Cholinergic Drugs (Direct acting) Part-1

Cholinergic Agonists (direct acting)

 • Cholinergic agonists mimic the effect of acetylcholine by binding directly to cholinoceptors (muscarinic & nicotinic). 

 • These agents are classified into 2 groups;

    (1) Choline esters : it includes endogenous ACh and synthetic esters of choline. Such as Carbachol &Bethanechol.

    (2)Naturally occuring Alkaloids : Nicotine & Pilocarpine.  

 • All direct-actings Cholinergic drugs have longer duration of action than Acetylcholine. 

  (1) ACETYLCHOLINE

  • ACh is the quaternary ammonium compound that cannot penetrates membranes. 

  • It is nuerotransmitter of parasympathetic, somatic nerves & autonomic ganglia. 

  • It lacks the therapeutics importance b/c of multiple actions and its rapid inactivation by the cholinesterases. 

  • ACh has both muscarinic and nicotinic activity. 

  Functions : 

   (a) Decrease in heart rate and cardiac output : 

    • ACh mimics the effects of vagal stimulation on the heart. 

    • If injected intravenously, ACh produce a brief decrease in cardiac rate(bradycardia) and cardiac output due to reduction in rate of firing at the SA Node. 

   (b) Decrease in Blood Pressure : 

    • Injection of ACh cause vasodilation which on furthur cause lowering of Blood pressure. 

ACh mechanism:

   • ACh activates==> M3 receptors of smooth muscles ==> produce Nitric oxide from arginine ==> which diffuse in vascular smooth muscle cells ==> it furthur stimulates the Protein kinase G production ==> which leads to hyperpolarization & smooth muscle relaxation(vasodilation) via phosphodiesterase inhibition ==> it furthur leads to decrease in blood pressure. 

   • ACh is never released in blood in significant quantities so in the absence of cholinergic drugs, the vascular cholinergic receptors have no known functions. 

  • Atropine blocks these muscarinic receptors and prevents ACh from producing vasodilation. 

  (C) Other Functions 

    Gastrointestinal tract : 

     • ACh increase salivary seceration.   

     • Increase Gastric Acid seceration. 

     • Stimulates intestinal secerations and motility.   

    Lungs : 

    • ACh inhance the brochiolar secerations. 

    • ACh cause bronchioconstriction. 

   Genitourinary tract : 

    • ACh increase the tone of detrusor muscle, causing urination. 

    Eye :

   • In eye ACh cause stimulation of ciliary muscle contraction for near vision and in constriction of pupillae sphincter muscle, causing miosis(marked constriction of pupil). 

  (2) BETHANECHOL : 

    • Bethanochol is an carbomoyl ester, structurally related to ACh. 

    • It is not hydrolyzed by AChEsterase due to esterification of carbamic acid. Although it is inactivated through hydrolysis by other esterases. 

   • It lacks nicotinic actions due to addition of methyl group. But have muscarinic activity. 

   • Its major functions are on the smooth musculature of Bladder and GI tract. 

   • It has about 1 hour duration of action. 

Functions : 

   (A) Actions : 

    • Bethanechol directly stimulates muscarinic receptors, causing increased intestinal motility and tone. 

   • Also stimulates the detrusor muscle of bladder, where as trigone and sphincter muscles are relaxed. These effects stimulates urination. 

   (B) Therapeutic uses :

    • In urologic treatment , bethanechol is used to stimulates the atonic bladder, particularly in postpartum or postoperative , non obstructive urinary retention. 

    • Bethanechol may also be used to treat neurogenic atony as well as megacolon. 

    (C) Adverse Effects :

   • Bethanechol can cause generalized cholinergic stimulation  with ;

     => Sweating, Salivation, Flushing, Decrease BP, Nausea, Abdominal pain, Diarrhea, & Bronchospasm. 

• Atropine sulfate may be administered to overcome severe cardiovascular or bronchoconstrictor responses to this agent.