MT2 Flashcards by Richard Huynh

What are examples of Topical administrations that causes Localized Ocular Effects/Reactions?

Topical Steroids* - can cause catract/increase IOP
Topical Anti-glaucoma medications * - conjunctival changes
Ophthalmic ointments and gel * - temporary blur
Topical anesthetic drops for analgesia (relief of pain) - corneal epithelial cell loss

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Ocular preservatives?

Causes localized ocular effects –> leads to superficial punctate keratitis (SPK)

Contact Sensitivity/Dermatitsis

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Antibiotic Drug Classes:
Classes of Systemic Effect/Reactions

Penicillin (beta-lactam class)**
Cephalosporins (beta-lactam class) **
Sulfonamides (sulfa drugs)**
tetracycline

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Non- Antibiotic Drug Classes:
Classes of Systemic Effects/reactions

Anticonvulsants
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Allopurinol
Antihypertensives

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CYP 450 Substrates

Anti-HIV Agents
Benzodiazepines **
Calcium Channel Blockers
Immunosuppressants **
Macrolide Antibiotics
Statins

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CYP 450 Inhibitors

Erythromycins
Grapefruit Juice
Antifungal Agents
Anti-HIV agents
Calcium channel blockers
Macrolide Antibiotics

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CYP 450 Inducers

Antiepileptics
Anti-Seizure medications
Anti-HIV agents
Rifamycin
Anti-TB medication

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Three Main Categories of ADEs

Allergy or Drug Hypersensitivity reactions
Infection
Drug Toxicity: Ocular

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What is the more severe drug-related skin reaction

Drug Induced Exfoliative dermatitis**
- stevens Johnson syndrome (SJS)*
- Toxic epidermal necrolysis (TEN)*
- Erythema Multiforme (less severe than SJS and TEN)

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Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

*severe mucocutaneous reactions by medications
*Characterized by extensive epidermal necrosis and detachment of epidermis, sloughing of mucous membranes

signs: Hemorrhagic crusts on lips, extensive sloughing of epidermis

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Erythema Multiforme (EM)

acute, immune mediated condition characterized by distinctive target-like lesions on skin

commonly induced by infection (herpes simplex virus)

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Difference between Minor vs Major Erythema Multiforme

Minor EM - without mucosal involvement

Major EM - with mucosal involvement

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How can Infection (ADEs) occur?

Contamination of the dropper or applicator tip – need to educate patients on sterile technique

dispose of expired/unused medications

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Drug Toxicity: Ocular

SPK secondary to preservatives
SPK leads to Corneal inflammation, punctate corneal epithelial loss or damage

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Decisions for Healthcare Providers

Patient presentation: SIGN and SYMPTOMS
Knowledge of natural disease process
potential for morbidity: Risk Vs Benefit
ID any ocular or medical contraindications based on review of pt’s medical and medicine hx

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Choice of Drug

Efficacy in relation to alternatives
- side effects (ADEs)
Drug Interactions
- Warnings or Precautions relative to co-morbidities/other diseases
- Compliance with dosage regiment
- Cost and insurance coverage

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Communicating with Other providers of Care

SBAR
Situation, Background, Assessment, Recommendation

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Baseline Measurements are taken PRIOR to administration of diagnostic or therapeutic ocular drugs

Biomicroscopy - topical anesthetics can compromise corneal epithelium & evaluation of aqueous and anterior chamber angle depth is ESSENTIAL before mydriatic agents

Tonometry - record IOP before mydriatics

Assess BP prior to administration of drugs

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Minimizing Systemic Adverse Drug Effects: General

systemic absorption with ocular administration is usually minimal
topically applied drugs avoid first pass

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How would absorption into systemic circulation occur?
drugs enter into systemic circulation VIA blood vessels of :

*Conjunctival sac - conjuc. capillaries
*lacrimal drainage system - nasal mucosa –> oral pharynx –> GI tract
*Episclera (outermost layer of sclera) - via superficial and deep episcleral vessels

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Ways to REDUCE systemic absorption of topical applied drugs

Mechanical or Physical
- wiping excess* or manual nasolacrimal occlusion*

Prescribing Strategies
- use lowest conc.* and least number of doses per day* (MINIMIAL DOSAGE FREQ)

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Ways to reduce Accidental Drug Exposure

store all medication out of reach of children
consider lockable medication storage areas

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Percentage Solution

% weight/volume = # grams of solute in 100ml

1% = 1gm/100ml
0.5% = 0.5gm/100ml

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How many drops in 1 ml?

50microliter = 1gtt

**1ml = 20 drops (gtts)

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Warnings & Precautions: Systemic vs Ocular Administration

types of patients included under warnings and precautions! - Cardiac conditions - Pulmonary conditions - CNS conditions

Dangers of Atropine 1% - P.E.

Advise patients to store all medications out of reach of children - twenty drops (=10mg) may be fatal

Pharmacokinetics (review)

eyes have speical pharmacokinetics properties - what the body does to the drug - drugs are ADME- absorbed, distributed, metabolized, eliminated - - determines onset, intensity, and duration of drug action

Drug Absorption of Eye depends on

- Molecular properties of drug - viscosity of drug vehicle - function status of tissue (barrier to drug penetration)

What types of drugs have a better ability to pass through plasma membranes?

lipid-soluble drugs -- smaller molecular structure -- not ionized

Barriers of Eye : Static vs Dynamic

Static (like solids) - cornea, sclera, blood aqueous and blood- retinal barriers Dynamic (with movement) - choroidal and conjunctival blood flows, lymphatic clearance, and tear dilution

Prodrug (review)

inactive or weakly active substance that has an active metabolite. Requires Metabolic conversion to a pharmacologically active product Ex: Nepafenac (Nevanac and ilevro) - NSAID Ex: Clopidogrel (Plavix) Ex: Codeine

Drug metabolites may be inactive, less or more active than parent drug

*Metabolic enzymes are utilized in prodrug *Some drugs undergo biotransformation by enzymes in the eye to an inactive form associated with fewer side effects than parent form

Ocular Tissue Structure and Pharmacokinetics

avascularity at clear tissues of the eye, allows for direct route for ocular drug penetration via topical meds without high degree of absorption of systemic circulation

Tear Structure and Chemical Properties: tears are responsible for supply ________ to the ______ ___________

Tears are responsible for supplying Oxygen requirements of Corneal Epithelium

What are the layer of the tear film?

Oily Layer (Lipid) Center layer (Aqueous) Basal or Inner Layer (Mucinous)

Outermost Lipid Layer

- lipid monolayer, produced by meibomian glands - stabilizes surface to prevent evaporation

Aqueous Layer

- secreted by lacrimal glands - provides oxygen to corneal epithelium - antibacterial activity - wash away debris

Mucinous Layer

- composed of glycoproteins -- secreted by goblet cells - lubricates - permits wetting - thin hydrophilic coating - cleanses the tears of particulate debris

Tear Structure and Chemical Properties

tear pH = 7.4 (slightly basic) normal volume = 8-10 ml 1 drop of medication is 0.05ml, 5-6x the normal tear reservoir

Where does the excess drop of medication go?

*nasolacrimal duct rapidly drains the excess - some medication is blinked out of eye onto lid

Does increasing drop size increase penetration of medication into the cornea?

increasing drop size does NOT result in penetration of more medication into cornea - excess via nasolacrimal duct - spillage

What would be the impact of ocular irritation on absorption of ophthalmic medication?

conc. of drug available in the tears for transcorneal absorption is inversely proportional to the tear flow Increase tear flow = increase washout = decrease conc. Decrease tear flow = decrease washout = increase conc.

Concentration of drug available in tears for transcorneal absorption is inversely proportional to tear flow due to

- drug dilution* - drug removal by nasolacrimal duct* - eyelid spillover*

Dry Eye Patients: a decrease in tear flow rate will lead to -->

- lead to diagnosis of dry eye or keratoconjunctivitis sicca

Patient groups more susceptible to keratoconjunctivitis siccca*

- Elderly* - Rheumatoid arthritis* - Peri-menopausal and post-menopausal women* - exposure keratitis associated with dry climate*

Potential for increased drug absorption with lower tear flow rate

Total tear volume with less than normal volume may: - increased drug absorption --- as medication is not diluted well - prolonged residence time -- increase absorption - *presence of epithelial surface damage --> increase absorption

Corneal Layers

*Epithelium - Depot for lipophilic drugs Boman's Layer *Stroma - Depot for hydrophilic drugs, stores lipophilic drugs in keratocyes Descemet's Membrane Endothelium

Cornea

- major functional barrier to ocular penetration - Major site of absorption for topically applied medication

Corneal Nutrients

diffusion from aqueous humor for metabolic needs

What layer of the cornea have major influence on pharmacodynamics?

Epithelium and Stroma - constitutes depots/reservoirs for lipophilic and hydrophilic drugs

Corneal Epithelium

Surface Squamous Layer -- resists penetration of hydrophilic drugs Intermediate wing cells basal "germinative" layer - source of new cells (regenerates)

Surface Squamous Layer* -- resists penetration of hydrophilic drugs

- tight junctions or zona occludens * - lipid soluble drugs penetrate tight junctions due to phospholipid membrane - ionization decreases lipid solubility and increases water solubility ex: sodium fluorescein

What does a drug need to possess to effectively penetrate the cornea*** (transcorneal permeability)

drug must possess a BALANCE of hydrophilic and lipophilic properties - be able to partition between both media

Partition Coefficient

U- Shaped Parabola curve -- - drugs with too low a P.C (low transcorneal permeability) -- do not penetrate well - Drugs with a too high P.C. (high transcorneal permeability) -- tend to remain in epithelium and partition into anterior chamber slowly -

Bowman's Layer

- tough and provides substantial resistance to corneal injury/infection - cannot regenerate -- will scar if damage

Cornea Stroma - 90% thickness of cornea

- depots for hydrophilic drugs - stores lipophilic drugs in keratocytes - major determinant of corneal transparency - disruption of stroma --> potential scarring

Cornea Stroma - 90% thickness of cornea

- depots for hydrophilic drugs - stores lipophilic drugs in keratocytes - major determinant of corneal transparency - disruption of stroma --> some potential scarring, possible regeneration

Which layers are not known to be drug depots?

- Bowman's Layer - Descemet's Layer - Endothelium Layer

Corneal Sclera and Conjunctiva

have limited drug penetration -- less than 1/5 of all drug absorption - due to extensive vascularization

Iris

- pigmented tissue - Major function - adjust the amnt of light entering the retina - two groups of muscles - sphincter and ilator muscles

Sphincter/Circular Muscle

Cholinergic innervation - miosis - - innervation by sympathetic

Dilator/Radial Muscle

Adrenergic innervation - mydriasis - - innervation by parsympthetic

Aqueous Humor Flow and Angle

fluid generated from ciliary body exits via trabecular meshwork/conventional outflow

Ciliary Body

Produces aqueous humor by pigmented and nonpigmented ciliary epithelium *pigmented ciliary epithelium can store drugs - major ocular source of drug metabolizing enzymes** - important for Phase I CYP 450 Metabolism - detoxification -- via Phase II conjugation

Anterior Lens Epithelium

Most active metabolic region of lens * most prone to damage by drugs/toxic substances - major barrier for entry of hydrophilic, high molecular weight drugs - **lipophilic drugs can be absorbed slowly

Phase I Metabolism

- involve formation of new or modified functional group/cleavage - Oxidation, Hydrolysis, reduction - CYP450 enzyme is important -- located in liver endoplasmic reticulum

Phase II Metabolism

- glucuronic Acid conjugation - sulfate conjugation - glutathione conjugation

Lens associated with Cataracts

cataract formation can be increased by some miotics, *steroids, and phenothiazines

blood-retinal barrier of Retina and Optic Nerve

(tight junctional complexes/ zonula occludens) - prevents most hydrophilic drugs from penetrating or being absorbed from blood to retina and vitreous

Systemic Agents that cause Retinal Toxicity

* Hydroxychloroquine * sildenafil = phosphodiesterase inhibitor

Toxic Effects --> Optic Neuritis

* Phosphodiesterase inhibitors * amiodarone

Ocular Tissue: Removal of Drugs and Metabolites

- two different circulatory pathways in the eye - retinal vessels - uveal vessels - one non-circulatory pathway - direct outflow pathway

Retinal Blood Vessels (Circulatory Pathway)

removes drugs from vitreous humor and retina by ACTIVE transport

Uveal Blood vessels (circulatory pathway)

- removes drugs by BULK transport from iris and ciliary body (endocytosis/exocytosis) - requires energy

Direct Outflow Pathway (non-circulatory pathway)

- aqueous humor through trabecular meshwork and canal of schlem

Compartment Theory

- region of tissue or fluid which drugs can diffuse and equilibrate with relative ease - concentration gradients

Fick's Law of Diffusion

rate of diffusion across a barrier is proportional to the conc. gradient b/n compartments

Drug Diffusion of Cornea - Corneal Absorption

Factors that affect drug bioavailability - preservatives - infection - inflammation - neuronal control

First- Order Kinetics

More- common situation in ocular drug movements - rate of drug movement is proportional to conc difference - passive diffusion across non-saturated barrier

Zero- Order Kinetics

- release of drug is constant over time and is INDEPENDENT of conc. present - implantable device that releases drug at constant rate - ex: Fluocinolone (Iluvien and retisert) - ex: Dexamethasone (ozurdez) ^^ steroid ocular implants for diabetic macular edema