PHARMACOLOGY Ocular Pharmacotherapeutics

AY 2020-2021 JHANSSEN FAUST CASTILLO, M.D.

Special Senses Module 11/06/2020

TOPIC OUTLINE II. PERIPHERAL NERVOUS SYSTEM
I. Nervous System

II. Peripheral Nervous System
a. Autonomic a. Autonomic Nervous System
b. Somatic • Largely independent in the activities that are not under
III. Adrenergic Agents direct conscious control
IV. Adrenergic Receptors • Acts on smooth muscles and glands
V. Adrenergic Drugs • Controls and regulates the heart, respiratory system, GI
VI. Adrenergic Agonist tract, bladder, eyes, and glands
VII. Adrenergic Antagonist • Involuntary - person has little or no control
VIII. Cholinergic • Has 2 sets of neurons: Afferent and efferent
IX. Cholinergic Agonist o Afferent (sensory)
X. Cholinergic Antagonist § sends impulses to the CNS for
XI. Carbonic Anhydrase Inhibition interpretation
XII. Prostaglandin Analogues o Efferent
XIII. Anti-Cholinergic § receives impulses or information
XIV. Anti-inflammatory agents from the brain and transmits from the
XV. Antibiotics spinal cord to the effector organ cells
XVI. Antifungals § has 2 branches: sympathetic and
XVII. Antiviral agents parasympathetic nervous system
XVIII. Anti-parasitic § adrenergic also known as
sympathetic
LEARNING OBJECTIVES § cholinergic also known as
1. Gain a grasp of the different medications used in parasympathetic
the treatment of most common eyes diseases
2. Understand its mechanism of action and systemic
side effects

LEGEND
PPT Clinical Guide Lecturer
Book
Correlation/SGDs Questions
• v

How do topical medications work?

• Topical medications in optha are in the form of eyedrops
Transcorneal absorption

Accumulation in aqueous
humor

Distribution to intraocular
structures SYMPHATETIC NERVOUS SYSTEM (ADRENERGIC)
• main neurotransmitter is norepinephrine
• drugs that mimic sympathetic response
Trabecular meshwork o adrenergic drugs, sympathomimetics, or
adrenomemetics
Distribution to systemic • drugs that block sympathetic response
circulation o adrenergic blockers, sympatholytic, or
adrenolytic
• Adrenergic agonists - drugs that initiate a response
I. NERVOUS SYSTEM • Adrenergic antagonist - prevent a response
• Anatomically divided into CNS and PNS
• Central Nervous System (CNS) PARASYMPHATETIC NERVOUS SYSTEM (CHOLINERGIC)
o brain and spinal cord • main neurotransmitter is acetylcholine
• Peripheral Nervous System (PNS) • drugs that mimic parasympathetic response
o located outside the brain and spinal cord o cholinergic drugs, or parasympathomimetic
o PNS receive stimuli from the CNS and initiates • drugs that block parasympathetic response
response to the stimuli after it's interpreted by o anticholinergic, or parasympatholytic
the brain • Cholinergic agonists - drugs that initiate a response
o Functionally divided into Autonomic and • Cholinergic antagonist - prevent a response
Somatic
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b. Somatic Nervous System ADRENORECEPTORS

• concerned with consciously controlled functions such as
movement, respiration, and posture a1 a2 b1 b2
• Voluntary – person has control (innervates the skeletal
inhibition of NE
muscle) vasoconstriction
release
Tachycardia vasodilation

­peripheral
III. ADRENERGIC AGENTS resistance
inhibition of NE ­lipolysis slightly ¯peripheral
resistance
• Receptors: Adrenergic receptors ­myocardial
­BP
• Neurotransmitter: contractility
bronchodilation
o epinephrine (adrenaline)
Mydriasis
o norepinephrine (NE) ­muscle and liver
glycogenolysis
• All adrenergic receptors are G protein coupled ­closure of internal
receptors; however, different subtypes are connected to sphincter of the ­release of
bladder glucagon
different signaling system
• The transmitter of most sympathetic postganglionic relaxed uterine
smooth muscle
fibers is norepinephrine
• Four categories of adrenergic receptors: a1, a2, b1, b2
• May be:
o Direct-acting agonists V. ADRENERGIC DRUGS
o Indirect-acting agonists • Drugs that mimic the action of epinephrine and
o Antagonist norepinephrine
• Note: effects of catecholamines are mediated by cell
IV. ADRENERGIC RECEPTORS surface receptors – these receptors are coupled by G
Four types of adrenergic receptor organ cells: proteins
1. Alpha-1: vasoconstriction of blood vessels including • G proteins of particular importance for adrenoceptor
blood return to heart, ­ circulation, ­BP function:
2. Alpha-2: Inhibits release of norepinephrine, ¯ o GS – stimulatory G protein of adenylyl cyclase
vasoconstriction, ¯BP o Gi – inhibitory G protein of adenylyl cyclase
3. Beta-1: increase in heart rate and force on contraction o Gq – the protein in coupling a receptors to
4. Beta-2: relaxation of smooth muscle in bronchi, uterus, phospholipase C
peripheral blood vessels
**Beta-1: heart; Beta-2: mostly in lungs

• Dopaminergic
o dilates vessels, ­ blood flow
o only dopamine activates this receptor

VI. ADRENERGIC AGONIST

a. Direct-acting adrenergic agonist
• directly stimulates receptors (epinephrine or
norepinephrine)

• Direct-acting a1 adrenergic agonist
a) Phenylephrine
**an eye drop used in the clinic for dilated
examination of the eye to see the retina
o Primary clinical use: Mydriasis, stimulation of
iris dilator muscle
o Systemic absorption can lead to ­BP

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• Direct-acting a2 adrenergic agonist a. Alpha-adrenergic antagonist

a) Apraclonidine aka ALPHA BLOCKERS
**antihypertensive drugs not being used widely
§ Clonidine derivative a) Thymoxamine
§ Prevents release of NE at nerve o a1 adrenergic tone to-dilator muscle of iris –
terminals Miosis
§ ¯aqueous production, ¯episcleral o no effect on ciliary muscle contraction
venous pressure o no significant change in anterior chamber
§ Improves trabecular outflow depth, facility of outflow, IOP, or
accommodation
b) Brimonidine tartrate
**for lowering intraocular pressure, anti-glaucoma b) Dapiprazole hydrochloride (Rev-Eyes)
§ ¯aqueous production, ­uveoscleral o a-adrenergic blocking agent-dilator muscle of
outflow iris – Miosis
o no effect on ciliary muscle contraction
• Direct-acting b2 adrenergic agonist o no significant change in anterior chamber
o L-epinephrine – an a and b agonists depth, facility of outflow, IOP, or
o Lower IOP by: ­uveoscleral outflow, ­outflow accommodation
through trabecular meshwork
o ­cAMP in the ciliary epithelium and in the b. Beta-adrenergic antagonist
aqueous humor aka BETA BLOCKERS
• MOA: ¯ IOP by reducing aqueous humor production as
b. Indirect-acting adrenergic agonist much as 50%
• stimulates release of NE from terminal nerve endings • Site of Action: Ciliary Body
(amphetamine) • 6 agents are approved for tx of Glaucoma
o Timolol maleate*
a) 4% Cocaine eyedrops o Timolol hemihydrate
§ Cocaine blocks reuptake of NE into the o Metipranolol
presynaptic vesicles= Mydriasis o Carteolol
§ The injured side will have less o Levobunolol
accumulation and show less dilation o Betaxolol*

b) 1% hydroxy amphetamine (Paredrine Test) a) Timolol maleate and levobunolol
§ Differentiates preganglionic lesion vs o Mixed b1 and b2 antagonists
postganglionic o Tests of more specific beta blockers suggest
**these agents are used to test for and localize defects in that b2 antagonists have a greater effect on
sympathetic innervation to the iris dilator muscle aqueous secretion than b1 antagonists

c. Mixed-acting (indirect and direct) b) Betaxolol
• stimulates receptor sites and release of NE from nerve o Selective b1 antagonist
endings (ephedrine) o Safer than non-selective beta blockers:
pulmonary, cardiac, CNS and systemic
conditions
VII. ADRENERGIC ANTAGONIST
o Useful in: Patients with hx of bronchospastic
disorders
**B agonist and B antagonist: It is curious that both B agonist and B
antagonist drugs can lower IOP. This paradox is compounded by the
observation that B agonist and B antagonist drugs have slightly
additive effects in lowering IOP.

VIII. CHOLINERGICS
• Simulates the parasympathetic nervous system
• Mimic the neurotransmitter acetylcholine
• 2 types of cholinergic receptors:
1. Muscarinic – stimulates smooth muscle and
slows heart rate
2. Nicotinic – affects skeletal muscle
• Many – nonselective and affect both receptors
• Some affect only the muscarinic receptors and not the

nicotinic receptors.

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IX. CHOLINERGIC AGONIST b. Indirect-acting cholinergic agonist

• Major uses: stimulate bladder and GI tone, constrict pupils • Inhibits the action of the enzyme choline esterase
(miosis), neuromuscular transmission (acetylcholine esterase – AChE)
• Primary effect of these drugs is at the active site of AChE –
enhances the effect of acetylcholine since its metabolism is
inhibited

• Nicotinic Drug
a) Edrophonium
§ The only cholinesterase inhibitor used
by ophthalmologists
§ A competitive inhibitor of
acetylcholinesterase that binds to the
enzyme’s active site
§ Used in the diagnosis of Myasthenia
Acetylcholine gravis
• Myasthenia gravis
Bethanecol
o Neuromuscular autoimmune disease
Direct Acting
Carbachol
characterized by muscle weakness and marked
fatigability of skeletal muscles, ptosis and
Pilocarpine diplopia
o Antibodies are produced against the main
Physostigmine
Cholinergic
immunogenic region found on alpha-1 subunit of
Agonists Indirect Acting
(reversible)
Neostigmine nicotinic receptor-channel complex
o *a small dose of edrophonium will cause
Edrophonium
improvement in patients with MG
Indirect Acting
Isoflurophate
(irreversible)
Reactivation of
X. CHOLINERGIC ANTAGONIST
Acetylcholine Esterase
• Antimuscarinic agents
• Ganglionic blockers
a. Direct-acting cholinergic agonist • Neuromuscular blockers
• Act on the receptors to activate a tissue response Atropine
• Binds directly to and activates muscarinic or nicotinic Antimuscarinic Agents
receptors Scopolamine

• Can be divided into: (based on chemical structure)

Nicotine
o Choline esters Ganglionic Blockers
o Alkaloids Cholinergic
Trimethaphan
Antagonists
• Many have effects on both receptors, Acetylcholine is
typical Tubocurarine

• Few are highly selective for either muscarinic or nicotinic

Pancuronium
receptors Neuromuscular
Blockers
Gallamine
a) Acetylcholine (not used in ophtha)
o Does not penetrate the corneal epithelium well, Succinylcholine

and it is rapidly degraded by Muscarinic antagonist
acetylcholinesterase a) Atropine and Scopolamine – topically applied muscarinic
b) Carbachol (intracameral used) antagonists
a. Miostat and Miochol o React with post synaptic muscarinic receptors
i. when used, pupil will constrict o Block the action of acetylcholine
immediately o Result: paralysis of the iris sphincter and ciliary
ii. are available for intracameral use in muscles
anterior segment surgery o Pupillary dilation or mydriasis
iii. produce prompt and marked miosis o Treatment of iritis because it reduces contact
between the posterior iris surface and the anterior
which helps avoid iris capture by the
lens capsule, thereby preventing the formation of
optic of posterior chamber lenses and
iris-lens adhesions or posterior synechiae
may prevent iris incarceration in **iritis – condition in which iris are inflamed because of
surgical wounds trauma
c) Pilocarpine (eye drop) o Systemic absorption: dose-related toxicity especially
a. Used in the treatment of primary open-angle in children
glaucoma because they lower IOP by increasing § Flushing, fever, tachycardia,
outflow facility bronchoconstriction and even delirium
**atropine – muscle relaxant for the eye to rest the muscle

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XI. CARBONIC ANHYDRASE INHIBITION (CAI) • MOA:

• Systemic: Acetazolamide o The ocular anti-inflammatory action of
• Topical: Dorzolamide, Brinzolamide glucocorticoids is achieved by separate cell-
o decrease the formation of aqueous humor, an specific effects on lymphocytes, macrophages,
effect that will produce a reduction of polymorphonuclear leukocytes, vascular
intraocular pressure in the setting of glaucoma endothelial cells, fibroblasts, and other cells
• MOA: o Inhibition of the enzyme cyclooxygenase
o aqueous humor is secreted into the posterior
(COX)
chamber by the nonpigmented epithelium of
the ciliary process § required to convert arachidonic acid
o Secretion is dependent on Na, K, -ATPase on the into thromboxane, prostaglandins, and
surface of non-pigmented epithelial cells prostacyclin
o Inhibition of Na, K, -ATPase reduces secretion
of aqueous humor STEROID VS. NSAIDS
• Systemic effect: v Corticosteroids inhibits the conversion of Phospholipid
o decrease proximal tubular reabsorption of HCO, to Arachidonic Acid
in the kidneys by noncompetitive inhibition of
v NSAID Inhibits the conversion of Cyclooxygenase to
luminal and cellular carbonic anhydrase
prostaglandins
o Hypokalemia is caused by increased sodium
delivery to the distal nephron and its v Prostaglandins are the inflammatory component.
reabsorption there in exchange for potassium
**acetazolamide – given as a rescue drug to decrease intraocular
pressure immediately

XII. PROSTAGLANDIN ANALOGUES
• PG analogues: Latanoprost, also an anti-glaucoma drug
• Relatively new class of ocular hypotensive agents
• Lowers IOP by enhancing uveoscleral outflow
• Side effect:
o darkening of the iris and periocular skin as a
result of increased numbers of melanosomes
o Hypertrichosis of the eyelashes

XIII. ANTI-CHOLINERGICS • Effect: inhibition of arachidonic acid release from
phospholipids
• MOA: block the response of acetylcholine at the receptor o Liberated arachidonic acid is converted to PGs,
• Agents leukotrienes, and thromboxane, which are
o Atropine potent mediators of inflammation
o Cyclopentolate • Inhibits:
o Tropicamide, no side effect of increase HR o Bradykinin
• Not routinely used in glaucoma treatment o Nitric oxide
• Use: Inflammatory and Malignant Glaucoma o Antigen presenting cells & T-cell macrophages
o Histamine production
XIV. ANTI-INFLAMMATORY AGENTS o Eosinophil release
• Ocular inflammation can be treated with: • Topical Anti-inflammatory
o Glucocorticoids o Dexamethasone 0.1% (long acting)
o NSAIDs o Betamethasone (long acting)
o Antihistamines o Fluorometholone 0.1%
o Antibiotics o Prednisolone 1% (short acting)
• Side Effects
Glucocorticoids o Ocular
• used to treat viral conjunctivitis, iritis, and inflammation § Glaucoma
due to trauma § Cataract
§ Activation of infection
• Steroids are applied topically to prevent or suppress § Delayed wound healing
corneal graft rejection, anterior chamber reaction,
filtering bleb scarring, and immune or traumatic iritis and Mast-cell Stabilizers & Antihistamines
uveitis • Allergic conjunctivitis is an immediate hypersensitivity
• Route: reaction in which triggering antigens couple to reaginic
o Subconjunctival and retrobulbar injections for IgE on the cell surface of mast cells and basophils, leading
severe ocular inflammation to release of histamine
o Topical as eye drops (more common)

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• Histamine causes capillary dilation and increased Guide Questions:

permeability leading to conjunctival injection and 1. When administering eye medications on hypertensive patients, we
swelling don’t want the administered drug to reach the systemic circulation.
How can we achieve this?
• Generic names:
a. Eye injection c. Duct blockage
o Emedastine: H1-antagonist
b. Punctal occlusion d. Oral ingestion
o Ketorolac: NSAID 2. Which adrenergic receptor inhibits the release of norepinephrine
o Naphazoline/pheniramine: which results to a decrease in vasoconstriction?
Antihistamine/decongestant a. Alpha1 c. Beta1
**side effect: rebound redness b. Alpha2 d. Beta2
o Olopatadine: H1-antagonist/mast-cell inhibitor 3. This drug is an a1 adrenergic tone to the dilator of the muscle of the
iris and results in pupil constriction. What is the name of the drug?
a. Thymoxamine c. Levobunolol
XV. ANTIBIOTICS b. Dapiprazole hydrochloride d. Betaxolol
Anti-Bacterial MOA Drug Available
4. Which of the following statements are false?
Aminoglycosides* Protein Synthesis Gentamycin,
a. The ciliary muscle holds the lens via zonular fibers;
inhibitors Tobramycin, &
Amikacin b. Contraction of the ciliary muscle causes it to push the lens causing
Fluoroquinolones * DNA Gyrase Inhibitors Ciprofloxacin, it to bend thus allowing it to focus;
Gatifloxacin & c. Accommodated lens appear as flat and has a greater focusing
Moxifloxacin power;
Macrolides * Protein synthesis Azithromycin & d. Ciliary muscle relaxation results to pulling of lens thus flattening it.
inhibitors by inhibiting Erythromycin 5. How does B2-adrenergic agonist lowers the intraocular pressure?
the translocation on 50s
a. It increases the uveoscleral outflow;
ribosome.
Sulphonamides Anti-Folate Antibiotics Chloramphenicol, b. Increases outflow through the trabecular meshwork;
Sulphacetamide c. Lowers production of aqueous humor;
Cephalosporins Cell Wall Synthesis Cefazoline d. A and C;
Inhibitors e. A and B.
*Mostly used to treat Bacterial infection 6. Which of the following is the action of beta-blockers in the eyes?
a. It inreases the uvoscleral outflow;
XVI. ANTIFUNGALS b. Increases outflow through the trabecular meshwork;
Drug Toxicity Indications c. Lowers production of aqueous humor;
Natamycin* Hypersensitivity Yeast & Fungal d. A and C;
Reaction keratitis e. A and B.
Amphotericin B * Hypokalemia Infusion Yeast, Fungal Keratitis 7. In the event that you need to lower the patient’s IOP fast, which of the
related toxicity & Endophthalmitis following drugs would you prescribe?
Ketoconazole Allergic Rash, Yeast & a. Timolo maleate c. Betaxolol
Teratogenic Endophthalmitis b. Metipranolol d. Carteolol
Fluconazole Allergic Rash, Yeast &
8. Which of the following cholinergic agonists acts indirectly and is
Teratogenic Endophthalmitis
Itraconazole Poor penetration so Yeast, Fungal Keratitis irreversible?
used in combination & Endophthalmitis a. Acetylcholine c. Neostimine
VorIconazole No damage to the eye Invasive aspergillosis b. Edrophonium d. Isoflurophate
9. What would be the route of steroid drugs if the patient has severe
XVII. ANTIVIRAL AGENTS ocular inflammation?
a. Subconjunctival injection
Drug Route Ocular Toxicity
Trifluridine Topical Punctuate Keratopathy b. Retrobulbar injection
Hypersensitivity c. Punctal occlusion
Acyclovir* Oral d. A and C
Valacyclovir* Oral e. A and B
B, C, A, C, E, C, A, D, E, B

Famciclovir Intravenous, Intravitreal 10. What is the mechanism of cholinesterase drugs?

Vidarabine Ointment Lacrimation, FB a. They directly attach on the receptors which causes the
Sensation, Photophobia constriction of ciliary muscles
b. they bind and deactivate the AChE
XVIII. ANTI-PARASITIC c. they stimulate the production of acetylcholine
Protozoal Keratitis (Acanthamoeba) d. it mimic the acetylcholine thus increasing its amount
• Using Contact Lenses while Swimming on a pool, fresh
water lake, and, hot tub
Topical Agents Drugs Topical Agents References:
Diamidines Propamidine, Hexamidine Diamidines
• Katzung, B., Masters, S., & Trevor, A. (2012). Basic &
Biguanides Polyhexamethyl Biguanides
Clinical Pharmacology (12th edition.)
Biguanide, Chlorhexidine
Aminoglycoside Neomycin, Paromycin Aminoglycoside • Lecture by Dr. Castillo
Imidazoles Clotrimazole, Miconazole Imidazoles

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