Parasympathetic or Cholinergic drugs mimic the action of acetylcholine (ACh), a neuro-transmitter at the postganglionic parasympathetic junction, as well as at other autonomic, somatic and central synapses.
Ach is synthesized by “Choline Acetyltransferase” enzyme and produces its effects by binding to cholinergic receptors at the effector site.
Cholinergic drugs act either through direct stimulation of cholinergic receptors or indirectly through inhibition of the “Cholinesterase”, thereby protecting endogenous Ach.
Cholinergics affect intra-ocular pressure (IOP) by an agonist-induced, muscarinic receptor-mediated contraction of the ciliary muscle.
There are two ways in which ciliary muscle contraction can affect aqueous outflow.
One, ciliary muscle contraction obliterates the intermuscular spaces within the ciliary muscle. This obstructs uveoscleral outflow.
Secondly, there is intimate relationship of the anterior tendons of the ciliary muscle bundles with the scleral spur, peripheral cornea, trabecular meshwork and inner wall of Schlemm’s canal. Ciliary muscle contraction results in an unfolding of the trabecular meshwork and widening of Schlemm’s canal, facilitating aqueous outflow from the anterior chamber through the meshwork into the canal lumen and thence into the venous collector channels and finally, the general venous circulation.
However, the facilitation of outflow via the trabecular meshwork (conventional pathway) more than compensates for the obstruction of the uveoscleral (unconventional) route. The net effect of ciliary muscle contraction, therefore, is to decrease IOP.
Another effect of ciliary muscle contraction is accommodative myopia by the cholinomimetic agents. This is a major drawback, especially in young individuals.
Induced miosis can be a problem for elderly patients with immature cataracts.
Muscarinic agents are of 2 types:
Directly acting= They stimulate the iris sphincter to cause miosis, and stimulate the ciliary muscle to increase outflow facility, decrease uveoscleral outflow and produce accommodative changes.
Examples of directly acting cholinergic agents include pilocarpine aceclidine, arecoline, acetyl-B-methylcholine.
Indirectly acting= They block cholinesterase (AChE) preventing metabolic inactivation of Ach released from parasympathetic nerve endings. When AChE is blocked, the local concentration of endogenously released Ach and its time of action are increased. This increases and prolongs the response of endogenous cholinergics.
Examples of indirectly acting agents include physostigmine, demecarium, echothiaphate, and isoflurophate.
PILOCARPINE
History and source:
It is an alkaloid produced from the leaflets of South American shrubs of the genus Pilocarpus (P. microphyllus). Pilocarpine was foirst introduced as an anti-glaucoma agent in 1877.
Pharmacology:
Pilocarpine acts by direct stimulation of muscarinic cholinergic receptors. It duplicates the muscarinic effects of Ach, but not its nicotinic effects.
Clinical pharmacology:
It produces miosis through contraction of the iris sphincter muscle, which pulls the iris root away from the trabecular meshwork in angle-closure glaucoma. It also causes ciliary muscle contraction, resulting in accommodation and increased tension on and opening of the trabecular meshwork spaces, facilitating aqueous humor outflow and lowering IOP in open-angle glaucoma.
Pharmacokinetics:
Pilocarpine penetrates the cornea well. Animal studies have shown that the cornea absorbs pilocarpine rapidly and then releases it slowly to the aqueous humor. Onset of miosis with a 1% solution is within 10-30 minutes. Maximum reduction in IOP occurs in 75 minutes when a solution is used. The duration of action for miosis is about 4-8 hours. The reduction in IOP lasts for 4-14 hours.
In brown eyed patients 4% solution maybe required for maximum effect, whereas in extremely dark individuals 8-10% solution is the most effective. The differences are due to the binding of the drug by pigment within the eye, making it unavailable to the relevant muscarinic receptors.
The drug is inactivated by tissues of the anterior segment of the eye, partly by reversible binding of the drug to tissues and also by enzymatic hydrolysis to the primary metabolite, pilocarpic acid.
Resistance to the IOP lowering effect may occur after prolonged use.
Therapeutic use:
Pilocarpine is generally used in a concentration of 0.5-4.0% aqueous solution four times per day.
In acute angle closure it can be instilled 2-3 times over a 30-minute period.
Side effects and toxicity:
Transient stinging and burning are common. Conjunctival vascular congestion and true allergy are unusual. Prolonged use of pilocarpine may alter the conjunctival tissues to make subsequent glaucoma filtration surgery more likely to fail. Intraocular vascular congestion may occur in and aggravate uveitic conditions. Ciliary spasm, temporal or supraorbital headache and induced myopia may occur. Reduced visual acuity in dim illumination may occur in elderly with central lens opacities. Accelerated development of lens opacities is also reported. Retinal detachment in susceptible individuals may occur.
Sweating and gastro-intestinal over activity usually occurs in children. Over dosage can produce sweating, salivation, nausea, tremors, slowing of pulse and decreased blood pressure.
High-risk groups:
Pilocarpine is not advised in conditions where pupillary constriction and intraocular vascular congestion are undesirable, such as in acute iritis.
It should also be avoided in individuals prone for retinal detachment, severe asthma, or bronchial obstruction or acute infectious conjunctivitis or keratitis.
Caution should also be exercised when prescribing to children.
CARBACHOL
History and source:
Carbachol is a carbamyl ester of choline and synthesized in 1930s.
Pharmacology:
It has direct sympathomimetic actions as well as an indirect mechanism of action by inhibition of AChE.
Pharmaceutics:
Isopto Carbachol (0.75, 1.5, 2.25 and 3.0%) solution is administered every 8 hourly.
Miostat (0.01%) solution is used as intracameral injection during surgery.
Pharmacokinetics:
Carbachol is not lipid soluble and therefore, penetrates intact cornea poorly.
Maximum reduction of IOP occurs within 4 hours and lasts about 8 hours. Miosis lasts 4-8 hours.
Intracameral miostat produces maximal miosis within 5 minutes and lasts about 24 hours.
Therapeutic use:
0.75-3.0% solution is used 3 times daily.
Side effects and toxicity:
Same as Pilocarpine.
High risk groups:
It is contra-indicated in the presence of iritis. Caution is advised in the presence of corneal abrasion to prevent excessive intraocular penetration.
Caution is also advised in the presence of acute cardiac failure, bronchial asthma, active peptic ulcer, hyperthyroidism, gastrointestinal spasm, urinary tract obstruction, Parkinson’s disease, recent myocardial infarction, systemic hypertension or hypotension.
ECHOTHIOPHATE
History and source:
Eserine was isolated from Calabar beans. The alkaloid (physostigmine) was introduced as an anti-glaucoma agent in 1877 by Laqueur.
Official name:
Echothiophate is chemically Echothiophate iodide, 2-[(Diethoxyphosphinyl)-thio]-N,N,N-trimethylethanaminium iodide;2-mercaptoethyl) trimethylammonium iodide O,O-diethyl phosphorothiotae C9H23INO3PS.
Pharmacology:
This indirectly-acting parasympathomimetic agent is classified as a cholinesterase inhibitor or anticholinesterase. Cholinesterase inhibitors prolong the effect of Ach by inactivating the choliesterase enzymes which break it down.
Clinical pharmacology:
Echothiophate inactivates pseudocholinesterase and incompletely inactivates AChE, enhancing and prolonging the effects of AChE endogenously released from parasympathetic nerve endings.
Pharmaceutics:
A 0.125% solution is usually used.
Pharmacokinetics:
Onset of miosis is within 1 hour, IOP reduction occurs within 4 hours. Maximum miosis occurs within 2 hours and maximum IOP reduction within 24 hours. Miosis and IOP reduction can last for several weeks but usually lasts around 24-48 hours.
Therapeutic use:
Echothiophate is rarely used because of toxic effects. It was used in primary open-angle glaucoma, angle closure glaucoma after iridectomy and in accommodative esotropia.
Side effects and toxicity:
Side effects include corneal toxicity, conjunctival and intraocular vascular congestion, fibrinous iritis, individuals predisposed to retinal detachment, lacrimal canalicular stenosis, formation of posterior synechiae, iris cysts and cataracts.
Systemic toxic effects include diarrhea, nausea, abdominal cramps, general fatigue and weakness, hypotension and bradycardia.
Topical echothiophate makes patients more susceptible to prolonged paralysis following use of depolarizing muscle relaxants such as succinylcholine and procaine.
High risk groups:
Caution is advised in the following groups: Bronchial asthma, bradycardia, hypotension/hypertension, Down’s syndrome (echothiphate may cause hyperactivity), epilepsy, gastrointestinal disturbance, hyperthyroidism, iritis, myasthenia gravis, myocardial infarction, Parkinsonism, peptic ulcer, retinal detachment, urinary tract obstruction.
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