MT2 Flashcards
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
Ocular preservatives?
Causes localized ocular effects –> leads to superficial punctate keratitis (SPK)
Contact Sensitivity/Dermatitsis
Antibiotic Drug Classes:
Classes of Systemic Effect/Reactions
- Penicillin (beta-lactam class)**
- Cephalosporins (beta-lactam class) **
- Sulfonamides (sulfa drugs)**
- tetracycline
Non- Antibiotic Drug Classes:
Classes of Systemic Effects/reactions
Anticonvulsants
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Allopurinol
Antihypertensives
CYP 450 Substrates
Anti-HIV Agents
Benzodiazepines **
Calcium Channel Blockers
Immunosuppressants **
Macrolide Antibiotics
Statins
CYP 450 Inhibitors
Erythromycins
Grapefruit Juice
Antifungal Agents
Anti-HIV agents
Calcium channel blockers
Macrolide Antibiotics
CYP 450 Inducers
Antiepileptics
Anti-Seizure medications
Anti-HIV agents
Rifamycin
Anti-TB medication
Three Main Categories of ADEs
Allergy or Drug Hypersensitivity reactions
Infection
Drug Toxicity: Ocular
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)
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
Erythema Multiforme (EM)
acute, immune mediated condition characterized by distinctive target-like lesions on skin
commonly induced by infection (herpes simplex virus)
Difference between Minor vs Major Erythema Multiforme
Minor EM - without mucosal involvement
Major EM - with mucosal involvement
How can Infection (ADEs) occur?
Contamination of the dropper or applicator tip – need to educate patients on sterile technique
dispose of expired/unused medications
Drug Toxicity: Ocular
SPK secondary to preservatives
SPK leads to Corneal inflammation, punctate corneal epithelial loss or damage
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
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
Communicating with Other providers of Care
SBAR
Situation, Background, Assessment, Recommendation
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
Minimizing Systemic Adverse Drug Effects: General
- systemic absorption with ocular administration is usually minimal
- topically applied drugs avoid first pass
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
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)
Ways to reduce Accidental Drug Exposure
- store all medication out of reach of children
- consider lockable medication storage areas
Percentage Solution
% weight/volume = # grams of solute in 100ml
1% = 1gm/100ml
0.5% = 0.5gm/100ml
How many drops in 1 ml?
50microliter = 1gtt
**1ml = 20 drops (gtts)
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
