4 - Pharmacology and meds

Question 1

Challenges of eye’s natural defences on topical drug administration and effectiveness.

Answer 1

Blink out drops applied.
Tear film dilutes medications applied.
Corneal epithelium is biphasic barrier so drugs cannot get through very easily so have to have both hydrophilic and hydrophobic properties.
Normal drainage removes drugs from the eyes quickly.
CALT may mount reaction to some drugs put into the eye

Question 2

Internal ocular homeostasis.

Answer 2

Blood ocular barrier - second-line physical and chemical barrier – stops infectious organisms and inflammatory debris getting into the eye and disrupting it, so also a barrier to drugs.
- protects vision by maintaining clear ocular media.
Anything that goes into the eye must come out of the eye so drugs must have certain properties as no lymphatic drainage and exit through the BOB.
Production should be equal to drainage.

Question 3

1. Administration and treatment routes as a general rule based on target site.
2. Owner (and patient) compliance.

Answer 3

1. Surface and anterior segment = topicals.
   Posterior segment = systemic.
2. High frequency regime?
   Cost?
   Pain/head-shy?

Question 4

Ideal property of topical eye drug.

Answer 4

Non-irritant - maximises patient acceptance and owner compliance.
- Irritants induce inflammation > increased tear osmolarity > increased drug protein-binding > reduces drug availability for absorption > less efficacy.
- Irritants > epiphora > dilution.
- pH 4.5-9 quoted for comfort.
- Normal tear pH 7.4 is best.

Question 5

2 main routes of topical medication penetration.

Answer 5

Transcellular = across corneal epithelial cell.
Paracellular = in between individual cells.

Question 6

Corneal structure and drug passage.

Answer 6

Corneal epithelium is a largely lipophilic barrier so lipid soluble drugs cross this more easily.
Corneal stroma is hydrophilic so polar water soluble drugs cross more easily.
Descemet’s membrane is a supporting membrane.
Endothelium is a lipophilic barrier (although less significant than the epithelium) so lipid soluble drugs cross more easily.

Question 7

What does the transcellular route rely on the molecule being?
What does the paracellular route rely on the molecule being?

Answer 7

Lipophilic-hydrophilic balanced drug e.g. chloramphenicol.
Small molecular weight to pass between tight junctions (0.6-3nm).

Question 8

Where would the target site of an aqueous drug tend to be and why?

Answer 8

Ocular surface as unable to achieve intraocular penetration very well as less lipid soluble but generally adequate for surface disease such as allergic conjunctivitis.

Question 9

In what instances should use of steroids in the eye be avoided? - why?

Answer 9

Corneal ulcers - steroids stop the immune system allowing the healing of the ulcer.

Question 10

How else can topical drug penetration into the eye be improved?

Answer 10

Combining drugs with organic salts e.g. prednisolone acetate - slightly changes the chemical formula.
Addition of preservatives that disrupt the corneal epithelial barrier to allow further penetration so can delay healing in some situations. - recommend preservative free if >q4hrs (often slightly more expensive).
Some drugs designed to be less irritant by being formulated to a uniform and micronized suspension to improve tear retention.

Question 11

Relationship between particle size and retention time.

Answer 11

Larger the particles, the longer the retention time and persistence of therapeutic drug concentration.

Question 12

Properties and advantages of topical eye ointments.
Disadvantages?

Answer 12

Lipophilic character so retained in surface of tear film and retained for extended periods on ocular surface.
As low as 0.5% dose volume clearance per minute so significant amounts retained 4hrs after dosing.
Suitable for BID dosing (e.g. easier for equines).
Can be difficult to get as close to the patient as is needed to apply sufficiently.
Can be difficult to squeeze the tube as thicker substance.

Question 13

Order of application of eye drops.

Answer 13

Solution > micronised > Gel > Ointment.

Question 14

Retention in tear of…
1. solution.
2. suspension.
3. gel.
4. ointment.

Answer 14

1. 5-10 mins max.
2. Up to an hour.
3. Few hours.
4. Several hours.

Question 15

Ease of admin of…
1. solution.
2. suspension.
3. gel.
4. ointment.

Answer 15

1. easy to drop.
2. thicker.
3. close to the eye.
4. more challenging.

Question 16

Frequency of application of…

Answer 16

1. q1-6hrs.
2. q2-12hrs.
3. q2-6hrs.
4. q4-12hrs.

Question 17

1. What is the normal volume of human tear film?
2. Normal tear turnover.
3. Average volume of 1 eye drop?
4. Max volume palpebral fissure can hold?

Answer 17

1. 7-10 microlitres.
2. ~1 microlitre per min.
3. 40 microlitres.
4. 25-30 microlitres.

Question 18

How long should be left between different topical medication application on the eye?

Answer 18

10 mins.

Question 19

How is the use of subconjunctival injections useful?
Advantage?
Disadvantage?

Answer 19

Where patient compliance is low for drops that need to be given over a couple of days.
Some of the drug is absorbed across the sclera and episclera, some absorbed into anterior chamber via limbal blood vessels.
Leaks slowly onto the conjunctival and corneal surfaces, slow release medication administration via injection site (for a day or 2) – aqueous will last for ~12hrs at most.
– BUT, once drug is in, cannot take it out.

Question 20

Sustained release implants.
Types of conditions effective for?

Answer 20

Drug within silicone vehicle e.g. cyclosporine.
Implanted subconjunctivally/episcleral.
Equine Recurrent Uveitis, Kaeratoconjunctivitis Sicca (canine).

Question 21

1. What does the penetration of systemic medication for the eye depend on?
2. Common choices for systemic tx of the eye.

Answer 21

1. Integrity of BAB and BRB, which is reduced in uveitis.
   Lipid solubility.
   Molecular weight of the drug - low molecular weight molecules cross most easily.
   Degree of protein binding.
2. Chloramphenicol, doxycycline (small), trimethoprim/sulphonamides (lipid), amoxy/clav.

Question 22

Ocular therapeutic classes.

Answer 22

Antimicrobial.
Anti-inflammatory.
Anti-glaucoma drugs.
Mydriatics.
Local anaesthetics.
Tear replacement and stimulants.
Anti-collagenase.
*many topical drops human meds, few licensed vet products, be aware of cascade, gain informed consent.

Question 23

Bacteriostatic antimicrobial eye medications.

Answer 23

Chloramphenicol (gram+ and gram-).
Fusidic acid (gram+) – prescription only (Isathal).
Macrolides (toxo).
Trimethoprim/sulphonamide (KCS risk).
Tetracyclines (chlamydia) (q3-4hrs).

Question 24

Bactericidal antimicrobial eye medications.

Answer 24

Aminoglycosides (gentamicin) (2/3 line).
Bacitracin (gram +).
Cephalosporins.
Fluoroquinolones (NOT 1st line) (Exocin).
Penicillins (NOT 1st line).
Polymixin (gram-).
Vancomycin.

Question 25

Antifungal eye medications…
1. Target for most?
2. Fungicidal or fungistatic).
- requirement from patient?

Answer 25

1. Most target fungal cell wall.
2. Fungistatic.
   - functional host immune system.

Question 30

Antivirals…
1. What do they target?
2. Virostatic or virocidal?
3. Formulations?
4. Requirement from patient?

Answer 30

1. Viral replication cycle.
2. virostatic.
3. drops (frequent application)
4. Functional immune system

Question 31

Anti-glaucoma drugs.
- function.
– examples.

Answer 31

Prostaglandin G analogues.
- increase outflow of aqueous.
– latanoprost, travoprost.
(increase inflammation - do not use where inflammation already).
(cause miosis and spasm which may be uncomfortable).

Carbonic Anhydrase inhibitors.
- decrease aqueous production.
– dorzolamide, brinzolamide.

Beta blockers.
- decrease aqueous production.
– timolol, betaxolol.

Question 31

Anti-inflammatory eye medications.
- indications.
– contraindications.

Answer 31

Corticosteroids.
- Reduce inflammation e.g. in uveitis.
– infections, corneal ulcers, diabetes, lipid or calcific keratopathy, laminitis.

NSAIDs.
- Reduce inflammation, analgesia, anti-pyrexia.
– Gastric ulceration, renal disease, (hypovolaemia), topical use may worsen corneal ulceration (malacia, viral keratitis).

Question 32

Local anaesthetics.

Answer 32

Proxymetacaine.
- onset 1 min.
- peak effect at 15 mins.
- duration 45 mins in dogs.
Tetracaine.
- onset ~1min.
- duration ~45mins.
- more topical irritation possibly better effect in horses.
Lignocaine.
- rapid onset of action.
- duration 45-60mins.
Bupivacaine.
- lasts 5-10hrs.
- 4x more potent.

Useful to exam eye that is painful.
Can apply sequential drops to improve penetration but one drop generally enough (proxy).

Question 32

mydriatics.

Answer 32

Atropine.
- Slower onset (~40 mins).
- 1-14d duration.
- Therapeutic use.
– cases of spasm e.g. reflex uveitis, or other uveitis.
- Marked paralysis.
- Contraindicated in glaucoma and KCS cases.
- Dries up secretions.
- Bitter taste.
Tropicamide.
- Rapid onset (~10-20mins).
- 6-8hrs duration.
- Diagnostic use.
- Moderate relaxation of iris.
- Contraindication: reduces tears in cats.

Both typically come in minims.

Question 33

Tear replacement and stimulation.

Answer 33

Replacements:
- Aqueous – Hypromellose / Tears naturale.
- Mucinomimetics – Carbomer gel –> Lubrithal/Viscotears.
- Viscoelastics – Hyaluronic acid –> available in different concetrations –> Clinitas/Remend.
- Lipid based substitutes – Lacrilube / Hylonight.
Cyclosporine:
- Blocks activation of T cells vs. immune-mediated KCS.
- 0.2% ointment – Optimmune (prescription only).
- Tear stimulant/pigment reducing.

Question 34

1. What do anti-collagenases treat?
   - How does this condition develop?
   - What does this condition look like?

Answer 34

1. keratomalacia.
   - Corneal ulcer > corneal epithelial cells, bacteria or host WBCs can release collagenase enzymes in excess which “melt” collagen of cornea. Can digest through the eye in less than 24hrs, can lead to rupture.
   - Gelatinous, not solid, sometimes leaking from the eye and down the face.

Question 35

1. Different anti-collagenases.
2. Application frequency.

Answer 35

1. Serum and plasma drops.
   - Take blood and spin it down.
   EDTA drops - chelates zinc which is a cofactor in collagenases.
   Tetracyclines - orally or topically.
   Acetylcysteine - Stromese drops.
2. q1-2hrs - where the condition is active.

Question 36

Medications - owner factors.

Answer 36

Topical application can be difficult.
Tabletting can be difficult.
Time commitments with regular applications and drops.
Off license issues.
Written prescriptions - affordability.
Client support leaflets.