Administration of Drug to Reach a Given Clinical Endpoint: Treatment Or Prevention of Disease Therapeutic Dose Depends On

4/24/2018

.Administration of drug to reach a given clinical endpoint: treatment or prevention of disease .Therapeutic dose depends on patient age, Part One: General Pharmacology Principles; sex, race, other meds taken and other medical Drug Delivery Systems; Topical Anesthetics; conditions Viscoelastics; Dilating Solutions for Cataract Surgery Christopher J. McDevitt, M.D.

. Eye drops avoid first pass metabolism by the liver and . Pharmacokinetics: . Pharmacodynamics: increases systemic bioavailability . Substances cycling through . Biological and chemical effects biological tissue of chemical on the biological . Systemic toxicity may be more then expected from topical system . Absorption dose . Tissue receptor for the drug . Distribution . Neonates, infants have less developed drug metabolism . Metabolism . Intracellular changes initiated by the drug and excretion . Excretion . Categorized by the receptor . Local toxicity is more common than systemic toxicity with . With the dose of the med these for the drug i.e. alpha agonist determine the bioavailability at type I (IgE) mediated hypersensitivity or delayed reaction the site of intended action type 4

. Preservatives can be toxic to ocular surface can enhance . Disappearing preservatives theoretically should have no corneal permeability. Common preservatives in ophthalmic toxicity to the corneal surface preparations: . Preservative dissipates with exposure to light or to ions in . Benzalkonium chloride (BAK) the tear film . Thimerosal . Disappearing preservatives: oxychloro complex breaks . Chlorobutanol down into sodium chloride and water. Sodium perborate . Parahydroxybenzoates breaks down to hydrogen peroxide then to hydrogen and . Aromatic alcohols water

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. Need to be lipophilic and . .Ionic buffer with borate, sorbitol, propylene glycol hydrophobic epithelium and Solutions vs suspensions: and zinc breaks down on exposure to tear film endothelium; stroma is hydrophilic solubility in the tear film meds and lipophobic with poor water solubility are cations . Meds must be lipophilic and formulated as suspensions hydrophilic .Poly quad (polyquaternium-1): detergent that is . Lipid solubility to water solubility . Viscosity increases the repelled by corneal epithelium ratio retention of the such as Timolol . Non-ionic pass through cell GFS membranes more readily . Preservative-free single-use preparations are also . pH of medication can be changed to . Limits to the amount of increase the percentage in a non- viscosity: sticky sensation may an alternative ionic form of the medication to increase absorption result and may cause surface irritation

. Less lean body mass . Extends the half life of most mediations in the elderly . Less body water and albumin . The action of the drug is . Higher relative percentage of potentiated adipose tissue . Therapeutic and toxic effects of . Results in alterations in tissue a medication may be altered binding and drug distribution by the aging process . Take multiple meds that can independent of the drug affect metabolism dosage . Hepatic and renal systems also Topical, Systemic, Periocular, decrease with age Intracameral, Intravitreal

. Concentration of the medication .Subconjunctival and sub-Tenon injection allow . Solubility drugs to bypass corneal and conjunctival epithelial . Viscosity barriers and enter sclera and intraocular by . Lipid solubility . Drug’s pH concentration gradient . Ionic form .Intraocular injections: intracameral (into the . Molecular size anterior segment) and intravitreal: instantly delivers . Chemical structure effective concentration to target site . Surfactants . Reflex tearing

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. Blood-ocular barrier: vascular endothelium of retina non-fenestrated with tight junctions . Choroid and ciliary body sequestered from delivery of systemic meds . Drugs with high lipid solubility i.e. chloramphenicol penetrates eye much better that penicillin . Binding of drug with plasma proteins limits free serum levels and must be exceeded . Bolus IV exceeds the binding capacity of plasma proteins leading to higher intraocular levels of drug when compared with IV drip

. Oral meds: Diamox in sustained release sequel reduces .Encapsulated cell technology IOP for 20 hours compared with 10 hours for the standard Diamox tablet .Nanostructure tethadur: using nanoparticles to protect active molecules and provide sustained . Ocusert: pilocarpine used in past delivery; Nano-capsules, Nano-spheres, Nano- . Surgical implant Ganciclovir for 5-8 months; fluocinolone suspension and emulsions acetonide steroid .Refillable reservoir . Dexamethasone biodegradable polymer matrix (NOVADUR) injection into vitreous cavity Ozurdex for .Refillable pump diabetic macular edema

. Porcine scleral tissue extracted and . Poorly tolerated as they are . soak contact lens in drug . Use molecular imprinting molded into contact lens-soak uncomfortable shields . Monomers in contact lens technique wherein contact . Treatment of bacterial keratitis in lens hydrogels are . Useful in delivery system prolonging early stages hydrogels with target contact time between drug and drugs organized for high affinity cornea binding of the drug . Drugs incorporated into collagen . Drug –loaded colloidal matrix during manufacturing process nanoparticles into the or absorbed into the shield at rehydration or applied topically matrix of the contact lens while on the eye . Shield dissolves in 12, 24 or 72 hours

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. Punctal plug mediated delivery systems . Genetically engineered . Application for AMD with . Core with drug cells designed to anti-VEGF, anti-PDGF overproduce protein of . Cap with pores which the drug is released . ECT with VEGF receptor interest decoy in clinical trials . Advantage: dose reduction, controlled release patient . Multi-year implant have demonstrated compliance viability beneficial decrease in . Encapsulated in retinal thickness . Iontophoresis: moving charged molecules by electric nonbiodegradable system current; limited by discomfort and ocular damage

. Injectable peptide microparticule . Eggs in and egg carton analogy adsorption of target molecule into customized molecular pores . Release from matrix over periods of days to months . Peptide is mixed with Tethadur particles and administered to patient

. Inactive derivatives are activated by enzymes inside the . Pharmacy compounding accreditation board (PCAB) eye provide evidence of adherence to compounding standards . Ester and amide prodrugs are hydrolyzed by esterase and . State and federal licensing amidases as they penetrate cornea and conjunctiva . Appropriate training aseptic compounding meeting USP . Prodrug is more permeable to cornea than active med. guidelines . Prostaglandin analogues such as latanoprost, travoprost, . www.pcab.org/accredited-pharmacies unoprostone (esters prodrugs) and bimatoprost (amide) . Record lot number of medication and lot number of syringes in patient record

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Tetracaine, lidocaine gel

. Proparacaine, tetracaine . Lidocaine 4% for injection can be used topically as well as lidocaine 2% jelly . Bupivacaine 0.75% (Marcaine) has longer duration of action but increased risk of corneal toxicity . Intraocular lidocaine: 0.3cc of 1% isotonic nonpreserved lidocaine administered intracamerally. Onset of action 10 seconds. Reduces amount of local and IV sedation needed

Intracameral non-preserved 2% Topical lidocaine gel . Topical, intracameral, local retrobulbar, peribulbar eyelid blocks lidocaine . Local anesthetics block sympathetic vascular tone and dilate blood vessels

. Epinephrine added to slow vascular absorption . Topical: disrupt tight junctions interfere with corneal repair and metabolism and cannot be used for chronic pain relief . Lidocaine (Xylocaine), bupivacaine (Marcaine) . Hyaluronidase increases tissue permeability and increases dispersal of local anesthetic. . Hylenex a recombinant human substitute used instead of hyaluronidase

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.Proparacaine (Alcaine, Ophthetic): least irritating, onset of action 15 seconds and lasts 20 minutes .Benoxinate oxybuprocaine (Fluress, Flurox) similar to proparacaine .Tetracaine and tetravisc: action and duration similar to proparacaine but with more extensive corneal epithelial toxicity

. Patients respond well to intravenous fentanyl and midazolam (Versed) in conjunction with topical and intracameral anesthesia. . “Vocal local”: calmly provide verbal instructions and reassurance and verbal guidance during the procedure. . Many patients experience more anxiety when surgery is performed on their second eye. Viscoelastics . Propofol may be added IV in these instances or in general in more anxious patients.

. Rheological properties determine the classification, include: Dispersive to . Viscosity cohesive: . Viscoelasticity . Pseudoplasticity Dispersives, . Surface tension cohesives, . Building blocks: combination . Sodium hyaluronidate (Na HA) agents, visco- . Chondroitin sulfate(CS) adaptive . Hydroxypropyl methycellulose (HPMC)

. The molecular size, weight and concentration of each determine the characteristics of the OVD

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Cohesive: higher viscosity: Dispersive: lower viscosity: coat Cohesive (Viscoat) and intraocular structure, retained when Dispersive: HPMC pressurize eye, create space injected Dispersive (Provisc) Duo Visc

. Other dispersives: . Full spectrum of dispersive . Healon D, Viscoat, Ocucoat and cohesive in one syringe: . DiscoVisc and Amvisc . Other cohesives: . Healon, Healon GV, Provisc, Amvisc Plus

. Other two syringe systems: . Duovisc: Viscoat and Provisc; Healon D and H; . Healon D and GV . Amvisc and Ocucoat

.Soft-shell technique for New class: cataract surgery super- .Combines dispersive cohesive and cohesive OVD viscoelastic used simultaneously and provide injecting dispersive first then cohesive protection of dispersives

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.Out of the bottle .Combinations of phenylephrine, cyclogyl and tropicamide from bottle. solution soaked sponges applied to eye .Cyclomydryl gel .others

Stains anterior capsule enhance Inject into eye before capsulorhexis visualization Added to irrigating solution prior to intraocular surgery Maintains pupil dilation and decreases pain Phenylephrine and ketorolac (NSAID)