Pharmacology of Ganglion stimulants, blockers and Glaucoma

Autonomic tone & effect of ganglionic blockade

Organ
Heart BV Iris Ciliary muscles Intestines Bladder Sexual function Salivary glands Sweat

Dominant tone
Para Symp Symp Para symp Parasymp Parasymp Para-symp Para symp Parasymp Symp

Effect
Tachycardia Dilatation Mydriasis Cycloplegia Decreased motility Decreased tone Inhibition of erection&ejaculation Dryness Anhydrosis

Ganglion blocking agents:
Competitive blockers: ‡ Hexamethonium ‡ Trimethaphan camphor sulfonate ‡ Mecamylamine Persistent depolarising blockers: ‡ Nicotine ( Large doses) ‡ Anticholinesterases ( Large doses)

Therapeutic uses of ganglion blockers: Trimethaphan, because of its very brief action is given by IV infusion for producing controlled hypotension for short periods during - Surgery. - Dissection of aorta.

Ganglionic stimulants:
Selective nicotinic agonists: ‡ Nicotine- (Transdermal patches for smoking cessation) ‡ Varenicline ± (NN partial agonist for smoking cessation) ‡ Lobeline Nonselective muscarinic/nicotinic agonists: ‡ Acetylcholine ‡ Carbachol ‡ Anticholinesterases

Glaucoma [Silent thief of sight]
‡ ‡ ‡ ‡ ‡ ‡ Group of diseases Progressive optic nerve damage Characteristic loss of field of vision Often associated with raised IOT Exact etiology is not known. Treatment is to reduce IOT

Glaucoma-Types
‡ Open angle[wide angle, chronic simple]  Genetic??  Insidious and progressive  Ocular hypotensives ‡ Angle closure [Narrow angle, Acute congestive]  Acute attack  Precipitated by mydriatics  Emergency-Drug therapy and surgery

Aqueous humor dynamics

Increased drainage ‡Pilocarpine ‡PG analogues
Inhibitors of AH production ‡Beta blockers ‡CAH inhibitors ‡A2 agonists

AH-Synthesis Ciliary body
2-Receptor

Stimulation Reduced secretion

Ciliary Vessels

Carbonic anhydrase

ß 2-Receptor Blockade-decreases secretion

1-Receptor

Stimulation Reduction of synthesis

AH- Outflow

Drugs for glaucoma
1. Prostaglandin analogues 
Latanaprost 
Unoprostone, Travoprost, Bimatoprost

4. Carbonic anhydrase inhibitors
‡ Acetazolamide, Dorzolamide, Brinzolamide

2. Adrenergic blockers

‡ Timolol, levobunolol, carteolol, 5. Miotics ‡ Pilocarpine, anticholinesterases metipranolol [nonselective]; betaxolol and levobetaxolol [ 1
selective]

3.

Adrenergic agonists

6. Drugs used in acute congestive

‡ Apraclonidine,brimonidine, dipivefrine, adrenaline

Prostaglandin F2 analogues 
Latanaprost, Unoprostone, Travoprost, Bimatoprost
o o o o o MOA- Increases permeability of tissues in ciliary muscles Increases uveo-scleral outflow Treatment started with these Alone [0.005%] or in combination 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 AH Equally effective as miotics, sustained action for weeks Ocular side effects Stinging, redness, dryness, allergic Conjuctivitis, blurred vision ‡ Systemic side effects[absorption] ‡ Brocnhospasm, bradycardia[ß2/ ß1]

Advantages of topical ß blockers over miotics: ‡ ‡ ‡ ‡ ‡ No change in size of pupil. No induced myopia. No headache. No fluctuations in IOT. Convenient twice/once daily application.

Ciliary body
2-Receptor

Stimulation Reduced secretion

Ciliary Vessels

Carbonic anhydrase

1-Receptor

ß 2-Receptor Blockade-decreases secretion

Stimulation Reduction of synthesis

Adrenergic agonists:
‡ Adrenaline: ‡ 1 ±Ciliary vasoconstrictionReduce AH synthesis ‡ 2- Ciliary epithelium-Reduce secretion ‡ ß 2 ± Increased U.scleral & trabecular flow ‡ Not used ± ‡ Poor penetration,ocular intolearnce & Systemic action
‡ Dipivefrine ± ‡ Prodrug of adrenaline ± rarely used ‡ Apraclonidine ± ‡ Primary 2 receptor action ( Only for short term use due to side effects)

‡ Brimonidine ± ‡ More selective 2 receptor action ‡ Less 1 side effects ‡ 3rd choice drug

Adverse effects-adrenergic agonists
‡ ‡ ‡ ‡ Itching Mydriasis Dryness of mouth and nose Eye lid retraction.

Carbonic Anhydrase inhibitors
‡ PT, Gastric mucosa, Pancreas, CILIARY BODY, Brain, RBC ‡ H2O+CO2
CAH

H2CO3
-

H +HCO3

+

-

‡ AH is rich in HCO3
‡ Inhibition of enzyme

decreased synthesis of AH

‡ More than 99% inhibition is required

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 duration  Ciliary spasm  Vision disturbances  Inconsistent response Because of several drawbacks they are used only as the last option 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.

General principles of Glaucoma Therapy
‡ Asthma and COPD with a bronchospastic component are relative contraindications to the use of topical beta adrenergic receptor antagonists ‡ Cardiac dysrhythmias (i.e., bradycardia and heart block) also are relative contraindications to beta adrenergic antagonists for similar reasons; ‡ H/O nephrolithiasis can be a contraindication for carbonic anhydrase inhibitors (CAIs); ‡ 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 be used with caution since retinal tears could occur due to altered forces at the vitreous base produced by drug-induced ciliary body contraction.

Angle closure (narrow angle,acute congestive) glaucoma:
‡ Occurs in individuals with a narrow iridocorneal angle and shallow anterior chamber. ‡ Sudden raise in IOT ‡ Attack is precipitated by mydriasis ( 40-60mm of Hg ). ‡ It is an emergency and failure to lower IOT quickly 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 12th hourly. ‡ Apraclonidine (1%) / Latanoprost ( 0.005%) may be added. Definitive treatment of angle closure glaucoma is surgical or laser iridotomy.

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