PrincDrugAdmin24_ho (1-9-24).pdf

Principles of Oc Drug Administration Pharm II Principles of Ocular Drug Administration D I A N E T. A DA M C Z Y K , O D, FA AO S TATE U N I V E RS I T Y O F N E W YOR K S TATE COL L EG E O F O P TOM E T RY 1 Diane T. Adamczyk, OD_Copyright © 2024 1 Principles of Oc Drug Administration Pharm...

Principles of Oc Drug Administration Pharm II Principles of Ocular Drug Administration D I A N E T. A DA M C Z Y K , O D, FA AO S TATE U N I V E RS I T Y O F N E W YOR K S TATE COL L EG E O F O P TOM E T RY 1 Diane T. Adamczyk, OD_Copyright © 2024 1 Principles of Oc Drug Administration Pharm II Ocular Pharmacotherapy 2 Diane T. Adamczyk, OD_Copyright © 2024 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 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 4 Principles of Oc Drug Administration Pharm II 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 5 Principles of Oc Drug Administration Pharm II Ocular Pharmacotherapy Medical History Considerations Systemic Conditions ◦ Renal/Hepatic Disease ◦ Cardiovascular Disease ◦ Hypertension: Adrenergic agonists (phenylephrine especially 10%) ◦ Congestive Heart Disease, bradycardia, AV block: beta blockers 6 Diane T. Adamczyk, OD_Copyright © 2024 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 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 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) 9 Diane T. Adamczyk, OD_Copyright © 2024 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 Principles of Oc Drug Administration Pharm II Drug Labeling and Population Considerations: Pregnancy, Lactation, Fertility, Pediatric, Geriatric 11 Diane T. Adamczyk, OD_Copyright © 2024 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) 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 12 Principles of Oc Drug Administration Pharm II 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 Principles of Oc Drug Administration Pharm II 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 ◦ Summary of risk ◦ Data supporting summary ◦ Prescribing and counseling info (clinical considerations) ◦ Lactation ◦ Summary of risk ◦ Data supporting summary ◦ Prescribing and counseling info (clinical considerations) ◦ Females and Males of Reproductive Potential ◦ Summary of risk ◦ Data supporting summary ◦ Prescribing and counseling info (clinical considerations) 14 Diane T. Adamczyk, OD_Copyright © 2024 14 Principles of Oc Drug Administration Pharm II 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 ◦ 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 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 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 17 Principles of Oc Drug Administration Pharm II Pataday 18 Diane T. Adamczyk, OD_Copyright © 2024 18 Principles of Oc Drug Administration Pharm II Beovu 19 Diane T. Adamczyk, OD_Copyright © 2024 19 Principles of Oc Drug Administration Pharm II PharmacoKinetics Compartments OF THE EYE 21 Diane T. Adamczyk, OD_Copyright © 2024 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 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 Barrier ◦ Region of lower permeability or restricted diffusion between compartments 23 Diane T. Adamczyk, OD_Copyright © 2024 22 Principles of Oc Drug Administration Pharm II Pharmacokinetics Drug absorption depends on: ◦ Molecular properties of the drug ◦ Viscosity of its vehicle ◦ Functional status of the tissue forming barrier to penetration 24 Diane T. Adamczyk, OD_Copyright © 2024 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 Principles of Oc Drug Administration Pharm II B&J 5th ed (fig 2.6 c modification) Routes of Drug Kinetics 7-Intravitreal Administration 2-NonCorneal (sclera/conjunctiva) 6-Drug cross bl-ret barrier 1-Transcorneal 4-Drug eliminate via TM, Schlemm’s Canal 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 Principles of Oc Drug Administration Pharm II Ocular Penetration Routes for Topic Ophthalmic Drug Administration In situ-forming hydrogels for sustained ophthalmic drug delivery (NanjawadeBK, Manjappa AS) JControlRelease 122(2007)119-34 27 Diane T. Adamczyk, OD_Copyright © 2024 26 Principles of Oc Drug Administration Pharm II OcularAbsorption Fig. 2. Schematic diagram of ocular absorption. In situ-forming hydrogels for sustained ophthalmic drug delivery (NanjawadeBK, Manjappa AS) JControlRelease 122(2007)119-34 28 Diane T. Adamczyk, OD_Copyright © 2024 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 Principles of Oc Drug Administration Pharm II 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 Principles of Oc Drug Administration Pharm II 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 Principles of Oc Drug Administration Pharm II Cornea Properties Epithelium: ◦ 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 Principles of Oc Drug Administration Pharm II Cornea Properties Epithelium: ◦ Lipophilic drugs ◦ Why enters: epithelial barrier composed of phospholipid membrane ◦ Reservoir 33 Diane T. Adamczyk, OD_Copyright © 2024 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 Principles of Oc Drug Administration Pharm II 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 Principles of Oc Drug Administration Pharm II Iris Properties Sphincter: cholinergic Dilator: adrenergic Pigment: absorb lipophilic drugs ◦ Nonspecific or low affinity binding ◦ Reversible ◦ Drug release over time 36 Diane T. Adamczyk, OD_Copyright © 2024 35 Principles of Oc Drug Administration Pharm II 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 Principles of Oc Drug Administration Pharm II 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 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 Principles of Oc Drug Administration Pharm II Vitreous Properties Depot: injected or surgically implanted drugs 40 Diane T. Adamczyk, OD_Copyright © 2024 39 Principles of Oc Drug Administration Pharm II 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 Principles of Oc Drug Administration Pharm II Retina Properties The barrier ◦ Protects entry of metabolites, toxins, hydrophilic drugs ◦ Lipophilic drugs cross barrier easily ◦ Retinal toxicity from: ◦ Digitalis, phenothiazines, quinine, others ◦ Systemic hydrophilic drugs do not cross 42 Diane T. Adamczyk, OD_Copyright © 2024 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 Principles of Oc Drug Administration Pharm II Drug Kinetics Drug diffusion across barriers ◦ Active transport ◦ Law of thermodynamics ◦ Higher concentration to lower 44 Diane T. Adamczyk, OD_Copyright © 2024 43 Principles of Oc Drug Administration Pharm II 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 Principles of Oc Drug Administration Pharm II Drug Kinetics  Fick’s first law of diffusion:  [Drug] in cornea = tears no drug penetration  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 4th ed 46 Diane T. Adamczyk, OD_Copyright © 2024 45 Principles of Oc Drug Administration Pharm II 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 Principles of Oc Drug Administration Drug Kinetics Pharm II 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 Principles of Oc Drug Administration Pharm II 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 Principles of Oc Drug Administration Pharm II Systemic Drug Pharmacokinetics 50 Diane T. Adamczyk, OD_Copyright © 2024 49 Principles of Oc Drug Administration Pharm II Oral Medication Overview 51 Diane T. Adamczyk, OD_Copyright © 2024 50 Principles of Oc Drug Administration Pharm II 52 Diane T. Adamczyk, OD_Copyright © 2024 51 Principles of Oc Drug Administration Pharm II 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 Principles of Oc Drug Administration Pharm II Prodrugs Soft Drugs Site Specific Drugs DRUG DESIGNS 54 Diane T. Adamczyk, OD_Copyright © 2024 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 Principles of Oc Drug Administration Pharm II 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 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 prodrug of acyclovir 57 Diane T. Adamczyk, OD_Copyright © 2024 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 60 Diane T. Adamczyk, OD_Copyright © 2024 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 62 Diane T. Adamczyk, OD_Copyright © 2024 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 63 Diane T. Adamczyk, OD_Copyright © 2024 59 Principles of Oc Drug Administration Pharm II Prodrug Hard Drug Soft Drug Site Specific Drug Inactive (or less active) derivative of active drug that is converted (by enzymatic or non- enzymatic reaction) to active drug/metabolite (after tissue penetration) Non-metabolizable drugs or drugs metabolized to biologically active metabolites (frequently toxic) Rapidly metabolized by enzyme to inactive metabolite/form Site specific agent transformed by intrinsic tissue esterases into inactive metabolite after entering target tissue One step metabolism May have multiple metabolisms More active at receptor site than parent drug Metabolized rapidly to non-toxic product after achieving therapeutic role. Absorption, distribution, metabolism, excretion optimized Fewer side effects Toxic Fewer side effects Valacyclovir is a prodrug of acyclovir Heroin Loteprednol is analog of prednisolone Fewer side effects 64 Diane T. Adamczyk, OD_Copyright © 2024 60 Principles of Oc Drug Administration Pharm II Biologics 65 Diane T. Adamczyk, OD_Copyright © 2024 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 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 Principles of Oc Drug Administration Pharm II 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 Principles of Oc Drug Administration Pharm II Types of Monoclonal Antibody 69 Diane T. Adamczyk, OD_Copyright © 2024 65 Principles of Oc Drug Administration Pharm II Monoclonal Antibodies: Names…. Suffix or surname: ◦ -mAB (=monoclonal antibody)* Middle name or infix: is site of action ◦ Cardiovascular = ci Bone= soTumor = tu Source: how obtained ◦ Human = u 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 71 Diane T. Adamczyk, OD_Copyright © 2024 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 Principles of Oc Drug Administration Pharm II Drug Formulation 73 Diane T. Adamczyk, OD_Copyright © 2024 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 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 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 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 Principles of Oc Drug Administration Pharm II Drug Formulation Properties Preservatives oClass: oDetergent oOxidative oChelating Preservatives ◦ Types: ◦ Surfactants ◦ Ionically charged molecules disrupt plasma membrane ◦ 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 Principles of Oc Drug Administration Pharm II Drug Formulation Properties Preservatives: Detergent (Surfactant) ◦ Benzalkonium chloride (BAC or BAK) ◦ 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 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 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 81 Diane T. Adamczyk, OD_Copyright © 2024 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 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 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 (in eye) 84 Diane T. Adamczyk, OD_Copyright © 2024 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 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 Principles of Oc Drug Administration Pharm II Drug Formulation Properties PRESERVATIVES: MISCELLANEOUS ◦ Methylparaben, propylparaben ◦ Artificial tears ◦ Ethylenediaminetetraacetic acid (EDTA): ◦ Chelating agent ◦ Chelates calcium for cell junction formation ◦ ◦ ◦ ◦ Not sufficient antimicrobial alone 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 ◦ Composed of boric acid, propylene glycol, sorbitol, zinc chloride ◦ In Travatan Z 87 Diane T. Adamczyk, OD_Copyright © 2024 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 ◦ 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 Principles of Oc Drug Administration Pharm II 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 Principles of Oc Drug Administration Pharm II 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 Principles of Oc Drug Administration Pharm II Let’s Go for a Drive… 91 Diane T. Adamczyk, OD_Copyright © 2024 86 Principles of Oc Drug Administration Pharm II 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 Principles of Oc Drug Administration Pharm II 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 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 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 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 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 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 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 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 Principles of Oc Drug Administration Pharm II 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 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 ◦ Xanthan gum vehicle ◦ Heteropolysaccharide ◦ Falcon gel-forming (timolol) 102 Diane T. Adamczyk, OD_Copyright © 2024 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 Principles of Oc Drug Administration Pharm II Amberlite-Cation Exchange Resin Drug + Resin Free Drug Carbopol gel (ex. Carobopol 934P) =gelling agent, viscosity enhancer + Tears (Na)=> + Na-Resin 104 Diane T. Adamczyk, OD_Copyright © 2024 99 Principles of Oc Drug Administration Pharm II 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 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 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 Principles of Oc Drug Administration Pharm II Ophthalmic Drug Delivery 108 Diane T. Adamczyk, OD_Copyright © 2024 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 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 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 Principles of Oc Drug Administration Pharm II 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 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 ml/drop===20 drops/1 ml of medication ◦ 5ml bottle=100 doses (QD OU=60 drops/month) ◦ 2.5ml bottle=50 drops Vs (these numbers can vary depending on source) 2.5ml bottle: Lumigan (96.7 drops); Xalatan (94 drops); Travatan Z (81.7 Drops) (IOVS March 2012, 53:5025) 113 Diane T. Adamczyk, OD_Copyright © 2024 108 Principles of Oc Drug Administration Pharm II Ophthalmic Drug Delivery B&J 4th ed 115 Diane T. Adamczyk, OD_Copyright © 2024 109 Principles of Oc Drug Administration Pharm II 116 Diane T. Adamczyk, OD_Copyright © 2024 110 Principles of Oc Drug Administration Pharm II • 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 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 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 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 Principles of Oc Drug Administration Pharm II Ophthalmic Drug Delivery Solid Delivery Devices ◦ SCL ◦ Drug soaked CL-higher efficiency in drug delivery compared to conventional eye drops ◦ Short term drug release ◦ 1st order kinetics ◦ 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 121 Diane T. Adamczyk, OD_Copyright © 2024 115 Principles of Oc Drug Administration Pharm II 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): 47–64 123 Diane T. Adamczyk, OD_Copyright © 2024 116 Principles of Oc Drug Administration Pharm II Ophthalmic Drug Delivery Solid Delivery Devises ◦ Filter paper strips (fl, rose bengal) ◦ Artificial tear inserts (Lacrisert) 124 Diane T. Adamczyk, OD_Copyright © 2024 117 Principles of Oc Drug Administration Pharm II 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. 125 Diane T. Adamczyk, OD_Copyright © 2024 118 Principles of Oc Drug Administration Pharm II 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 126 Diane T. Adamczyk, OD_Copyright © 2024 119 Principles of Oc Drug Administration Pharm II 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 Principles of Oc Drug Administration Pharm II 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 128 Diane T. Adamczyk, OD_Copyright © 2024 121 Principles of Oc Drug Administration Pharm II Complications of Retrobulbar or Peribulbar Injections Anterior Segment ◦ Conjunctival and eyelid ecchymosis ◦ Lid swelling ◦ Ptosis ◦ Chemosis ◦ Exposure keratopathy ◦ Elevated IOP ◦ EOM palsy ◦ Pupillary abnormalities 129 Diane T. Adamczyk, OD_Copyright © 2024 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 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 ◦ Endophthalmitis, CMV retinitis, macular edema ◦ Antifungal, bacterial, viral ◦ Implant 131 Diane T. Adamczyk, OD_Copyright © 2024 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 Principles of Oc Drug Administration Pharm II Ophthalmic Drug Delivery 133 Diane T. Adamczyk, OD_Copyright © 2024 126 Principles of Oc Drug Administration Pharm II 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 Principles of Oc Drug Administration Pharm II 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 Principles of Oc Drug Administration Pharm II Advantages & Disadvantages Various Ocular Drug Delivery Systems Advantage Disadvantage-Limitations Drops Easy application Least invasive Good pt acceptance Poor Suspensions Prolonged Shake Emulsion No shake Improved drug solubility and bioavailability May Gelifying Systems Enhance drug retention relative to drops Increased drug absorption Reduced dosing frequency Possible better compliance Duration Nanotechnology Low irritation Potential contact time ocular bioavailability Sometimes short duration Ineffective posterior seg Potential ocular/systemic toxicity from high concentration or frequent instillation (pt compliance) Hx of generic poorly suspend, dropper tip clog be thermodynamically unstable of drug activity ^ by hours not days or weeks toxicity Adequate bioavailability Ocular tissue compatibility Current & future ophthalmic drug delivery systems. Drug Discovery Today, del Amo EM, Urtti A. 12-2007 (in part reference) 136 Diane T. Adamczyk, OD_Copyright © 2024 129 Principles of Oc Drug Administration Pharm II Advantages & Disadvantages Various Ocular Drug Delivery Systems Injections (Intravitreal, periocular, subconjunctival) Implants NonBiodegradable Biodegradable Systemic Administration Advantage Disadvantage-Limitations Improved drug absorption vs systemic or topical Drug delivery to post seg, no systemic toxicity Drug delivery to target site First Alternate to repeat injections Biodegradable-no removal Zero order kinetics Nonbiodegradable-surgical More Most effective for post seg diseases vs drops order kinetics Short half life (repeat inject) Side Effects: pain, discomfort, IOP^, intraocular bleed, potential infection, RD, endophthalmitis Patient acceptance remove Invasive procedure Side Effects: RD, intravitreal heme do not pass bl-oc barrier Potential systemic toxicity Current & future ophthalmic drug delivery systems. Drug Discovery Today, del Amo EM, Urtti A. 12-2007. (In part reference) 137 Diane T. Adamczyk, OD_Copyright © 2024 130 Principles of Oc Drug Administration Pharm II Research continues for new and improved Drug Delivery Systems 138 Diane T. Adamczyk, OD_Copyright © 2024 131 Principles of Oc Drug Administration Pharm II Pediatric Considerations 139 Diane T. Adamczyk, OD_Copyright © 2024 132 Principles of Oc Drug Administration Federal Food, Drug and Cosmetic Act defines pediatric persons: Age 21 and younger Pharm II Pediatric cohorts Pediatric Age Neonates -- birth to < 1 month Neonates: newborn to 1 month Infants -- age 1 month to < 2 years Infants: 1 month – 2 years Children -- ages 2 to < 12 years Children: 2 years – 12 years Adolescents -- ages 12 to < 17 years Adolescents: 12 years – 16 years Neonates: birth to 28 days Infants: 29 days to <2 years Children: 2 years to <12 years Adolescents: 12-21 (up to but not including 22nd birthday) https://www.fda.gov/medical-devices/products-and-medicalprocedures/pediatric-medical-devices https://www.accessdata.fda.gov/s cripts/cderworld/index.cfm?action https://www.fda.gov/drugs/data=newdrugs:main&unit=4&lesson= standards-manual-monographs/pediatricexclusivity-study-age-group 1&topic=5 Pediatric Prescribing Considerations 140 Diane T. Adamczyk, OD_Copyright © 2024 133 Principles of Oc Drug Administration Pharm II Pediatric Dosing Considerations Young’s Rule (based on age) ◦ Ped Dose = Adult dose X Age (years)/Age+12 Clark’s Rule (based on weight) ◦ Ped Dose = Adult dose X Wt (kg)/70 Or Adult dose X Wt (lb)/150 141 Diane T. Adamczyk, OD_Copyright © 2024 134 Principles of Oc Drug Administration Pharm II You have a 40lb, 8 year old female in need of an oral antibiotic. You decide to give Amoxicillin. The adult dosage of Amoxicillin is 500 mg Q8H. Based on Young’s Rule, what would you prescribe? (The drug comes in 125, 200, 250, 300, 500mg tablets) 1. 125mg Q8H 2. 125mg Q4H 3. 200mg Q8H 4. 200mg Q4H 5. 500mg Q8H 142 Diane T. Adamczyk, OD_Copyright © 2024 135 Principles of Oc Drug Administration Pharm II You have a 40lb, 8 year old female in need of an oral antibiotic. You decide to give Amoxicillin. The adult dosage of Amoxicillin is 500 mg Q8H. Based on Young’s Rule, what would you prescribe? (The drug comes in 125, 200, 250, 300, 500mg tablets) 1. 125mg Q8H 2. 125mg Q4H 3. 200mg Q8H 4. 200mg Q4H 5. 500mg Q8H 143 Diane T. Adamczyk, OD_Copyright © 2024 136 Principles of Oc Drug Administration Pharm II Pediatric Dosing Considerations You have a 40lb, 8 year old female in need of an oral antibiotic. You decide to give amoxicillin. The adult dosage of amoxicillin is 500 mg Q8H. Based on Young’s Rule, what would you prescribe? (The drug comes in 125, 200, 250, 300, 500mg tablets) ◦Young: ◦Adult dose x Age (years)/Age+12 ◦500mg x 8/(8+12)=500x0.4=200mg Q8H >>>200mg Q8H 144 Diane T. Adamczyk, OD_Copyright © 2024 137 Principles of Oc Drug Administration Pharm II You have a 40lb, 8 year old female in need of an oral antibiotic. You decide to give Amoxicillin. The adult dosage of Amoxicillin is 500 mg Q8H. Based on Clark’s Rule, what would you prescribe? (The drug comes in 125, 200, 250, 300, 500mg tablets) 1. 125mg Q8H 2. 125mg Q4H 3. 200mg Q8H 4. 200mg Q4H 5. 500mg Q8H 145 Diane T. Adamczyk, OD_Copyright © 2024 138 Principles of Oc Drug Administration Pharm II You have a 40lb, 8 year old female in need of an oral antibiotic. You decide to give Amoxicillin. The adult dosage of Amoxicillin is 500 mg Q8H. Based on Clark’s Rule, what would you prescribe? (The drug comes in 125, 200, 250, 300, 500mg tablets) 1. 125mg Q8H 2. 125mg Q4H 3. 200mg Q8H 4. 200mg Q4H 5. 500mg Q8H 146 Diane T. Adamczyk, OD_Copyright © 2024 139 Principles of Oc Drug Administration Pharm II Pediatric Dosing Considerations You have a 40lb, 8 year old female in need of an oral antibiotic. You decide to give amoxicillin. The adult dosage of amoxicillin is 500 mg Q8H. Based on Clark’s Rule, what would you prescribe? (The drug comes in 125, 200, 250, 300, 500mg tablets) ◦ Clark: ◦ ◦ ◦ ◦ ◦ Adult dose x lb/150 (or kg/70) 2.2lb=1kg 40lb=18.18kg 500mg x 40/150=133 mg >>>125mg Q8H 500mg x 18.18/70=129.87>>>125mg Q8H 147 Diane T. Adamczyk, OD_Copyright © 2024 140 Principles of Oc Drug Administration Pharm II Pediatric Dosing Considerations Body Surface Area (BSA) ◦ Weight and height considerations ◦ Average BSA: ◦ Adult: 1.73 m² ◦ Child 2 years: 0.5 m² Child 10 years: 1.14 m² ◦ Child 12-13 years: 1.33 m² ◦ Various formulas to determine BSA ◦ Example: Dubois and Dubois BSA formula: ◦ BSA = ((Weight(kg) 0.425 x Height(cm) 0.725)) x 0.007184 ◦ Pediatric Dosing Formula: ◦ Dose = (Child’s BSA/1.7m2 ) X adult dose 148 Diane T. Adamczyk, OD_Copyright © 2024 141 Principles of Oc Drug Administration Pharm II Pediatric Dosing Considerations You have a 40lb 8 year old female, 57 inches tall, (BSA = 0.9) in need of an oral antibiotic. You decide to give amoxicillin. The adult dosage of amoxicillin is 500 mg Q8H. Based on Body Surface Area, what would you prescribe? (The drug comes in 125, 200, 250, 300, 500mg tablets) ◦ BSA: ◦ (Child’s BSA/1.7m2 ) X adult dose ◦ (0.9/1.7) X 500 = 0.5294 X 500 = 264.7 mg ◦ 250mg Q8H 149 Diane T. Adamczyk, OD_Copyright © 2024 142 Principles of Oc Drug Administration Pediatric Dosing Considerations: Example Pharm II A 40lb 8 year old female, 57 inches tall, (BSA = 0.9) is given amoxicillin. The adult dosage of amoxicillin is 500 mg Q8H. (The drug comes in 125, 200, 250, 300, 500mg tablets). Following is the dosage based on various dosage formulas: ◦ Clark: ◦ Adult dose x lb/150 (or kg/70) ◦ 2.2lb=1kg or 40lb=18.18kg ◦ 500mg x 40/150=133 mg >>>125mg Q8H ◦ 500mg x 18.18/70=129.87>>>125mg Q8H ◦ Young: ◦ Adult dose x Age (years)/Age+12 ◦ 500mg x 8/(8+12)=500x0.4=200mg Q8H >>>200mg Q8H ◦ Based on BSA: ◦ (Child’s BSA/1.7m2 ) X adult dose ◦ (0.9/1.7) X 500 = 0.5294 X 500 = 264.7 mg >>>250mg Q8H 150 Diane T. Adamczyk, OD_Copyright © 2024 143 Principles of Oc Drug Administration Pharm II Epocrates Drugs.com 151 Diane T. Adamczyk, OD_Copyright © 2024 144 Principles of Oc Drug Administration Pharm II Epocrates.com 152 Diane T. Adamczyk, OD_Copyright © 2024 145 Principles of Oc Drug Administration Amoxicillin Dosing: 8 yo, 40 lb (18.18kg) Dose: 20-40 mg/kg/day q8h 1-Chose 40 mg/kg/day 2-Weight 18.18 kg 3-Dose is 727.2 mg per day or 242.40 mg TID 4- Chose 250 mg chewable TID OR SUSP: 1- Comes 125mg/5mL 2-Dose 29.09mL per Day or 9.7mL TID Note: 1tsp=5mL Pharm II 727.2/3=242.4 TID 250 mg chewable TID OR 29.09/3= 9.7 mL TID liquid dose 250 mg chewable TID OR 9.7 mL TID liquid dose Dosage forms: CAP: 250 mg, 500 mg; TAB: 500 mg, 875 mg; ER TAB: 775 mg; CHEWABLE: 125 mg, 250 mg; SUSP: 125 mg per 5 mL, 200 mg per 5 mL, 250 mg per 5 mL, 400 mg per 5 mL [>3 mo] Dose: 25-45 mg/kg/day PO divided q12h; Max: 875 mg/dose; Alt: 20-40 mg/kg/day PO divided q8h; Info: dose, duration vary by infection type/severity 153 Diane T. Adamczyk, OD_Copyright © 2024 146 Principles of Oc Drug Administration Pharm II 8 yo, 40 lb (18.18kg) 125 mg chewable TID ??? mg chewable TID 250 mg chewable TID Dosage forms: CAP: 250 mg, 500 mg; TAB: 500 mg, 875 mg; ER TAB: 775 mg; CHEWABLE: 125 mg, 250 mg; SUSP: 125 mg per 5 mL, 200 mg per 5 mL, 250 mg per 5 mL, 400 mg per 5 mL [>3 mo] Dose: 25-45 mg/kg/day PO divided q12h; Max: 875 mg/dose; Alt: 20-40 mg/kg/day PO divided q8h; Info: dose, duration vary by infection type/severity 154 Diane T. Adamczyk, OD_Copyright © 2024 147 Principles of Oc Drug Administration Pharm II Pediatric Dosing Considerations Topicals: ◦ Infrequently adjust dosage ◦ Approximate considerations: ◦ Birth to 2 yo: ½ adult dose ◦ 2-3yo: 2/3 adult dose 155 Diane T. Adamczyk, OD_Copyright © 2024 148 Principles of Oc Drug Administration Pharm II Review WHAT IS IMPORTANT TO KNOW ABOUT YOUR PATIENT AND WHY – BEFORE YOU USE ANY PHARMACEUTICAL AGENT? 156 Diane T. Adamczyk, OD_Copyright © 2024 149 Principles of Oc Drug Administration Pharm II What you need to know about your patients: ◦ Medical conditions ◦ ◦ ◦ ◦ ◦ ◦ ◦ ◦ Kidney/liver Cardiac Respiratory Etc. Other medications >>Drug Interactions Allergies (e.g. sulfa) Family history (e.g. POAG) Ocular history (e.g. inflammation) 157 Diane T. Adamczyk, OD_Copyright © 2024 150 Principles of Oc Drug Administration Pharm II Review How does the drug get into the eye? Your considerations? ◦ Pharmacokinetics ◦ Absorption ◦ Topicals mainly absorbed….where? ◦ Considerations: ◦ Molecular properties of the drug (also prodrugs, metabolites) ◦ Viscosity of its vehicle ◦ Tissue barriers (compartments) ◦ Distribution (Fick, Zero, First Order) 158 Diane T. Adamczyk, OD_Copyright © 2024 151 Principles of Oc Drug Administration Pharm II Over-View History Pregnancy/Pediatric Considerations The Drug Absorption ◦ Compartments ◦ Drug Kinetics Drug removal Formulation Delivery 159 Diane T. Adamczyk, OD_Copyright © 2024 152