Prof. Hanan Hagar

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Pharmacology of drugs acting on the eye

• Prof. Hanan Hagar
• Pharmacology Unit
• Physiology Department
• College of Medicine
• King Saud University

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Routes of drug administration into the eye

• Drugs can be delivered to ocular tissue as
• Locally (Topically) more common
• Eye drop
• Ointment
• Injection
• Periocular injection
• e.g. subconjunctival, peribulbar, or
  retrobulbar
• Intraocular injection
• e.g. Intracameral or intravitreal
• Systemically
• Orally
• IV

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Eye drops
Ointment

• Eye drops- most common
• one drop 50 µl
• volume of conjunctival cul-de-sac 7-10 µl

• Increase the contact time of ocular medication to
  ocular surface thus better effect
• Disadvantages
• The drug has to be high lipid soluble with some
  water solubility to have the maximum effect as
  ointment

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Intraocular injections
Peri-ocular injections

• Intracameral or intravitreal
• E.g.
• Intracameral acetylcholine (miochol) during
  cataract surgery
• Intravitreal antibiotics in cases of
  endophthalmitis
• Intravitreal steroid in macular edema

• subconjunctival, peribulbar, or retrobulbar
• reach behind iris-lens diaphragm better than
  topical application
• bypass the conjunctival and corneal epithelium
  which is good for drugs with low lipid solubility
  (e.g. penicillins)
• steroid and local anesthetics can be applied this
  way

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Systemic drugs

• Oral or IV
• Factor influencing systemic drug penetration into
  ocular tissue
• lipid solubility of the drug more penetration
  with high lipid solubility
• Protein binding more effect with low protein
  binding
• Eye inflammation more penetration with ocular
  inflammation

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Physiological Anatomy of the Eye
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Pharmacology of drugs acting on the eye

• Drugs used for the treatment of eye
• Drugs that can produce harmful effects on the eye

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Ophthalamic Uses of Drugs

• Autonomic drugs
• Affect the size of the pupil
• Miotics
• Mydriatics
• Affect accommodation (Cycloplegics).
• Anti-inflammatory drugs
• Glucocorticoids
• NSAIDs
• Chemotherapeutics (antibacterial, antifungal and
  antiviral agents).
• Local Anesthetic drugs

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Drugs used for treatment of the eye
Autonomic drugs
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Autonomic Nerve supply of the Eye

• Parasympathetic N.S.
• Constriction of the pupillary sphincter muscle
  (miosis)
• Contraction of the ciliary muscle (accommodation
  for near vision).
• Decrease in intraocular pressure ? IOP.
• increases aqueous outflow through the trabecular
  meshwork into canal of Schlemm by ciliary muscle
  contraction
• Increased lacrimation
• Conjunctival Vasodilatation

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The aqueous humor is secreted by the ciliary
body. Produced by a combination of active
transport of ions and ultrafiltration of
interstitial fluid. The fluid flows over the
surface of the lens, out through the pupil into
the anterior chamber. Flows through the
trabecular meshwork into Schlemms canal and is
collected in the scleral veins.
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Autonomic control of pupil (A) and site of
action of mydriatics (B) and miotics (C)
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Accomodation
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• Sympathetic N.S.
• Contraction of dilator Pupillae ( Mydriasis) a1
• Relaxation of ciliary muscles (accommodation for
  far vision) ß receptors
• Increase in intraocular pressure
• Lacrimation a1
• Vasoconstriction of conjunctival blood vessels
  a1
• ß receptors in the blood vessels of the ciliary
  processes ?production of aqueous humour.
• ß antagonists reduces the production of aqueous
  humor
• a agonists increase outflow of aqueous humor and
  ? IOP

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Sympathetic N.S. Parasympathetic N.S. Eye
Contraction (Mydriasis) a1 No effect No effect Contraction (miosis) M3 Iris radial muscle circular muscle
Relaxation ß2 Contraction M3 Ciliary muscle
accommodation for far vision for near vision Accommodation
Conjunctival Vasoconstriction Conjunctival Vasodilatation Conjunctival blood vessels
Narrow filtration angle Decrease Intraocular pressure(IOP)
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Pupillary Muscles
Miosis
Mydriasis
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Drugs acting on parasympathetic system

• Cholinergic agonists
• Direct agonists
• Methacholine, carbachol, pilocarpine
• Indirect acting agonists (anticholinesterases)
• Reversible Physostigmine
• Irreversible Ecothiophate
• USES
• -Glaucoma (open angle glaucoma)
• -Counteract action of mydriatics
• To break adhesions
• in accommodative esotropia (ecothiophate)

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•  Adverse Effects of cholinergic agonists
• Miosis
• Salivation
• Sweating
• bronchial constriction
• vomiting and diarrhea
• CNS effects high doses (physostigmine
  pilocarpine)
• Ocular side effects diminished vision (myopia),
  headache,
• Contraindications of cholinergic agonists
• Bronchial asthma.
• Peptic ulcer.
• Angina pectoris
• Incontinence
• Intestinal obstruction

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Cholinergic drugs
Ocular uses Drugs
Induction of miosis in surgery Glaucoma Acetycholine Carbachol Methacholine
In open angle glaucoma Pilocarpine
Glaucoma, accommodative esotropia Physostigmine
Glaucoma, accommodative esotropia Ecothiophate
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Cholinergic antagonists (Muscarininc antagonists)

• Passive mydriasis
• due to relaxation of circular muscles
• Cycloplegia (loss of near accommodation) due to
  relaxation of ciliary muscles
• Loss of light reflex.
• increased I.O.P glaucoma.
• ? Lacrimal secretion ? sandy eye

Duration of effect Drugs
7-10 days 3-7 days Natural alkaloids Atropine Scopolamine (hyoscine)
1-3 days 24 hour 6 hour Synthetic atropine substitutes Homatropine Cyclopentolate Tropicamide
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• USES
• To prevent adhesion in uveitis iritis
• Funduscopic examination of the eye
• Measurement of refractive error
• Side effects blurred vision, tachycardia,
  constipation,
• urinary retention, dryness of mouth , dry sandy
  eyes, fever
• CNS effects sedation, hallucination, excitation
  (toxic dose).
• Contraindications of antimuscarinic drugs
• Glaucoma (angle closure glaucoma)
• Tachycardia, Prostate hypertrophy in old
  patients.
• Constipation, paralytic ileus.

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Drugs acting on sympathetic system

• Adrenergic agonists
• Non-selective agonists (a1, a2, ß1, ß2), eye
  drops
• e.g. epinephrine, depevefrin (pro-drug of
  epinephrine)
• Uses open angle glaucoma
• Mechanism ? uveoscleral outflow of aqueous humor
• Side Effects cardiovascular arrhythmia,
  tachycardia
• C/I in closed angle glaucoma in patients with
  narrow angles
• a1 agonists e.g. phenylepherine
• mydriasis (without cycloplegia), decongestant
• Uses
• Funduscopic examination of the eye
• To prevent adhesion in uveitis iritis
• Decongestant in minor allergic hyperemia of eye
• C/I in closed angle glaucoma in patients with
  narrow angles
• Can cause significant increase in blood pressure

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• a2 agonists
• e.g. apraclonidine (eye drops)
• Uses glaucoma treatment, prophylaxis against IOP
  spiking after
• glaucoma laser procedures
• Mechanism ? production of aqueous humor
• Side Effects Lethargy, fatigue, dry mouth
• apraclonidine is a derivative of clonidine
  (antihypertensive)
• which cannot cross BBB to cause systemic
  hypotension.

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• ß blockers
• non-selective timolol, carteolol
• selective betaxolol (beta 1 cardioselective)
• Given topically as eye drops
• Uses open angle glaucoma
• Mechanism Act on ciliary body to ? production of
  aqueous humor
• Advantages can be used in patients with
  hypertension/ischemic heart disease
• Contraindications
• Bronchospasm (less with betaxolol)
• Cardiovascular (bradycardia, hypotension,
  asystole, syncope)
• Depression
• C/I in asthmatic patients or patients with
  pacemaker.

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Treatment of open angle glaucoma (chronic)

• The main goal is to decrease IOP and this can be
  obtained by
• Decreasing production of aqueous humor
• Beta blockers
• Alpha-2 agonists
• Carbonic anhydrase inhibitors
• Increasing outflow of aqueous humor
• Prostaglandins
• Adrenergic agonists, nonspecific
• Parasympathomimetics
• Prostaglandins and Beta blockers are the most
  popular drugs.

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• Carbonic anhydrase inhibitors
• e.g. acetazolamide (oral), dorzolamide (topical)
• Mechanism ? production of aqueous humor by
  blocks carbonic anhydrase enzyme required for
  production of bicarbonate ions (transported to
  posterior chamber, carrying osmotic water flow).
• Side Effects
• myopia, malaise, anorexia, GI upset, headache
• metabolic acidosis, renal stone
• bone marrow suppression aplastic anemia
• Contraindication
• sulpha allergy

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Prostaglandins

• Latanoprost, travoprost
• Are prostaglandins F2a analogs
• Mechanism
• uveoscleral outflow by relaxing ciliary body
  muscle
• Uses open angle glaucoma
• Administration Topical drops
• Side Effects Iris color change

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Drug Therapy of acute angle closed
glaucoma(narrow angle)

• Is associated with occlusion of the outflow
  drainage pathway
• Acute, painful increases of pressure
• emergency situation that require treatment
  before surgery (Iridectomy)
• The use of drugs is limited to
• Oral Acetazolamide
• Topical cholinomimetics e.g. pilocarpine
• Dehydrating agents IV infusion Of hypertonic
  solution ( Mannitol, Glycerol)
• Analgesics pethidine or morphine (for pain)

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Osmotic agents

• Dehydrate vitreous body which reduce IOP
  significantly
• E.G.
• glycerol 50 syrup (cause nausea, hyperglycemia)
• Mannitol 20 IV (cause fluid overload and not
  used in heart failure)

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Corticosteroids

• Mechanism inhibition of arachidonic acid release
  from phospholipids by inhibiting phosphlipase A2
• Topical
• E.g. prednisolone, dexamethasone, hydrocortisone
• Uses postoperatively, anterior uveitis, severe
  allergic conjunctivitis, scleritis, prevention
  and suppression of corneal graft rejection
• Systemic
• E.g. prednisolone, cortisone
• Uses posterior uveitis, optic neuritis

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Corticosteroids

• Side effects
• Glaucoma, cataract, mydriasis
• Suppression of pituitary-adrenal axis
• Hyperglycemia, Osteoporosis
• Peptic ulcer, Psychosis, susceptibility to
  infections

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NSAID

• E.g. ketorolac, diclofenac
• Mechanism inhibition of cyclo-oxygenase
• Uses postoperatively, mild allergic
  conjunctivitis, episcleritis, mild uveitis,
  cystoid macular edema, preoperatively to prevent
  miosis during surgery
• Side effects stinging

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Harmful drugs for the Eye

• Drugs that ? IOP
• Mydriatic cycloplegics, tricyclic
  antidepressants
• Chronic steroid use
• Cataractogenic drugs
• steroids, phenothiazines, heavy metals

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• Drugs causing corneal deposits
• chloroquine, amiodarone,
• Amiodarone , a cardiac arrhythmia drug
• causes optic neuropathy (mild decreased vision,
  visual field defects)
• causes corneal keratopathy which is pigmented
  deposits in the corneal epithelium.
• Digitalis , cardiac failure drug
• Causes chromatopsia (objects appear yellow) with
  overdose

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Other agents

• methanol optic atrophy and blindness
• Ethambutol optic neuropathy
• Hypervitaminosis A yellow skin and conjunctiva,
  retinal hemorrhage.
• Hypovitaminosis A night blindness (nyctalopia).