Lecture 1 PrincDrugAdmin.pdf

Principles of Oc Drug Administration Pharm II Principles of Ocular Drug Administration DIANE T. ADAMCZYK, OD, FAAO STATE UNIVERSITY OF NEW YORK STATE COLLEGE OF OPTOMETRY 1 Diane T. Adamczyk, OD_Copyright © 2024 10 1 Principles of Oc Drug Administration Pharm II Ocular Pharmacotherapy 2...

Principles of Oc Drug Administration Pharm II Principles of Ocular Drug Administration DIANE T. ADAMCZYK, OD, FAAO STATE UNIVERSITY OF NEW YORK STATE COLLEGE OF OPTOMETRY 1 Diane T. Adamczyk, OD_Copyright © 2024 10 1 Principles of Oc Drug Administration Pharm II Ocular Pharmacotherapy 2 Diane T. Adamczyk, OD_Copyright © 2024 10 2 Principles of Oc Drug Administration Pharm II Ocular Pharmacotherapy Use of drugs for ocular: ◦ Examination ◦ Diagnosis ◦ Treatment 3 Diane T. Adamczyk, OD_Copyright © 2024 10 3 Principles of Oc Drug Administration Pharm II Ocular Pharmacotherapy Ocular History Considerations ◦ Use of other ocular medications ◦ Current ocular conditions: inflammation may have an effect on drug effectivity 4 Diane T. Adamczyk, OD_Copyright © 2024 10 4 Pharm II Principles of Oc Drug Administration Ocular Pharmacotherapy Medical History Considerations ◦ Drug interactions ◦ MAO inhibitors or tricyclic antidepressants ◦ Plus Phenylephrine may result in a cardiovascular effect ◦ Allergy/drug sensitivity ◦ Family Hx: POAG + topical steroid may see ^IOP 5 Diane T. Adamczyk, OD_Copyright © 2024 10 -MAOs breaks down catecholamines so if you take a drug that inhibits the breakdown such as MAOIs it will increase the amount of catecholamines and if you add a drug such as phenylephrine it will increase the level of catecholamines and result in an increase in BP -people who are POAG if given steroid, are more predisposed to it to having a steroid response where their IOP rises 5 Principles of Oc Drug Administration Pharm II Ocular Pharmacotherapy Medical History Considerations Systemic Conditions ◦ Renal/Hepatic Disease ◦ Taking oral and systemic drugs are metabolized in the kidney and liver so diseases to those organs can alter how the drug is metabolized ◦ Cardiovascular Disease ◦ Hypertension: Adrenergic agonists increase BP (phenylephrine especially 10%) ◦ Congestive Heart Disease, bradycardia (below 60), AV block: beta blockers 6 Diane T. Adamczyk, OD_Copyright © 2024 10 -beta blockers are topically used to treat glaucoma and can get into the system and decrease heart rate and can affect those with heart disease or asthma 6 Principles of Oc Drug Administration Pharm II Ocular Pharmacotherapy Medical History Considerations Systemic Conditions ◦ Respiratory Disorders: ◦ Beta blockers 7 Diane T. Adamczyk, OD_Copyright © 2024 10 7 Principles of Oc Drug Administration Pharm II Ocular Pharmacotherapy Medical History Considerations Systemic Conditions ◦ Thyroid Disease ◦ Adrenergic agonists with vasopressor activity: ◦ Because of increased catecholamine activity associated with hyperthyroidism use of phenylephrine may result in increase bp 8 Diane T. Adamczyk, OD_Copyright © 2024 10 -adrenergic agonist = increase catecholamine so increase use of phenylephrine will increase BP 8 Principles of Oc Drug Administration Pharm II Ocular Pharmacotherapy Medical History Considerations Systemic Conditions ◦ Diabetes Mellitus ◦ Systemic steroid use exacerbate diabetes ◦ Pupil dilation (poor dilation) à have to use an extra drop to get the pupil dilated 9 Diane T. Adamczyk, OD_Copyright © 2024 10 9 Principles of Oc Drug Administration Pharm II Ocular Pharmacotherapy Medical History Considerations Systemic Conditions ◦ CNS Disorders ◦ Stimulants (may also have opposite effect): cyclopentolate ◦ Beta blockers: ◦ depression ◦ fatigue ◦ anxiety 10 Diane T. Adamczyk, OD_Copyright © 2024 10 -when taking beta blockers, patient will complain of fatigue and anxiety 10 Principles of Oc Drug Administration Pharm II Drug Labeling and Population Considerations: Pregnancy, Lactation, Fertility, Pediatric, Geriatric 11 Diane T. Adamczyk, OD_Copyright © 2024 10 11 Principles of Oc Drug Administration Pharm II Ocular Pharmacotherapy Medical History Considerations ◦ Pregnancy Pregnancy Categories (Prior 2015) ◦ Category A: no risk to fetus (Vitamin B6) ◦ Category B: no evidence of risk (Erythromycin, brimonidine(treat glaucoma) ) ◦ Category C: risk to fetus cannot be ruled out (latanoprost) ◦ Category D: risk to fetus, but benefit outweigh risk (tetracycline) ◦ Category X: definite fetal risk; avoid ◦ This category system over-simplification ◦ 2015 updated labeling helps to inform health care providers with: ◦ Prescribing decisions and ◦ Patient counseling on use of prescription drug 12 Diane T. Adamczyk, OD_Copyright © 2024 10 -C: increased level of suspicion à most ocular drugs that we use are C such as glaucoma drugs -punctual occlude pregnant patient so drug remains on the ocular surface -D/X are more chemotherapy type medications, something oncologist deals with 12 Pharm II Principles of Oc Drug Administration Pregnancy and Lactation Prescription Drug and Biological Product Labeling Updated labeling includes 3 subsections: ◦ Pregnancy ◦ Lactation ◦ Females and Males of Reproductive Potential 13 Diane T. Adamczyk, OD_Copyright © 2024 13 13 Pharm II Principles of Oc Drug Administration Pregnancy and Lactation Prescription Drug and Biological Product Labeling Updated labeling includes 3 subsections: Subsections must include: • Summary of the risks using drug during pregnancy and breastfeeding • Discussion of the data supporting the summary • Prescribing and counseling information to help health care provider make clinical considerations ◦ Pregnancy ◦ Sum m ary of risk ◦ Data supporting sum m ary ◦ Prescribing and counseling info (clinical considerations) ◦ Lactation ◦ Sum m ary of risk ◦ Data supporting sum m ary ◦ Prescribing and counseling info (clinical considerations) ◦ Females and Males of Reproductive Potential ◦ Sum m ary of risk ◦ Data supporting sum m ary ◦ Prescribing and counseling info (clinical considerations) 14 Diane T. Adamczyk, OD_Copyright © 2024 14 -trying to avoid using animal study (mice, monkeys) but don’t have anything to substitute the animals -phase 1 à animal study -phase 2 à normal population -phase 3 à broad base and patients who have the disease and results includes risks/benefits 14 Pharm II Principles of Oc Drug Administration Pregnancy and Lactation Prescription Drug and Biological Product Labeling Pregnancy subsection information includes: ◦ Potential risks to developing fetus ◦ Registry information must be reported ◦ Includes data on how pregnant women affected by drug or biological product ◦ When there is an adverse effect of a drug, it is reported to registry to monitor the drug on broad bases ◦ 3 subheadings - provides detailed information: ◦ Risk summary ◦ Clinical considerations ◦ Data (may include) ◦ human and animal data on use of drug ◦ adverse reactions for pregnant women 15 Diane T. Adamczyk, OD_Copyright © 2024 15 15 Principles of Oc Drug Administration Pharm II Pregnancy and Lactation Prescription Drug and Biological Product Labeling Lactation subsection information includes: ◦ Amount of drug in breast milk ◦ Potential effects on the breastfed child ◦ 3 subheadings - provides detailed information: ◦ Risk summary ◦ Clinical considerations ◦ Data ◦ Examples: ◦ human and animal data on use of drug ◦ adverse reactions for lactating women 16 Diane T. Adamczyk, OD_Copyright © 2024 16 16 Principles of Oc Drug Administration Pharm II Pregnancy and Lactation Prescription Drug and Biological Product Labeling Females and Males of Reproductive Potential subsection information includes the following as it relates to the drug used: ◦ Pregnancy testing ◦ Contraception ◦ Infertility 17 Diane T. Adamczyk, OD_Copyright © 2024 16 17 Pharm II Principles of Oc Drug Administration Pataday 18 Diane T. Adamczyk, OD_Copyright © 2024 16 -pataday: pregnancy category C (before) 18 Principles of Oc Drug Administration Pharm II Beovu 19 Diane T. Adamczyk, OD_Copyright © 2024 19 19 Principles of Oc Drug Administration Pharm II PharmacoKinetics Compartments OF THE EYE 21 Diane T. Adamczyk, OD_Copyright © 2024 20 20 Principles of Oc Drug Administration Pharm II Pharmacokinetics An administered drugs course of: ◦ Absorption ◦ Distribution ◦ Metabolism ◦ Elimination 22 Diane T. Adamczyk, OD_Copyright © 2024 21 21 Principles of Oc Drug Administration Pharm II Compartment Theory Compartment: ◦ Region of tissue or fluid through which a drug can diffuse and equilibrate ◦ Each compartment separated by barrier ◦ Ex. Cornea: corneal epithelium might be a barrier for some drugs but is also where drugs are absorbed Barrier ◦ Region of lower permeability or restricted diffusion between compartments 23 Diane T. Adamczyk, OD_Copyright © 2024 22 22 Principles of Oc Drug Administration Pharm II Pharmacokinetics Drug absorption depends on: ◦ Molecular properties of the drug à type of drug and how is it influenced by the barrier ◦ Viscosity of its vehicle à what is the drug being delivered by and by which influences and how well it can pass thru the barriers ◦ Functional status of the tissue forming barrier to penetration 24 Diane T. Adamczyk, OD_Copyright © 2024 23 23 Principles of Oc Drug Administration Pharm II Pharmacokinetics Drug distribution and bioavailability ◦ Interrelationships of the compartments and barriers of the eye Metabolism ◦ Eliminates drugs and toxic byproducts 25 Diane T. Adamczyk, OD_Copyright © 2024 24 24 Pharm II Principles of Oc Drug Administration B&J 5th ed (fig 2.6 c modification) Routes of Drug Kinetics 7-Intravitreal Administration 2-NonCorneal (sclera/conjunctiva) 1-Transcorneal 4-Drug eliminate via TM, Schlemm’s Canal 6-Drug cross bl-ret barrier 3-Drug Distribution from Bloodstream via bl-aq barrier into ant chamber 8-Drug eliminate via bl-ret barrier 5-Drug Elimination from aq to Bloodstream via bl-aq barrier 9-Drug eliminate fr vitreous 26 Diane T. Adamczyk, OD_Copyright © 2024 25 -2: drug can get thru these ave -3: does drug cross blood aqueous barrier -6: can drug cross blood retinal barrier -4: drug is eliminated through those areas -5: can be eliminated by bl a barrier or bloodstream -topical agents, mainly focused on the anterior portion of the eye - 25 Principles of Oc Drug Administration Pharm II Ocular Penetration Routes for Topic Ophthalmic Drug Administration In s itu -fo rm in g h y d ro g e ls fo r s u s ta in e d o p h th a lm ic d ru g d e liv e ry (N a n ja w a d e B K , M a n ja p p a A S ) J C o n tro lR e le a s e 1 2 2 (2 0 0 7 )1 1 9 -3 4 27 Diane T. Adamczyk, OD_Copyright © 2024 26 -shows how the drug gets to the systemic circulation -taking a drop and putting it in the eye, it is similar to IV -first pass: oral drugs are metabolized in the gut and liver so when it goes into systemic circulation, the amount in the bloodstream is less effective -IV drug bypasses first pass and not breaking down so you get more effective amount in the bloodstream, similar to drops bc it bypasses first pass as well -if you’re treating one eye it can affect the other eye bc it bypasses first pass so it can go to the contralateral eye -beta blockers are the exception we see systemic effects and if used to decrease IOP in one eye, it can decrease IOP in the other eye as well 26 Pharm II Principles of Oc Drug Administration OcularAbsorption Fig. 2. Schematic diagram of ocular absorption. In s itu -fo rm in g h y d ro g e ls fo r s u s ta in e d o p h th a lm ic d ru g d e liv e ry (N a n ja w a d e B K , M a n ja p p a A S ) J C o n tro lR e le a s e 1 2 2 (2 0 0 7 )1 1 9 -3 4 28 Diane T. Adamczyk, OD_Copyright © 2024 27 - 27 Principles of Oc Drug Administration Pharm II Tear Properties pH: 7.4 ◦ Ophthalmic solution: slight alkaline environment is more compatible with epithelium than neutral or acid Volume: ◦ Total held: 30ul ◦ Tear layer only: 8-10ul ◦ Note drop size can be excessive and may vary up to 50 ul (0.05ml) (even 70 ul) 29 Diane T. Adamczyk, OD_Copyright © 2024 28 -if a drop is more acidic or too basic, it will sting -drop sizes can vary but if you’re giving a drop that is 50 ul and your eye can only hold 30 ul, the drop itself will overspill so you want to give an adequate amount 28 Pharm II Principles of Oc Drug Administration Sclera and Conjunctiva Properties Sclera and Conjunctiva are: ◦ Vascular structures with: ◦ Drug removal ◦ Less than one-fifth of drug absorption gets to iris and CB >>this is because of the vascular removal through the sclera and conjunctiva 30 Diane T. Adamczyk, OD_Copyright © 2024 29 -before drop can get into the eye, the sclera and conj bloodstream are already absorb some of the drug 29 Pharm II Principles of Oc Drug Administration Cornea Properties Major functional barrier to ocular penetration Major site of absorption Pharmacodynamics ◦ Epithelium: lipophilic ◦ Stroma: hydrophilic ◦ Corneal penetration: biphasic solubility 31 Diane T. Adamczyk, OD_Copyright © 2024 30 -drugs that tend to be more lipophilic will get thru the epithelium more easily -biphasic: likes both lipophilic and hydrophilic drug -lipophilic drugs can still get thru the stroma but it will have a harder time and similar to hydro drugs, they will have a harder time getting thru the epithelium but will get thru -doesn’t mean drug isn’t getting thru, it just means there is a barrier towards that drug 30 Pharm II Principles of Oc Drug Administration Cornea Properties Epithelium: Lipophilic ◦ Hydrophilic drugs ◦ Resists penetration ◦ Why: healthy epithelium continuous layer of plasma membrane to tear film ◦ Epithelial erosion or cationic preservatives increase penetration 32 Diane T. Adamczyk, OD_Copyright © 2024 31 -epithelial defect such as an erosion increases penetration -cationic properties help to get the drug thru the epithelium better and increase penetration 31 Pharm II Principles of Oc Drug Administration Cornea Properties Epithelium: ◦ Lipophilic drugs ◦ Why enters: epithelial barrier composed of phospholipid membrane ◦ Reservoir 33 Diane T. Adamczyk, OD_Copyright © 2024 32 32 Principles of Oc Drug Administration Pharm II Cornea Properties Stroma: ◦ Stromal reservoir: hydrophilic drugs ◦ Keratocytes: lipophilic reservoir Endothelium and Descemet’s: ◦ NOT a reservoir 34 Diane T. Adamczyk, OD_Copyright © 2024 33 33 Pharm II Principles of Oc Drug Administration Aqueous Humor Role of aqueous in Drug route: ◦ Cornea > aqueous > exit: 1. 2. 3. >TM > Schlemm Canal > low pressure episcleral veins > general circulation (conventional) > iris > uveoscleral route 35 Diane T. Adamczyk, OD_Copyright © 2024 34 34 Principles of Oc Drug Administration Pharm II Iris Properties Sphincter: cholinergic à NT: AcH within the PNS Dilator: adrenergic à NT: Epinephrine and NE within the SNS Pigment: absorb lipophilic drugs ◦ Nonspecific or low affinity binding ◦ Reversible ◦ Drug release over time 36 Diane T. Adamczyk, OD_Copyright © 2024 35 -pigment effects how fast the patient can dilate, if they have a darker pigment then extra drop is needed 35 Pharm II Principles of Oc Drug Administration Ciliary Body Properties Capillaries: ◦ No tight junctions to limit drug diffusion Nonpigmented ciliary epithelium: ◦ Apical tight junctions: limit drug diffusion 37 Diane T. Adamczyk, OD_Copyright © 2024 36 36 Pharm II Principles of Oc Drug Administration Ciliary Body Properties Ciliary Body is major source of drug metabolizing enzymes ◦ Drug detoxification ◦ Drug removal Systemic drugs enter ant/posterior chambers through CB vasculature 38 Diane T. Adamczyk, OD_Copyright © 2024 37 37 Principles of Oc Drug Administration Pharm II Lens Properties Anterior lens epithelium ◦ Most active metabolically ◦ Prone to damage from drugs or toxic substances Epithelium: ◦ Barrier to hydrophilic drugs (high molecular weight) Cortex ◦ Lipid soluble drugs pass to and through cortex 39 Diane T. Adamczyk, OD_Copyright © 2024 38 -star like formation of cataract -middle age lens à due to some yellow pigment seen in lens -once you get the Thorazine cataract, its permanent even if you stop taking the drug 38 Principles of Oc Drug Administration Pharm II Vitreous Properties Depot: injected or surgically implanted drugs 40 Diane T. Adamczyk, OD_Copyright © 2024 39 -topical drugs don’t have much of a chance getting to the posterior segment however intravitreal injections can -topical drugs that can get to the vitreous à non-steroidal -non-steroidal also have an effect on causing macular edema 39 Pharm II Principles of Oc Drug Administration Retina Properties Zonula occludens of RPE: ◦ Prevent drug movement from blood to vitreous/retina Retina capillaries ◦ Close-walled endothelial cells (blood retinal barrier) 41 Diane T. Adamczyk, OD_Copyright © 2024 40 40 Principles of Oc Drug Administration Pharm II Retina Properties The barrier ◦ Protects entry of metabolites, toxins, hydrophilic drugs ◦ Lipophilic drugs cross barrier easily à Can cross blood retinal barrier so has affect on the retina ◦ Retinal toxicity from: ◦ Digitalis, phenothiazines, quinine, others ◦ Systemic hydrophilic drugs do not cross 42 Diane T. Adamczyk, OD_Copyright © 2024 41 41 Principles of Oc Drug Administration Pharm II Drug Kinetics Molecular property of drug influence: ◦ Which tissues act as reservoir vs barrier Drug distribution depends on: ◦ Rate of passive diffusion ◦ Barrier resistance 43 Diane T. Adamczyk, OD_Copyright © 2024 42 42 Pharm II Principles of Oc Drug Administration Drug Kinetics Drug diffusion across barriers ◦ Active transport ◦ Law of thermodynamics ◦ Higher concentration to lower 44 Diane T. Adamczyk, OD_Copyright © 2024 43 43 Pharm II Principles of Oc Drug Administration Drug Kinetics Fick’s first law of diffusion: ◦ Rate of drug diffusion is proportional to concentration gradient between the compartments on either side of the barrier ◦ Absorption affected by: ◦ Other drugs, preservatives, infection, inflammation, neuronal control 45 Diane T. Adamczyk, OD_Copyright © 2024 44 -drop on the ocular surface à more concentration on one side and as it diffuses through the barriers of the cornea it balances out -going from higher to lower concentration -if somebody has an infection it assists how fast the drug crosses which can be beneficial or harmful -preservatives help get the drug across 44 Pharm II Principles of Oc Drug Administration Drug Kinetics Ø Fick’s first law of diffusion: l [Drug] in cornea = tears àno drug penetration l Tear concentration of fluorescein falls rapidly as the drug is transferred to cornea >>> the cornea is then depot of fluorescein for the aqueous >>> which over time both cornea and aqueous show parallel concentrations Total mass drug=Mt Tear concentration=Cd Cornea concentration=Cc Aqueous concentration=Ca B&J th ed 46 Diane T. Adamczyk, OD_Copyright © 2024 45 -fluoresceine has can cross the cornea and while most of drains through the puncta it can also get into the anterior chamber when diffusing, giving a more foggy appearance causing cells and flare -graph shows the fluoresceine going from higher concertation to lower concertation as it passes through 45 Pharm II Principles of Oc Drug Administration Drug Kinetics First Order Kinetics ◦ Most common ocular drug movement ◦ Rate of movement is directly proportional to the concentration difference across the barrier ◦ Rate changes with time as the concentration differential across the barrier changes 47 Diane T. Adamczyk, OD_Copyright © 2024 46 -if you’re giving a drop and the dosage time is once every 4 hours, the drop is either higher or below the optimal level but is never really at the therapeutic level 46 Pharm II Principles of Oc Drug Administration Drug Kinetics Zero-order Kinetics ◦ Release of drug is constant over time ◦ Concentration of drug released over time is independent of concentration ◦ Lacrisert 48 Diane T. Adamczyk, OD_Copyright © 2024 47 -more drugs are being administered in this manner à zero order kinetics -lubrication such as lacrisert usually lasts about 12 hours before needing to be switched and is being constantly being released due to zero order kinetics 47 Pharm II Principles of Oc Drug Administration Drug Removal Retinal vessels via active transport Uveal vessels via bulk transport Direct outflow: TM > Schlemm Canal > episcleral vessels 4-Drug eliminate via TM, Schlemm’s Canal 8-Drug eliminate via bl-ret barrier 5-Drug Elimination from aq to Bloodstream via bl-aq barrier 9-Drug eliminate fr vitreous 49 Diane T. Adamczyk, OD_Copyright © 2024 48 48 Principles of Oc Drug Administration Pharm II Systemic Drug Pharmacokinetics 50 Diane T. Adamczyk, OD_Copyright © 2024 49 49 Principles of Oc Drug Administration Pharm II Oral Medication Overview 51 Diane T. Adamczyk, OD_Copyright © 2024 50 -oral agent goes into stomach starts breaking down and goes into the liver and breaks down through cyto enzymes and distributed systemically 50 Principles of Oc Drug Administration Pharm II 52 Diane T. Adamczyk, OD_Copyright © 2024 51 51 Pharm II Principles of Oc Drug Administration Extended vs Immediate Release Medications Immediate release: ◦ Released within minutes of ingestion/go into the system quickly Extended release (XR or ER): ◦ Pill is formulated so drug is released slowly over time (usually 12-24 hours) ◦ E.g. capsule has beads with some starting to work right away, rest slowly released ◦ Last longer in the body ◦ Need less daily doses compared to immediate release ◦ Potential for fewer side effects since drug level more consistent A Review on: Sustained Release Technology. Intrnl J Therapeutic Applications, Volume 8, 2012, 18 - 23 53 Diane T. Adamczyk, OD_Copyright © 2024 52 -extended release, is nice because it is released overtime through the system but the exception is during emergency cases -in emergency cases à immediate release is required 52 Principles of Oc Drug Administration Pharm II Prodrugs Soft Drugs Site Specific Drugs DRUG DESIGNS 54 Diane T. Adamczyk, OD_Copyright © 2024 53 53 Principles of Oc Drug Administration Pharm II Prodrugs Inactive derivative of drug converted to active form after tissue penetration Drug metabolite more active at receptor site than the parent form Advantage: ◦ Better penetration ◦ Less undesirable effects 55 Diane T. Adamczyk, OD_Copyright © 2024 54 -can use prodrugs at lower concentrations 54 Pharm II Principles of Oc Drug Administration Prodrugs Dipivalyl epinephrine ◦ Pivalyl groups removed by esterases in cornea > leaving epinephrine to act at receptor ◦ Epithelial penetration ^10 fold ◦ One tenth concentration = epinephrine ◦ Decreased systemic absorption VS 56 Diane T. Adamczyk, OD_Copyright © 2024 55 -derivative of epinephrine -has the epinephrine group but also has 2 groups of pivalyl groups and when it penetrates epithelium the 2 groups drop so you’re left with epinephrine -epinephrine has a 10fold increase in epithelial penetration -least amount of drug, least amount of time, greatest effect -using a prodrug, it is a lower concentration and once it gets through the barriers it works much greater and decrease in systemic absorption 55 Principles of Oc Drug Administration Pharm II Prodrugs Latanoprost, travoprost, tafluprost ◦ Ester-linked group is cleaved off after penetrating cornea ◦ Free acid remains in aqueous Valacyclovir is the prodrug of acyclovir 57 Diane T. Adamczyk, OD_Copyright © 2024 56 56 Principles of Oc Drug Administration Pharm II Soft Drugs Compound (analog) rapidly transformed by enzymes to inactive form Fewer side effects Loteprednol etabonate ◦ Analog of prednisolone 57 Diane T. Adamczyk, OD_Copyright © 2024 57 -advantage of that is once the drug has done its job, it becomes inactive and less likely to get adverse effects -ex. Would be steroids can cause a rise in IOP but pt who responds to those steroids are steroid responders (pressure went from 15-30mm Hg) and can be seen in pt with history of glaucoma -loteprednol is a better steroid topical bc it is less likely to cause rise in IOP but can still cause a rise 57 Principles of Oc Drug Administration Pharm II Site Specific Drugs Site specific: ◦ Intrinsic tissue esterases transform site specific agents into inactive metabolite shortly after entering target tissue ◦ In the literature site specific and soft drugs sometimes interchanged/overlap 57 Diane T. Adamczyk, OD_Copyright © 2024 58 -site specific and soft drugs are used interchangeably -drug goes to the site of action and is rapidly broken down 58 Principles of Oc Drug Administration Pharm II Definition Summary Hard Drug = nonmetabolized drug or if metabolized often results in toxic product ◦ E.g. Cocaine Soft Drug = metabolized to inactive metabolite (non toxic) ◦ E.g. Loteprednol (similar to prednisolone acetate=differs position 20 absent ketone group) Site Specific Drug = transformed to inactive metabolite ProDrug=inactive compound -> convert by enzymes to active form or effective drug ◦ E.g. Valacyclovir is converted by esterase to acyclovir ◦ Prostaglandin analog is another example 57 Diane T. Adamczyk, OD_Copyright © 2024 59 59 Pharm II Principles of Oc Drug Administration Prodrug Hard Drug Soft Drug Site Specific Drug Inactive (or less active) derivative Non-m etabolizable drugs or Rapidly m etabolized by enzym e Site specific agent of active drug that is converted (by enzym atic or non- enzym atic reaction) to active drugs m etabolized to biologically active m etabolites (frequently toxic) to inactive m etabolite/form transform ed by intrinsic tissue esterases into inactive m etabolite after drug/m etabolite (after tissue penetration) entering target tissue M ore active at receptor site than One step m etabolism M ay have m ultiple parent drug M etabolized rapidly to non-toxic m etabolism s Absorption, distribution, m etabolism , excretion optim ized product after achieving therapeutic role. Fewer side effects Toxic Fewer side effects Valacyclovir is a prodrug of Heroin Loteprednol is analog of acyclovir Fewer side effects prednisolone 57 Diane T. Adamczyk, OD_Copyright © 2024 60 -summary chart 60 Principles of Oc Drug Administration Pharm II Biologics 65 Diane T. Adamczyk, OD_Copyright © 2024 61 -ex. anti VEGF to treat AMD, Humira treatment for RA as well as uveitis -biologics: derived from something living (human, animal, microorganism), component is biologic, it also has a diff process of approval for FDA -traditional drugs are chemical compound 61 Principles of Oc Drug Administration Pharm II Biologics Biologics: Used to treat and cure many health conditions ◦ e.g. autoimmune diseases, cancer, rheumatoid arthritis, psoriasis, others Biologics are: ◦ Produced/developed from living organisms (human, animal, microorganism) OR ◦ Contain components of living organisms (blood, proteins) by using biotechnology Differ from conventional drugs which are chemically synthesized 66 Diane T. Adamczyk, OD_Copyright © 2024 62 -very first biologic was insulin 62 Principles of Oc Drug Administration Pharm II Biologics Include vaccines, genes/gene therapy, recombinant proteins, blood/blood components, cells, allergens, monoclonal antibodies (mAB) Biologics = primarily mAB and immune modulators target specific cellular components to alter molecular pathways Given by injection or infusion Biologic examples: bevacizumab, ranibizumab, aflibercept, interferon 67 Diane T. Adamczyk, OD_Copyright © 2024 63 -monoclonal antibodies go after one specific infection vs antibodies that are more broad, usually given for RA and is given via injection -highlighted first 2 were the first type of anti-VEGF against mac degen and are also used in cancer therapy - 63 Pharm II Principles of Oc Drug Administration Biologics: Monoclonal Antibodies Monoclonal antibodies: used oncology to rheumatology to eyecare ◦ Are proteins made in laboratories that act like antibodies in our body ◦ Lab made clones of the body’s antibodies >>>to stimulate immune system ◦ Monoclonal antibodies (mAB) that are specific for single antigen ◦ vs Antibodies in humans are polyclonal (recognize variety of different antigens) 68 Diane T. Adamczyk, OD_Copyright © 2024 64 64 Principles of Oc Drug Administration Pharm II Types of Monoclonal Antibody 69 Diane T. Adamczyk, OD_Copyright © 2024 65 -diff types of monoclonal antibodies 65 Pharm II Principles of Oc Drug Administration Monoclonal Antibodies: Names…. Suffix or surname: ◦ -mAB (=monoclonal antibody)* Middle name or infix: is site of action ◦ Cardiovascular = ci Source: how obtained ◦ Human = u Bone= soTumor = tu Mouse = o Chimeric = xi Humanized = zu Prefix: ◦ Inventor choice *Suffix note: After 2022 depending on pattern of epitope (part of antigen molecule antibody attaches to) preferred suffix: –tug, -bart, -mig, or –ment 69 Diane T. Adamczyk, OD_Copyright © 2024 66 -bevacizumab treats cancer but also used to treat macular degeneration and diabetic retinopathy 66 Principles of Oc Drug Administration Pharm II Biologic vs Biosimilar Naming biosimilars: ◦ Distinguishing suffix without meaning and ◦ Composed of 4 lowercase letters attached to core name of original biological Example: ◦ Reference product: Humira (adalimumab) ◦ Biosimilar: Idacio (adalimumab-aacf) 72 Diane T. Adamczyk, OD_Copyright © 2024 67 -aacf or letters after the drug means it is a biosimilar and works the same way as biologic and cheaper 67 Principles of Oc Drug Administration Pharm II Drug Formulation 73 Diane T. Adamczyk, OD_Copyright © 2024 68 68 Principles of Oc Drug Administration Pharm II Drug Formulation Properties Biopharmaceuticals ◦ Optimum dosage forms for drug delivery ◦ E.g. Unit dose medications Bioavailability ◦ Drug amount present at receptor site Drug absorption affected by: ◦ Preservatives, buffers, vehicles 74 Diane T. Adamczyk, OD_Copyright © 2024 69 69 Principles of Oc Drug Administration Pharm II Drug Formulation Properties Osmolarity ◦ The concentration of a solution in terms of osmoles (the molecular weight of a solute, in grams, divided by the number of ions or particles into which it dissociates in solution) of solutes per liter of solution 75 Diane T. Adamczyk, OD_Copyright © 2024 70 - 70 Principles of Oc Drug Administration Pharm II Drug Formulation Properties Osmolarity ◦ Hypotonic formulation (290 mOsm) =0.9% saline ◦ Ophthalmic and IV meds ◦ Hyperosmolar tears: ◦ ◦ ◦ ◦ ◦ Attract water from the corneal epithelial Interfere with metabolism Decrease cell vitality Reduce microvilli Disrupt mucin layer 76 Diane T. Adamczyk, OD_Copyright © 2024 71 -most IV mens are hypotonic -if the tears are hyperosmolar and you give the tears something hypotonic, it balances it out -if you give the tears something hyperosmolar when the tears are at normal state, it will suck out the fluid from the cornea -the only time you would give hyperosmolar only if the cornea has edema 71 Principles of Oc Drug Administration Pharm II Drug Formulation Properties Preservatives ◦ A substance or preparation added to a product to destroy or inhibit the multiplication of microorganisms ◦ Nonselective against all cells vs specific antimicrobials 77 Diane T. Adamczyk, OD_Copyright © 2024 72 -antibiotics are specific as they go after gram pos and gram neg and preservatives are nonspecific meaning they go after anything à impt point to remember -preservatives allow for any solution or gel to not get infected so pt can use it multiple times for treating glaucoma or uveitis -preservatives can sometimes create havoc to the ocular surface 72 Pharm II Principles of Oc Drug Administration Drug Formulation Properties Preservatives oClass: oDetergent oOxidative oChelating Preservatives ◦ Types: ◦ Surfactants ◦ Ionically charged molecules disrupt plasma membrane (corneal epithelium) ◦ Usually bactericidal ◦ Chemical toxins ◦ Mercury, iodine, alcohols ◦ Block normal metabolic processes of cell ◦ Bactericidal/static ◦ Oxidative ◦ Penetrate cell membranes or walls ◦ Interfere with cellular function 78 Diane T. Adamczyk, OD_Copyright © 2024 73 73 Principles of Oc Drug Administration Pharm II Drug Formulation Properties Preservatives: Detergent (Surfactant) ◦ Benzalkonium chloride (BAC or BAK) à most common ◦ Quaternary surfactant (detergent) ◦ Cationic ◦ Stable, antimicrobial, long shelf life ◦ Effective G+ and G- in low concentrations(especially when combined with EDTA) ◦ Concentrations vary 0.004%-0.02% ◦ Causes bacterial cell death by interacting with lipid components in the cell membrane, making the membrane unstable ◦ Results in release of cell contents ◦ Increase corneal drug penetration ◦ Toxic inflammatory effect 79 Diane T. Adamczyk, OD_Copyright © 2024 74 -disrupts the corneal epithelium 74 Principles of Oc Drug Administration Pharm II Drug Formulation Properties Preservative: Detergent (Surfactant) oPolyquaternium-I (Polyquad) ◦ Polymeric quaternary ammonium molecule (detergent) ◦ Hydrophilic cationic polymer ◦ Molecular size is ~27x larger than BAK ◦ Size affects cell interaction ◦ Disrupts microbial cell membranes, but too larger to enter mammalian cells ◦ Minimizes toxic effect ◦ Damages bacterial cytoplasmic membrane, with leakage of cell contents as well as causes coagulation of cytoplasm ◦ Mainly antibacterial 80 Diane T. Adamczyk, OD_Copyright © 2024 75 -disrupts the cell membrane but is not as toxic and is similar to benzalkonium -more gentle alternative 75 Principles of Oc Drug Administration Pharm II Drug Formulation Properties Preservatives ◦ Chlorhexidine ◦ A biguanide compound ◦ Has antibacterial activity ◦ Also used as antiseptic that affects integrity of microbial cell membrane ◦ Does not alter corneal permeability as BAC ◦ Structurally different ◦ Cannot intercalate into lipid layer as BAC ◦ BAC dives into the cell membrane and then destroys it 81 Diane T. Adamczyk, OD_Copyright © 2024 76 -disrupts cell membrane and is much more gentle compared to benzalkium - 76 Principles of Oc Drug Administration Pharm II Drug Formulation Properties Preservatives: Chemical ◦ Mercurials ◦ Thimerosal ◦ Contact sensitivity/allergic reactions 82 Diane T. Adamczyk, OD_Copyright © 2024 77 -rarely see or prescribe it due to contact sensitivity and allergic reactions are very common -still in the market 77 Principles of Oc Drug Administration Pharm II Drug Formulation Properties Preservatives: Detergent (NOT surfactant) ◦ Chemical: Alcohols ◦ Chlorobutanol ◦ < effective antimicrobial than BAC ◦ Fewer allergic reactions ◦ More effective when combined with EDTA (Ethylenediaminetetraacetic acid) 83 Diane T. Adamczyk, OD_Copyright © 2024 78 -not as effective as an antimicrobial -EDTA is not a preservative but when combined with preservative the drug works better 78 Principles of Oc Drug Administration Pharm II Drug Formulation Properties Preservatives: Oxidative ◦ Neutralized by cells, no accumulation ◦ Effective microorganism, low toxicity ◦ Stabilized Oxychloro Complex (Purite) ◦ Refresh Tears ◦ Dissipates into water and sodium chloride (light exposure) ◦ Sodium Perborate ◦ GenTeal ◦ Converted to hydrogen peroxide and then oxygen and water when in contact with the eye (in eye) 84 Diane T. Adamczyk, OD_Copyright © 2024 79 -seen in ocular lubricants à refresh tears—put drop in the eye and dissipates into water and sodium chloride which is basically tears when exposed to light 79 Principles of Oc Drug Administration Pharm II Drug Formulation Properties Preservative: Stabilized oxychloro complex (SOC) (Purite®): ◦ Broad antimicrobial effect (bacterial, fungal, viral) ◦ Composed of chlorite (99.5%), chlorate (0.5%), trace chlorine dioxide ◦ SOC + Light dissociates >>> water, oxygen, sodium and chlorine free radicals ◦ Mechanism by oxidizing antimicrobial activity ◦ Chlorine free radical believed to inhibit microorganism protein synthesis within cells via glutathione oxidation resulting in microbe cell death 85 Diane T. Adamczyk, OD_Copyright © 2024 80 -summary slide 80 Principles of Oc Drug Administration Pharm II Drug Formulation Properties Preservative: Sodium perborate (GenAqua®, Dequest®) ◦ Oxidative preservative ◦ Effective against bacteria and fungus (Aspergillus niger) ◦ Alters protein synthesis within bacterial cells by oxidizing cell membranes and altering membrane-bound enzymes causing enzymatic inhibition ◦ When combined with water, sodium perborate is converted to hydrogen peroxide ◦ When applied to the eye, catalyzed by enzymes on oc surface ( e.g. catalase) to decompose to water, and oxygen ◦ Hydrogen peroxide kills microbes ◦ Low concentration of hydrogen peroxide can cause sting, but definitive clinical data lacking with sodium perborate 86 Diane T. Adamczyk, OD_Copyright © 2024 81 -summary slide 81 Pharm II Principles of Oc Drug Administration Drug Formulation Properties PRESERVATIVES: MISCELLANEOUS ◦ Methylparaben, propylparaben ◦ Artificial tears ◦ Ethylenediaminetetraacetic acid (EDTA): ◦ Chelating agent ◦ Chelates calcium for cell junction formation ◦ Not sufficient antimicrobial alone unless combined with preservative ◦ Assist action of thimerosal, BAC ◦ Contact dermatitis ◦ May be cytotoxic prolonged use PRESERVATIVES: MISCELLANEOUS ◦ Sorbate (sorbic acid) ◦ Limited antimicrobial activity ◦ Passes through plasma membrane, dissociate in cytoplasm, release protons, inhibit growth via acidification ◦ Results in inefficient intracellular activities ◦ SofZia à preservative that is gentle ◦ Composed of boric acid, propylene glycol, sorbitol, zinc chloride ◦ In Travatan Z 87 Diane T. Adamczyk, OD_Copyright © 2024 82 82 Principles of Oc Drug Administration Pharm II Preservatives (Class Overview) Detergent preservatives ◦ Cause bacterial cell death by interrupting lipid component of cell membrane ◦ E.g. Benzalkonium chloride, chlorobutanol, polyquad ◦ Chlorobutanol (unlike BAK) does not act like a surfactant. Action is cell lysis via disruption of microbial cell membrane lipid configuration Oxidative preservatives à breakdown into oxygen and water when in contact with the tears ◦ Penetrate membrane and alter DNA, protein and lipid components of the bacterial cell ◦ E.g. sodium perborate, stabilized oxychloro complex Ionic-buffered preservatives ◦ Similar to oxidizing preservatives ◦ E.g. SofZia 88 Diane T. Adamczyk, OD_Copyright © 2024 83 83 Pharm II Principles of Oc Drug Administration Preservative Class (Type) Points Benzalkonium chloride Detergent (Surfactant) *Corneal cell disruption *Excellent antimicrobial Chlorobutanol Detergent (Alcohol) Less toxic than BAK Polyquaternium-1 (Polyquad) Detergent Less toxic than BAK Stabilized oxychloro complex (Purite) Oxidative *Dissociates into water, oxygen, sodium and chlorine free radicals Sodium perborate Oxidative *Catalyzed into hydrogen peroxide; water and oxygen *Less toxic than BAK SofZia Oxidative (ionic buffered) *Less toxic than BAK 89 Diane T. Adamczyk, OD_Copyright © 2024 84 -summary slide 84 Pharm II Principles of Oc Drug Administration Steven DW, et al. Br J Ophthalmol 2018;102:1497–1503. doi:10.1136/bjophthalmol-2017-311544 90 Diane T. Adamczyk, OD_Copyright © 2024 85 85 Principles of Oc Drug Administration Pharm II Let’s Go for a Drive… 91 Diane T. Adamczyk, OD_Copyright © 2024 86 86 Pharm II Principles of Oc Drug Administration Vehicle Body= Viscosity Wax shine = wetting agent Undercoat=Preservative Bumper=Buffer Convertible top up or down = tonicity Air System Filters = Antioxidant Driver=Drug 92 Diane T. Adamczyk, OD_Copyright © 2024 87 87 Pharm II Principles of Oc Drug Administration Vehicle (also known as excipient=which are various components but not the drug) Wetting agent Thickness = Viscosity Antioxidant Preservative Buffer Tonicity (can also be same as buffer) Drug 93 Diane T. Adamczyk, OD_Copyright © 2024 88 88 Principles of Oc Drug Administration Pharm II Excipients Defined Excipients are components of a finished drug product other than the active pharmaceutical ingredient (API) and are added during formulation for a specific purpose. Although listed as inactive ingredients by FDA, excipients generally have well-defined functions in a drug product. USP Guideline for Submitting Requests for Revision to USP-NF V3.1 April 2007 U S. PHARMACOPEIA 94 Diane T. Adamczyk, OD_Copyright © 2024 89 -excipient is another term for vehicle, its everything within the drug without the actual drug -these components have an effect on the ocular surface to penetrate thru the ocular tissue 89 Principles of Oc Drug Administration Pharm II Drug Formulation Properties Vehicles (Excipient) ◦ Provide proper tonicity, buffering, and viscosity to complement drug action ◦ Increased viscosity ◦ Delay washout, increase drug bioavailability ◦ Petrolatum or oil based ointments: longer retention, temporary lipid depot 95 Diane T. Adamczyk, OD_Copyright © 2024 90 -increase viscosity of the drug it has more staying power on the ocular surface it allows the drug to act but the bad thing is it causes blur factor 90 Principles of Oc Drug Administration Pharm II Ophthalmic Formulations Excipients Antioxidants ◦ Sodium sulfites ◦ Ethylenediaminetetraacetic acid (EDTA) Wetting agents ◦ Polysorbate ◦ Poloxamer ◦ Tyloxapol 96 Diane T. Adamczyk, OD_Copyright © 2024 91 91 Principles of Oc Drug Administration Pharm II Ophthalmic Formulations Excipients Buffers ◦ A chemical system that prevents the change in concentration of another chemical system; To give a solution the property of resisting a change in pH ◦ Examples: ◦ ◦ ◦ ◦ ◦ Acetic, boric, hydrochloric acids Potassium and sodium bicarbonate Potassium and sodium borate Potassium and sodium phosphate Potassium and sodium citrate 97 Diane T. Adamczyk, OD_Copyright © 2024 92 -buffers give the drug the resistance to change in pH 92 Principles of Oc Drug Administration Pharm II Ophthalmic Formulations Excipients Tonicity agents ◦ The osmotic pressure or tension of a solution, usually relative to that of blood ◦ Examples ◦ ◦ ◦ ◦ ◦ ◦ Buffers Dextrans (high molecular wt polymer of D-glucose) Dextrose (D-glucose monosaccharide) Glycerin Propylene glycol Potassium and sodium chloride 98 Diane T. Adamczyk, OD_Copyright © 2024 93 93 Principles of Oc Drug Administration Pharm II Ophthalmic Formulations Excipients Viscous agents ◦ Methylcellulose (MC) ◦ Polyvinyl alcohol (PVA) ◦ Polyvinylpyrrolidone (povidone) (PVP) ◦ Propylene glycol ◦ Polysorbate 80 ◦ Dextran ◦ Gelatin ◦ Carbomers (e.g. 934P, 940) 99 Diane T. Adamczyk, OD_Copyright © 2024 94 -allows more staying power but more blur factor 94 Principles of Oc Drug Administration Pharm II Drug Formulation Properties Vehicles and viscosity ◦ Include: ◦ ◦ ◦ ◦ Polyvinyl alcohol (PVA) Polyvinylpyrrolidone (povidone) (PVP) Hydroxypropyl methylcellulose (HPMC) Carboxymethlycellulose ◦ Shear thinning: shear exposure (blinking), viscosity decreases ◦ High viscosity in open eye ◦ Mucin, sodium hyaluronate (SH) 100 Diane T. Adamczyk, OD_Copyright © 2024 95 -everytime you blink it’s like a windshield wiper so when theres a thicker viscous, you need to blink more to clear up the drug 95 Pharm II Principles of Oc Drug Administration Drug Formulation Properties Vehicles and viscosity ◦ Gel-Forming Systems ◦ ◦ ◦ ◦ Large molecules exhibit reversible phase transitions Aqueous drop reversibly gel on contact precorneal tear film Longer contact time Viscous property changes induced by: ◦ Alterations in temperature, pH, electrolyte composition 101 Diane T. Adamczyk, OD_Copyright © 2024 96 -ex. Gluacoma drug timolol has a transformation from liquid to gel and translates clinically into taking the drug instead of twice a day you can take it once a day or decrease the concentration from 0.5% to 0.25% bc of viscosity it has a longer staying time 96 Principles of Oc Drug Administration Pharm II Drug Formulation Properties Vehicles and viscosity ◦ Gel-Forming Systems ◦ Gelrite ◦ Polysaccharide, low-acetyl gellan gum forms clear gel in presence of mono/divalent cations in tear ◦ Enhance corneal penetration, prolongs drug action ◦ Timoptic XE à brand name for timolol ◦ Xanthan gum vehicle ◦ Heteropolysaccharide ◦ Falcon gel-forming (timolol) 102 Diane T. Adamczyk, OD_Copyright © 2024 97 97 Principles of Oc Drug Administration Pharm II Drug Formulation Properties Vehicle: Cation Exchange Resin (Amberlite) ◦ Binding agent (polyacrylic acid polymer carbopol 934P) ◦ Enhance stability ◦ Ease of resuspendability 103 Diane T. Adamczyk, OD_Copyright © 2024 98 -enhances the stability of the drop -resuspension means that the drug is scattered through the liquid but if the bottle is sitting for a while the drug will settle at the bottom like sementation so you have to shake the bottle before putting the drops in bc if they don’t shake it pt is just putting liquid without the actual drug - 98 Pharm II Principles of Oc Drug Administration Amberlite-Cation Exchange Resin Drug + Resin Carbopol gel (ex. Carobopol 934P) =gelling agent, viscosity enhancer + Tears (Na)=> Free Drug + Na-Resin 104 Diane T. Adamczyk, OD_Copyright © 2024 99 -vehicle has carbopol gel -within the vehicle, there is a drug that will be attached to a resin -when the amberlite cation exchange system comes into contact with the tears, the sodium in the tears frees the drug from the resin so you’re just left with the drug -makes the drug more effective since it will guarantee the getting of the drug 99 Pharm II Principles of Oc Drug Administration Drug Formulation Properties Vehicle: Cation Exchange Resin (Amberlite) ◦ Betaxolol suspension (Betoptic S) ◦ Drug binds with cation exchange resin >> ◦ Reduced free drug in solution, enhanced comfort ◦ Plus vehicle (with carbopol 934P) ◦ Increase viscosity, contact time ◦ 4 weeks no resuspending ◦ Betaxolol 0.25% suspension = 0.5% solution 105 Diane T. Adamczyk, OD_Copyright © 2024 100 -S stands for suspension -drug is utilizing amberlite system so it doesn’t need to be shaken before putting in the drops -when you put this drug in contact with the tears, it’s liberated 100 Principles of Oc Drug Administration Pharm II Drug Formulation Properties Vehicles ◦ Polyacrylic Acids ◦ Carbopol gels (component of cation exchange resin) ◦ Decrease viscosity with increase shear rate, blink ◦ Drug examples: Betoptic S, Azopt 106 Diane T. Adamczyk, OD_Copyright © 2024 101 101 Principles of Oc Drug Administration Pharm II Drug Formulation Properties Vehicles (see Drug Delivery) ◦ Ointments ◦ Drug Release Systems ◦ Examples: ◦ SCL, collagen shields ◦ Punctal plugs ◦ Intravitreal implant 107 Diane T. Adamczyk, OD_Copyright © 2024 102 102 Principles of Oc Drug Administration Pharm II Ophthalmic Drug Delivery 108 Diane T. Adamczyk, OD_Copyright © 2024 103 103 Principles of Oc Drug Administration Pharm II Ophthalmic Drug Delivery Topical Administration ◦ Most common ophthalmic drug route ◦ Convenient, noninvasive, simple, self-administered ◦ Drug loss: diffusion into circulating blood ◦ BV of conjunctiva, episclera, intraocular vessels, nasal mucosa, oral pharynx ◦ Little benefit posterior segment ◦ Second passage: liver biotransforms ◦ Vs oral meds: metabolized before “first pass” (<toxic than topical drugs) 109 Diane T. Adamczyk, OD_Copyright © 2024 104 104 Principles of Oc Drug Administration Pharm II Ophthalmic Drug Delivery Topical Administration ◦ Solutions ◦ Advantage: easy installation, <affect vision ◦ Disadvantage: short contact time, imprecise, contamination, injury ◦ Suspensions ◦ ◦ ◦ ◦ Shake Prolonged contact time Steroids Generic: suspend poorly, clog dropper tip ◦ 1% prednisolone acetate suspension 110 Diane T. Adamczyk, OD_Copyright © 2024 105 -purpose of suspension is to prolonged contact time in the eye 105 Principles of Oc Drug Administration Pharm II Ophthalmic Drug Delivery Topical Administration ◦ Emulsions ◦ No Shake ◦ Improved drug solubility and bioavailability ◦ Oil in water 111 Diane T. Adamczyk, OD_Copyright © 2024 106 106 Pharm II Principles of Oc Drug Administration Ophthalmic Drug Delivery Standard bottle cap colors ◦ Yellow, blue: beta blocker ◦ Red: mydriatic, cycloplegic ◦ Green: miotic ◦ Orange: CAI ◦ Gray: NSAIDs ◦ Pink: steroid ◦ Brown or tan: anti-infective 112 Diane T. Adamczyk, OD_Copyright © 2024 107 107 Principles of Oc Drug Administration Pharm II Ophthalmic Drug Delivery Eyedrop size varies: ◦ Traditional:50-70ul ◦ Range: 27-70 ul ◦ 5-15ul should be adequate ◦ Standard eyedropper dispenses: ◦ 0.05 m l/ 1 drop===20 drops/1 m l of m edication ◦ 5m l bottle=100 doses (QD OU=60 drops/m onth) ◦ 2.5m l bottle=50 drops Vs (these num bers can vary depending on source) 2.5m l bottle: Lum igan (96.7 drops); Xalatan (94 drops); Travatan Z (81.7 Drops) (IOVS M arch 2012, 53:5025) 113 Diane T. Adamczyk, OD_Copyright © 2024 108 -if the drop is more than what the ocular surface can hold, it will spill out -1 mL is about 20 drops -if pt is required to put 1 drop a day for a month in both eyes, that’s two drops or 60 drops for the month so pt would need a 5ml bottle to have enough drops -2.5 mL bottle is about 90 drops à for glaucoma drops -the key point to understand here is that there is a wide variety of drop range within the same bottle size 108 Pharm II Principles of Oc Drug Administration Ophthalmic Drug Delivery B&J 4th ed 115 Diane T. Adamczyk, OD_Copyright © 2024 109 -want to keep things in the ocular surface and don’t want it to drain out so you would punctual occlude and prevents it from going into systemic circulation -it is shown that pt who have glaucoma and punctual occlude can change either IOP from 1-2 mmHg which is a big diff 109 Principles of Oc Drug Administration Pharm II 116 Diane T. Adamczyk, OD_Copyright © 2024 110 -spray bottle dilation drop for child that is not cooperative 110 Pharm II Principles of Oc Drug Administration • Poor eye drop instillation technique negatively impacts the patient’s ability to achieve good IOP control. • Study: • Examined medication administration adherence by observing patient experience with 3 eye drop instillation aids • Take assigned device home and use for 6 weeks. • Over 60% found AutoDrop and AutoSqueeze drop instillation easier, and would use long-term. • Less positive response for SimplyTouch device. J Glaucoma Volume 30, Number 8, August 2021 117 Diane T. Adamczyk, OD_Copyright © 2024 111 -pts who have arthritis can use this to help squeeze the bottle to get adequate instillation 111 Principles of Oc Drug Administration Pharm II Ophthalmic Drug Delivery Ointment ◦ Slower systemic absorption ◦ Blurred vision ◦ Petrolatum, mineral oil (allows vehicle to melt at body temperature), lanolin (absorb water) ◦ Increase contact time ◦ 2x blinking eye ◦ 4x patched 118 Diane T. Adamczyk, OD_Copyright © 2024 112 112 Principles of Oc Drug Administration Pharm II Ophthalmic Drug Delivery Gels ◦ Pilocarpine: carbomer gel vehicle ◦ QD ◦ SPK, corneal haze ◦ Artificial tears ◦ GenTeal: carbopol 980 ◦ Transforms gel to liquid on contact with ocular tissue ◦ Minimize blurred vision 119 Diane T. Adamczyk, OD_Copyright © 2024 113 113 Principles of Oc Drug Administration Pharm II Ophthalmic Drug Delivery Gels ◦ Converted by temperature changes and ionic movement into a gel like viscosity ◦ Prolonged contact ◦ Gellan gum (Gelrite) and heteropolysaccharide (xanthan gum): timolol ◦ 0.5% gel QD = BID solution ◦ Well tolerated, no blurred vision, no discomfort 120 Diane T. Adamczyk, OD_Copyright © 2024 114 114 Principles of Oc Drug Administration Pharm II Ophthalmic Drug Delivery Solid Delivery Devices ◦ SCL (soft CL) ◦ Drug soaked CL-higher efficiency in drug delivery compared to conventional eye drops ◦ Short term drug release ◦ 1st order kinetics à going from higher to lower concentrations ◦ However…alterations to SCL designed to deliver drugs may result in zero order kinetics ◦ Development of particle laden CL, with drug entrapped in vesicles (e.g. liposome, nanoparticles) and then vesicles dispersed in CL 127 Diane T. Adamczyk, OD_Copyright © 2024 115 -zero order kinetics: developing a CL in which drug is continuously being released -in some drugs you want to advise the pt to put the drug before or after CL removal to decrease toxicity to the ocular surface -in other drugs, if they don’t have the preservative, then it’s less bothersome 115 Pharm II Principles of Oc Drug Administration Ophthalmic Drug Delivery Nanotechnology: systems with appropriate particle size designed to ensure low irritation, adequate bioavailability and ocular tissue compatibility Include: World J Pharmacol. 2013 ; 2(2): 47–64 127 Diane T. Adamczyk, OD_Copyright © 2024 116 -small particles that help deliver the drug 116 Principles of Oc Drug Administration Pharm II Ophthalmic Drug Delivery Solid Delivery Devises ◦ Filter paper strips (fl, rose bengal) ◦ Artificial tear inserts (Lacrisert) 127 Diane T. Adamczyk, OD_Copyright © 2024 117 117 Pharm II Principles of Oc Drug Administration Ocular Drug Delivery Punctal Plug DEXTENZA (dexamethasone ophthalmic insert) indicated for: *Treatment of ocular inflammation and pain following ophthalmic surgery. *Treatment of ocular itching associated with allergic conjunctivitis. 127 Diane T. Adamczyk, OD_Copyright © 2024 118 -punctual plug contains dexamethasone a which is a steroid due for inflammation and plain or for allergic conjunctivitis -zero order kinetics and is constantly releasing drug to the ocular surface and dissolves overtime 118 Pharm II Principles of Oc Drug Administration Ophthalmic Drug Delivery Periocular Administration ◦ Higher drug concentration delivered ◦ Subconjunctival Injection ◦ Between anterior conjunctiva and Tenon’s capsule ◦ Severe corneal disease (bacterial ulcer), endophthalmitis, anesthesia 127 Diane T. Adamczyk, OD_Copyright © 2024 119 -where the injection is put varies depending on what you are treating -anti-inflammatory à subjconj or tenon’s capsule -anesthetics the entire globe à retrobulbar conj 119 Pharm II Principles of Oc Drug Administration Ophthalmic Drug Delivery Periocular Administration ◦ Anterior Sub-Tenon’s Injection ◦ Vs subconjunctival: ◦ < drug, > risk ◦ Severe uveitis ◦ Posterior Sub-Tenon’s Injection ◦ Equatorial, midzone posterior uveitis, CME 127 Diane T. Adamczyk, OD_Copyright © 2024 120 -uveitis à intravitreal injection 120 Pharm II Principles of Oc Drug Administration Ophthalmic Drug Delivery Periocular Administration ◦ Peribulbar Injection ◦ Not into muscle cone B&J 4th ed Periocular Administration ◦ Retrobulbar Injection ◦ Anesthetize globe ◦ Muscle cone http://iv.nucleusinc.com 127 Diane T. Adamczyk, OD_Copyright © 2024 121 121 Principles of Oc Drug Administration Pharm II Complications of Retrobulbar or Peribulbar Injections Anterior Segment ◦ Conjunctival and eyelid ecchymosis (black eye) ◦ Lid swelling ◦ Ptosis (lid droops due to build up of fluid in the lid) ◦ Chemosis ◦ Exposure keratopathy ◦ Elevated IOP ◦ EOM palsy ◦ Pupillary abnormalities 129 Diane T. Adamczyk, OD_Copyright © 2024 122 -potential side effects with doing these infections 122 Principles of Oc Drug Administration Pharm II Complications of Retrobulbar or Peribulbar Injections Posterior Segment ◦ Central retinal artery/vein occlusion ◦ Optic atrophy Orbital ◦ Retrobulbar hemorrhage ◦ Proptosis 130 Diane T. Adamczyk, OD_Copyright © 2024 123 123 Principles of Oc Drug Administration Pharm II Ophthalmic Drug Delivery Intracameral ◦ Anterior chamber injection ◦ Viscoelastic substances: cataract and glaucoma filtering surgeries ◦ Protect endothelium and flat anterior chamber ◦ Implant Intravitreal à try to suppress an infection ◦ Endophthalmitis, CMV retinitis, macular edema ◦ Antifungal, bacterial, viral ◦ Implant 131 Diane T. Adamczyk, OD_Copyright © 2024 124 124 Principles of Oc Drug Administration Pharm II Sustained Release Biodegradable Implant Bimatoprost (Durysta) Biodegradable implant of sustained release bimatoprost Intracameral-settles inferior angle, eventually reabsorbed Currently approved for single administration 132 Diane T. Adamczyk, OD_Copyright © 2024 125 -implant sits in the anterior chamber and over the course of time it dissolves and continuously releases it and also reabsorbs it -good for pts who its hard to get drops into 125 Principles of Oc Drug Administration Pharm II Ophthalmic Drug Delivery 133 Diane T. Adamczyk, OD_Copyright © 2024 126 -steroids, anti-VEGF, etc, 126 Pharm II Principles of Oc Drug Administration Retisert World ' s first intravitreal drug implant for chronic non-infectious posterior segment uveitis (steroid: fluocinolone) Delivers sustained levels of drug directly to the back of the eye for 30 months 134 Diane T. Adamczyk, OD_Copyright © 2024 127 -releases the steroid fluocinolone and delivers the drug to the back of the eye for 30 months 127 Pharm II Principles of Oc Drug Administration Ophthalmic Drug Delivery Iluvien • Non-erodible, intravitreal implant ◦ Cylindrical polyimide tube ◦ Contains steroid: fluocinolone acetonide (FA) Low, steady, daily, sustained release of FA ◦ Over 24-36 month period Intravitreal injection Use: treatment of Diabetic Macular Edema (DME) 135 Diane T. Adamczyk, OD_Copyright © 2024 128 -intravitreal implant and releases a steroid and lasts 2-3 years 128 Pharm II Principles of Oc Drug Administration Advantages & Disadvantages Various Ocular Drug Delivery Systems Advantage Disadvantage-Limitations ØEasy application ØPoor ocular bioavailability ØLeast invasive ØSometimes short duration ØGood pt acceptance ØIneffective posterior seg Suspensions ØProlonged contact time ØShake (pt compliance) Emulsion ØNo shake Gelifying Systems ØEnhance drug retention relative to drops ØDuration of ØIncreased drug absorption weeks Drops ØPotential ocular/systemic toxicity from high concentration or frequent instillation ØHx of generic poorly suspend, dropper tip clog ØMay be thermodynamically unstable ØImproved drug solubility and bioavailability drug activity ^ by hours not days or ØReduced dosing frequency ØPossible better compliance Nanotechnology ØLow irritation ØPotential toxicity ØAdequate bioavailability ØOcular tissue comp