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Pharmacology of Ganglion stimulants, blockers

andGlaucoma



Organ Dominant tone EffectHeart Para Symp Tachycardia

BV Symp Dilatation

Iris Para symp Mydriasis

Ciliary muscles Parasymp Cycloplegia

Intestines Parasymp Decreased motility

Bladder Para-symp Decreased tone

Sexual function Para symp Inhibition of erection&ejaculation

Salivary glands Parasymp Dryness

Sweat Symp Anhydrosis

Autonomic tone & effect of ganglionic blockade



G anglion blocking agents:

Competitive blockers:Hexamethonium

Trimethaphan camphor sulfonateMecamylamine

Persistent depolarising blockers:

Nicotine ( Large doses)Anticholinesterases ( Large doses)



Therapeutic uses of ganglion blockers:

Trimethaphan, because of its very brief action isgiven by IV infusion for producing controlled

hypotension for short periods during- Surgery.- Dissection of aorta.



G anglionic stimulants:

Selective nicotinic agonists:Nicotine- (Transdermal patches for smokingcessation)Varenicline ± (N N partial agonist for smokingcessation)Lobeline

Nonselective muscarinic/nicotinic agonists:AcetylcholineCarbachol

Anticholinesterases



G laucoma

[Silent thief of sight]G roup of diseasesProgressive optic nerve damage

Characteristic loss of field of visionOften associated with raised IOT

Exact etiology is not known.Treatment is to reduce IOT



G laucoma-Types

Open angle[wide angle, chronic simple]G enetic??

Insidious and progressiveOcular hypotensivesAngle closure [Narrow angle, Acute congestive]

Acute attack Precipitated by mydriaticsEmergency-Drug therapy and surgery



Inhibitors of AH productionBeta blockers

CAH inhibitorsA2 agonists

Increased drainagePilocarpineP G analogues

Aq ueous humor dynamics



C arbonic anhydraseC iliary Vessels

2-Receptor Stimulation

Reduced secretion

ß 2-Receptor Blockade-decreases secretion


Reduction of synthesis

AH -Synthesis

C iliary body



AH - Outflow





Drugs for glaucoma

1. Prostaglandin analoguesLatanaprostUnoprostone, Travoprost, Bimatoprost

2. Adrenergic blockersTimolol, levobunolol, carteolol,metipranolol [nonselective] ;

betaxolol and levobetaxolol [ 1selective]

3. Adrenergic agonistsApraclonidine,brimonidine,dipivefrine, adrenaline

4. Carbonic anhydraseinhibitorsAcetazolamide, Dorzolamide,

Brinzolamide5. Miotics

Pilocarpine, anticholinesterases

6. Drugs used in acutecongestive



Prostaglandin F 2 analogues

Latanaprost, Unoprostone, Travoprost, Bimatoprosto MOA- Increases permeability of tissues in ciliary muscleso Increases uveo-scleral outflowo Treatment started with theseo Alone [0.005%] or in combinationo Advantage-Once a day, no systemic side effects

Side effects ± Irritation, Blurring of vision, increased iris pigmentation, thickening and darkening of eyelashes.



ß Adrenergic blockers:

Timolol, levobunolol, carteolol, metipranolol[nonselective] ; betaxolol and levobetaxolol [ 1 selective]

MOA: Decreased synthesis and secretion of AHEqually effective as miotics, sustained action for weeksOcular side effectsStinging, redness, dryness, allergic

Conjuctivitis, blurred visionSystemic side effects[absorption]Brocnhospasm , bradycardia[ ß

2/ ß1]



Advantages of topical ß blockers overmiotics:

No change in size of pupil.No induced myopia.

No headache.No fluctuations in IOT.Convenient twice/once daily application.



C arbonic anhydraseC iliary Vessels


Reduced secretion

ß 2-Receptor Blockade-decreases secretion1-Receptor

StimulationReduction of synthesis

C iliary body



Adrenergic agonists:Adrenaline:

1 ± Ciliary vasoconstriction-Reduce AH synthesis

2- Ciliary epithelium-Reduce

secretionß 2 ± Increased U.scleral &trabecular flowNot used ±

Poor penetration,ocularintolearnce & Systemic action

Dipivefrine ± Prodrug of adrenaline ± rarely usedApraclonidine ± Primary 2 receptor action( Only for short term use due to sideeffects)

Brimonidine ± More selective 2 receptoractionLess 1 side effects3rd choice drug



Adverse effects-adrenergic agonists

ItchingMydriasis

Dryness of mouth and noseEye lid retraction.



Carbonic Anhydrase inhibitors

PT, Gastric mucosa, Pancreas, CILI ARYBODY, Brain, RB C

H 2O+CO2 H2C O3 H++H C O3 -

AH is rich in HC O3-

Inhibition of enzyme decreased synthesis of AH

More than 99% inhibition is re q uired

C AH



Carbonic anhydrase inhibitors«.

Acetazolamide: ( Oral route)Used for short term indications-Angle closure, before surgery,supplement to other drugs

Side effects ± Paresthesia, hypokalemia, acidosis, anorexia.Dorzolamide: ( Topical application)Add on drug

Side effects ± Burning and itching sensation in the eye.

Brinzolamide



Miotics:

Topical pilocarpine and antiChEs.They lower IOT by improving trabecular outflow

Disadvantages:Short durationCiliary spasmVision disturbances

Inconsistent response

Because of several drawbacks they are used only as the lastoption in open angle glaucoma.



Treatment of open angle

Start with latanoprost or a ß -blocker.

(Inadequate response)Change over to the alternative drug or

use both concurrently. (Inadequate response)

Add Brimonidine/Dorzolamide/Dipivefrine

(Inadequate response)

Oral CAIs [Acetazolamide SR or methazolamide](Inadequate response)

laser or incisional surgical treatment.



G eneral principles of G laucoma Therapy

A sthma and COPD with a bronchospastic component are relativecontraindications to the use of topical beta adrenergic receptor antagonistsCardiac dysrhythmias (i.e., bradycardia and heart block) also are relativecontraindications to beta adrenergic antagonists for similar reasons;

H/O nephrolithiasis can be a contraindication for carbonic anhydrase inhibitors(C A Is);Young patients usually are intolerant of miotic therapy secondary to visual blurring from induced myopia;

Direct miotic agents are preferred over cholinesterase inhibitors in ³phakic´ patients (i.e., those patients who have their own crystalline lens), since the latter drugs can promote cataract formation; and

Patients who have an increased risk of retinal detachment , miotics should beused with caution since retinal tears could occur due to altered forces at thevitreous base produced by drug-induced ciliary body contraction.



Angle closure (narrow angle,acutecongestive) glaucoma:

Occurs in individuals with a narrow iridocornealangle and shallow anterior chamber.Sudden raise in IOTAttack is precipitated by mydriasis -( 40-60mm of Hg ).It is an emergency and failure to lower IOTquickly may result in loss of sight.



Drug therapy of Angle closure glaucoma:

Hypertonic mannitol (20%) 1.5-2gm /kg or glycerol (10%) ± by IV route.

Acetazolamide 0.5 gm IV followed by twice daily orally.

Miotic ± Pilocarpine 1-4% every 10 min initially.Timolol 0.5% eye drops instilled 12 th hourly.Apraclonidine (1%) / Latanoprost ( 0.005%)

may be added.

Definitive treatment of angle closure glaucoma is surgical or laseriridotomy.