Ординатура / Офтальмология / Английские материалы / Basic Sciences in Ophthalmology_Velayutham_2009
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15 Routes of
Administration of Drugs
for Ocular Conditions
There are various ways to administer drugs to the diseased site.
Eye Drops: In the eye, drugs can be administered easily as drops into the conjunctival sac. This is of great advantage as the systemic absorption is very minimal. But there are some problems like — very little of the drops applied i.e., about 20% is retained in the eye. If the drops cause stinging sensation, there will be watering and further dilution of the drug. As there is continuous secretion of tears, whatever drug is retained gets diluted further. Only 50% of the drug that was retained in the conjunctival sac remains after 4 minutes. This is the reason for applying antibiotic drops every five minutes initially to build up the concentration of antibiotics in the conjunctival sac. If more than one drop is applied it will be a waste, as the excess amount will overflow. Hence, if two drops have to be applied atleast five minutes interval must be given between the two.
Compression at the medial canthus also will prevent exit of tears through the naso lacrimal duct. This will also reduce absorption of the drugs through the nasal mucosa. Another important matter that has to be remembered is that the epithelium and the endothelium of the cornea are impermeable to the drugs as they have tight intercellular junctions. If there is any disruption of the epithelium drugs can penetrate the cornea in a better manner. Various methods are undertaken to get over this hurdle. Upto a limit the concentration of the solutions can be increased. Increasing the viscosity will increase the contact time and may help in penetration.
Complications of drops: Short contact time, inconsistent delivery of drug, frequent contamination and injury while applying the drops. Solutions are watersoluble and suspensions are for lipid soluble drugs. When suspensions are used they must be shaken well before use, which is not done properly. The suspended particles also may clog the dropper tip.
Lipid solubility: Both epithelium and endothelium are lipid barriers. The stroma allows water-soluble elements. Lipid solubility of the drugs is more important to make the drug get through the corneal epithelium. To achieve this, drugs are prepared in a slightly alkaline base. Addition of acetates and alcohol increases lipid solubility.
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Surfactants: The preservatives that are added to the eye drops act on the epithelium of the cornea in the same way it affects the bacterial cell wall. These preservatives will increase the absorption of drugs. The preservatives inhibit growth of organisms or kill them e.g. quarternary ammonium compounds like benzalkonium to which EDTA can be added for enhancing the effect, mercurials (thiomersal) and alcohols (chlorbutanol) and esters of para hydroxy benzoic acids. But the preservatives are toxic to the epithelium and reduce the lipid part of tear film.
Addition of tear substitutes: If there is a stinging sensation after application of any drops the tearing will dilute the drops. Hence, tear substitutes are added to reduce irritation.
Change of base: Oil-based ointments contain petrolatum and mineral oil. These two substances are lipid solvents and help in better absorption of drugs. But the drugs must be lipid soluble to diffuse through the ointment and watersoluble to dissolve in the tears, e.g, Fluoromethalone, chloramphenicol and tetracycline.
Ointments should not be used when surgical wound opposition is not good, when the corneal ulcer is deep and when there is impending perforation.
Subconjunctival and subtenon's injections: These injections act as a depot and stay in the eye for a longer time. The drug also can enter the eye without encountering the conjunctival and corneal hurdles. Drugs, which are not lipid soluble, must be given subconjunctivally. But these injections are painful. It may perforate the eye causing retinal detachment and preretinal membrane formation.
Anterior subtenon's injections are similar to subconjunctival injections and have a greater danger of perforation. But in severe uveitis corticosteroids are, given in this site.
Posterior subtenon's injection is also given for delivering steroids. Here a canula is inserted under the conjunctiva and Tenon's anteriorly and then pushed backwards to deliver the drug in the posterior quadrant.
Intravitreal injections: Indications for intra vitreal injections are for endophthalmitis where the drug can be given directly into the site where it is needed. Triamcinolone is also given intra-vitreally for diabetic maculopathy. Only very low concentration of the drugs can be given in this method. Polymyxin B can be given in the anterior chamber but only 0.1mg can be given.
Retrobulbar injections are given to deliver anaesthetics, vasodilators, steroids and alcohol.
Peribulbar injections: Due to the danger of perforating the eyeball or the optic nerve during retro bulbar injection and also respiratory arrest due to the drug entering the subarachnoid space now peribulbar injections are given to deliver anaesthetics. Retrobulbar haemorrhage is also less with peribulbar injections. Here the drug seeps into the muscle cone instead of being directly delivered there.
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Retrobulbar and peribulbar injections also cause ecchymosis, exposure keratitis, increased intra ocular tension, bradycardia, CRA, CRV occlusion, optic atrophy, decreased visual acuity, chemosis, pain shock and perforation.
Systemic drugs: Similar to blood brain barrier the retinal vessels which are nonfenestrated will not allow the drugs to enter the eyeball. Choroidal and ciliary body blood vessels are fenestrated but the pigmentary epithelium will prevent any drug from entering the eye. Lipid soluble drugs can overcome this barrier e.g., Chloramphenicol. If drugs are bound to plasma proteins e.g., Sulfonamides, they cannot overcome this barrier.
Intravenous injections: Continuous IV infusion can maintain high intraocular levels. Antibiotics like ampicillin, erythromycin, and chloramphenicol penetrate the eye and maintain high levels for four hours if given as one IV injection. Inflammation will help in better penetration. When drugs are given intravenously, high levels are found only in the conjunctiva and sclera. Smaller amounts are found in the iris and ciliary body. Some amount is seen in cornea, aqueous humor, choroid and retina. Very low levels are seen in the lens and vitreous.
Prodrugs: Are compounds that are inactive until enzymatically activated e.g., Dipivefrin is a prodrug for epinephrine. Prodrugs penetrate the eye better and after entering become the active compound. Because of better penetration the concentration needed is low. Consequently systemic side effects are also low.
Soft drugs: When inactive or nontoxic metabolite of a drug is instilled it becomes active at the site where it is needed. Then it becomes inactive.
Sustained release devices and gels: If more than required amount of drug is given to achieve higher concentration more side effects will be seen. To prevent this, drugs must be released at the required site at a steady level. Various methods are available to achieve this.
Ocuserts: This method is commonly used for antiglaucoma drugs like pilocarpine and timolol maleate. The ocusert is 13mm / 5.7mm in size. They are of two types. Pellets of hydroxy propyl methyl cellulose, which absorbs the tear fluid, and from the conjunctival sac and the capillaries. It then softens and dissolves slowly releasing the methylcellulose into the conjunctival sac. The second type contains the drug in between two membranes, which controls the release of the drug. There is a white ring around the device, which helps in handling the device.As there is a sustained release the patients are not dependent on others for instillation of drops.
When pilocarpine is given as an ocusert it releases 40 micro gram of the drug /hour which is equal in effect to 2% drops given q.i.d. So, only a small amount of the drug is used to get an equal and consistent effect. This results in lesser amount of induced miosis and accommodation, which is very disturbing to young patients.
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The sustained release timolol preparation contains heteropolysaccharide that becomes a gel when it comes in contact with tear film and acts as a local reservoir.
Ocuserts can get displaced and lost. They also create blurring of vision after sometime.
Gancyclovir is an intravitreal sustained release drug. The gancyclovir sustained release intravitreal device (GIOD) has the drug in ethyl vinyl acetate disc coated with polyvinyl alcohol. This device is suspended from the sclera into the vitreous cavity. Polyvinyl alcohol allows only a minimal amount of drug to be released.
Gels contain carboxy methylcellulose sodium. Gels of lubricating drops contain agents, which have a high water binding capacity. Once instilled the gel becomes liquid. Blurring of vision is less with gels than in ointments.
Collagen shields: The scleral tissue of pigs or cattle is molded into shields, which look similar to contact lenses. Drugs can be incorporated into the collagen matrix or absorbed into the shield during rehydration of the shield. Drops can also be applied on the shield after application. The drugs will be retained for a long time in this method. Before application the shield must be soaked in some solution for 3 minutes. The duration of the presence of the shield in the eye depends on the type of manufacturing process. Usually they dissolve after 12, 24 or 72 hours. They create some irritation, which is a disadvantage.
They are used in bacterial ulcers, after surgery, trauma and erosions. It should not be used in bullous keratopathy and chemical injuries, as it will trap the polymorphs and metalloproteinases causing worsening of the condition.
Liposomes: These are synthetic microspheres in which drugs can be incorporated. A water-soluble drug can be incorporated inside with a single or multilayered lipid membrane envelope. Alipid soluble drug is incorporated into the liposomal wall of the sphere.
Drugs impregnated in filter paper strips are used in staining. The strips allow us to use minimum amount of drug in a sterile form.
16
Anti-inflammatory
Agents
Ocular inflammation is controlled by drugs, which can be administered either locally as drops subconjunctival injections or as subtenons injections. It can be given orally and systemically also.
The types of drugs used are:
a.Steroids.
b.Non-steroidal anti-inflammatory drugs.
c. Antihistaminics.
d.Histamine release blockers.
e.Antifibrotics.
f.Immunosuppressive agents.
STEROIDS
Steroids are the most widely used anti-inflammatory drugs. They are used to control allergic conjunctivitis, vernal conjunctivitis, episcleritis, scleritis, chemical injuries, keratitis, iritis, uveitis, retinal inflammations, optic neuritis, etc. Steroids can bring about rapid reduction in inflammation especially during acute attacks. But there are many side effects when they are used long term. Newer drugs are developed to bring about anti-inflammatory action with minimal side effects. The anti-inflammatory action is seen whatever may be the cause for it i.e., allergic, traumatic or infectious.
The steroids:
a.Inhibit migration of neutrophils into the diseased area.
b.Prevent adherence of neutrophils to the vascular endothelium.
c. Inhibit macrophages.
d.Interfere with lymphocytic activity.
e.Decrease the number of B and T lymphocytes.
f.Affect protein production in immunologically competent cells.
g.Decrease histamine release.
h.Inhibit phospholipase A2 thereby preventing biosynthesis of arachidonic acid and subsequent formation of prostacyclin, thromboxane A, prostaglandins, PGE2, PGF2 and leucotrienes.
i.Suppresses release of lytic enzymes from lysozomes.
j.Decrease capillary permeability and fibroblast formation.
k.Decrease collagen deposition.
The last two qualities will affect wound healing.
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Steroids are available as drops, ointments, oral and intramuscular preparations. For systemic administration, preparations with minimal mineralocorticoid activity must be used. Methyl prednisolone, which does not have sodium-retaining activity, is preferred for systemic use. When prednisolone is given orally 20-40 mgs are given in the beginning, if there is severe inflammation 40-60 mgs are given for 2 days and the dose is increased if there is no response. Steroids must always be tapered off after clinical improvement unless very small dose has been given for a short period. Reduction is by 10mgs for larger doses or 5mgs for smaller doses at 3-4 days intervals. If there is recurrence of inflammation it should be increased again.
Side Effects
Long-term steroid use will give rise to osteoporosis, hypertension, peptic ulcer, and muscle weakness, adrenal insufficiency, cushing's syndrome, diabetes, increase of infection, delayed wound healing, mood changes and inhibition of growth in children. To reduce the side effects oral steroids can be given on alternate days as a single dose so that the body can recuperate during the interval. This can be done only with prednisolone, which has a short half-life. The single dose has to given at about 8.00am when the cortisol level of the body is also high. But this method will not be as effective as daily dose.
Because of the above side effects topical administration is preferred in anterior segment inflammations. Frequent application of drops and subconjunctival injections should be given for additional effect.
Different Types of Steroids in Use
In general, acetate and alcohol derivatives are more effective whether the epithelium is intact or not. Alcohol derivatives are in suspension form.
Prednisolone:Available as 0.125% and 1%. The acetate form is better attached to the receptor and hence has a better effect.
Dexamethasone: 0.1% solution, suspension or ointments which contain 0.5% of the drug. It has a long half-life and the drug is found in the anterior chamber even after 12 hours. The above two drugs are synthetic cortisol derivatives.
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Fluoromethalone: 0.1% is an analog of progesterone. It does not elevate the intraocular tension as it is metabolized quickly in the anterior chamber. The acetate derivative is metabolized slightly slowly compared to alcohol and is more effective in treatment of conjunctival and scleral inflammation.
Medrysone is also a progesterone derivative. As it penetrates the cornea poorly it does not elevate the intraocular pressure. But because of this it is not suited for treating intra ocular inflammation.
Loteprednol etabonate is a soft drug, which becomes transiently active in the place where it is needed. It gets activated in the cornea, aqueous, iris and ciliary body. It is useful in treating giant papillary conjunctivitis, allergic conjunctivitis, and postoperative iridocyclitis.
Rimoxalone also is a derivative of progesterone and is available as 1 % suspension.
Side Effects in the Eye
This is usually due to long term use and complications like glaucoma are seen more in susceptible people. Posterior capsular cataract, increase in infection, secondary infection, defective wound healing, reduction in collagen formation which leads on to corneal and scleral thinning, uveitis and epithelial erosions are some of the other complications. The cause for glaucoma is not known but in these cases, endoreplication of DNA and aberrant polypeptide production are seen. The drug may directly affect the trabecular meshwork and alter outflow facility. Mydriasis and ptosis are sometimes seen perhaps due to the vehicles.
NON-STEROIDAL ANTI-INFLAMMATORY DRUGS
The anti-inflammatory effect of NSAIDS are lesser compared to steroids but the complications are also less. These drugs by blocking the cyclooxigenase pathway prevent formation of prostaglandins from arachidonic acid.
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Salicylates |
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aspirin, mefenamic acid, tolfenamic acid. |
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Indoles |
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indomethacin. |
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Phenyl alkanoic derivatives |
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diclophenac, flurbiprofen, ketoralac, |
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piroxicam. |
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Pyrozolones |
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oxyphen butazone, phenyl butazone. |
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To understand the effect of NSAIDS some knowledge about the agents causing the inflammation is essential.
PGD2 is present in the mast cells. It increases conjunctival microvascular permeability. This causes erythema, chemosis and accumulation of eosinophils. PGD2 is more potent than histamine.
PGE2 causes erythema and itching. PGI2 causes itching.
PGF2 alpha increases uveo scleral outflow.
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After any injury PGE2 and PGF2 alpha will be released.
It must be remembered that the cyclooxigenase has two types of action. Cox 1 in normal conditions and Cox 2 during inflammation. Both are inhibited by NSAIDS. Newer drugs inhibit only the Cox 2 action. These drugs have lesser gastro intestinal problems.
Protaglandin inhibitors are used to prevent intra operative miosis, postoperative inflammation, cystoid macular edema and allergic conjunctivitis. In diabetics, miosis is not prevented effectively by these drugs.
In allergic conjunctivitis, disruption of mast cells occur. This causes release of preformed mediators like histamine and eosinophil chemotactic factor, and initiation of prostaglandin synthesis. NSAIDS help in breaking this activity. Ketorolac is effective in reducing itching. It also reduces pain in conditions like corneal erosion, corneal ulcer and post-surgical conditions.
In uveitis and postoperative conditions the usage of steroids can be reduced if NSAIDS are added.
Side effects: Stinging sensation and delayed wound healing. Lysis of keratocytes is also noticed in some patients. Inhibition of prostaglandins can give rise to asthma and nasal polyp.
ANTIFIBROTIC AGENTS
Drugs like 5 flurouracil and mitomycin C are used to prevent excessive fibrosis after antiglaucoma surgeries.
5 flurouracil inhibits cellular proliferation, which occurs following inflammation and reduces the chances of failure of the bleb due to fibrosis.
Mitomycin C inhibits DNA synthesis and fibroblast proliferation. It is prepared from the fungus Streptomyces caespitosus. It is used after pterygium surgery as drops and during glaucoma surgery as a single application. But it can cause wound leakage, hypotony and scleral melting.
For pterygium, topical application of 0.02%—0.04% drops is used 4 times daily for one or two weeks. It can cause corneal edema, perforation, iritis and cataract formation.
IMMUNOSUPPRESSANTS
Human body requires minimum reaction to bacteria, virus etc., to protect the tissues. But if itself is recognized as an antigen; an autoimmune reaction results. This will destroy tissues. To prevent this immunosuppressants are needed.
Steroids and NSAIDS are milder forms of immuno suppressants. If these fail other substances which are more potent but have more side effects may have to be used. They control the immune reactions by:
a.Blocking lymphocyte proliferation—cytotoxic drugs.
b.Blocking synthesis of lymphokines-immunomodulators.
c. Reducing the inflammatory response.
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IMMUNOSUPPRESSIVE (ANTI-NEOPLASTIC) AGENTS
These agents primarily developed for the treatment of neoplastic disease can also be employed in the treatment of autoimmune diseases. In ophthalmology be they have been primarily used for resistant uveitis cases and occasionally used in Grave's disease, pseudotumor of the orbit. Triethylenemelamine (TEM) has been used as adjuvant in the treatment of retinoblastoma and anti-neoplastic are used for ocular neoplastic disease.
They can be classified as
•Alkylating agents
•Antimetabolites
•Antibiotics
•Vinca alkaloids
•Radioactive isotopes
Basically these drugs act by blocking protein synthesis at different levels - precursor stages leading to RNA - DNA synthesis or subsequent activity of RNA and DNA. The commonly used drugs in ophthalmology are discussed below.
Fluorouracil(5- fluorouracil)
This fluorinated pyrimidine blocks the methylation reaction of deoxyuridylic acid to thymidylic acid by inhibiting thymidylate synthase resulting in interference in the synthesis of DNA and RNA. It has been used to prevent closure of conjunctival filtering blebs after glaucoma surgery, and for the prevention of massive preretinal proliferation and epiretinal membrane formation. Gastrointestinal and hematopoietic reactions are common. Subconjunctival injection of 3 mg are given after glaucoma surgery and at repeated intervals to prevent the closure of subconjunctival filtration blebs. For prevention of preretinal membranes, intravitreal dose of 1.25mg for several successive days have been tried.
Mitomycin C
Isolated from Streptococcus calspitosus, mitomycin reacts with DNA in ways similar to alkylating agents. It cross-links DNA and inhibits its synthesis. It is a highly effective antimitotic agent. The major systemic side effect is myelosuppression.
The ocular indications for mitomycin C are recurrent pterygium and glaucoma surgeries. Single application of mitomycin C, in a sponge, at the end of pterygium surgery and at the end of glaucoma surgery.
Potential complications of topical mitomycin C ocular therapy appear to be limited to instances of abuse and negligence, to instances in which drug dosage error occurred, and to instances in which the drug was used in patients with ocular surface disorders such as sicca syndrome and ocular rosacea.
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Mitomycin C is antineoplastic antibiotic that is active against gram positive bacteria. It is very cytotoxic because it causes cross-linking of DNA. Mitomycin C also inhibits RNA and protein synthesis.
Topically applied mitomycin (1.0 mg/ml) caused conjunctival irritation, excessive lacrimation, and mild superficial punctate keratitis; these adverse effects were minimized with the lower (0.4 mg/ml) dosage; this lower dose was equally effective in preventing pterygium recurrence, and no systemic toxicity after topical administration was noted.
Mitomycin C in doses of 0.2 to 0.5 mg/ml has been used in glaucoma filtering surgery to inhibit fibroblast proliferation. Limbus based conjunctival flap is made and mitomycin C is applied in a sponge avoiding the edges of conjunctival flaps. O.2 mg is placed for 45 - 60 seconds and 0.4 mg is applied for around 30 seconds, and the area is completely irrigated with copious amount of normal saline. Adverse effects include sequelae of wound healing inhibition, such as bleb and wound leaks.
Bleb failure is heralded by a gradual but definite increase in the IOP, with flattening of the bleb occurring at any time during the postoperative period. When this occurs at an early stage, the inflammatory response with thickening and vascularity of the bleb eventually results in poor control of IOP. There are many ways that a bleb can fail; Tenon's cyst has been described as a stage in bleb failure. The initial stage of fibrovascular proliferative processes occurs early in the postoperative filtering state but can be altered by the use of mitomycin-C intraoperatively and 5-FU postoperatively. The possibility of sclerectomy obstruction must be evaluated any time when bleb failure is anticipated. Careful gonioscopy can reveal the presence of iris or a ciliary process prolapse into the sclerectomy, and laser or surgical removal is necessary. A clear membrane can occasionally be perforated by Nd.YAG laser.
Cytotoxic agents
Cyclophosphamide: Is an alkylating agent of nitrogen mustard type. By suppressing both T suppressor cells and T helper cells both humoral and cell mediated immune responses are reduced by this drug. It is useful in treating scleritis, cicatricial pemphigoid, Behcet's syndrome, Mooren's ulcer, rheumatoid arthritis, Wegener's granulomatosis.
Dose: 2 mg / kg / day, oral or intravenous.
Side effects: Nausea, vomiting, dizziness, liver toxicity, increased pigmentation and ulcers on the mucosal surfaces.
Chlorambucil: Suppresses T and B-lymphocytes and is used in Behcet's syndrome and sympathetic ophthalmia.
Dose: 0.1mg / kg /day.
Side effect: Bone marrow toxicity.
Methotrexate: Is a cytotoxic agent with antifolate activity. It affects synthesis of purines and thymidylate by inhibiting enzyme dihydro folate reductase.