Components of lubricating agents

components of lubricating agents and dyes

1. COMPONENTS OF LUBRICATING AGENTS AND DYES SMRITI RANABHAT M. OPTOM TIO

2. contents Tear film structure and components History Artificial tear Ophthalmic demulcents Lubricating eye drops ( CMC , HPMC,HPC,PVA) Sodium chloride and zinc sulphate Carbomers and ointments Dyes (Sodium fluorescein, lissamine , ICG, Rose Bengal stain) Other dyes References

3. Autologous serum Natural tears are made up of components not found in artificial tear products EGF epidermal growth factor, fibronectin which supports proliferation , maturation , migration, differentiation of corneal and conjunctival epithelia. Also contains Ig G , lysozymes and complement which has bacteriostatic properties.

4. history Eye baths ( they called collyrium )were used in ENGLAND in 16th century To u se the eye cups ( cobalt blue glass bottle), the patient applied it to the eye with the head bowed forward, threw the head back with eyes wide open, ensured lavage by blinking several times and then removed the cup with the head once more bowed forward.

5. Lubricants preparation formulated as artificial tears usually contains; Inorganic electrolyte Preservative Water soluble polymeric system

6. Lubricants ; replacement of tear Indication of use Symptomatic relief of dry eye Symptomatic relief of irritants and Symptomatic relief of exposure Refreshment of contact lenses and prosthesis As a basis for topical medication( e.g. fort antibiotic drop)

7. Solvent water Active ingredient Water soluble polymer Viscosity Polymers concentration Preservatives Prevention of contamination Electrolytes Balanced tonicity Buffers ph Antioxidants Vit A sometimes Lipids Phospholipids sometimes

8. WHAt makes tear substutue ideal ?

9. FDA ; 6 groups of ophthalmic demulscents Cellulose derivatives - CMC, HPMC, HPC Liquid polyols Dextran 70 Gelatin Povidone Hyaluronic acid

10. polyols Propylene glycol 0.3% ( glycerine ) Polyethylene glycol 0.4% Sugar hydrogenated carbohydrates- polyhydric alcohols forms cross linked mucomimetic layer Combined with HP guar

11. Dextran -70 High molecular weight polysaccharides Enhances demulcent nature of HMC Increases retention time Use in evaporative dry eyes Tear naturale-0.3% HPMC+0.1% dextran 70

12. gelatin 0.01% seldom included gelling agent

13. povidone Demulscent property Increases solubility 0.1 to 2% Lubricating and soothing Lipid that integrates with existing oil layer, thickening it and reducing evaporation Povidone iodine has been widely used as a disinfectant including the care of contact lenses.

14. Hyaluronic acid Binds multiples of its weight in water, lowers tear osmolarity Adheres to ocular surface Stabilizes and evens out the tear film Highly viscous until blink thins it out Topical sodium hyaluronate (0.18%) is non-cytotoxic and has been used in the treatment of dry eyes when other artificial tear products have failed to achieve satisfactory results . It has been found to improve goblet cell density and to reduce inflammation of the ocular surface (Aragona et al 2002 )

15. Tear substitute Eye drops Gels Ointments

16. 1) CARBOXYMETHYL CELLULOSE(CMC) Carboxymethyl cellulose is a cellulose derivative that consists of the cellulose backbone made up of glucopyranose monomers and their hydroxyl groups bound to carboxymethyl groups. Added in food products as a viscosity modifier or thickener and emulsifier O ne of the most common viscous polymers used in artificial tears, and has shown to be effective in the treatment of aqueous tear-deficient dry eye symptoms and ocular surface staining . The viscous and mucoadhesive properties as well as its anionic charge allow prolonged retention time in the ocular surface Sodium carboxymethylcellulose is the most commonly used salt. Methyl cellulose is a hydrophilic white powder in pure form and dissolves in cold (but not in hot) water, forming a clear viscous solution or gel. Used to be marketed under trade name tylose .

17. PHARMACODYNAMICS In a randomized clinical study of patients with mild or moderate forms of eye dryness, ophthalmic treatment with sodium carboxymethylcellulose resulted in a diminished frequency of symptoms compared to the placebo group . Carboxymethylcellulose interacts with human corneal epithelial cells to facilitate corneal epithelial wound healing and attenuate eye irritation in a dose-dependent manner . It exhibits protective actions on the ocular surface in various applications; it mediates cytoprotective effects on the ocular surface when applied prior to contact lenses and reduces the incidence of epithelial defects during LASIK .

18. MECHANISM OF ACTION Carboxymethyl cellulose binds to the surface of corneal epithelial cells via its glucopyranose subunits binding to glucose receptors GLUT-1 . The residence time of carboxymethylcellulose bound to corneal cells is approximately 2 hours as indicated by a short-term binding assay. Binding of carboxymethylcellulose to the matrix proteins stimulated corneal epithelial cell attachment, migration, and re-epithelialization of corneal wounds

19. Half life For methyl cellulose – 4.2 minutes

20. preparation It is synthesized by the alkali-catalyzed reaction of cellulose with chloroacetic acid. The polar (organic acid) carboxyl groups render the cellulose soluble and chemically reactive. The resultant mixture produces about 60% CMC plus 40% salts (sodium chloride and sodium glycolate). This product is the so-called technical CMC which is used in detergents. A further purification process to remove these salts produces the pure CMC used for food, pharmaceutical, and dentifrice (toothpaste) applications. F unctional properties of CMC depend on the degree of substitution of the cellulose structure (i.e., how many of the hydroxyl groups have taken part in the substitution reaction), as well as the chain length of the cellulose backbone structure and the degree of clustering of the carboxymethyl substituents .

21. EYEDROP CONCERNTRATION Vial( ml) Relub 0.5% w/v 10 Relub ds 1.00% w/v 10 Moist max 0.5% w/v 10 Glytears 0.5% w/v 10 Lubrica 0.5% w/v 10 Lubrex 0.5% w/v 10 Lubrex ds 1.00% w/v 10 Refresh tears 0.5%w/v 10 Siotears 1.00 % w/v 10

22. uses Ocular uses -Carboxymethylcellulose is an artificial substitute for tears . - It is used as a lubricant for dry eyes. It is also used for the temporary relief of burning, irritation and/or discomfort due to dryness of eyes. -Moreover , it is used to lubricate and re-wet soft and rigid gas permeable contact lenses. Systemic uses - It is also used as laxatives, diverticulosis, hemorrhoids and irritable bowel syndrome. Culinary uses -Chewing gums, peanut butters , biscuits as an emulsifier

23. Enzymology -CMC is a highly specific substrate for endo-acting celluloses, as its structure has been engineered to decrystallize cellulose and create amorphous sites that are ideal for endoglucanase action. Used in the manufacture of capsules in nutritional supplements. Its edible and nontoxic properties provide a vegetarian alternative to the use of gelatin.

24. absorption V irtually unabsorbed and little or no degradation of absorbable products occurs in the human digestive tract . In humans, virtually 100 percent of orally ingested methyl cellulose can be recovered in the feces within four days, indicating that absorption does not occur.

25. Side effects Visual disturbances and eye discharge while using this medicine. Some other side effects of this medicine include redness of the eye, eye irritation, burning and discomfort , eyelid swelling and itching of the eye.

26. DRUG INTERACTION The risk or severity of adverse effects can be increased when CMC is used with; - acetazolamide -alloin -amiloride The therapeautic efficacy of CMC is decreased when used with; -aclidinium -amantadine -amlodipine -

27. 2) Hypromellose Hypromellose , short for hydroxypropyl methylcellulose (HPMC), is a semisynthetic, inert, viscoelastic polymer that forms colloid solution when dissolved in water. It is a solid, and is a slightly off-white to beige powder in appearance and may be formed into granules. The compound forms colloids when dissolved in water. This non-toxic ingredient is combustible and can react vigorously with oxidizing agents . A cts as a thickening agent, coating polymer, bio adhesive, solubility enhancer in solid dispersions, and binder in the process of granulation and in modified release formulations C ommonly used as a controlled delivery component in oral medicaments that provides the release of a drug in a controlled fashion, effectively increasing the duration of release of a drug to prolong its therapeutic effect.

28. indication Used as an ophthalmic protectant and lubricant, in artificial tears , and as a diagnostic aid (contact lens procedures; gonioscopy ). Hydroxypropyl methylcellulose 0.3% as a contact lens solution is clear, viscous, and easy to apply; does not require irrigation after use; and has levels of convenience, safety, and visual recovery superior to the standard 2.5% solution characteristics. The 0.3% gel could be used as an effective and convenient gonioscopic and ophthalmoscopic contact medium.

29. pharmacodynamics Hypromellose is considered an inert substance – a methyl and hydroxypropyl mixed e ther of cellulose as it has no direct pharmacological activity . The viscosity promoting properties of hypromellose prolong the retention time and improve adhesion of synthetic tears to the cornea and conjunctiva. As a result, the tear film breakdown time is prolonged and/or the tear film stability is enhanced. A stable tear film protects the cornea from dryness .

30. Mechanism of action Promotes corneal wetting by the stabilization and thickening the precorneal tear film and prolonging the tear film breakdown time, which is usually shortened in dry eye conditions. Hypromellose also acts to lubricate and protect the eye . In the typical dry eye, and particularly in case of mucin deficiency; surface activity and its adsorptive capacity make hypromellose optimal for this use . Hypromellose has a physical-chemical action and leads to, in an aqueous solution, a reduced surface tension as well as an increased level of viscosity. Hypromellose adheres well to the cornea and conjunctiva and provides ample moisture .

31. Adverse effects Hypromellose is considered low toxicity to non-toxic . Adverse events may include blurred vision and contact dermatitis . Hypersensitivity and intolerance reactions may occur (for example, eye burning, pain, increased lacrimation, a sensation of foreign body, conjunctival hyperemia, eyelid swelling, pruritus). The stickiness sensation of the eyelids, the decreased sense of smell, photosensitivity .

32. uses Ophthalmic applications -as a semisynthetic substitute for tear-film -Its molecular structure is predicated upon a base celluloid compound that is highly water-soluble. Post-application, celluloid attributes of good water solubility reportedly aid in visual clarity. -When applied, a hypromellose solution acts to swell and absorb water, thereby expanding the thickness of the tear-film. Hypromellose augmentation therefore results in extended lubricant time presence on the cornea, which theoretically results in decreased eye irritation, especially in dry climates, home, or work environments - On a molecular level, this polymer contains beta-linked D-glucose units that remain metabolically intact for days to weeks . -Hypromellose 2% solution has been documented to be used during surgery to aid in corneal protection and during orbital surgery.

33. Excipient/tableting ingredient - hypromellose has been used as an excipient in oral tablet and capsule formulations, where, depending on the grade, it functions as controlled release agent to delay the release of a medicinal compound into the digestive tract . - used as a binder and as a component of tablet coatings Use in construction materials HPMC is used primarily in construction materials like tile adhesives and renders where it is used as a rheology modifier and water retention agent.

34. preparation 1) H ypromellose is joined in hot water, be mixed with hypromellose mixture; 2) add remaining cold water, be placed in ice-water bath, be stirred to the viscous solution that forms clarification. In step 1), the temperature of hot water is between 70～100 ° of C, and preferably temperature is 80～90 ° of C. 2.5% for gonioscopy traditionally Opcare 0.3%, 0.5%, 0.7% Moisol 0.5% ( 5ml, 10 ml)

35. 3) Hydroxypropyl cellulose Hydroxypropyl cellulose is an ether of cellulose where some of the hydroxyl groups of the cellulose have been hydroxypropylated . HPC has a combination of hydrophobic and hydrophilic groups , so it has a lower critical solution temperature (LCST) at 45 °C. At temperatures below the LCST, HPC is readily soluble in water; above the LCST, HPC is not soluble. HPC forms liquid crystals and many mesophases according to its concentration in water. Such mesophases include isotropic, anisotropic, nematic and cholesteric. The last one gives many colors such as violet, green and red.

36. pharmacodynamics Hydroxypropyl cellulose (cellulose, 2-hydroxypropyl ether) is a derivative of cellulose with both water solubility and organic solubility. It acts to stabilize and thicken the precorneal tear film and prolong the tear film breakup time which is usually accelerated in patients with dry eye states . Hydroxypropyl cellulose also acts to lubricate and protect the eye . It usually reduces the signs and symptoms resulting from moderate to severe dry eye syndromes, such as conjunctival hyperemia, corneal and conjunctival staining , exudation, itching, burning, foreign body sensation, smarting, photophobia, dryness and blurred or cloudy vision. Progressive visual deterioration which occurs in some patients may be retarded, halted, or sometimes reversed.

37. Mechanism of action Hydroxypropyl cellulose is a derivative of cellulose that is soluble in both water and organic solvents. It is particularly good at trapping water and producing a film that serves as a barrier to water loss . Hydroxypropyl cellulose possesses good surface activity but does not gel as it forms open helical coils . In general Hydroxypropyl cellulose is a water-soluble thickener, emulsifier and film-former often used in tablet coating.

38. absorption Studies conducted in rats fed 14 C-labeled hydroxypropyl cellulose demonstrated that when orally administered, hydroxypropyl cellulose is not absorbed from the gastrointestinal tract and is quantitatively excreted in the feces.

39. uses Lacrisert , is a formulation of HPC used for artificial tears . It is used to treat medical conditions characterized by insufficient tear production such as keratoconjunctivitis sicca), recurrent corneal erosions, decreased corneal sensitivity, exposure and neuroparalytic keratitis . HPC is also used as a lubricant for artificial eyes. HPC is used as a thickener, a low level binder and as an emulsion stabiliser . In pharmaceuticals it is used as a binder in tablets. HPC is used as a sieving matrix for DNA separations by capillary and microchip electrophoresis. HPC is the main ingredient in Cellugel , which is used in book conservation . Cellugel is described as "A safe, penetrating consolidant for leather book covers affected by red rot" and is produced by Preservation Solutions.

40. preparation It is manufactured by reacting alkali cellulose with propylene oxide at elevated pressure and temperature to yield a highly substituted cellulose ether, with 3.4–4.1 mol of hydroxypropyl substituent per mole of anhydroglucose backbone units . Lacisert – 5 mg insert

41. 4) Poly vinyl alcohol Polyvinyl alcohol is a water-soluble synthetic polymer obtained by polymerization of vinyl alcohol. It is white and odorless.

42. Mechanism of action As a synthetic resin with hydrophilic properties , it increases the persistence of tear film and therefore lubricates and soothes dry/irritated eyes .

43. absorption Polyvinyl alcohol is poorly absorbed from gastrointestinal tract , and readily eliminated from the body .

44. Half life When injected intravenously , polyvinyl alcohol has a half-life of 90 min. Intraocularly , in eye drop form, the half-life is 7.2 minutes .

45. uses PVA is used in a variety of medical applications because of its biocompatibility , low tendency for protein adhesion , and low toxicity . Polyvinyl alcohol is found in ophthalmic solutions as a lubricant to prevent irritation or to relieve dryness of the eyes . Specific uses include cartilage replacements, contact lenses . Polyvinyl alcohol is used as an aid in suspension polymerizations . Another application is photographic film . Nowadays PVA-based polymers are being used widely in additive manufacturing . For example, 3D printed oral dosage forms demonstrate great potential in the pharmaceutical industry. It is possible to create drug-loaded tablets with modified drug-release characteristics where PVA is used as a binder substance. Medically , it may also used as the embolic agent in a Uterine Fibroid Embolectomy (UFE)

46. Adverse effect Adverse effects include eye pain and changes of vision, and redness or irritation of the eye . Mild stinging or irritation of the eye, crusting of eyelid, eye pain, ocular hyperemia, eye pruritus, foreign body sensation, eye discharge, and increased lacrimation may also occur .

47. preparation PVA is prepared by hydrolysis of polyvinyl acetate or sometimes other vinyl ester-derived polymers with formate or chloroacetate groups instead of acetate. The conversion of the polyvinyl esters is usually conducted by base- catalysed transesterification with ethanol: [CH2CH( OAc )]n + C2H5OH → [CH2CH(OH)]n + C2H5OAc The properties of the polymer are affected by the degree of transesterification .

48. 5)Sodium chloride( nacl ) Sodium chloride, also known as salt, common salt, table salt or halite, is an ionic compound with the chemical formula NaCl , representing a 1:1 ratio of sodium and chloride ions. Sodium chloride is the primary salt in seawater and in the extracellular fluid of many multicellular organisms. It is listed on the World Health Organization Model List of Essential Medicines . This product is used to reduce swelling of the surface of the eye (cornea) in certain eye conditions. Decreasing swelling of the cornea may lessen eye discomfort or irritation caused by the swelling. This product works by drawing fluid out of the cornea to reduce swelling.

49. indication This intravenous solution is indicated for use in adults and pediatric patients as a source of electrolytes and water for hydration. Also, designed for use as a diluent and delivery system for intermittent intravenous administration of compatible drug additives . Corneal edema Increased intraocular pressure

50. pharmacodynamics Sodium, the major cation of the extracellular fluid, functions primarily in the control of water distribution, fluid balance, and osmotic pressure of body fluids. Sodium is also associated with chloride and bicarbonate in the regulation of the acid-base equilibrium of body fluid. Chloride, the major extracellular anion, closely follows the metabolism of sodium, and changes in the acid-base balance of the body are reflected by changes in the chloride concentration.

51. absorption Absorption of sodium in the small intestine plays an important role in the absorption of chloride, amino acids, glucose, and water. Chloride, in the form of hydrochloric acid ( HCl ), is also an important component of gastric juice, which aids the digestion and absorption of many nutrient.

52. Mechanism of action Sodium and chloride — major electrolytes of the fluid compartment outside of cells (i.e., extracellular) — work together to control extracellular volume and blood pressure. Disturbances in sodium concentrations in the extracellular fluid are associated with disorders of water balance.

53. metabolism The salt that is taken in to gastro intestinal tract remains for the most part unabsorbed as the liquid contents pass through the stomach and small bowel. On reaching the colon this salt, together with the water is taken in to the blood. As excesses are absorbed the kidney is constantly excreting sodium chloride, so that the chloride level in the blood and tissues remains fairly constant. Further more, if the chloride intake ceases, the kidney ceases to excrete chlorides.

54. toxicity The rare inadvertent intravascular administration or rapid intravascular absorption of hypertonic sodium chloride can cause a shift of tissue fluids into the vascular bed, resulting in hypervolemia, electrolyte disturbances, circulatory failure, or augmented hypertension . Eye discomfort, burning, redness, or temporary blurred vision may occur.

55. Route of elimination Substantially excreted by the kidneys

56. Half life 17 minutes

57. Drug interaction Lithium carbonate Lithium citrate Lithium hydroxide - Sodium chloride may increase the excretion rate of drugs above which could result in a lower serum level and potentially a reduction in efficacy. Tolvaptan - The risk or severity of adverse effects can be increased when Sodium chloride is combined with Tolvaptan .

58. uses Optical usage Defect-free NaCl crystals have an optical transmittance of about 90% for infrared light, specifically between 200 nm and 20 µm. They were therefore used in optical components (windows and prisms) operating in the spectral range. Firefighting Sodium chloride is the principal extinguishing agent in fire extinguishers (Met-L-X, Super D) used on combustible metal fires such as magnesium, potassium, sodium, and NaK alloys (Class D). Thermoplastic powder is added to the mixture, along with waterproofing (metal stearates) and anti-caking materials ( tricalcium phosphate) to form the extinguishing agent. When it is applied to the fire, the salt acts like a heat sink, dissipating heat from the fire .

59. Food industry and agriculture -Many microorganisms cannot live in a salty environment: water is drawn out of their cells by osmosis. For this reason salt is used to preserve some foods, such as bacon, fish, or cabbage. Medicine -Sodium chloride is used together with water as one of the primary solutions for intravenous therapy. Nasal spray often contains a saline solution . Water softening

60. preparation Sodium chloride will be synthesized by reacting sodium bicarbonate with hydrochloric acid . Ph – 7 0.9% Nacl 2 to 4% used in corneal oedema

61. dosage For swelling of the cornea : 2 to 4% For ophthalmic dosage form (eye drops): -Adults—Use 1 or 2 drops every 3 or 4 hours, or as directed by your doctor. - Children—Use and dose must be determined by your doctor. For ophthalmic dosage form (eye ointment): -Adults—Apply small amount (1/4 inch) to the inside of the eyelids every 3 or 4 hours, or as directed by your doctor. -Children—Use and dose must be determined by your doctor .

62. 6) zinc sulphate Zinc sulfate is the inorganic compound with the formula ZnSO4 and historically known as "white vitriol“( white powder)is odorless. It is on the World Health Organization's List of Essential Medicines , a list of the most important medication needed in a basic health system. Zinc sulfate, an astringent helps to reduce redness and irritation. A locally acting pharmacologic agent which, by precipitating protein, helps to clear mucous from the surface of the eye

63. pharmacodynamics Zinc has been identified as a cofactor for over 70 different enzymes, including alkaline phosphatase, lactic dehydrogenase and both RNA and DNA polymerase. Zinc facilitates wound healing, helps maintain normal growth rates, normal skin hydration and the senses of taste and smell.

64. Mechanism of action Zinc improves the absorption of water and electrolytes, improves regeneration of the intestinal epithelium, increases the levels of brush border enzymes, and enhances the immune response, allowing for a better clearance of the pathogens.

65. absorption Approximately 20 to 30% of dietary zinc is absorbed, primarily from the duodenum and ileum . The amount absorbed is dependent on the bioavailability from food. Zinc is the most bioavailable from red meat and oysters . After absorption, zinc is bound in the intestine to the protein metallothionein . Endogenous zinc can be reabsorbed in the ileum and colon, creating an enteropancreatic circulation of zinc.

66. distribution After absorption zinc is bound to protein metallothionein in the intestines. Zinc is widely distributed throughout the body. It is primarily stored in RBCs, WBCs, muscles, bones, Skin, Kidneys, Liver, Pancreas, retina, and prostate.

67. Route of elimination Primarily fecal (approximately 90%); to a lesser extent in the urine and in perspiration.

68. Half life 3 hours

69. uses Medicine In medicine it is used together with oral rehydration therapy (ORT) and an astringent Manufacturing It is also used as an electrolyte for zinc electroplating, as a mordant in dyeing, and as a preservative for skins and leather .

70. toxicity Zinc sulfate powder is an eye irritant. Ingestion of trace amounts is considered safe, and zinc sulfate is added to animal feed as a source of essential zinc, at rates of up to several hundred milligrams per kilogram of feed. Excess ingestion results in acute stomach distress, with nausea and vomiting appearing at 2–8 mg/Kg of body weight .

71. Drug interaction Zinc sulfate can cause a decrease in the absorption of - Ciprofloxacin - Carbamazepine - Gatifloxacin - Tetracycline resulting in a reduced serum concentration and potentially a decrease in efficacy.

72. Food interactions Avoid milk and dairy products. Separate the use of zinc from these products by at least 2 hours before administration. Separate for 2 hours after administration if these products also contain phosphorus. Do not take with bran and high fiber foods. For optimal absorption, take zinc at least 2 hours before or after eating high-fiber foods. Take on an empty stomach. Take at least 1 hour before and 2 hours after eating for optimal absorption. Zinc can be taken with food to reduce gastrointestinal upset.

73. preparation Zinc sulfate is produced by treating virtually any zinc-containing material (metal, minerals, oxides) with sulfuric acid . Specific reactions include the reaction of the metal with aqueous sulfuric acid: Zn + H2SO4 + 7 H2O → ZnSO4•7H2O + H2 Pharmaceutical-grade zinc sulfate is produced by treating high-purity zinc oxide with sulfuric acid: ZnO + H2SO4 + 6 H2O → ZnSO4•7H2O 0.25% w/v

74. carbomers Carbomer 980 (polyacrylic acid) is the viscolizer used in Viscotears and Gel Tears. The gel has good water-binding properties, which help to form a stable tear film . It shows thixotropic properties (i.e. the gel is reversible ). During blinking, liquefaction of the gel occurs followed by a reformation of the gel to reduce elimination from the tear film. Marquardt ( 1986)found that liquid gels had a retention time seven times greater than PVA . They can provide protection during sleep when few natural tears are produced. Liquivisc , viscotears 0.2%

75. ointments These are normally mixtures of various paraffins (relatively inert hydrocarbon chemicals) . Liquid paraffin and paraffin yellow soft(simple eye ointment) melt at ocular temperature and their greasy nature allows them to be retained for a longer period than eye drops. Because they blur vision, they are usually used, often as an adjunct, at bedtime

76. Dyes

77. 1) fluorescein Fluorescein is an organic compound and dye. It is available as a dark orange/red powder slightly soluble in water ( yellow)and alcohol. D ibasic dye of xanthine series ( C20H12O5Na), has a low molecular weight (376.27 Da ) Biologically inert Dye concentration and pH can affect the intensity of fluorescence. Maximum fluorescence occurs at a pH of 7.4 , approximately 80% of the dye molecules bind to plasma proteins.

78. Historical perspective 1871 ; First fluorescein dye was made by Bayer M Straub ( 1888 ) used dye for vital staining if eye Burk (1910 ) used to detect retinal disease

79. Mechanism of action Fluorescein sodium is used extensively as a diagnostic tool in the field of ophthalmology . Fluorescein is a fluorescent compound or fluorophore having a maximum absorbance of 485 to 500 nm and an emission maximum of 520 -530 nm . The yellowish-green fluorescence of the compound can be used to demarcate the vascular area under observation, distinguishing it from adjacent areas . It is applied topically in the form of a drop or it can be injected intravenously to produce a fluorescein angiogram. Topical fluorescein is a useful tool in the diagnosis of corneal abrasions, corneal ulcers, herpetic corneal infections, and dry eye. Fluorescein angiography is used to diagnose and categorize macular edema, diabetic retinopathy, inflammatory intraocular conditions, and intraocular tumors.

80. Route of elimination Fluorescein and its metabolites are mainly eliminated via renal excretion within 24 to 36 hours of administration. Dark yellow or orange urine

81. uses

82. In ophthalmology -Tear film drainage studies- Jones test -Contact lens fitting assessment -Fluorescein angiography -Test for dry eye-TBUT -Applanation tonometry -Staining techniques;siedels test, staining for epithelial defects

83. Plant science Fluorescein has often been used to track water movement in groundwater to study water flow and observe areas of contamination or obstruction in these systems. Oilfield application Fluorescein dye solutions, typically 15% active, are commonly used as an aid to leak detection during hydrostatic testing of subsea oil and gas pipelines and other subsea infrastructure. Leaks can be detected by divers carrying an ultraviolet lig ht.

84. Side effects Extravasation and local-tissue necrosis Inadvertent arterial injection Nausea Vomiting Vasovagal reaction (circulatory shock, myocardial infarction) Allergic reaction, anaphylaxis (hives and itching, respiratory problems, laryngeal edema, bronchospasm ) Neurologic problems (tonic- clonic seizures) Thrombophlebitis Pyrexia Death

85. DRUG INTERACTION The excretion of Fluorescein can be decreased when combined with Acetazolamide Acyclovir Amoxicillin

86. contamination Liable to become infected with bacteria and, at the same time, are frequently used on damaged tissue that is prone to infection , very great care must be taken in their use. Ps . aeruginosa is an especially dangerous pathological microorganism with which fluorescein eye drops are inclined to become invaded . Phenyl mercuric acetate or nitrate in 0.002% strength is the best bactericide for preserving these particular eye drops. However , the safest method of their employment is sterile single-dose units or sterile fluorescein-impregnated paper strips, both of which are readily available and to be highly recommended.

87. preparation Fluorescein is an organic compound that has wide use as a synthetic coloring agent. It is prepared by heating phthalic anhydride and resorcinol over a zinc catalyst, and it crystallizes as a deep red powder . Also called resorcinolpthalein Available as fluorescein strip 2 % Solutions containing 500 mg fluorescein are available in vials of 10 mL of 5% fluorescein or 5 mL of 10% fluorescein. Also available are 3 mL of 25% fluorescein solution .

88. Rose bengal Belonging to class of organic compound xanthene- brownish red in colour . Its disodium salt in ophthalmic solutions has been used as a diagnostic agent in suspected damage to conjunctival and corneal cells. The stain is also used in the preparation of Foraminifera for microscopic analysis, allowing the distinction between forms that were alive or dead at the time of collection . Rose Bengal is a pink stain derived as an analogue of fluorescein. A form of rose Bengal is also being studied as a treatment for certain cancers and skin conditions. The cancer formulation of the drug, known as PV-10, is currently undergoing clinical trials for melanoma, breast cancer . and neuroendocrine tumors. The company also has formulated a drug based on rose Bengal for the treatment of eczema and psoriasis; this drug, PV-10, is currently in clinical trials as well .

89. indication Indicated as a diagnostic agent in routine ocular examinations or when superficial conjunctiva or corneal tissue change is suspected, and as an aid in the diagnosis of keratoconjunctivitis sicca, keratitis, abrasions or corrosions as well as the detection of foreign bodies.

90. pharmacodynamics Rose Bengal is a staining agent that visualized ocular surfaces of both diseased and dead cells in vivo . Various studies demonstrate the cytotoxic effects of rose bengal in different cell cultures, including smooth-muscle cells from human intestine, endothelial cells from bovine pulmonary artery, rabbit Tenon fibro-blasts, and rabbit and human corneal epithelial cells .

91. Mechanism of action Rose Bengal stains both the nuclei and cell walls of dead or degenerated epithelial cells of the cornea and conjunctiva, and stain the mucus of the precorneal tear film . It is proposed that the staining ability of rose Bengal is dependent on the status of tear film protection rather than cell viability, as tear components such as albumin and mucin can block the rose Bengal uptake . It induces intrinsic cytotoxic effects by causing cellular morphologic changes, subsequent loss of cellular motility, cell detachment, and cell death . It mediates inhibitory actions on bovine corneal endothelial cells and attenuates cell proliferation.

92. Protein binding Tear component comprising of different proteins, such as albumin (although not very common as tear component), lactoferrin, and transferrin, can bind to rose Bengal dye and act as diffusion barrier to prevent dye uptake by cells and subsequent cell staining. Lysozymes in tear film can also bind to rose Bengal to form precipitates to attenuate cell uptake .

93. Route of elimination Rose Bengal undergoes biliary excretion

94. uses Derivatives and salts Rose Bengal can be used to form many derivatives that have important medical functions. One such derivative was created so to be sono sensitive but photo insensitive, so that with a high intensity focused ultrasound, it could be used in the treatment of cancer. Dendritic keratitis: Rose Bengal will stain the areas of the dendritic ulcer . It is restricted to the processes of the ulcer and does not diffuse to surrounding areas. Keratoconjunctivitis sicca: The parts that are stained are the exposed triangular areas in the interpalpebral conjunctiva. Such staining constitutes a better diagnostic indication of dry eye than the Schirmer tear test.

95. Exophthalmos: this is great enough to deny the eye of the normal protection of the lids, drying will occur, which will lead to changes in the exposed area . • Pressure areas due to contact lens wear: P ractitioners can use rose Bengal during their initial assessment of patients for contact lens tolerance . It is equally useful in follow-up visits, when stains might be found on the cornea or bulbar or palpebral conjunctiva and,although not serious, provide an indication that modification of the lens.

96. Rose Bengal is used to suppress bacterial growth in several microbiological media, including Cooke's rose Bengal agar . Rose Bengal dye is mixed with the homogenate of Brucella and pH of the solution is maintained at 3.8, and this dye is used to diagnose Brucellosis by agglutinating the suspected serum. Rose Bengal is slightly irritating and toxic to the eye . It has also been used as an insecticide .

97. Rose Bengal strip 1.3/1.5 mg

98. Indocyanine green ICG is a tricarbocyanine, anionic dye. Its structural formula is 2,2’-indo-6,7,6’,7’-dibenzocarbocyanine sodium salt with a molecular weight of 774.96 Da. ICG sodium salt is normally available in powder form and can be dissolved in various solvents; 5% (< 5% depending on batch) sodium iodide is usually added to ensure better solubility. ICG was developed in the Second World War as a dye in photography and tested in 1957 at the Mayo Clinic for use in human medicine by I.J. Fox. The absorption and fluorescence spectrum of ICG is in the near infrared region.

99. ICG absorbs mainly between 600 nm and 900 nm and emits fluorescence between 750 nm and 950 nm . The fluorescence spectrum is very wide. Its maximum values are approx. 810 nm in water and approx. 830 nm in blood. About 98% of ICG is bound to plasma protein, in particular to globulins.

100. Half life ICG has a half-life of 2.5 to 3 minutes .

101. Mechanism of action Indocyanine Green for Injection USP undergoes no significant extrahepatic or enterohepatic circulation; simultaneous arterial and venous blood estimations have shown negligible renal, peripheral, lung or cerebro -spinal uptake of the dye . Indocyanine Green for Injection USP is taken up from the plasma almost exclusively by the hepatic parenchymal cells and is secreted entirely into the bile. Indocyanine Green Injection USP a helpful index of hepatic function.

102. Route of elimination The dye is excreted in bile in unconjugated form by liver. Clearance of dyes which are removed from the circulation principally by the liver constitutes one of the best methods for evaluating hepatic function.

103. uses In ophthalmology Indocyanine green angiography ( ICGA) is a diagnostic procedure used to examine choroidal blood flow and associated pathology. Standard dosage is 25 mg of ICG dissolved in 3 ml saline, and 1 mL of the solution is injected. The near infrared light used in ICGA penetrates ocular pigments such as melanin and xanthophyll, as well as exudates and thin layers of sub-retinal vessels . Indocyanine green angiography is widely used to study choroidal neovascularization in patients with exudative age-related macular degeneration. In non exudative AMD, ICGA is used in classification of drusen and associated sub retinal deposits.

104. ICG has the ability to bind 98% to plasma proteins – 80% to globulins and 20% to alpha-lipoprotein and albumin – and thus, in comparison with fluorescein as a marker, has a lower leakage (slower emergence of dye from the vessels, extravasally ).Because of the plasma protein binding, ICG stays for up to 20 to 30 minutes in the vessels ( intravasally ). When the eye is examined, it thus stays for a long time in tissues with a higher blood flow, such as the choroid and the blood vessels of the retina . Capsulorhexis Capsulorhexis is a technique used to remove the lens capsule during cataract surgery. Various dyes are used to stain lens capsule during cataract surgery. In 1998, Horiguchi et al. first described the use of indocyanine green dye (0.5%) for capsular staining to assist cataract surgery.ICG-enhanced anterior and posterior capsulorhexis is useful in childhood cataract surgery. Although ICG is approved by US FDA, still there is no approval for intraocular use of the dye .

105. Selectively over-heating cells (especially cancer) -ICG absorbs near infra-red, especially light with a wavelength of about 805 nanometers. A laser of that wavelength can penetrate tissue . That means, dying tissue with injected ICG allows an 800 nm to 810 nm laser to heat or overheat the dyed tissue without harming the surrounding tissue . -That works particularly well on cancer tumors, because tumors naturally absorb more ICG than other tissue. When ICG is injected near tumors, tumors react to the laser 2.5 times as much as the surrounding tissue does. -ICG and laser therapy has been shown to kill human pancreatic cancer cells. - ICG and an infrared laser have also been used the same way to treat acne vulgaris .

106. Toxicity and side effects ICG is metabolized microsomally in the liver and only excreted via the liver and bile ducts; since it is not absorbed by the intestinal mucous membrane, the toxicity can be classified as low. It has been known since September 2007 that ICG decomposes into toxic waste materials under the influence of UV light, creating a number of still unknown substances. A study published in February 2008, however, shows that ICG (the substance without UV effect) is basically, as such, of only minor toxicity. Occasionally – in one out of 42,000 cases – slight side-effects occur in humans such as sore throats and hot flushes.

107. ICG as a pregnancy category C drug, meaning that adequate studies of safety have not been conducted. Effects such as anaphylactic shock, hypotension, tachycardia, dyspnea and urticaria only occurred in individual cases; the risk of severe side-effects rises in patients with chronic kidney impairment. Caution should also be observed in patients affected by liver diseases.

108. Drug interaction Atropine Atenolol Cyclosporine Dexamethasone E rythromycin may decrease the excretion rate of Indocyanine green acid form which could result in a higher serum level.

109. preparation Each vial of Indocyanine Green for Injection USP contains 25 mg of Indocyanine Green as a sterile lyophilized powder with no more than 5% sodium iodide . Indocyanine Green for Injection USP has a pH of approximately 6.5 when reconstituted .

110. Lissamine green This vital stain was introduced in 1973 by Norn as an alternative to rose Bengal for assessing the ocular surface. It is an organic dye that is synthetically produced and its molecular weight is 576.6 Daltons. Lissamine green is a diphenyl- naphthyl methane derivative of the phenylmethane dye, whereas fluorescein and rose Bengal fall into the category of xanthine dyes . The DEWS II Report recommends that lissamine green (along with Fluorescein assessment) should be used when evaluating ocular surface damage. Using both stains is the most appropriate diagnostic technique for evaluating ocular surface damage and that the benefits of using lissamine green outweighed any risks .

111. Norm’s original research concluded lissamine green ‘shows a high level of affinity in staining degenerated cells, dead cells and mucous fibrils, with this staining being well defined and easily visualized with a slit lamp. There is general agreement that lissamine green is useful when assessing conjunctival integrity but has limited use in corneal integrity assessment due to poor visibility against dark iris backgrounds . . However, lissamine green appears to be underutilized in routine optometric practice and there are a number of potential reasons for this: Lack of understanding Belief that use of Fluorescein is sufficient Making decisions based on other clinical findings or reported symptom

112. However, the staining properties of lissamine green makes it the best choice for evaluating the integrity of the bulbar conjunctival epithelium and the marginal zone of the conjunctiva (Marx’s line) when looking for lid margin changes such as lid wiper epitheliopathy (LWE)

113. Lissamine green has a peak absorption at 624-635nm, the red end of the visible spectrum. When illuminated with white light our eyes will see the reflected or non-absorbed coloured light which is bluish green for lissamine green. Using a red filter (figure 3), for example Hoya 25A or Kodak Wratten 92, enhances visualisation of the dye by transmitting the wavelengths that lissamine green absorbs giving a black appearance, any staining therefore indicates where the dye is present.

114. Lissamine green is dose dependent, instilling too little will result in a limited amount of staining. In clinics, impregnated paper strips are popular, these are moistened with about 10-20ul of saline10 applied to the lower fornice.One percent is the optimal concentration, as mild ocular irritation has been reported with 2% and 3% solutions, whereas 1% is generally well tolerated. Kim and Foulks12 concluded that the optimal time for evaluating conjunctival staining is between one and four minutes after instillation. Instant viewing of the staining pattern could result in misinterpretation due to any pooled dye which has not dissipated In contact lens patients, circumlimbal staining observed with lissamine green may be an indicator of contact lens induced conjunctival staining (CLICS)—indicating that the lens is too tight or has a sharp edge design .

115. For clinical use, lissamine green is available as 1.5mg impregnated strips.

116. Other dyes Alcain blue -A complex copper-containing compound used in 1% solution and specific for staining mucus. Alcian blue is used to counterstain rose Bengal, which, in addition to staining dead cells, also stains mucus (Norn 1972). Trypan blue This stains mucus and dead cells which have undergone structural changes Bromothymol blue This is a narrow range pH indicator that changes color around pH 7 and stains degenerate and dead cells and mucus. It is used to assess the damage caused by chemical agents such as lime.

117. Tetrazolium and iodotetrazolium -Both these compounds have been used for the vital staining of tumors and assessing corneal grafts (Norn 1972). -They are by nature pro-stains because the compounds are reduced inside cells to a red dye formazan. The color takes about 4 min to develop. Tetrazolium stains degenerate – not dead or living – cells. Living healthy cells are not stained because of the impermeability of the cell membrane and dead cells are not stained because the enzymes needed to reduce the dye to formazan are not present.

118. references Ophthalmic drugs diagnostic and therapeutic effects –Graham Hopkins and Richard pearson Drugs in ophthalmology , Donald s fong s Internet