Eye

Structures in the external eye

• Bony orbit

• Extraocular muscles

• Superior and inferior oblique

• Lavatory palpebrae (eyelid)

• Fat

• Conjunctiva

External Eye

Bony orbit

• Cavity in the skull in which the eye and appendages sit

• Prevents mechanical injury

External Eye

Extraocular muscles

• Muscles that control eye movement

• Allows the eye to move up, down, left, right and rotate

• There are 6 extraocular muscles:

  • Superior rectus 

  • Inferior rectus 

  • Lateral rectus 

  • Medial rectus 

External Eye

Extraocular muscles

• Superior rectus

• Inferior rectus

• Medial rectus

• Lateral rectus 

• Superior rectus » moves eye upwards

• Inferior rectus » moves eye downwards

• Medial rectus » moves eye toward the nose

• Lateral rectus » moves eye away from the nose

External Eye

Extraocular muscles

Superior and inferior oblique

• Counteract head movement - so keep vision stable when your head tilts to the side

Superior oblique: rotates the top of the eye towards the nose, helps stabilise vision when the head tilts to the opposite side 

Inferior oblique: rotates the top of the eye away from the nose, helps stabilise vision when the head tilts to its own side 

External Eye

Levator palpebrae (eyelid)

Protects and lubricates the eye

External Eye

Fat

• Surrounds eye within the bony orbit

Functions:

• Allows smooth movement of eye muscles

• Acts as a lubricant so eye can move around

External Eye

Conjuctiva

• Thin mucus membrane covering the sclera

• Folds and joins the inner lining of the upper and lower eyelids » forms a bag-like structure called conjunctival sac

• Lubricates the eye with mucus and tears

Label the overall structure of the eye

2 chambers of the eye

• Anterior chamber » front of the eye

• Posterior chamber » back of the eye

Anterior Chamber

Structures in the anterior chamber of the eye

• Sclera

• Cornea

• Iris

• Lens 

• Aqueous humour 

Anterior Chamber

Sclera

• ‘White of the eye’

• Protective function

• Made up of non-uniform collagen and elastic fibres

• Extraoccular muscles are attached to the eye via the sclera

Anterior Chamber

Cornea

• Continuous with the sclera

• Transparent with no blood vessels

• Major refractive structure of the eye - bends light entering the eye

• Responsible for 2/3 of the eye’s total refractive power

Anterior Chamber

Cornea 

Why does the cornea refract light when it enters the eye

Light changes direction when it moves from one medium to another as it changes speed

Anterior Chamber

Cornea

Even thought it accounts for most of the eye’s focusing power, the corneas focus is fixed. Why is this?

• The corneas focus is fixed because the cornea cannot change its shape 

• Therefore, it cannot change its refractive power 

Anterior Chamber

Iris

• Gives the eye colour » depending on melanin content

• Controls light levels in the eye via the pupil

The iris contains 2 muscles which control pupil size ;

1. Sphincter muscle

• Around the edge of the pupil

• Bright light causes the sphincter muscle to contract causing the pupil to constrict

2. Dilator muscle 

• Run through the iris radially (like spokes on a wheel)

• Dim lighting causes the dilator muscle to contract causing the pupil to dilate 

Anterior Chamber

Lens

• Transparent

• Biconvex structure - 2 outward-curving surfaces

• Refracts light to focus it on the retina

• Makes up the remaining 1/3 of the total refractive power of the eye

• Unlike with the cornea, the focus is not fixed

• This is because the lens can change shape to focus on images at various distances - accommodation

Anterior Chamber

Lens

How does the lens change shape

The ciliary muscles relax and contract, causing the lens to become thicker or thinner 

Anterior Chamber

Lens

Shape of the lens when object is closer

Lens is thicker as needs to bend light more

Anterior Chamber

Lens

Shape of the lens when object is further away

Lens is thinner as doesn’t need to bend light as much

Anterior Chamber

Summary of the refraction of the light by the cornea and lens

• Both refract light entering the eye 

• The cornea makes up 2/3 of the eyes total refractive power, the lens makes up 1/3

• When light enters the eye, the cornea bends the light a fixed amount (as it is unable to change shape)

• The lens then changes shape to focus the light on the retina » allows us to see the image more clearly

• So both work together to refract light to focus it on the retina 

Anterior Chamber

Aqueous humour

• Clear, watery fluid that is bordered by the cornea and the lens

• Similar to the blood plasma but has a low concentration of proteins

• Provides nutrients to the cornea and lens

• Gives the eye shape

• Maintains the intraocular pressure

Anterior Chamber

Aqueous humour

Production and drainage of aqueous humour AKA how does aqueous humour end up in the anterior chamber?

Aqueous humour is continuously produced and drained:

1. It is secreted from the epithelial cells of the ciliary body behind the iris 

2. It migrates into the anterior chamber by flowing between the iris and the lens

At the same time as the aqueous humour is being produced, it is being drained:

3. It is drained through the pores of the trabecular meshwork

4. It passes into the Canal of Schlemm, then into veins of the orbit via the episcleral vein

Anterior Chamber

Aqueous humour

What happens if there are problems with production or drainage of aqueous humour?

• This will change intraocular pressure:

  • If production > drainage = fluid builds up = IOP rises

  • If production < drainage = fluid is drained faster than it is made = IOP drops

• Intraocular pressure is only stable when production = drainage 

Posterior Chamber 

Structures in the posterior chamber of the eye

• Vitreous humour 

• Retina

Posterior Chamber

Vitreous humour

• Bordered by the lens and the retina

• More gelatinous than the aqueous humour - made of water and collagen

• Not continuously produced and drained like aqueous humour - it is stagnant

• Helps maintain eye structure at the back of the eye and pushes retina back in place

Posterior Chamber

Vitreous humour

What happens to the vitreous humour with age?

• The electrostatic forces that keep the collagen fibres apart diminish

• So the vitreous humour becomes more watery

• This causes it to move away from the retina 

Posterior Chamber

Retina

• Light-sensitive tissue that lines the back of the eye

• Covers 65% of the interior surface of the eye

• Contains rods and cones - photosensitive cells which convert light into signals that are carried to the brain by the optic nerve

• Rods function in dim light and provide black and white vision

• Cones function in the daytime and provide colour vision

Posterior Chamber

Retina

By looking at the retina, how can doctors see if there are any problems with the CNS?

The retina is the only part of the CNS that can be seen externally 

Posterior Chamber

Retina

Label the optic disc and the fovea and describe their function

• Optic disc » where the optic nerve meets the retina

• Fovea » darker than the rest of the retina as high concentration of rod and cone cells

Drainage systems of the eye

1. Aqueous humour » drains into the systemic uveoscleral circulation

2. Aqueous humour » drains into the trabecular meshwork then the Schlemm’s canal

3. Vitreous humour » drains via diffusion into the anterior chamber

4. Posterior route » movement of fluid from the retina across the blood-retinal barrier into the choroid circulation

Drug pathways in the eye

1. Trans-corneal route

• Transport across the cornea

• Most common route to aqueous humour

2. Blood-retinal barrier

• Drugs can cross the BRB to reach the retina

• The BRB prevents drugs/toxins in the blood from entering the posterior eye » so difficult for drugs to enter

3. Intravitreal delivery route

• Injection into the vitreous humour 

Tear Film

What are the 3 main layers of the tear film?

• Lipid layer

• Muco-aqueous (aqueous layer)

• Mucous layer + Glycocalyx

Tear Film

Which glands produce the lipid layer of the tear film?

What is the lipid layer composed of?

What is the main function of the lipid layer?

Produced by: Meibomian glands located in the eyelids

Composed of: sterol esters, waxes and fatty acids

Functions: The lipid layer reduces water evaporation from the surface of the eye

Tear Film

What produces the aqueous layer of the tear film?

What is the aqueous layer composed of?

Produced by: The lacrimal gland and accessory glands

Composed of:

• Dissolved ions e.g HCO3-, Na+, K+, Cl-

• Proteins

• Lubricants

• Soluble mucins produced by goblet cells 

Tear Film

What do the lacrimal glands secrete that make up the bulk of the aqueous layer of the tear film?

the lacrimal fluid (tear fluid)

Tear Film

What is the average viscosity of lacrimal fluid and what contributes to it?

• About 3cp

• The protein content of lacrimal fluid increases its viscosity

Tear Fluid 

What type of fluid is lacrimal fluid in terms of Rheology and what does this mean?

• Pseudoplastic (shear-thinning)

• As force is applied, viscosity decreases, allowing the lacrimal fluid to spread more easily over the surface of the eye

Tear Film

What produces the mucus layer in the tear film

What is the function of the mucus layer?

Produced by: Conjunctival goblet cells

Function: stabilises the tear film and helps maintain a slippery surface on the eye

Tear Film

What is the glycocalyx and where is it located?

• A layer of membrane-bound mucins

• Located on stratified squamous cells of the cornea and conjunctiva

Why are tears considered a major barrier in ocular drug delivery?

• Because they cause significant pre-corneal drug loss

• This reduces the amount of drug available for corneal absorption

What are the 2 main causes of pre-corneal drug loss?

1. Tear turnover and drainage

2. Systemic absorption via the nasolacrimal duct

How does tear turnover reduce drug concentration? 

causes dilution of the drug as fresh tears continuously replace the tear film 

What is the normal tear volume of the eye?

7 uL

What is the tear turnover rate?

1.2 uL/min

What is the maximum volume the tear film can hold?

What is the typical volume of one eye drop?

Why does this mean that most of an eye drop ends up on the cheek?

Max volume of tear film: 30uL

Volume of eye drop: 50uL

• Tear volume is already 7uL

• So tear volume + eye drop volume = 57uL

• This exceeds the maximum tear film volume of 30uL leading to overflow and drainage 

How much tear fluid is displaced with each blink?

about 10uL

Why does blinking increase drug loss?

• Blinking spreads and clears out 10uL of tear fluid

• This pushes excess volume into drainage pathways

In addition to just falling down your cheek, what happens to excess tear volume in the eye?

Cleared by the naso-lacrimal apparatus

Role of the nasolacrimal duct?

drains tears into the nose 

What triggers drainage through the nasolacrimal apparatus?

a reflex reaction to excess tear volume

Where do tears drained by the nasolacrimal duct ultimately go?

into the GI tract after passing through the nose

Why can you sometimes taste eye drops 

• The drug drains through the nasolacrimal duct 

  • Into the nose

  • Then into the GI tract

• This allows it to reach taste receptors

What is a clinical implication of drainage of drug-containing tears into the GI tract?

Potential systemic absorption of the drug

What is the most significant barrier to ocular drug administration?

the cornea

Structures of the Cornea

Describe the structures of the cornea

1. Epithelium

• 5 - 6 layers

• 500 - 100um

• Hydrophobic barrier

2. Bowman’s membrane layer

• 8 - 12um irreplaceable collagen layer

• Acts as a basement layer for the epithelium

• Unlike the Descemet’s membrane, is not regenerative

3. Stroma

• Provides most of the corneal thickness (90%)

• 80% water, 20% collagen + polysaccharides

4. Descemet’s Membrane

• 6um

• High tensile strength

• Regenerative » repairs itself if damaged

5. Endothelium

• Regulates stromal hydration

• Supplies nutrients

Structures of the Cornea

What may happen if the surface of the cornea is scratched?

• Bowman’s membrane unable to regenerate

• Scar tissue may form

• Causes blurred vision

How does the cornea act as a barrier?

1. Epithelium

• Barrier to water (hydrophobic), microbes and xenobiotics - prevents them from entering the eye through tight junctions

2. Tight junctions

• Very restrictive

• Prevents tear fluid from penetrating the cornea » this maintains osmotic pressure

Pros and ons of topical ocular delivery

Pros: 

• Convenient route

• By-passes 1st pass metabolism 

Cons:

• Very inefficient - only 1-5% of the total dose reaches the aqueous humour

What are the 3 main barriers that reduce drug permeation in topical ocular delivery?

1. Nasolacrimal drainage

2. Conjunctival absorption into systemic circulation

3. Corneal barrier

Ocular Metabolism

What phases of metabolism occur in ocular tissue?

Where does metabolism occur?

What enzymes are involved

• Both Phase I and Phase II metabolism occur in ocular tissue

Occurs in:

• Ciliary body

• Most active in the Retinal Pigment Epithelium (RPE)

Enzymes:

• Esterases are abundant

• However, weak expression of CYP450s

Prodrugs

What is a prodrug

an inactive form of a drug which becomes activated when metabolised in the body

Prodrugs

Why might prodrugs be used in ocular drug delivery?

If formulation cannot improve delivery, the development of a prodrug is used as a last resort to improve delivery

Prodrugs

Major drawback of creating a prodrug

• The prodrug form of a drug is a new chemical entity

• Therefore, there are regulatory hurdles » must demonstrate safety and efficacy of thee new molecule

Prodrugs

Why do free acids show low corneal permeation at ocular pH?

because they are ionised = so less lipophilic

Prodrugs

How do esters improve drug delivery for corneal permeation?

• Increase lipophilicity » so able to enter corneal epithelium

• They are cleaved by esterases once inside the eye

Prodrugs

What is an example of a prodrug used in ocular delivery?

Latanoprost » an isopropyl ester of free acid

• The addition of the isopropyl group makes it much better at getting into the eye as the polar COOH is masked

• This makes it more lipophilic = able to enter corneal epithelium

Prodrugs

What antiviral drugs are available as amino acid prodrugs?

• Acyclovir

• Ganciclovir

Prodrugs

How do anti-viral amino acid prodrugs enhance corneal uptake?

via the PEPT transporters expressed in the corneal epithelium

Prodrugs

What products are currently in development for prodrug ocular delivery?

• Antiviral drugs e.g. ganciclovir, acyclovir 

• Available as amino acid prodrugs which enhance uptake into the cornea via PEPT transporters

What are the 2 main methods for drug absorption in the eye?

• Conjuctival / scleral route (ie. The white of the eye)

• Corneal absorption route

Where do we want the drug to be absorbed into?

the anterior chamber

Is the conjunctival / scleral route a good choice for targeting the anterior chamber?

• Not really

• Poor choice for targeting the anterior chamber (AC)

• Instead, it gets absorbed into the SYSTEMIC CIRCULATION

Which route is the best for targeting the anterior chamber?

Corneal absorption route

Corneal Absorption Route

What is the primary barrier in the corneal absorption route?

corneal epithelium

Corneal Absorption Route

What is the lifespan of the corneal epithelium?

7 - 10 day lifespan

Corneal Absorption Route

What are the 3 transport routes across the corneal epithelium?

1. Paracellular (between cells)

2. Transcellular (through cells)

3. Active transport

Corneal Absorption Route

How do the different layers of the cornea affect the absorption of the drug:

1. Epithelium

2. Stromal layer

3. Endothelium

1. Corneal epithelium

• Rate-limiting barrier as:

  • Hydrophilic drugs cannot easily pass through the corneal epithelium

  • Drug molecules must be <=1nm to get through the tight junctions

• If the corneal epithelium is infected or damaged, this can increase permeability

2. Stromal layer

• Higher permeability

• Can slow down lipophilic drugs because they dont dissolve well in the water-rich stroma

3. Corneal endothelium

• Single layer

• High permeability

Corneal Absorption Route

What do we have to consider to ensure the drug is able to permeate the layers of the cornea?

• Molecular size

• Diffusion coefficient

• LogP

Corneal Absorption Route

How does molecule size affect corneal absorption?

larger molecules cross cell membranes more slowly than smaller molecules

Corneal Absorption Route

What is the paracelllar pathway in the cornea like?

Restrictive - limits the passage of substances between cells

Corneal Absorption Route

How does the diffusion coefficient affect corneal absorption?

A reduced diffusion coefficient slows the diffusion of larger molecules

Corneal Absorption Route

How are some polar molecules absorbed quickly across the cornea?

active uptake transporters facilitate the fast transport of certain polar molecules

Corneal Absorption Route

What logP range was found optimal for beta blocker corneal permeation?

• logP 2 - 3

• Higher logP values = unable to pass through the stroma (too lipophilic to dissolve well)

• Lower logP values = unable to pass through the epithelium

Blood-retinal barrier

What is it and what is its function?

Protects the retina by preventing drugs in the systemic circulation from entering the eye

Blood-retinal barrier

What structures make up the blood-retinal barrier?

• Outer retinal pigment epithelium

• Inner endothelium of retinal vessels

Blood-retinal barrier

How do tight junctions in the BRB affect drug transport?

Restrictive - prevent hydrophilic drugs from passing through

Blood-retinal barrier

What transporters exist in the BRB and what do they do?

• Efflux transporters e.g. P-glycoprotein » protect the retina from toxins

• Uptake transporters e.g. glucose, amino acid transporters » bring in nutrients 

Blood-retinal barrier

How does the BRB make systemic delivery of drugs to the retina difficult?

the BRB restricts drug entry and expresses protective efflux transporters

What other ocular route of administration is send when topical delivery is not possible?

Intravitreous injection » however, only used in a hospital setting

Types of formulations for the eye

Liquids

• Solutions

• Suspensions / emulsions

Semi-solids

• Ointments

• Gels 

Ocular Solutions

Advantages

• Cheapest

• Easiest to manufacture

• Drug is already dissolved so no dissolution step = faster corneal permeation = faster onset

Ocular Solutions

Disadvantages

Have the shortest residence time » thin and less viscous so drained from the eye quickly

Ocular Solutions

What are ocular solutions commonly used for?

• Anaesthetics

• Diagnostics

• Pre-operative drugs like mydriatrics

Ocular Solutions

Which muscarinic antagonist used in ocular solutions causes mydriasis and ciliary muscle paralysis

cyclopentolate

Ocular Solutions

Which Sympathomimetic in ocular solutions is used to induce mydriasis?

Phenylephrine

What formulation can be used to improve the short residence time of ocular solutions?

Ocular suspensions 

Ocular Suspensions

Why are some drugs formulated as ocular suspensions instead of solutions?

because they have low aqueous solubility and cannot be dissolved into a solution

Ocular Suspensions

Where do suspended particles collect after administration of an ocular suspensions?

in the ocular cul-de-sac between the eyelid and the eyeball 

Ocular Suspensions

How do ocular suspensions provide sustained drug delivery?

• The particles collect in the cul-de-sac between the eyelid and the eyeball

• The suspended particles gradually dissolve to deliver the drug over a period of time