Transcript L1-pharmacology of t..

Pharmacology of drugs
acting on the eye
Prof. Hanan Hagar
Pharmacology Unit
Physiology Department
College of Medicine
King Saud University
Routes of drug administration into the eye
• Drugs can be delivered to ocular tissue as:
– Locally (Topically): more common
1) Eye drop
2) Ointment
3) Injection :
–Periocular injection
e.g. subconjunctival, peribulbar, or retrobulbar
–Intraocular injection
e.g. Intracameral or intravitreal
– Systemically:
• Orally
• IV
Eye drops
• Eye drops- most common
• one drop = 50 µl
• volume of conjunctival
cul-de-sac 7-10 µl
Ointment
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
Intraocular injections
• Intracameral or intravitreal
• E.g.
– Intracameral acetylcholine
(miochol) during cataract
surgery
– Intravitreal antibiotics in
cases of endophthalmitis
– Intravitreal steroid in
macular edema
Peri-ocular injections
• 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
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
Physiological Anatomy of the Eye
Pharmacology of drugs
acting on the eye
• Drugs used for the treatment of eye
• Drugs that can produce harmful effects on the
eye
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
Drugs used for treatment of the eye
Autonomic
drugs
Anti-inflammatory
drugs
Chemotherapeutic
agents
Local anesthetics
Miotics
Mydriatics
Cycloplegics
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
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 Schlemm’s canal and is collected in the scleral veins.
Autonomic
control
of pupil (A)
and site
of action of
mydriatics (B)
and
miotics (C)
Accomodation
Sympathetic N.S.
 Contraction of dilator Pupillae ( Mydriasis) α1
 Relaxation of ciliary muscles (accommodation for far
vision) β receptors
 Increase in intraocular pressure
 Lacrimation α1
 Vasoconstriction of conjunctival blood vessels α1
 β receptors in the blood vessels of the ciliary processes
→production of aqueous humour.
 β antagonists reduces the production of aqueous humor
 α agonists increase outflow of aqueous humor and ↓ IOP
Eye
Parasympathetic N.S.
Sympathetic N.S.
No effect
Contraction (miosis)
M3
Contraction M3
Contraction (Mydriasis) α1
No effect
Accommodation
for near vision
Conjunctival
blood vessels
Conjunctival
Vasodilatation
accommodation for far
vision
Conjunctival
Vasoconstriction
Intraocular
pressure(IOP)
Decrease
Narrow filtration angle
Iris
radial muscle
circular muscle
Ciliary muscle
Relaxation β2
Pupillary Muscles
Miosis
Mydriasis
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)
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
Cholinergic drugs
Drugs
Ocular uses
Acetycholine
Carbachol
Methacholine
Pilocarpine
Induction of miosis in surgery
Glaucoma
In open angle glaucoma
Physostigmine
Glaucoma, accommodative esotropia
Ecothiophate
Glaucoma, accommodative esotropia
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
Drugs
Natural alkaloids
 Atropine
 Scopolamine (hyoscine)
Synthetic atropine substitutes
 Homatropine
 Cyclopentolate
 Tropicamide
Duration of
effect
7-10 days
3-7 days
1-3 days
24 hour
6 hour
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.
Drugs acting on sympathetic system
Adrenergic agonists
Non-selective agonists (α1, α2, β1, β2), 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
α1 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
α2 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.
β 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.
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.
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
Prostaglandins
Latanoprost, travoprost
Are prostaglandins F2α analogs
Mechanism:
uveoscleral outflow by relaxing ciliary body muscle
Uses: open angle glaucoma
Administration: Topical drops
Side Effects: Iris color change
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)
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)
Anti-inflammatory
corticosteroid
NSAID
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
Corticosteroids
Side effects:
– Glaucoma, cataract, mydriasis
– Suppression of pituitary-adrenal axis
– Hyperglycemia, Osteoporosis
– Peptic ulcer, Psychosis, susceptibility to infections
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
Harmful drugs for the Eye
Drugs that ↑ IOP:
 Mydriatic cycloplegics, tricyclic antidepressants
 Chronic steroid use
Cataractogenic drugs:
steroids, phenothiazines, heavy metals…
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
Other agents
• methanol – optic atrophy and blindness
• Ethambutol – optic neuropathy
• Hypervitaminosis A – yellow skin and conjunctiva,
retinal hemorrhage.
• Hypovitaminosis A – night blindness (nyctalopia).