Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Ocular Pharmacology Dr. med. Markus Tschopp Pharmacology Studies the actions and applications of chemicals/drugs interacting with the body -> Pharmacodynamics: effect of the drug to body -Glaucoma, Anti-inflammatory, Mydriatics -> Pharmacokinetics: body affects drug with time Ocular Pharmacology - studies the applications and actions of drugs which affect the eye Pharmacology Studies the actions and applications of chemicals/ drugs interacting with the body Pharmacodynamics: effect of the drug to body Pharmacokinetics: body affects drug with time Ocular Pharmacology - studies the applications and actions of drugs which affect the eye Pharmacokinetics “body affects drug with time”: is the absorption, distribution, metabolism, and excretion of the drug Pharmacology Studies the actions and applications of chemicals/ drugs interacting with the body Pharmacodynamics: effect of the drug to body Pharmacokinetics: body affects drug with time Ocular Pharmacology - studies the applications and actions of drugs which affect the eye Drug Absorption Drug must be absorbed from its site of administration Diffusion (passive): Non-polar, size, lipid-solubility Fick‘s law: rate of diffusion= KA(x1- x2 )/D Active transport (requires energy): carrier mediated Factors affecting (oral administration): pH, mucus, motility, flora, blood flow Drug Delivery in Eyes Topical Periocular Intraocular Systemic drop Subconj. Intracameral oral Subtenon Intravitreal intravenous ointment gel Peribulbar Retrobulbar Intramuscular Pharmacology Studies the actions and applications of chemicals/ drugs interacting with the body Pharmacodynamics: effect of the drug to body Pharmacokinetics: body affects drug with time Ocular Pharmacology - studies the applications and actions of drugs which affect the eye Drug Distribution Distribution depends on route of administration Intravenous, intramuscular, buccal, topical à drug availability ↑↑ Oral à first pass Factors affecting: Plasma protein binding, tissue protein binding, blood flow, Ocular Distribution; systemic therapy Blood-ocular barriers – composed: 1. blood-aqueous - iris blood vessels and ciliary body epithelium - some breakdown with inflammation - 2. blood-retinal - retinal pigment epithelium and capillaries -harder for drug to penetrate even during significant inflammation Pharmacology Studies the actions and applications of chemicals/ drugs interacting with the body Pharmacodynamics: effect of the drug to body Pharmacokinetics: body affects drug with time Ocular Pharmacology - studies the applications and actions of drugs which affect the eye Drug Elimination Distribution depends on route of administration Intravenous, intramuscular, buccal, topical à drug availability ↑↑ Oral à first pass Metabolism (liver):Oxygenation(P450), conjugation (acetyl, sulphate, glycine) Factors affecting: Plasma protein binding, blood flow, age, smoking, alcohol, genetics Urinary or/and biliary excretion Ocular pharmacokinetic Separate from the body direct absorption elimination into the body Difficult clinical evaluation Ocular Pharmacokinetics (drops) Absorption, Distribution, Metabolism, Excretion Ocular absorption: Corneal barrier it is a lipid - water - lipid layer the lipid content of the epithelium and the endothelium is 100 times more than that of stroma; and therefore allows lipophilic rather than to hydrophilic substance. because of the dual nature of the corneal barriers, drugs possessing both lipid and water solubility penetrate the cornea more readily. Ocular absorption: Corneal barrier immediate 1 to 2 minutes Ocular absorption: Sclera Sclera (14.5 x 10-6 cm/ sec) X Ciliary Body Cornea (3.24 x 10-6 cm/ sec) Penetration/ absorption Bimatoprost Sclera is 4fold cornea! Ocular absorption: eye drops Rate and extent of absorption in the eye are extremely difficult to measure experimentally. BUT there is evidence of: Competition from non-corneal absorption from lids and adnexa Drainage is responsible for suppressing the absorption Tear secretion promotes the dilution, and blinking facilitates removal Drainage more rapid than absorption -> poor absorption: 1% -8% (systemic > 75%) Residual time: 3-5 min., improvement by increase of residual time (ointment gel), or drug modification Ocular absorption: eye drops Tear Film drop added cause an increasing in blinking, squeezing which propels tears towards the sac. the drugs passes on iris & ciliary body lacrimal sac nasolacrimal system bypass the liver systemic circulation Ocular absorption: eye drops Drop (Gutta)- simplest and more convenient mainly for day time use 1 drop=50 microlitre Conjuctival sac capacity=7-13 micro liter so, even 1 drop is more than enough measures to increase drop absorption: -wait 5-10 minutes between drops -compress lacrimal sac -keep lids closed for 5 minutes after instillation Ointments Increase the contact time of ocular medication to ocular surface thus better effect, may not always increase drug bioavailability The drug has to be high lipid soluble with some water solubility to have the maximum effect as ointment It has the disadvantage of vision blurring Allergies to lanolin component Factors influencing local drug penetration into ocular tissue Drug concentration and solubility: the higher the concentration the better the penetration e.g pilocarpine 1-4% but limited by reflex tearing Viscosity: addition of methylcellulose and polyvinyl alcohol increases drug penetration by increasing the contact time with the cornea and altering corneal epithelium Lipid solubility: because of the lipid rich environment of the epithelial cell membranes, the higher lipid solubility the more the penetration Amphipathic- epithelium/endothelium----lipophilic stroma---hydrophilic Factors influencing local drug penetration into ocular tissue Surfactants: the preservatives used in ocular preparations alter cell membrane in the cornea and increase drug permeability e.g. benzylkonium and thiomersal pH: the normal tear pH is 7.4 and if the drug pH is much different, this will cause reflex tearing Drug tonicity: when an alkaloid drug is put in relatively alkaloid medium, the proportion of the uncharged form will increase, thus more penetration Molecular weight and size Composition (eye drops) Active drug (or prodrug) OH COOCH(CH3)2 Preservative OH Buffer Adhesive OH OH COOH OH OH Composition (eye drops): Drug Composition (eye drops): Preservative Composition (eye drops): Buffer Composition (eye drops): Adhesive Distribution (Dexamethason) Trace (0,1) 0,37 (0,37) 0,3 (0,6) 0,5 (8,6) 9,5 (0,66) 0,8 0,23 0,23 (0,5) (0,5) Trace 0,15 (0,1) Spur Trace Dexamethason concentration after 1 (2) h. after drop Trace Applications Intraocular Parabulbar Drops Systemic 100% 10% 1% 0.1% Periocular injections They reach behind iris-lens diaphragm better than topical application Increased local concentrations and avoid systemic toxicity Increased penetration Useful in kids or poor compliance patient Subconjunctival - Good for drugs with low lipid solubility (e.g. penicillins) Drugs which can’t penetrate cornea due to large size Penetrate via sclera Subtenon- ant. Subtenon– disease ant to the Lens Post Subtenon– disease posterior to the lens Retrobulbar- Optic neuritis/ papillitis; posterior uveitis; Anesthesia Peribulbar- Anesthesia 31 Intraocular injections Intracameral acetylcholine (miochol) during cataract surgery; antibiotics Intravitreal antibiotics in cases of endophthalmitis Intravitreal in diabetic macular edema, CRVO, retinal surgeries Intraocular implants: Gancicyclovir for CMV retinitis; Ozurdex Retisert (Fluocinolone) for posterior uveitis Systemic drugs Oral or Intravenous Factor influencing systemic drug penetration into ocular tissue: • lipid solubility of the drug: more penetration with high lipid solubility • protein binding: more effect with low protein binding • better penetration in the inflamed eye Systemic effect Why can there be a systemic effect: no " first pass effect “ Good absorption Example of systemic effect Clonidin: Epinephrin: Cyclopentalat: Betablocker: Lowers blood pressure Tachycardia Extrasystole Hallucination Epilepsia Exacerbation of asthma AV-Block Pharmacology Studies the actions and applications of chemicals/ drugs interacting with the body Pharmacodynamics: effect of the drug to body Pharmacokinetics: body affects drug with time Ocular Pharmacology - studies the applications and actions of drugs which affect the eye Pharmacodynamics It is the biological and therapeutic effect of the drug (mechanism of action) Most drugs act by binding to regulatory macromolecules, usually neurotransmitters or hormone receptors or enzymes If the drug is working at the receptor level, it can be agonist or antagonist If the drug is working at the enzyme level, it can be activator or inhibitor 37 Pharmacodynamics Autonomic Nervous System Physiologic antagonists 1. Parasympathetic - cholinergic system acetylcholine (Ach) neurotransmitter 2. Sympathomimetic - adrenergic system norepinephrine (Nor) neurotransmitter at the effector organ Adrenergic System “Fight” or “Flight” response Ach neurotransmitter at PREganglionic Norepinephrine (NOR) is the POSTganglionic neurotransmitter NOR action terminated by: – 1. Reuptake – 2. Transformation by MOA or COMT – 3. Diffusion from neuro. junction Sympathetic system Two types of receptors: – 1. Alpha (a) receptors – 2. Beta (b) receptors Further subdivided into: – alpha (a) 1 (smooth muscle contraction) – alpha (a) 2 (feedback inhib. sympath nerves) – beta (b) 1 (heart) – beta (b) 2 (lungs) Sympathetic system ALPHA - increase BP, in eye mydriasis (iris dilator), elevation of lid (Muller’s Muscle) BETA - increase heart rate, relaxation of bronchi; in eye BLOCKADE of receptor produce decrease in aqueous fluid formation Cocaine 2-10% Indirect sympathomimetic agent - blocks reuptake of NOR Diagnostic agent - Horner’s Mydriasis Local anesthetic - toxic to corneal epithelium Hydroxyamphetamine Indirect sympathomimetic causing release of NOR from terminals. Diagnostic agent - Horner’s Testing should not be within a few days of cocaine testing. If postganglionic lesion, terminal is degenerated and pupil will not dilate. Parasympathetic Cholinergic innervation Extraocular muscles, levator palpebrae, lacrimal & meibomian glands, iris sphincter & ciliary body Cholinergic agents are either direct-acting (imitators of Ach) and/or indirect-acting (agents preventing breakdown of Ach) Cholinergic stimulation in eye 1. Miosis 2. Contraction of ciliary muscle with effect on scleral spur & trabecular meshwork (opens up) 3. Lacrimation Cholinergic Agents Direct acting – Pilocarpine 0.25%-10% – Acetylcholine (Miochol-E) – Carbachol 0.75%-3% (Isopto Carbachol, Miostat) Indirect acting (Anticholinesterases) – Eiodide 0.03% - 0.25% (Phospholine Iodide) – Physostigmine 0.25% (Eserine) Demecarium 0.125-0.25% (Humorsol) - Edrophonium chloride (Tensilon) intravenous agents for diagnosis of myasthenia gravis Pilocarpine Pilocarpine (Spersacarpine) - POAG, AACG (if IOP < 60 mm Hg); effective conc. 1-4% (0.25%-10%); dark pigmented eyes may benefit from higher conc. Effects - Miosis, induces accommodation/ myopia, Ocular inflammation, reverse anticholinergics, - Diagnose Adie’s pupil 0.0625%-0.25% Salagen Pilocarpine Systemic SE’s - acute poisoning or acute glaucoma. – diarrhea, abdominal cramping – salivation, sweating – difficulty in breathing – cardiac irregularities Miotic side effects -ocular – pupillary constriction (miosis) – pupil. block (in pts. with narrow <cats.) – eye or brow ache – accommodative spasm – follicular conj. – allergic derm & conj. Cholinergic Antagonists Muscarinic antagonists/anticholinergic Relaxation of pupillary sphincter (dilation/mydriasis) - break synechiae, paralysis ciliary muscles, reduce pain from iridocyclitis. Caution in narrow angle or POAG Cholinergic Antagonists Atropine - 0.5-1% - longest acting (up to 2 weeks); most allergic rxs Scopolamine 0.25% - last up to 1 week; use in pts allergic to atropine Homatropine 2 & 5% - few days, weaker cycloplegic, OK atropine allergy Cyclopentolate 0.5-2% - up to 24 hours; potent cycloplegic Tropicamide 0.5-1% - 4-6hr, weak cycloplegic Mydriatics and cycloplegics Mydriatics are the drugs which dilate the pupil and cycloplegics are agents which causes paralysis of ciliary muscles Mydriatics Adrenergic agonist Adrenaline Cholinergic antagonists Phenylephrine Tropicamide Phenylephrine (2.5%)Adrenergic agonist acts on alpha 1 receptors of the dilator pupillae indication • pupil dilation • before intraocular surgeries contraindication • hypersensitive • narrow angle glaucoma • cardiac patients Side effects • systemic side effects include palpitation, tachycardia, headache, arrythmias • reflex bradycardia, pulmonary embolism, myocardial infaction Adrenaline- Adrenergic agonist acts on dilator fibres and directly produces dilation after instillation of four drops of 1:1000 solution may be combined with procaine and atropine to achieve mydriasis in severe iritis Mydriatics and cycloplegics Mydriatics are the drugs which dilate the pupil and cycloplegics are agents which causes paralysis of ciliary muscles Mydriatics Adrenergic agonist Adrenaline Cholinergic antagonists Phenylephrine Tropicamide Cycloplegic mydriaticsCholinergic antagonists parasympatholytic agents are commonly used blocks the action of cholinergic stimulation causing paralysis of accomodation and pupillary dilation indication • refraction • inflamation of uvea • malignant glaucoma adverse reaction • transient stinging and burning, increase in IOP, allergic lid reaction, hyperemia • flushing and dryness of skin, blurred vision, dryness of mouth and nose, anhidrosis, fever, bladder distention and CNS disturbances Cycloplegic mydriaticsCholinergic antagonists precautions • permanent mydriasis may occur in patients of keratoconus • longer acting agents may cause posterior synechiae formation when treating anterior segment inflammation • avoid driving or any other task requiring alertness overdosage • Administer parenteral physostigmine commonly used agents are atropine sulfate, homatropine, cyclopentolate, tropicamide Cycloplegic mydriaticsCholinergic antagonists Atropine is the most effective cycloplegic followed by Cyclopentolate (1%) & then Homatropine (2%) & Tropicamide (0.5-1%). Cyclopentolate should not be prescribed in uveitis as it has chemotactic effect on leucocytes. Mydriasis is quickest with Tropicamide among all parasympathomimetics (in 20 minutes) and is also shortest lasting 2.5% Phenylephrine (selective Alpha-1 agonist) along with anticholinergics like tropicamide 0.8 % induces maximum mydriasis Glaucoma Verstärkung des Inflow Kammerwasser-Abflusses über das Trabekelwerk Outflow Cholinergika α2Sympathomimetika -agonists/ Miotika β1-blockers CA inhibitors prostaglandins α2-agonists cholinergics Verstärkung des KammerwasserAbflusses uveoskleral Prostaglandine KammerwasserSuppression Betablocker Carboanhydrase-Hemmer Outflow: Prostaglandins The PGs derivates primarily lower IOP by enhancing the uveo-scleral outflow of the eye. two possible mechanism exists that have been studied are relaxation of the ciliary muscle and remodeling the extra cellular matrix of the ciliary muscle. first line for open angle glaucoma, ocular hypertension, exfoliation and pigmentary glaucoma contraindicated in allergic patient, pregnancy, uveitic glaucoma Outflow: Prostaglandins LATANOPROST TRAVOPROST • Increases uveoscleral outflow BIMATOPROST Decreases resistance to outflow • Duration of action 12-24 hrs • Wash out period 3-4 weeks • burning stinging, conjunctival hyperemia, iris pigmentation, anterior uveitis, hypertrichosis of eyelashes 0.005% OD 0.004% OD 0.03%, OD Safest and most efficacious Best in maintenance on diurnal variation of IOP Controls diurnal variation better than latanoprost contraindicated with pilocarpine stable, safe and well tolerable highest incidence red eye rate XALANTAN, 9PM TRAVATAN LUMIGAN, CAREPROST Outflow: Cholinergic agents Cholinergic drugs either act directly by stimulating cholinergic receptors or indirectly by inhibiting the enzyme cholinesterase Topically applied cholinergic agents causes contraction iris sphincter miosis circular muscles of ciliary body longitudinal muscle of ciliary body relaxing zonular tension & forward lens movement accommodation Tension on scleral spur Opening of trabecular meshwork aqueous outflow Side effects of cholinergic agents Lids: orbicularis muscle spasm and lid twitching, Conjunctiva: irritation,conjunctival hyperemia, allergic conjunctivitis Cornea: epithelial staining and vascularisation, atypical band keratopathy. Iris: hyperemia, pigment epithelial cyst formation, post operative iritis and synechiae formation. Lens: cataract, increase lens thickness – myopia Systemic: sweating, salivation and lacrimation, nausea, vomiting and abdominal cramps, night mare, bronchial spasm, asthma and pulmonary edema. Pilocarpine In open angle glaucoma In angle closure glaucoma Pilocarpine oldest and most widely used cholinergic agent, derived from the plant pilocarpus microphylus. Topical solution is available in two salts: • Pilocarpine hydrochloride in the strengths of 0.25, 0.50, 1, 2, 3, 4%. • Pilocarpine nitrate in the strengths of 1, 2 & 4%. produces a reduction in IOP that starts after one hour and lasts for 4 - 8 hours. IOP decrease is 15-20% Indications for pilocarpine First line for acute and chronic angle closure glaucoma, primary open angle glaucoma Less certain indications in neovascular glaucoma,uveitis related glaucoma Also used in laser trabeculoplasty, accommodative esotropia Diagnostically in Adie tonic pupil Outflow and production: N. Alpha adrenergic agonist Directly acting sympathomimetics • Epinephrine • Dipivefrin Alpha2 adrenergic agonists • Apraclonidine • Brimonidine Indicated in • open angle glaucoma • to control IOP spikes after laser procedures • ocular hypertension Brimonidine 2nd generation α-adrenergic receptor agonist, with high degree selective to α2 receptors. Dual action:it decreases aqueous humor production like β-blockers and also increases the uveo scleral out flow like prostagladins. has binding sites in the iris epithelium, ciliary epithelium, ciliary muscle, retina and retinal epithelium and choroid IOP reduction is 26% (2 hrs post dose) and has an additive neuroprotective action available in 0.2% (0.15%, 0.1% ) solution. Instil one drop 2-3 times daily. side effects include ocular allergy, follicular conjunctivitis, lid edema, dry mouth, headache contraindicated in patients receiving MAO inhibitor therapy, tricyclic antidepressant, produces cardiovascular instability in infants and is therefore contraindicated in the first 5 years of life. Production: Beta-blockers Production: Beta-blockers usually first line agent for treating most types of glaucoma excellent IOP lowering efficacy/ long duration of action/ few ocular side effects first commercially available β blocker for systemic use , was propanolol for topical use was timolol reduce IOP 20-30% with little or no effect on pupil size or accomodation (blurred vision associated with miotics is not seen here) Systemic Side effects and Contraindications of B blockers Side effects burning sensation hyperemia. superficial punctate Keratitis. corneal anesthesia. allergic blepharoconjunctivitis dry eye bronchospasm masking of hypoglycemia in diabetes heart failure in pulmonary edema A-V dissociation and cardiac arrest in patients with pre-existing partial heart block Contraindications bronchial asthma COPD sinus bradycardia 2nd or 3rd degree A-V block sexual dysfunction Timolol first β-blocker to be commercially used in ophthalmics in 1978 it is non selective. inhibits both β1 and β2 receptors peak level of drug within 1-2 hours clinical effect may last upto 2 weeks after last use available in 0.25% and 0.5% administered twice daily, also available in gel solution : hence can be administered once daily Short term escape due to receptor alteration Long term drift due to tachyphylaxis contraindicated in asthmatic, heart failure patients Production: Carbonic anhydrase inhibitors inhibits enzyme carbonic anhydrase present in pigmented and non pigmented epithelium of ciliary body prevents the bicarbonate and sodium influx and decreases aqueous formation useful in short term treatment of acute glaucoma onset of action within 1 hour and maximum effect in 4 hours Production: Carbonic anhydrase inhibitors DORZOLAMIDE BRINZOLAMIDE • local inhibition of CA in ciliary body minimizing side effects • adverse effects include burning, stinging, blurred vision, systemic side effect is rare • caution must be exercised in patients with compromised epithelium 2% solution, TDS 1% solution, TDS has better penetration safe and well tolerated DORZOX, TRUSOPT AZOPT Fixed combinations Advantages • Convenience • Compliance • Effectiveness • Cost effectiveness • Safety and tolerability Disadvantage • Not always as additive as expected Best scientific combination • one drug from group that reduce aqueous formation • one that increases aqueous outflow Fixed combinations Few combinations available are Timolol 0.5% and Dorzolamide 2% (Cosopt, Co-Dorzolamid, ….) Brimonidine 0.2% and Timolol 0.5% (Combigan) Latanoprost 0.005% and Timolol 0.5% (Xalacom, Co-Latanoprost) Travaprost 0.004% and Timolol 0.5% (Duotrav) Bimatoprost 0.03% and Timolol 0.5 (Ganfort) Systemic anti glaucoma Oral • Acetazolamide • Glycerine Intravenous • Mannitol Neuroprotective agents • • • • Calcium channel blockers Nitric oxide synthase inhibitors Vasodialators Antioxidants Acetazolamide oral carbonic anhydrase inhibitor (Diamox, Glaupax) Tablet 125mg/250mg, TDS/BD • onset of action within 1 hr • Peak at 4 hrs • Duration of action 8-12 hrs Slow release capsule • Given OD/BD • Duration of action upto 24 hrs Intravenous • 500mg vials • Immediate onset , peak action at 30 minutes useful in acute glaucoma, cystoid macular edema, altitude sickness, epilepsy, respiratory stimulant Adverse effects of oral CAIs intolerance due to their adverse effects common in elderly people neurological/psychiatric • Paresthesia, fatigue, malaise, • Depression, headache, decreased libido gastrointestinal • metallic taste and discomfort, • Nausea, abdominal cramps diarrhea renal/metabolic • Increased micturation frequency • Renal stones, hypokalemia (metabolic acidosis) • May cause exacerbation of gout hematological • Bone marrow depression,aplastic anemia teratogenic effect rarely: contraindicated in first trimester Hyperosmotic agents Increase the osmolarity of plasma Leads to absorption of water from ocular tissues (mainly vitreous) indication • acute glaucoma • secondary glaucoma, preparation of patients before OT • malignant glaucoma adverse effects • headache, nausea, vomitting • systemic hypertension • congestive heart failure and pulmonary edema • urinary retention and hyperglycemia Hyperosmotic agents Glycerol: diabetics may have problem due to caloric value, osmotic diuresis and dehydration Mannitol 15-25% intravenous agent - 1.5-2.5gm/Kg. - causes tissue necrosis and phlebitis - crystallization - not metabolized - peak action-within 30 mins - duration of action-upto 6hours - choice for intravenous therapy Glaucoma Therapy Prostagladins analogs, beta blockers, alpha2 agonist are reasonable choices for first line therapy Prostagladins with once daily dose are most effective agents for IOP lowering and provide good 24 hr IOP control Combining drops from different classes (ie, beta blocker plus prostaglandin, or beta blocker plus carbonic anhydrase inhibitor) can cause a greater reduction in the intraocular pressure than monotherapy. Adding a second medication is reasonable if initial monotherapy is not effective Ocular allergies Ocular allergies Typ I Type I hypersensitivity reactions are immediate (occurring within seconds or minutes) or anaphylactic reactions. They occur in atopic patients, i.e., genetically predisposed patients producing IgE in excessive quantities. Type I reactions are characterised by involvement of specific humoural factors: IgE and histamine release from mast cells. Typ IV Unlike type I, II and III reactions, type IV reactions involve T-cells (cellular) and are characterised by a delayed onset of action. Previously sensitised T-cells interact with the antigen bound to the surface of a cell. This results in the release of lymphokines and in tissue injury (inflammation, cell death). Ocular allergies Allergene Lösen sich im Tränenfilm Dringen in Kornea/ Konjunktiva ein Binden an IgE-Moleküle, die an Membranen der Mast-Zellen gekoppelt sind Mastzell-Stabilisatoren Mastzell-Degranulation ca. 50 Mio Mastzellen im Augenlid, in der Konkuntiva und anderen Geweben des Auges Antihistaminica NSAID, Steroide Steroide Voltaren, Ultracortenol Ultracortenol Histamin PG Leukotriene PAF Jucken Vasokonstriktoren Vasodilatation m. Hyperämie Papilläre Reaktion Hyperämie Vasodilatation Oedem Zelluläre Infiltration Oedem PlättchenAktivierung Human eye has about 50 million mast cells, which contains preformed chemical mediators Ocular allergies- Therapy Non- pharmacological • Avoidance of allergenes (Animals ...) • Cold compresses • Artifical tears (removal of allergenes) Pharmacological: z.B. Antiallergic (local, systemic) Antiinlammatory Immunosuppression Allergen desensitisation: reserved for severe cases Vasoconstrictors Vasoconstrictors, principally alpha-adrenergic agonists, reduce ocular redness by constricting blood vessels and thereby attenuating vascular hyperaemia associated with the allergic response. Due to their mechanism of action, they act very fast on acute symptoms. However, their duration of action is short, and overdose may result in rebound redness. Antihistamines Antihistamines compete with histamine for binding to the histamine H1-receptors on nerve endings and vascular endothelial cells and prevent the common symptoms of itching, redness, and chemosis. Due to their mechanism of action, they act very fast on acute symptoms. However, their duration of action is short, and overdose may result in rebound redness. Local antihistaminica offer faster relief of symptoms than oral agents Will not prevent the release of more histamine or other inflammatory mediators (no prophylactic treatment) Antazolin, Emedastin, Levocabastin Mast cell stabilisers Mast cell stabilisers prevent mast cell degranulation and inhibit the release of histamine and other mediators at their source - the mast cell. have a slow onset of action and require two to three weeks of treatment to achieve optimal efficacy. This long pre-treatment time is necessary because mast cell stabilisers do not act on inflammatory mediators that have already been released. Some immediate relief of symptoms that can be observed when mast cell stabilisers are applied topically, is likely to result from the “washing” effect, or dilution of the offending antigen. Therefore, mast cell stabilisers are more appropriately used as prophylactics for acute or chronic allergic conjunctivitis than for the immediate treatment of acute allergic symptoms. sodium cromoglycate, lodoxamide Dual action agents with combined antihistamine/mast cell stabilising activity provide effective relief from acute symptoms and prophylaxis Ketotifen, Olopatadine Class Mast cell inhibitor Generic name Mechanism Dosage Side effects Cromolyn sodium inhibit neutrophil, eosinophil, monocyte 0.01% BD does not provide immediate relief provides immediate relief and prevent further degranulation 0.05% BD ocular burning, stinging, dry eye Azelastine HCL H1 antagonist + mast cell inhibitor Epinastine HCL Ketotifen fumarate Nedocromil sodium rapid onset Olopatadine H1 antagonist + decongestant Naphazoline HCL/ phenaramine maleate 0.05%, 0.01% BD/ OD short term relief for mild allergy 0.05%/0.01% BD NSAIDs/Corticosteroids NSAIDs inhibit the activity of cyclo-oxygenase and, therefore, production of prostaglandins from arachidonic acid have been shown to be effective in relieving itching associated with allergic conjunctivitis. often produce significant stinging upon instillation, which may affect patient compliance generally not indicated for the treatment of allergic conjunctivitis prevention of post-op inflammation s/p cataract surgery/pain with photophobia s/p refractional surgery (ocular penetration better with topical than oral) Ketorolac (Acular) , Diclofenac (Voltaren) Corticosteroide Corticosteroids block the metabolic pathways involving arachidonic acid and have general anti-inflammatory and immunosuppressive effects • inhibition of lymphocytes proliferation, with a decrease of the cell-mediated immunity • inhibition of the degranulation of neutrophil granulocytes, macrophages, mastcells and basophil granulocytes. • decrease of vascular permeability • decrease of prostaglandin production Potentially prevents both early- and late-phase reactions , Corticosteroide Routes of administration: topical, periocular, intravitreal, oral, intravenous May elevate intraocular pressure, worsen diagnosed or undiagnosed infections, and cause or worsen cataracts -> must be administered with caution Prednisolon, Fluorometholon, Corticosteroide- Indications • post surgical inflammation • allergic conjunctivitis and blepharitis • vernal conjunctivitis, phylectunular keratoconjunctivitis • disciform and interstitial keratitis • corneal graft rejection • scleritis and episcleritis, anterior and posterior uveitis • traumatic inflammation of the eye • papillitis and retrobulbar neuritis • sympathetic ophthalmia • herpes zoster opahthalmicus • orbital pseudotumor Topical corticosteroids available as solution, suspension and ointment • Hydrocortisone 0.5-1.5% • Prednisolone 0.12, 0.25, 1 % • Dexamethasone 0.1% • Betamethasone 0.1 % • Triamcinolone 0.1% • Fluromethalone 0.1% • Loteprednol 0.2%,0.5% • Difluprednate 0.005% anti-inflammatory action * prednisolone acetate > fluorometholone acetate > dexamethasone acetate > betamethasone rise in IOP- maximum rise due to dexamethasone (0.1%) and fluorometholone 0.1% is least Topical corticosteroids Triamcinolone acetonide (40mg/ml) (Kenacort) was approved by FDA in 2007 for intraocular use in visualization during vitrectomy, chronic non infectious uveitis, diabetic macular edema Retisert (flucinolone actetonide) used as intraocular implantation for chronic uveitis OZURDEX® (Allergan, dexamethasone intravitreal implant 0.7mg), indicated in • macular edema following retinal vein occlusion • noninfectious posterior uveitis Systemic corticosteroids Oral prednisolone in a dose of 1-2 mg/kg/day (or alternate days) is used to treat orbital inflammations, panuveitis, postoperative inflammation and systemic diseases causing ocular problems alternate day therapy reduces the suppression of adrenal functions High dose of methylprednisolone i/v are given in pulses to treat optic neuropathies Topical cyclosporine Topical cyclosporine 1-2%; Cyclosporine emulsion 0.05% (Restasis) Control anterior segment external disease especially when steroids fail Restasis indicated for mod-severe dry eye. Dosed twice daily Past uses of compounded product include atopic & vernal keratoconjunctivitis, Mooren’s ulcer, ligneous conjunc.,ulcerative keratitis No measurable serum levels; local SE’s minimal except local irritation (burning and stinging; no increase in IOP, no secondary infections) 5-FluorouraciFluorouracil Antineoplastic agent – Fluorinated pyrimidine nucleoside analogue – Blocks thymidylate production interrupts DNA /RNA synthesis – Uses include: glaucoma filter (inhibit fibroblasts) pterygium prevention of PVR (1mg) – Subconj. injection 5mg (50mg/ml or 10mg/ml) daily x 1week, then 3 x’s following week – Possible just peri-operative use also SE’s - epithelial defects Mitomycin C Antineoplastic – Alkylating agents inhibits DNA synthesis and cross links DNA. Uses include: – Pterygium 0.02% - 0.04% topically intraop. (drops 2-4 x’s x 1-2 weeks – Use is cautioned! SE’s possible sight threatening complications (i.e. scleral/corneal melt, cataract, glaucomatous changes; contraindicated dry eye, Sjogren’s, meibomian gland dysfunction, etc.) – Filtering Surgery - Single topical application 0.2-0.5 mg/ml concentration Se’s - irrigate thoroughly – wound leak, K endothelial damage, hypotony, maculopathy, leaking blebs – Reduce haze after PRK? Immunosuppressive not used as primary therapy cases non responding to steroids or steroids responders or started having steroid complications avoided in children and pregnant women effect may take 1-4 weeks to develop, hence initial therapy with corticosteroids is needed Azathioprine, Cyclosporin, Methotrexate are commonly being used Drug Formulation Dosage Adverse effects Special points Methotrexate 2.5, 5, 7.5 mg Weekly GI symptoms, hepatotoxic ( LFT) Less cost, Well tolerated Azathioprine 25, 50 mg 1mg/kg Myelosuppressio n Onset take 4-5 weeks Cyclosporine 25, 50 mg 5mg/kg/day Nephrotoxic (urea, creatinine) Fast onset of action More efficacious Dry eye 0.05%,0.1% emulsion Mycophenolate mofetil 250, 500 mg 1gm BD Myelosuppressio n High cost Leflunomide 10, 20 mg 100mg/day GI upset, hepatotoxic Still under trial Antibiotics PENICILLINS MOA - Inhibit bacterial cell wall synthesis by binding to pencillin binding proteins (PBPs), which in turn inhibit final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis Vs. Streptococcus groups A, B, D, S. pneumoniae, anaerobes (non-penicillinase), Treponema, Neisseria Ophthalmic Use (OU) - rare IV 12 million U./day x 10 days neurosyphilis SE’s - allergic reaction ANTISTAPHYLOCOCCAL PENCILLINS Vs. gm + especially Staphylococcus aureus. Includes: cloxacillin, dicloxacillin, methicillin, nafcillin, oxacillin If methicillin resistant Staphylococcus (MRS; MRSA), ALL are resistant OU - oral - for superficial lid/skin laceration, adults preseptal cellulits, plastics SE’s - similar to PCN, cross-reactivity ANTIPSEUDOMONAANTIPSEUDOMONAL PENICILLIN (EXTENDED SPECTRUM ) Vs. gm -, Strep. Group, enteric bacilli (Klebsiella, Proteus), Pseudomonas aeruginosa carbenicillin, ticarcillin, piperacillin, mezlocillin, azlocillin OU - occasional eye drop in keratitis SE’s - watch in Penicillin allergic pts. PENICILLINS, Misc. Ampicillin/amoxicillin vs gm + (not Staph.), Neisseria, H. influenzae, Proteus. Amoxicillin/clavulanate (Augmentin oral) vs. Staph. (penicillinase producing not MRS), resistant H. influenzae, Strep. Sp. OU - amoxicillin if relapsing H. influ. conj. Augmentin in kids with preseptal cellulits - activity vs. H. flu, etc. SE’s - diarrhea, rash Imipenem/cilastatin (Primaxin) vs. gm + aerobes, Staph., gm - (P. aeurginosa) imipenem penetrates well into vitreous ticarcillin/clav. (Timentin- IV) vs. gm +, staph, gm - bacilli CEPHALOSPORINCEPHALOSPORINS MOA - Inhibit bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs) which in turn inhibit the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls 1st generation - very good gm+ esp.. S. pneumo & viridans, Staphylococcus (not MRS), E. coli, Klebsiella, Proteus mirabilis: cefazolin, cephalexin, cephalothin, cephradine, cefadroxil 2nd generation - more gm -, more H. influenzae/Neisseria (cefuroxime), anaerobic B. fragilis (cefoxitin, cefotetan) and cefaclor, cefmandole, cefmetazole CEPHALOSPORINS (cont.) 3rd generation - better gm - including facultative bacilli, H. influ., N. gonorrhoeae, P. aeruginosa (ceftazidime, cefoperozone), B. fragilis (ceftizoxime, moxalactam), and ceftriaxone, cefixime (PO), cefotaxime. 4th generation – good enterobacteriaceae, Pseudomonas, C. freundi. (cefepime, cefpirome) OU - topical cefazolin 50-133 mg/ml mainstay of bacterial keratitis, q 15-30’ alternate with aminoglycoside CEPHALOSPORINS (cont.) OU (cont). - IV cefazolin - 1-2 gm q 8hr for soft tissue, penetrating injury (repeat dose penetrate vitreous) - ceftriaxone - vs. H. flu, & Strep. Sp.for orbital cellulitis (+ nafcillin); Lyme dx, resistant GC; (concurrent tx of Chlamydia dox/tet/azithromycin) intravitreal cefazolin 1-2 mg replaced with vancomycin CEPHALOSPORINS (cont.CEPHALOSPORINS (cont.) ceftazidime intravitreal 2mg dose combined with vancomycin 1mg for endophthalmitis minimal risk of retinal toxicity vs. aminoglycosides (- risk) no synergy with vancomycin Vs Bacillus, enterococcus,etc.; no post-antibiotic effect (PAE); no concentration dependent killing effect. CEPHALOSPORINS (cont.) SE’s - well tolerated 1-10% cross reactivity with penicillins O.K. in penicillin allergy if not life threatening reaction (i.e. h/o anaphylaxis, immediate allergic rx). Bleeding disorders - moxalactam-worst!, cefmetazole, cefotetan, cefperazone, cefmandole) allergic rxs, diarrhea, PM colitis. AMINOGLYCOSIDES MOA - Interferes with bacterial protein synthesis by binding to ribosomal subunits (30S and 50S in gentamicin) resulting in defective bacterial cell membrane Vs. gm - bacilli, including Pseudomonas, Proteus mirabilis, Serratia, Enterobacter, some S.aureus. Gentamicin, tobramycin, amikacin, neomycin, netilmicin, streptomycin OU - topical fortified gent/tobra - mainstay of bacterial keratitis 10-15mg/ml. alternate with cefazolin AMINOGLYCOSIDES (cont.AMINOGLYCOSIDES (cont.) OU - intravitreal amikacin 200-400 mcg (< retinal toxic/> coverage vs.gent.100 mcg) for endophthalmitis + vancomycin 1mg IV gentamicin for penetrating injury prophylaxis or endophthalmitis (less often used) SE’s – topical - epithelial toxic (fort.); neomycin sensitivity – systemic - nephro. and oto. toxic - monitor serum levels – intravitreal - retinal toxic esp. gentamicin associated with > macular infarction (Arch Ophthal 109; 1991) TETRACYCLINES MOA - Tetracyclines bind to 30S subunit of the ribosome, blocking the attachment of aminoacyl-tRNA to messenger RNAribosome complex and therefore inhibit protein synthesis Vs. gm- & gm +, esp. Chlamydiae & Rickettsiae. Inhibit protein synthesis, reduce free fatty acids of normal flora, anticollagenolytic acitivity. OU -topical - ophthalmia neonatorum – systemic - Chlamydiae, phlyctenular keratoconj., blepharitis & meibomian gland infec. SE’s - tooth discoloration (PO) in kids; diary, anatacids, & iron reduce absorption Doxycycline 50-100mg qd or bid (minocycline 100 mg 1-2x’s daily) used for lid disease. VANCOMYCIN MOA - Inhibits bacterial wall synthesis by blocking glycopeptide polymerization through binding tightly to D-alanyl-D-alanine portion of cell wall precursor Vs. Gm + especially Streptococcus (viridans, pneumon., pyogenes, faecalis), Staphylococcus aureus & epidermidis (including MRS), Bacillus OU – topical - (25-50 mg/ml) – intravitreal 1 mg DOC for endophthalmitis – systemic IV administration SE’s – topical - irritating (pH 3.5-4.5) – systemic - oto/nephro toxic Vancomycin resistance CDC published guidelines for controlling vancomycin resistance in hospitals (Infection Control Hosp Epidemiol. 1995:16:105-113). Concerned vancomycin resistant enterococci (VRE) may pass to S. aureus & epidermidis Not recommend for topical/irrigating solution use treat pseudomembranous colitis with metronidazole first implications for Ophthalmology ? QUINOLONES MOA - Quinolone antibiotics inhibit DNA-gyrase, which is responsible mainly for bacterial DNA replication (4th generation inhibit topoisomerase also) Excellent spectrum of activity - including most gram aerobic (H. Influenzae, Pseudomonas, Enterobacteriaceae), gm + bugs, Rickettsia, Mycobacterium, Chlamydia & Mycoplasma Less resistance? (especially 4th generation) OU - Ofloxacin (OcufloxR) and ciprofloxacin (CiloxanR) ONLY commercial products APPROVED for bacterial keratitis; norfloxin (Chibroxin) & levofloxacin (Quixin), moxifloxacin (Vigamox), gatifloxacin (Zymar) conjunctivitis QUINOLONES (cont.) Systemic se’s - GI (N, V, etc.) CNS (HA, dizziness, etc.), contraindicated in pediatric pts. (arthropathy)[eye drops O.K. in peds] Ocular se’s - cipro (pH 4.5) white K ppt. All other FQ’s in the pH range 6-7 - more soluble, higher corneal & A.C. levels Resistance reported with gram + (especially Strep. Staph. 4th generation FQ’s (gatifloxacin/moxifloxacin) better gm+ coverage (Strep. Species), P. acnes, Mycobacterium, Nocardia, good intraocular penetration & less resistance SULFONAMIDESULFONAMIDES MOA - Inhibits bacterial growth by inhibiting bacterial folic acid synthesis through competitive antagonism of PABA Vs. gm (+) and gm (-) bacteria, Chlamydia, Actinomyces and Toxoplasmosis bacterial resistance a problem sodium sulfacetamide 10% common gtt OU - topical - blepharitis, conjunc., systemic - sulfadiazine for toxoplasmosis (1 gm q6 for 4-6 wks.) SE’s - hypersensitivity rx’s (SJ synd, rash, etc; topical - myopia (bilat, trans.) CLINDAMYCIN MOA - Reversibly binds to 50S ribosomal subunits preventing peptide bond formation thus inhibiting bacterial protein Bacteriostatic vs. gm +, including some Staph., anaerobes, (B. fragilis, P. acnes, etc.) Bacillus species safe in penicillin allergy OU - 300mg P.O. q6 hr x 4-6 wks in toxo intravitreal - up to 1 mg for P. acnes SE’s - pseudomembranous colitis (from Clostridium difficile) - tx metronidazole/vancomycin Macrolides (erythromycin) MOA - Inhibit RNA-dependent protein synthesis at the chain elongation step; binds to the 50S ribosomal subunit resulting in blockage of transpeptidation effective Vs gm + cocci, gm+ bacilli (Clostridium, Cornebac.,Listeria), N. gonorrhoeae, Chlamydia (not very effective vs. hospital acquired S. epidermidis). topical ery. for blepharitis, neonatal conjunctivitis. clarithromycin (BiaxinR) azithromycin (ZithromaxR) oral only, better tolerated, better spectrum, effective vs. M. avium. azithro. single dose 1gm. approved for Chlamydia urethritis, possibly conjunctivitis