Pharmacology

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2 Pharmacology

Ocular Pharmacology

Pharmacodynamics

the study of the biochemical and physiologic effects of drugs and their mechanisms of action.

Pharmacokinetics

the study of the factors that determine the relationship between drug dosage and the change in concentration over time in a biological system.

Bioavailability

amount of drug absorbed (penetration into ocular tissues)

Depends on concentration, rate of absorption, tissue binding, transport, metabolism, and excretion

Methods of improving bioavailability:

INCREASE CONCENTRATION: limited by solubility and tonicity (hypertonicity causes reflex tearing, which dilutes and washes drug from the eye)

SURFACTANTS: surface-active agents alter cell membranes, increasing permeability of the corneal epithelium

OSMOTICS: alter tonicity

INCREASE PH: increases nonionized (lipid-soluble) form of drug, increasing corneal penetration (pH of tears = 7.4)

INCREASE VISCOSITY: viscous additives (methylcellulose, polyvinyl alcohol) increase contact time and therefore penetration

INCREASE CONTACT TIME: gels and oil-based ointment formulations (mineral oil, petrolatum), polymer matrix (DuraSite); must be able to release drug

Therapeutic index

method of comparing potency of different antibiotics. A measure of relative effective (therapeutic) concentration of antibiotic at target site against a target organism.

Inhibitory quotient (IQ)

The most potent antibiotic has the lowest minimum inhibitory concentration (MIC) (or highest IQ).

Routes of Administration

Topical

absorption related to corneal penetration

1 drop = 50 µL (20–40 drops in most bottles)

Conjunctival cul-de-sac holds only 10 µL (20% of drop)

Drop diluted by reflex tearing and normal tear turnover: only ~50% of drug that reaches the cul-de-sac is present 4 minutes later (10% of drop)

Corneal barriers to penetration:

TIGHT JUNCTIONS (epithelium and endothelium): limit passage of hydrophilic drugs

STROMA (water rich): limits passage of lipophilic drugs

Methods of increasing absorption:

1 Add surfactants (disrupts epithelial integrity; e.g. benzalkonium chloride, topical anesthetic).

2 Promote punctal occlusion (decreases drainage).

3 Close eyelid after drops are placed.

4 Increase lipid solubility of drug (increases pH); more important than water solubility.

5 Increase frequency of drops.

Topical medications have systemic adverse effects because the drugs bypass hepatic ‘first-pass’ metabolism (cul-de-sac → nasolacrimal duct → mucosa → bloodstream)

Examples of other delivery systems:

PRODRUG: dipivalyl epinephrine (Propine; prodrug of epinephrine, less toxicity), nepafenac (Nevanac; prodrug of amfenac)

OINTMENT: drugs that have better uptake in ointment form, including tetracycline, chloramphenicol, and fluorometholone

SUSTAINED RELEASE GEL: pilocarpine (Pilopine HS; decreased dosing)

INSERT: pilocarpine (Ocusert; membrane-controlled system; slow release over 1 week); hydroxypropyl cellulose (Lacrisert; artificial tear slow-release pellet); collagen shield (bandage contact lens presoaked in antibiotic)

Subconjunctival / sub-Tenon’s

increases duration and concentration, bypasses conjunctival and corneal barriers, avoids systemic toxicity; useful if poor compliance

Retrobulbar / peribulbar

used for anesthesia; alcohol or chlorpromazine (to kill pain fibers and optic nerve [ON] in blind, painful eye)

Intraocular

direct ocular effects; beware toxicity (particularly from preservatives), retinal tear, retinal detachment (RD), endophthalmitis; used intraoperatively (intracameral, intravitreal) and in retinal diseases (intravitreal) including macular edema, choroidal neovascularization (CNV), endophthalmitis, cytomegalovirus (CMV) retinitis

Systemic

must cross blood–ocular barrier (blood–aqueous for anterior segment, blood–retinal for posterior segment); penetrance is improved with decreased molecular size, decreased protein binding, and increased lipid solubility

Concentration

1% solution = 1 g/100 mL = 10 mg/mL

Example: How much atropine is contained in 5 mL of a 2% solution?

Anesthetics

Mechanism

reversible blockade of nerve fiber conduction (block sodium channels); pH dependent (less effective at low pH [inflamed tissue])

Structure

2 classes; do not necessarily have allergic cross-reactivity

Ester: hydrolyzed by plasma cholinesterase and metabolized in liver; cocaine, tetracaine (amethocaine), proparacaine, procaine, benoxinate

Amide: longer duration and less systemic toxicity; metabolized in liver; lidocaine, mepivacaine, bupivacaine

Topical

disturb intercellular junction of corneal epithelium (increase permeability)

Proparacaine (Ophthaine): 10- to 30-minute duration, corneal toxicity; may cause allergic dermatitis (also common with atropine and neomycin); does not necessarily have allergic cross -reactivity with tetracaine

Tetracaine (Pontocaine): similar to proparacaine but longer duration and more toxic to corneal epithelium

Benoxinate: similar to proparacaine; combined with fluorescein (Fluress) for tonometry

Cocaine: greatest epithelial toxicity; excellent anesthesia, sympathomimetic effect (test for Horner’s syndrome)

Parenteral

may be used with epinephrine (1 : 100,000) to increase duration by preventing systemic absorption; also decreases bleeding; hyaluronidase (Wydase) 150 IU increases tissue penetration, but decreases duration. Side effect of retrobulbar anesthesia = respiratory depression, bradycardia

Toxicity: hypotension, convulsions, nausea, vomiting

Lidocaine (Xylocaine): 1-hour duration (2 hours with epinephrine); used for local anesthesia : akinesia

Procaine (Novocain): 30- to 45-minute duration

Mepivacaine (Carbocaine): 2-hour duration

Bupivacaine (Marcaine): 6-hour duration

General

all agents decrease IOP except ketamine, chloral hydrate, N₂O, and ether

Malignant hyperthermia: rare, autosomal dominant condition that occurs after exposure to inhalation agents (most commonly halothane, also succinylcholine, haloperidol); more common in children and males; thought to be due to calcium-binding disorder in sarcoplasmic reticulum that causes increased intracellular calcium, which stimulates muscle contraction

Interference with oxidative phosphorylation causes hypermetabolic crisis

FINDINGS: tachycardia (1st sign), elevated CO₂ levels, tachypnea, unstable BP, arrhythmias, cyanosis, sweating, increased temperature (later sign), muscle contractions; later, heart failure and disseminated intravascular coagulation (DIC) develop; laboratory tests show respiratory and metabolic acidosis and increased K, Mg, myoglobin, creatine phosphokinase (CPK), hypoxemia, hypercarbia, myoglobinuria

SCREENING: elevated CPK, muscle biopsy / contracture test, platelet bioassay (decreased adenosine triphosphate [ATP] in platelet exposed to halothane)

TREATMENT: stop anesthesia, hyperventilate with 100% oxygen, give sodium bicarbonate, cool patient (iced saline IV and lavage; surface cooling), mannitol and furosemide (Lasix), IV dantrolene (prevents release of calcium from sarcoplasmic reticulum), procainamide, insulin (do not use lactated Ringer’s solution, which increases potassium)

PROGNOSIS: 50-60% mortality

Autonomic System

Sympathetic

Extensive system for mass response (‘fight or flight’) (Table 2-1)

Table 2-1 Autonomic system responses

Organ / Function	Sympathetic (fight / flight)	Parasympathetic (homeostasis)
HR	Increase	Decrease
BP	Increase	Decrease
GI motility	Decrease	Increase
Bronchioles	Dilate	Constrict
Bladder	Constrict	Dilate
Vessels	Constrict	Dilate
Sweat	Decrease	Increase
Pupils	Dilate	Constrict
Eyelids	Elevate	Normal

Synapses near cord (superior cervical ganglion)

Long postganglionic nerves

Adrenergic receptors

α₁: smooth muscle contraction (arteries [decrease aqueous production by reducing ciliary body blood flow], iris dilator, Müller’s muscle)

α₂: feedback inhibition, ciliary body (decreases production and / or increases outflow)

β₁: cardiac stimulation

β₂: pulmonary and GI smooth muscle relaxation, ciliary body / trabecular meshwork (increase aqueous production, increase outflow facility)

Neurotransmitter

acetylcholine (ACh) at preganglionic terminal, epinephrine and norepinephrine (NE) at postganglionic terminal

Monoamine oxidase (MAO) breaks down NE in nerve terminal; blocked by MAO inhibitors (avoid with phenylephrine, epinephrine, and pseudoephedrine-based cold remedies)

Catechol-O-methyltransferase (COMT) breaks down NE in effector cell

Reserpine prevents storage of NE in nerve terminal

Cocaine, tricyclics block reuptake of NE by nerve terminal (thus potentiate its action)

Hydroxyamphetamine increases release of NE from nerve terminal

Cholinergic Drugs

Direct-acting agonists

act on end organ; therefore, do not need intact innervation; cause shallowing of anterior chamber (AC); disruption of blood–aqueous barrier, miosis, brow ache, and decrease in IOP

Acetylcholine (miochol: very short-acting, unstable, used intracamerally), methacholine, carbacholine (carbamylcholine, carbachol; direct and indirect acting), pilocarpine (less potent than ACh, but resistant to AChE; no miosis if IOP >40 mmHg)

Indirect-acting agonists

anticholinesterases (AChE inhibitor); strongest agents; cause miosis and decrease in IOP (contract longitudinal fibers of ciliary muscle = increased outflow of trabecular meshwork [TM]).

Reversible: carbacholine, physostigmine (eserine; treat lid lice), edrophonium (Tensilon; for diagnosis of myasthenia gravis): can cause bradycardia, treat with atropine

Irreversible: echothiophate (Phospholine Iodide; treat glaucoma and accommodative esotropia [ET]; may cause iris cysts and subcapsular cataracts), isofluorophate (very long-acting, not used clinically), demecarium

Adverse effects: cataract, RD, pupillary block, blocks metabolism of succinylcholine (prolonged respiratory paralysis) and ester anesthetics, can mimic acute abdomen (GI effects); antidote is pralidoxime (PAM) or atropine

Muscarinic antagonists

anticholinergics; cause deepening of AC, stabilization of blood–aqueous barrier, mydriasis, and cycloplegia

Atropine (1- to 2-week duration; most allergenic, supersensitivity seen in Down syndrome), scopolamine (hyoscine; 1-week duration; greater CNS toxicity than atropine), homatropine (1- to 3-day duration), cyclopentolate (Cyclogyl; 24-hour duration; beware CNS side effects with 2% solution, especially in children), tropicamide (Mydriacyl; 4- to 6-hour duration)

Toxicity: mental status changes, hallucinations, tachycardia, urinary retention, dry mouth / skin, fever

Antidote: physostigmine (1-4 mg IV)

Nicotinic antagonists

Nondepolarizing agents: gallamine, pancuronium; do not cause muscle contraction

Depolarizing agents: succinylcholine, decamethonium; cause muscle contraction and elevated IOP; contraindicated for ruptured globe (extraocular muscle [EOM] contraction can cause extrusion of intraocular contents)

Ocular Hypotensive (Glaucoma) Medications

β-Blockers

Mechanism

reduce aqueous production (inhibit Na⁺/K⁺ pump) by decreasing cyclic adenosine monophosphate (cAMP) production in ciliary epithelium; around 20% IOP reduction

Loss of effectiveness over time due to downregulation of β-receptors (long-term drift)

Adverse effects

dry eye syndrome (decreased corneal sensitivity), bradycardia, heart block, bronchospasm, impotence, lethargy, depression, headache, rarely diarrhea and hallucinations, alopecia, dermatitis; may mask hypoglycemia

Nonselective (β₁ and β₂)

timolol (Timoptic), levobunolol (Betagan), metipranolol (Optipranolol), carteolol (Ocupress)

10% do not show a therapeutic effect; inhibit lipoprotein lipase (break down chylomicrons and VLDL) and cholesterol acyltransferase (incorporate cholesterol into HDL); may cause decreased HDL levels

Carteolol has intrinsic sympathomimetic activity

Cardioselective (β₁ β₂)

betaxolol (Betoptic)

Fewer pulmonary adverse effects

Indications: patients with pulmonary problems who cannot tolerate nonselective β-blockers; often used for normal tension glaucoma; may not cause as much vasoconstriction of vessels supplying ON

α₂-Agonists

Apraclonidine (Iopidine), brimonidine (Alphagan P)

Mechanism: reduce aqueous production by decreasing episcleral venous pressure

Adverse effects: allergy, superior lid retraction, dry mouth, blanching of conjunctival vessels, miosis, lethargy, headache, stomach cramps; avoid in children especially <3 years of age: increased risk of somnolence, seizures, apnea due to CNS penetration

Dipivefrin (Propine)

prodrug of epinephrine (converted into epinephrine in cornea by esterases), lower concentration and increased solubility vs epinephrine (penetrates cornea 17× better); thus less toxicity and fewer adverse effects

Mechanism: improves aqueous outflow, slightly reduces aqueous production

Adverse effects: allergy, cystoid macular edema (CME) in aphakia, hypertension, tachycardia (fewer systemic adverse effects than epinephrine)

Epinephrine

1–2% is equivalent to Propine 0.1%; 3 salt forms: hydrochloride, borate, bitartrate (1st two are equivalent, 2% bitartrate is equivalent to 1% hydrochloride or borate)

Mechanism: improves aqueous outflow, slightly reduces aqueous production

Adverse effects: allergy, CME in aphakia (reversible), hypertension, tachycardia, arrhythmias, adrenochrome (black) deposits in conjunctiva

Miotics

Mechanism

increase aqueous outflow (contraction of ciliary muscle opens trabecular meshwork), decrease uveoscleral outflow

Pilocarpine

only direct cholinergic agonist; peak action at 2 hours, 8-hour duration

Beware for treatment of angle closure: causes shallowing of AC and narrowing of angle, but miosis pulls peripheral iris away from angle, balancing out the other effects

Adverse effects: headache, brow ache, accommodative spasm, increased range of accommodation, miosis (dimming, reduction of vision), induced myopia (forward shift of lens–iris diaphragm), pupillary block, follicular conjunctivitis, dermatitis, nyctalopia, rarely retinal tear or even RD

Other effects: breakdown of blood–aqueous barrier, reduction of uveoscleral outflow

Carbachol

direct and indirect cholinergic agonist; stronger effect and longer duration of action; poor corneal penetration; needs corneal surface disrupter (benzalkonium chloride); intraocular formulation (Miostat) used during surgery for pupillary miosis

Echothiophate (phospholine iodide)

indirect cholinergic agonist (cholinesterase inhibitor); 3-week duration; also used in accommodative esotropia

Adverse effects: greater orbicularis, ciliary, and iris muscle spasm; cataracts in adults (therefore, use only in aphakic or pseudophakic patients); iris cysts in children (proliferation of iris pigment epithelium; phenylephrine prevents cyst formation); decreased serum pseudocholinesterase activity (can accentuate succinylcholine effects during general anesthesia)

Carbonic Anhydrase Inhibitors (CAIs)

Mechanism

decrease bicarbonate formation in ciliary body epithelium; bicarbonate formation is linked to Na+ and fluid transport, so CAIs reduce aqueous production

Carbonic anhydrase catalyzes the reaction

CO₂ + H₂O ↔ H₂CO₃

Amount of carbonic anhydrase is 100× that needed for aqueous production; so, >99% must be inhibited to achieve IOP decrease

Sulfonamide derivative (do not administer to patients with sulfa allergy)

Oral

acetazolamide (Diamox; PO / IV), methazolamide (Neptazane, PO; more lipid soluble, less toxicity)

Adverse effects: dry eye syndrome (decreased tear production), metabolic acidosis (IV administration causes greater metabolic acidosis), kidney stones (reduced excretion of urinary citrate or magnesium), hypokalemia (especially when used with other diuretics; very dangerous with digoxin), paresthesias (hands / feet / lips), GI upset, diarrhea, lethargy, loss of libido, weight loss, metallic taste, aplastic anemia, Stevens-Johnson syndrome; transient myopia

Topical

dorzolamide (Trusopt), brinzolamide (Azopt)

Adverse effects: metallic taste, paresthesias, malaise, weight loss, depression, skin rash, corneal endothelial decompensation / toxicity (consider stopping prior to cataract surgery)

Prostaglandin Analogues / Prostanoids

Mechanism

increase uveoscleral outflow, around 30% IOP reduction

Latanoprost (Xalatan), bimatoprost (Lumigan), travoprost (Travatan), unoprostone isopropyl (Rescula)

prostaglandin F_2α analogues

Adverse effects: flu-like symptoms, hyperemia, eyelash growth, periocular skin and iris pigmentation (increases number of melanosomes, but not melanocytes), CME, reactivation of herpes simplex virus (HSV) keratitis

Hyperosmotic Agents

Mechanism

low-molecular-weight substances that increase serum osmolality to draw fluid out of eye (reduces vitreous volume)

Adverse effects: headache, thirst, nausea, vomiting, diarrhea, diuresis, dizziness, and rebound IOP elevation; IV agents can cause subarachnoid hemorrhage

Urea (IV; 30% solution)

not commonly used; extravasation causes tissue necrosis

Mannitol (Osmitrol; IV; 20% solution)

most potent; may exacerbate congestive heart failure

Glycerin (Osmoglyn; PO; 50% solution)

may cause hyperglycemia in diabetics (metabolized by liver into glucose)

Isosorbide (Ismotic; PO)

not metabolized (can be used in diabetics); secreted 95% unchanged in urine

Other hyperosmotic agents

used topically for corneal edema

Glycerin (Ophthalgan; topical; 100% solution): used to clear corneal edema for examination or laser procedure

Muro 128 (hypertonic saline; topical; drops or ointment; 2.5% or 5% strength): used to reduce epithelial edema of cornea, especially in treatment of recurrent erosions

Order of Allergy

Greatest to least

iopidine > epinephrine > Propine > brimonidine > β-blocker > pilocarpine

Anti-Inflammatory Drugs

The Inflammatory Pathway (Figure 2-1)

Figure 2-1 The inflammatory pathway. NSAIDs, nonsteroidal anti-inflammatory drugs; PG, prostaglandin; 5-HPETE, 5-hydroperoxyeicosatetraenoic acid.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Mechanism

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