t7c: Miotics and Prostaglandins

Overview of Aqueous Outflow Medications

  • Two main classes: Miotics and Prostaglandins - INCREASE AQUEOUS OUTFLOW

  • Key learning outcomes:

    • Understand the pharmacology, uses, and side effects of each class

    • Compare effectiveness of different agents

    • Select appropriate agent for intended use

Miotics

Pilocarpine

  • Pilocarpine hydrochloride 1%, 2%, 4%

    • Brand names: ISOPTO CARPINE, PILOCARPINE, PILOT, PV CARPINE

    • Packaging: 15 ml, containing benzalkonium chloride as a preservative. 5 repeats costs px up to $25 per bottle.

    • Dosage: One drop 4 times daily; effects last 4-8 hours

  • Minims (Single-dose): Pilocarpine nitrate 2%, 4%

Mode of Action

  • Directly acting parasympathomimetics (cholinergic agonists)

    • Bind to acetylcholine receptors on the iris sphincter and ciliary muscle

    • Mimic acetylcholine effects, causing:

    • Contraction of longitudinal muscle fibres in the ciliary muscle

    • Opening of the Trabecular Meshwork

    • Increased aqueous outflow

Clinical Uses

  • Acute Angle Closure Glaucoma: emergency treatment

    • Administer 2% pilocarpine every 5 minutes until miosis achieved

    • Contraindications for concentrations >2% due to risks

      • No more effective than 2% and can cause further shallowing of the anterior chamber intensifying the pupil block and leading to permanent PAS and permanent angle closure

    • If IOP >50-55mmHg pilocarpine ineffective due to ischaemia of the iris sphincter

  • Open-Angle Glaucoma:

    • Reduces IOP by contracting ciliary muscle which exerts a force on the scleral spur and stretches the trabeculae

    • Reduces IOP by %20-25 by reducing resistance to outflow

    • Works by contracting ciliary muscle

    • Effects generally last 6 hours; other agents are preferred for long-term use

    • Should only use 1% in fair skinned individuals and 2% in dark skinned individuals - gets pigment bound

IOP Effects

  • Reduces IOP significantly (e.g., from 26 to 17 mmHg)

  • Decreases maximum diurnal variation from 18.5 to 8.5 mmHg

Side Effects

  • Ocular:

    • Accommodative spasm causing brow ache, pseudomyopia (myopic shift)

    • miosis, dim vision for night driving

    • pupil block glaucoma

    • Conjunctival injection, allergic blepharoconjunctivitis

    • Rarely cataract and retinal detachment

  • Systemic:

    • Bronchoconstriction (respiratory distress in asthmatic patients)

    • gastrointestinal upset (nausea, vomiting, diarrhea)

    • increased salivation

    • CNS effects

Contraindications

  • Ocular: PSCC, neovascular and uveitic glaucoma, history of retinal detachment

  • Systemic: age under 40, pregnancy, asthma, peptic ulcers, Parkinson’s disease

Prostaglandin Analogues/Prostamides

Commercial Preparations

  • Latanoprost 0.005% (e.g., XALATAN)

  • Travoprost 0.004% (e.g., TRAVATAN)

  • Bimatoprost 0.03% (e.g., LUMIGAN) - only amide based (all other are esters)

  • Tafluprost 0.0015% (e.g., SAFLUTAN)

  • Dosage: Typically administered once daily, more effective at PM than AM

  • Common effect: increases uveoscleral outflow; peak IOP reduction lasts 8-12 hours

  • peak effect: one month

  • packaging: Xalatan and Saflutan require refrigeration Lumigan and Travatan at room temperature

Pharmacology of prostaglandins

  • Prostaglandins are naturally occurring compounds in the body.

  • They are synthesised following injury and play a role in the inflammatory response.

  • In 1981, it was observed that administering PG F2α to monkeys resulted in decreased intraocular pressure (IOP).

  • Natural PG F2α in the body also causes pain, headaches, and conjunctival hyperaemia.

  • Modifications have been made to create prodrugs with improved effect profiles.

  • These prodrugs have good corneal penetration and are fully hydrolysed to active acid forms as they pass through the cornea, making metabolism easier.

  • Latanoprost and travoprost act on PG FP receptors located on ciliary muscle cells.

  • The exact mechanism of their impact on uveoscleral outflow is unknown but is believed to involve transient changes in the extracellular matrix of the ciliary muscle.

  • Prostaglandins (PGs) are produced by cells within the outflow pathway of the human eye eg trabecular meshwork cells

  • PGs have a role in the normal regulation of aqueous outflow.

  • Minute amounts of topical exogenous PGs can reduce intraocular pressure (IOP) without causing inflammation.

Pathway / mechanism of action

  • The prostaglandin F2 (PGF2) analogues (eg latanoprost) act through FP and cause a COX2-dependent increase in prostaglandin E2 (PGE2) and matrix metalloproteinases (MMPs) levels which in turn cause tissue remodelling.

  • Prostaglandins activate a molecular transduction cascade that leads to increased biosynthesis of matrix metalloproteinases.

  • These proteinases cleave extracellular-matrix (ECM) components, such as collagen, within the ciliary muscle and sclera

  • The resulting reduction of the extracellular matrix may contribute to the mechanism of increased uveoscleral outflow

Mechanism of Action (summary)

  • Bind to FP receptors on ciliary muscle cells

  • Increase biosynthesis of matrix metalloproteinases (MMPs)

  • Cause extracellular matrix remodelling, enhancing aqueous outflow

Latanoprost (Xalatan)

  • selective prostanoid FP-receptor agonist that reduces intraocular pressure (IOP) by increasing the outflow of aqueous.

  • Onset of Action: Reduction of IOP starts within 3 to 4 hours after administration with peak concentration in the aqueous humor occurring in about 2 hours.

  • Maximum Effect: Maximum reduction in IOP is reached after 8 to 12 hours and is maintained for at least 24 hours.

  • Mechanism of Action: The main mechanism involves increased uveoscleral outflow, with some reports of increased outflow facility (decreased outflow resistance).

  • Aqueous Production: Latanoprost does not significantly affect aqueous production or the blood-aqueous barrier.

  • Systemic Effects: At clinical doses, it has not shown significant pharmacological effects on the cardiovascular or respiratory systems.

  • Repeats: latanoprost 0.005% eye drops, 2.5 ml x 5 (cost $22.58)

  • Contraindications: use in pregnant women is limited due to high incidence of abortion shown in animal experiments.

Travoprost (e.g. Travatan)

  • Bimatoprost is an ester prodrug of a prostaglandin F2alpha analogue.

  • It is hydrolyzed to the free acid as a full agonist of the prostaglandin FP receptor.

  • Reduces intraocular pressure (IOP) by increasing outflow via uveoscleral pathways and trabecular meshwork.

  • Onset of Action: IOP reduction starts about 2 hours after administration.

  • Maximum Effect: Maximum effect is reached after 12 hours.

  • Duration of Action: Significant lowering of IOP can be maintained for periods exceeding 24 hours with a single dose.

  • repeats: travoprost 0.004% eye drops, 2.5 mL x 5 (cost $39.50)

Bimatoprost (e.g. Lumigan)

  • Bimatoprost is a synthetic prostamide analogue that selectively mimics the effects of naturally occurring prostamide.

  • It is biosynthesized through a COX-2 pathway, leading to the synthesis of endogenous lipid amides that lower intraocular pressure (IOP). Bimatoprost reduces IOP by enhancing uveoscleral outflow and increasing aqueous humor outflow through the trabecular meshwork.

  • Onset of Action: Reduction of IOP starts approximately 4 hours after the first administration.

  • Maximum Effect: Maximum effect is typically reached within 8 to 12 hours.

  • Duration of Action: The reduction in IOP is maintained for at least 24 hours.

  • repeats: bimatoprost 0.03% eye drops, 3 mL x 5 (cost $39.50)

  • Minims: bimatoprost 0.03% eye drops, 30 x 0.4 mL unit doses

Tafluprost (Saflutan)

  • 12 x greater prostaglandin receptor-binding affinity than latanoprost

  • no real evidence that it is superior to the older agents

  • advantage: comes in preservative free form

  • Minims: 15 μg per mL (0.0015%), single dose units, 30 × 0.3mL unit doeses x 5 repeats (cost $39.50)

Clinical Use and Effectiveness

  • Average IOP reduction:

    • Latanoprost: 27%

    • Travoprost: 31%

    • Bimatoprost: 33%

  • Not effective for about 10-15% of patients

    • Travatan ~9%

    • Xalatan ~14%

    • Timolol ~23%

    • other prostaglandins may still be effective.

  • Patients with IOP in high teens may respond with IOP reduction up to 30%

  • In NTG, IOP reduction by ~20% with latanopros

  • Only glaucoma medication class with no cross over effect in non-treated eye

    • if you treat one eye, there is no effect in IOP in the other.

Prostaglandins: Comparison to Timolol

  • Early studies compared Prostaglandins to Timolol (the then gold-standard)

    • Xalatanbetter than Timolol bd when directly compared (35% vs. 27%)

    • 69% on Xalatan vs. 34% using Timolol had IOP <18 mmHg

    • Lumigantwice more likely to achieve an IOP <15mmg than Timolol

    • Effective in CNAG (chronic narrow angle glaucoma):

    • Better IOP control than Timolol (8.8mmHg vs. 5.7mmHg reduction)

Side Effects

  • Ocular:

    • Conjunctival hyperemia

    • iris pigmentation/heterochromia

      • More pronounced in blue, green, hazel eyes: irreversible increase in the size of the iris melanocytes

    • Hypertrichosis – longer, thicker, darker, more curled, distichiasis

    • Epithelial erosion, hypertrichosis, periorbital pigmentation, cystoid macular edema

    • stinging, burning

    • foreign body sensation

  • Systemic:

    • Rare headaches, respiratory symptoms, skin rash, diarrhea

Contraindications

  • Local: history of uveitis, cystoid macular oedema, herpes simplex keratitis, complicated cataract surgery

  • inflammatory glaucoma

  • no systemic contraindications

interactions:

  • topical NSAIDs have antagonistic effect

  • If used concurrently the effectiveness of prostaglandins is decreased by up to 30%

Summary of Comparisons

  • Travoprost is most effective for lowering IOP in African Americans

  • Lumigan has the greatest initial redness followed by Travatan

  • Xalatan has greatest periorbital pigmentation and greatest iris pigmentation at 6 months

    • Xalatan ~ 6.7% and ~16.1% at 12/12

    • Travatan ~ 3.1%

    • Lumigan~ 1.2% and ~1.5% at 12/12