anesthetic which acts on all parts of the body, while local anesthetic act on some parts of the body or part of the body.

General anesthetics include physiological state such as analgesia, amnesia, loss of consciousness, inhibition of sensory and autonomic reflexes and skeletal muscle relaxation. The extent to which individual anesthetic agent can exert these effects varies depending on the drug, the dosage and the chemical situation.

The local anesthetic can be grouped based on their chemical structure. The following are the chemical groups of local anesthetic commonly used by medical and dentist.

  1. Esters
  2. Ester of benzoic acid
  3. Cocaine (topical only)
  4. Butacaine
  • Ethyl aminobenzoate
  1. Benzocaine (topical only)
  2. Piperocaine
  3. Isobucaine
  • Meprycaine
  1. Esters of PABA
  2. 2-chloroprocain (nesacaine)
  3. Propoxycaine
  • Procaine (novocaine)
  1. Propoxycaine
  2. Butethamine
  3. Tetracaine
  4. Esters of meta amino benzoic acid
  5. Metabuthamine
  6. Primacaine
  • Amides
  1. Lidocaine (xylocaine)
  2. Bupivacaine
  3. Mepivacaine (carbocaine)
  • Dibucaine
  • Etiodocaine
  1. Articaine
  2. Prilocaine
  3. Quinolones
  4. Centbudine
  5. Injectable
  6. Low potency and short duration
  7. Procaine
  8. Chloroprocaine
  9. Intermediate potency and duration
  10. Lidocaine
  11. Prilocaine
  12. High Potency, long duration
  13. Tetracaine
  14. Bupivacaine
  • Dubucaine
  1. Surface anesthetic
  2. Soluble
  3. Cocaine
  4. Lidocaine
  • Tetracaine
  1. Insoluble
  2. Benzocaine
  3. Butyl amino benzoate (butamben)
  • Oxethazine

Common properties of various local anesthetic agents

  1. They are all synthetic
  2. They all contain amino groups
  3. They all form salts with strong acids
  4. The salt are water soluble
  5. Alkali increase the concentration of the unionized free base
  6. The unionized free base is soluble in lipids
  7. They are all either hydrolyzed by plasma cholinesterase or undergo biotransformation in the liver.
  8. The actions of drugs are irreversible.

Topical anesthetic could be absorbed in a conscious patient through the lacrimal apparatus to the nose where the nasal mucosa absorbs them rapidly to produce systemic effects (Verma et al., 1995). Life would have been so miserable and full of pain if there were no anesthetics. Pain are now eliminated or reduced during surgeries, foreign body removal, pterygium removal (scrapping), pinguecula scrapping, carrying out Schirmer test No.1, lacrimal drainage procedures, carrying out tonometry with indentation tonometer.

The primary action of these anesthetic drugs is to prevent impulse conduction when applied in an effective concentration to nerve tissues. They reversibly block the transmission of impulse through nerve fiber membrane but stabilize it in some kind of way. The effect of topical anesthetic is increased by lowering the sodium concentration of the fluid bathing the nerve. Possibly, it interferes with the specific increase of permeability to sodium which initiates the impulse. They are reversible in action (Verma et al., 1995).

But the primary aim of this study is to know the effect of these topically instilled anesthetic on tear production in human eye. Anesthetic stimulation or inhibition to tears may lead to pharmacological type of lacrimation.

Tears is produced by the lacrimal gland, which is situated at the upper and outer angle of the orbit, just within the orbital margin in a depression of the orbital plate of the frontal bone known as the fossa of the lacrimal gland. Anteriorly, the gland is deeply divide into two parts by the lateral expansion of the upper aponeurosis of the levator muscles, the upper orbital part and the lower palpebral part.

The duct of the lacrimal gland which are twelve in number passes through the palpebral lobe of the gland and open into the conjunctival sac which is 4-5mm above the upper border of the tarsal plate of the upper lid.

The minute structure of the lacrimal gland is similar to that of serous gland resembling a salivary gland.

  1. Accessory lacrimal gland: They are small glands of exactly the same structure as the lacrimal gland and there are two types which are
  2. Gland of Krause: These are about 30 in the upper lid and 8 in the lower lid and are deeply situated within the substantia propria of the conjunctiva near the fornix particularly on the lateral size.
  3. Gland of Wolfring: They are few in number situated in conjunctiva near the upper border of the tarsal plate
  • The complete tear fluid is considered as the product of the lacrimal gland without the admixture from secretion of the gland of the conjunctiva.
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1.1.1 Historical Background

History of topical anesthetics: topical anesthetics was introduced by Keller and William Hast between 1884 and 1885. But William Hast was credited for first defining and using regional anesthetics.

Among many anesthetics discovered by Niaman in 1860, when he isolated and noted its anesthetic effect on his own tongue after collecting the leaves from a cocoa plant (erythroxylon cocoa) and chewing it with some alkali which liberates its free base for rapid absorption across the mucosa.

The native of Peru knew of the anesthetic qualities of the cocoa plant. During the painful surgical procedures of cranial trephination, they provided local anesthesia by chewing leaves of cocoa plant (the active ingredient is cocaine) aid allowing their saliva to run into fresh incision (Stitzet, 1990).

1.1.2 Types of tears

There are two types of tears which are psychic tear and reflex tear. Reflex tears comes out when trigeminal nerve is stimulated; they are produced by lacrimal gland. Basic tear is produced by orifices beneath the lashes, does not have nervous control.

1.1.3    Sources and functions of tears

The tears are a mixture of secretion from the major and minor (accessory) lacrimal glands, the goblet cells and meibomian glands (Allansmith, 1998).

The functions of tears are;

  1. To make the cornea a smooth optical surface by abolishing minute surface of the corneal and conjunctival epithelium.
  2. Preventing damage to the epithelial cells and
  3. To inhibit the growth of microorganisms on the conjunctiva and cornea by mechanical flushing and antimicrobial action of the tear fluid.

1.1.4    Composition of tears

The normal volume is expected to be about 6µl in the eye and the average rate of turnover about 12µl/ min. Tear contains high concentration of protein: albumin, globulins and lysozymes.

Antimicrobial activities of tears is in the gamma globulin and lysozyme, fractions. The gamma globulin found in the normal tear film are IgA, IgG, and IgE. The average glucose concentration of tears includes K⁺, Na⁺, Ca⁺, Mg2⁺, CL⁻, HCO₃⁻, (Haeringen, 1981). The average pH of tear is 7.35 under normal condition. Tear fluid is isotonic, tears osmolality ranges from 295 to 309mosm/L.

According to Krogh et al. (1995) the tears are isosmotic with blood plasma. The normal tears also contain about 18% dissolved solid with an osmotic pressure equivalent to salt solution of 0.9% – 1.5%. But the actual sodium chloride content is 0.65% and the chemical composition of tear is very similar to that of blood, except that tear is more dilute (about 98.2% water).

Protein content is much less (0.4% albumin and 0.27% globulin) slightly alkaline with low hydrogen, pH is 7.49, index is 1.3337. The higher albumin and globulin in tear in comparison with corneal tissue fluid, produced considerably lower tension thus enabling the tear to spread easily and wet the epithelial surface in addition. The tear covers microscopic irregularity on the epithelial surface and produce a smooth surface on the cornea.

1.1.5   Relevant anatomy and physiology

The surface of the globe is kept moist by tears secreted by the lacrimal apparatus, together with the mucous and oily secretory organs and cells of the conjunctiva and lids (Khurana, 1998).

1.1.6   The lacrimal system

The lacrimal system is composed of glands that secrete tears and a drainage system that collects them. The glands consist of the lacrimal glands in the upper outer portion of the orbit, and the basic secretors located in the conductive and in the margin of the eyelids. The collecting system consists of the ampullae (vertical canaliculi) which are about 2mm long and form the most proximal part of the lacrimal system.

The horizontal canaliculi are about 8mm long in about 90% 0f individuals, the upper and the lower canaliculi form the common canaliculi which open into the lateral wall of the lacrimal sac. In the remainder each canaliculi opens separately. A small mucosa (valve of Rosenmuller) overhangs the entrance of the common canaliculi. The canaliculi are lined by stratified epithelium. The epithelial loop tube (the canaliculi) that extends from opening to the puncta located at the inner corners of the upper and lower eyelids to the lacrimal sac (10mm long) to the nasolacrimal duct (12mm long). The opening of the duct is partially covered by a mucosal fold (Valve of Heisner). The nasolacrimal duct and sac is lined by epithelium which contains a venous plexus. The mucous lining forms an imperfect valve at the orifice into the nose (Kanski, 1988).

Fig1: The Lacrimal Apparatus adapted from clinical ophthalmology 3rd edition, Butterworth Heinemann (1998)

1.1.7     Drainage of tears

The tear film is even spread over the surface of the eye when the lid close during a blink by the orbicularis muscle which ensures that punctum dips in the lacus lacrimal is by entering the lower lid excess tears now form a “tear lake” along the lower lid margin before passing through the upper and lower puncta. Tears entering the puncta pass through the canaliculi already shorter lacrimal sac. The lacrimal sac empties by means of the nasolacrimal duct into the nasal cavity where the tears become part of the fluid that moistens the mucous membrane of the lacrimal pump. In the absence of blinking there is a steady flow of tears into the sac which may be seen in the slit lamp biomicroscope after introduction of a carbon particle suspension Rosengre (1983).

1.1.8    Precorneal tear film

The precorneal tearfilm consists of the layers

  1. Outer lipid layer
  2. Middle aqueous layer
  3. Inner mucin layer.

Fig 2. The precorneal tearfilm

Adapted from: general ophthalmology 9th edition Lange medical publication (1980)

Outer lipid layer is a non-molecular layer secreted by the meibomian glands, glands of zeis and moll has the following functions:

  1. To retard evaporation of the aqueous layer of the tear film.
  2. To increase surface tension and thereby assist in the vertical stability of the tear film so that the meniscus does not overflow the lid margin.
  3. To lubricate eyelid as they pass over the surface of the globe.
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Middle aqueous layer, which is secreted by the major and minor lacrimal glands and contains water soluble substances (salts and proteins), has the following functions:

  1. To supply atmospheric oxygen to the avascular corneal epithelium.
  2. Antibacterial function
  3. To wash away debris
  4. To abolish any minute irregularities of the anterior corneal surface.

Inner mucin layer is composed of glycoprotein, mucin and overlies the corneal and conjunctival epithelial cells. The epithelium cell membrane are composed of lipoprotein ( hydrophobic) which plays an important role in wetting this surface absorbed into the corneal epithelium cell membrane by microvilli of the surface epithelial cells. Mucin is secreted by conjunctival goblet cells the crypts of henle and glands of manz. Its function is basically converting the corneal epithelium from a hydrophobic surface to a hydrophilic surface, so that it can be wetted by aqueous component of the tear film.

The three factors required for effective resurfacing of the tear film according to Kanski, (1998) are:-

  1. Normal blink reflex
  2. Congruity between the ocular surface of the eyelids and
  3. Normal corneal epithelium

1.1.9    Disorders of lacrimal system

Dry eye refers to any tear film abnormality usually with corneal epithelial abnormalities. The National Eye Institute of Ophthalmology classified dry eye into two categories:

  1. Aqueous layer deficiency (not enough tears are produced)
  2. Evaporative deficiency (what is produced disappears too quickly).

Dry eye result from decreased production, increased evaporation or decreased clearance of tears, (Afonso, 1999).

Dry eye produces irritation and ocular surface disease, termed Keratoconjunctivitis Sicca (KCS) that causes blurred, fluctuating vision and increase the risk of sight threatening corneal infection and ulceration. Meibomian Keratoconjunctivitis refers to inflammation of the cornea and conjunctiva resulting from excess deficient or abnormal meibomian gland secretion.

Sjorgren′s syndrome includes disorders from a combination of aqueous tear deficiency, salivary gland dysfunction, rheumatoid arthritis or other connective tissue disease. Many clinicians currently recognize two types of Sjorgren′s syndrome.

  1. Inflammation of multiple exocrine glands, usually the salivary gland and lacrimal gland without an associated systemic disorder.
  2. A systemic connective tissue disorder associated with dry eyes or dry mouth referred to as secondary Sjorgren′s syndrome.

A lacrimal hypersecretion is caused by stimulation of the lacrimal gland. Psychic lacrimation is normally associated with pain or emotional upsets. The fact that this type of lacrimation appears after the first few months of life explains why newborns do not produce tears when they cry. Neurologic lacrimation is brought about by reflex stimulator.

Eyestrain, corneal injury, foreign body, strong parasympathomimetic is the early case of inflammation. Epiphora is excessive tearing caused by a blockage of the puncta or evasion of the puncta or by canalicular or nasolacrimal duct obstruction. Paradoxic lacrimation (crocodile tears) is an acquired unilateral (very rarely bilateral) condition characterized by excessive tearing while eating. It occurs as a sequel to Bell′s palsy (facial nerve palsy) and is the result of aberrant regeneration of the facial nerve fibers. Mucin deficiency occurs in conjunctival disease such as ocular erythema multiforme (Stevens Johnson Syndrome) and ocular cicatricle pemphigoid. These disease also cause eventual loss of the lacrimal aqueous phase as a result of scarring of the secretory ducts. Vitamin A deficiency and chemical burns also cause a loss of mucin.

Failure to blink or infrequent or incomplete blinking may cause inadequate spread of tears with normal components. This occurs in neuroparalytic Keratitis and pterygium. An abnormality of the eyelids in which the globe is not fully covered may cause inadequate wetting of the ocular surface.

1.1.10    Actions and properties of anesthetics

The following drugs are effective when used topically on the eye such as lidocaine, tetracaine, proparacaine, benzocaine etc.

Topical anesthetics can block conduction of the axon and can prevent the sense organ from irritating on afferent impulse, motor and autonomic fibers are also blocked.

An ideal topical anesthetic should not produce any structural damage to the nerve fibers, it should possess low systemic toxicity because it will eventually be absorbed from the site of administration. There should be complete recovery from its effects, should have short onsets of anesthesia. Moreover, the duration of action should be such that there is adequate time for clinical procedure to be performed but not long enough to dramatically lengthen the recovery period. The anesthetic agent should be water soluble and stable in solution. Furthermore, an ideal anesthetic should withstand without deteriorating the temperatures of autoclaving during sterilization.

Topical anesthetics produces elevation in the threshold for electrical excitation when applied to the nerve fiber.

They prevent the generation and propagation of nerve impulses and the the principal site of action is the membrane of sodium ion. When the drug concentration approaches the maximum concentration, the nerve conduction is completely blocked (Laurence et al., 1997).

Topical anesthetics must reach the plasma membrane of the axon before it can act. In myelinated nerve, the Schwann cells encircles the axon with layers of dense lipid which are barriers of the diffusion of drugs and also to ion transport.

However, they act on myelinated fibers only at the nodes of Ranvier where the myelin is interrupted also jumps from node when used in therapeutic doses rarely lead to epithelial lesion.

They have low pH of about 2.4 which is responsible for its transient irritation and stringing sensation after instillation; also it has a deterious effect on the corneal epithelium by depressing healing and glycolysis. Repeated topical administration of drug leads to permanent corneal damage, hence thus agent is seldom. If ever prescribed for self-medication, its mechanism of action is on nerve membrane permeability. They are vasoconstrictors and has mydriatic effects. However, they are inactivated by pseudocholinesterase which occur in plasma, liver, skin, intestinal mucosa, smooth muscle and in the white matter of the central nervous system. On instillation of tetracaine or proparacaine (primax), pain is the first sensory modality that is blocked (Laurence et al., 1997).

1.1.11   Proparacaine (primax)

It is one of the most common topical anesthetic agent used for topical anesthesia in intraocular surgery (phacoemulsification, cataract surgery, excimer laser, PRK and Lasik surgery). It is also indicated in; corneal anesthesia of short duration, example; tonometry, gonioscopy, removal of corneal foreign bodies and for short corneal and conjunctival procedures. It is a benzoic acid ester.

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Proparacaine is available as 0.5% and 0.75% topical solution. It is used 2.5 minutes prior to intraocular surgery. Its effect starts within 15-20 seconds and lasts for 15 minutes. Potency is similar to that of tetracaine. Maximum dose is 10mg (about 20 drops of 0.5% solution on topical instillation).

Due to higher degree of potency and safety, it is the most appropriate choice for topical anesthesia. It is available as 0.5% proparacaine HCL solution and 0.25% fluorecein sodium.

1.1.12   Lidocaine (xylocaine)

It is an agent that acts at receptor site on internal surface or nerve membrane. It can also act by combination of receptor and receptor independent mechanism. Lidocaine is one of the most widely used local anesthetics; it produces more prompt, more intense, more expensive and long lasting anesthesia than an equal proportion of some anesthetics like procaine. Unlike procaine, it is an anesthetic agent of choice.

Lidocaine is relatively quickly absorbed after parenteral administration. In the presence of epinephrine, there is decrease in the rate of absorption and toxicity. Also the duration of action is prolonged (1hr). It is metabolized in the liver by the mucosal mixed function oxidase by deal-kylation to monoethyglycine and xylidide. The later compound retains significant local anesthetics and toxic activity. In men, about 75% of xylidide is excreted in the urine as the further metabolite, x-hydroxyl 2, -laniline. A notable side effect of Lidocaine is sleepiness and high incidence of dizziness. The later, may be caused by a metabolite than by lidocaine (Laurence et al., 1997).

1.1.13    Chemistry of topical anesthetics

The basic components in the structure of local anesthetics are the lipophilic aromatic portion intermediate chain, and the hydrophilic amine portion. In the intermediate chain there is either an ester linkage from combination of an aromatic and amino or amide.

Local anesthetics are chemically stable in vivo and in vitro, our current knowledge of pharmacokinetics of local anesthetics is most derived from a study of these compounds. Esters on the other hand are rapidly hydrolyzed by plasma cholinesterase, and in vivo measurement of these compounds have been more limited.

1.1.14    Methods of tear measurement

  1. Schirmer′s Test: This was first discovered by Kosler in 1900; Otto Schirmer modified Kosler′s method by reducing the width of the strips from 1cm to 0.5cm and their length from 20cm long to 3.5cm. This test measures the volume of tears produced during fixed period. It is performed by placing the folded 5mm end of a standard size number 41 Whatman filter paper strip over the lower lid between the middle third and lateral third of the conjunctival fornix. . The patient, with eye open in a dimly lit room, looks straight ahead and blinks normally. After 5 minutes the strip is removed, and the amount of wetting is measured from the fold. A normal result is over 15mm without anesthesia and slightly less with anesthesia. Between 5 and 10mm borderline and less than 5mm indicates impaired secretion (Newell, 1992). Some authorities suggest that the cut-off point between normal and abnormal is 6mm (Kanski, 1998).
  2. Tear Film Breakup Time: Is a clinical estimate of the length of time that the tear film remains stable and intact. Decrease in tear film breakup time is thought to be the hallmark of mucin-deficient tears and does not necessarily correlate with aqueous tear production as measured by Schirmer tests (Vauley, 2001). To measure the tear breakup time, a fluorescein strip is instilled into the lower fornix, and the patient is asked to blink several times to distribute the dye throughout the tear film.

Examiner encourages the patient without necessarily touching the lids, to stare straight ahead without blinking while he/she observes the cornea through the slit lamp biomiscroscope using the broad tangential illumination with cobalt blue filter. The time between a complete blink and the appearance of the first defect (black spot) in the fluorescein film is determined with a stop watch (Wright, 1997). Normal tear breakup time has been reported to be greater than or equal to 10 seconds. The occurrence of non-randomly distributed dry spots reflect the [presence of localized corneal surface irregularities and not just tear film dysfunction (Norm, 2000).

1.2      Statement of problem

Anesthetics especially primax and Lidocaine (xylocaine) are daily routine optometric/ ophthalmologic and other medical and paramedical practices use of the drug for both diagnostic and therapeutic purposes. In this study, it is necessary to know the extent to which primax and Lidocaine can affect tear production.

There is a need to find out if proparacaine and lidocaine stimulate or inhibit tear production.

1.3     Aim and Objectives

To determine if anesthetics (Lidocaine and Proparacaine) affect tear production.

Study objectives

  1. To determine the rate of such effects.
  2. To determine the effect of lidocaine and proparacaine on the different time lags.

1.4     Research question

          Is there any significant effect of lidocaine and proparacaine on tear production? If there is, to what extent?

1.5     Research hypothesis

H0: there is no significant effect of lidocaine and proparacaine on tear production.

H1: there is significant effect of lidocaine and proparacaine on tear production.

1.6     Scope of study

          The focus of this work is on lacrimal gland. This study involves subjects within the age bracket of 18-35 years irrespective of gender. This was chosen to avoid the interference of age on the outcome of experimental tests. The subjects were randomly chosen within Owerri, Imo State.

1.7    Approaches to Study

This study was carried out using 40 people randomly selected, both male and female genders, who have normal tear production. Tear breaking time would be carried out: first to screen out those that have abnormal tear production. Schirmer′s test would be carried out on the normal patients before instillation of Lidocaine and proparacaine to determine the amount of tear production after instillation of Lidocaine or proparacaine to determine if there was any change in tear production.

1.8   Significance of the Study

The significance of this study is to enhance knowledge on the effect, mechanism of action, and indications or contraindications of topical anesthetics (lidocaine and proparacaine).

To ascertain the effect of this topical anesthetic on the tear production.

Pages:  69

Category: Project

Format:  Word & PDF

Chapters: 1-5

Material contains Table of Content, Abstract and References.

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