Pcol 7&8

• Response of Eye - Sphincter muscle of Iris (M)

  Contraction (miosis)
• Response of Eye - Cilliary muscle (M)

  Contration (accommodation for near vision), cyctoplasm
• Response of Heart - Sinoatrial node (M)

  Decrease in rate (negative chronotropy)
• Response of Heart - Atria (M)

  Decrease in contractile force (negative inotrophy), decrease in refractory period
• response of Heart - Atrioventricular node (M)

  Decrease in conduction velocity (negative dromotropy), increase in refractory period
• response of Heart - ventricles (M)

  small decrease in contractile force
• response of blood vessels (M)

  Dilation via release of EDRF from endothelium
• response of bronchi (M)

  contraction (bronchoconstriction)
• response of gastrointestinal tract- motility (M)

  increase in smooth muscle contraction, increase peristalsis
• response of Gastrointestinal tract - Sphincters (M)

  decrease in tone, relaxation ( exception: gastroesophageal sphincter contracts)
• response of urinary bladder - detrusor (M)

  increase in contraction
• response of urinary bladder - trigone and sphicter (M)

  relaxation; voiding
• response of skeletal muscle (N)

  activation of neuromuscular end plates, contraction
• response of glands (exocrine) (M)

  increase secretion (thermoregulatory sweating, lacrimation, salivation, bronchial secretion, gastrointestinal glands)
• location of M1


  Nerve endings (CNS)
• location of M2


  Heart, some nerve ending
• location of M3


  Effector cells: smooth muscle, glands, endothelium
• post-receptor mechanisms of M1

  increase IP3, DAG cascade
• post-receptor mechanisms of M2 


  decrease cAMP synthesis
• post-receptor mechanisms of M3

  increase IP3, DAG cascade
• cAMP

  cyclic adenosine monophosphate
• DAG


  diacylglycerol
• IP3

  inositol-1,4,5-triphosphate
• Direct-acting cholinomimetic drugs comprise of choline esters & alkaloids
• Choline esters are quaternary ammonium compounds→charged
• Acetylcholine – acetic acid ester of choline
• Methacholine – acetic acid ester of B- methylcholine
• Carbachol & Bethanechol - carbamic acid of the same alcohol
• CHEMISTRY & PHARMACOKINETICS OF DIRECT-ACTING CHOLINOMIMETICS

  * Tertiary natural alkaloids (Pilocarpine, Nicotine,Lobeline) are well absorbed in most sites compared to quaternary amine (Muscarine)

  * These amines are excreted mostly in the kidneys

  * Acidification of urine accelerates clearance
• PHARMACODYNAMICSOF DIRECT-ACTING CHOLINOMIMETICS - Depends on the type of receptor they activate, location, & function
• Action of acetylcholine (Ach) released from the receptors are terminated by Acetylcholinesterase (AchE)
• Indirect acting cholinomimetics acts by inhibiting AchE
• Alcohols – Quaternary ammonium compound (Edrophonium)
• Carbamates – Carbamic acid ester of alcohol having tertiary (Physostigmine) & quaternary (Neostigmine, Pyridostigmine) ammonium group
• Organophosphates – Echothiophate, Pesticides (Malathion, Parathion), Nerve gases (Sarin, Tabun)
• Majority of cholinomimetics are used to treat diseases of the eye (Glaucoma, Accomodation esotropia), GIT/GUT(Post-operative atony & Neurogenic bladder), neuromuscular junction (Myasthenia Gravis), & to treat patients with Alzheimer’s disease
• DIRECT-ACTING CHOLINOMIMETICS (MUSCARINIC RECEPTORS)

  ○ CARBACHOL & BETHANECHOL

  ■ MOA: (+) M1-M3 receptors

  ■ USES: Bowel & Bladder atony

  ■ SE/AE: Excessive parasympathetic effects

  ■ TX: Atropine (Anticholinergic)

  
  

  ○ PILOCARPINE

  ■ MOA: (+) M1 receptors

  ■ USES: Glaucoma, Sjogren Syndrome

  ■ SE/AE: Miosis, Blurring of vision
• DIRECT-ACTING CHOLINOMIMETICS (NICOTINIC RECEPTORS)

  
  

  ○ NICOTINE, VARENICLINE, LOBELINE

  ■ MOA: (+) Nm & Nn receptors

  ■ USES: Smoking cessation

  
  

  ○ SUCCINYLCHOLINE

  ■ MOA: (+) Nm >>Nn

  ■ USES: Depolarizing neuromuscular blocker

  ■ SE/AE: Malignant hyperthermia

  ■ TX: Dantrolene
• Phase 1 - Membrane depolarizes, resulting in an initial discharge that produces transient fasciculations followed by flaccid paralysis
• Phase 2 - Membrane repolarizes, but receptor is desensitized to the effect of acetylcoline