M1 and M3 Receptor Locations, G proteins and Mechanisms
M1 - Nerves
M3- Glands, SM, Endothelium
Gq protein linked
IP3 and DAG cascade
M2 Receptor Location, G protein and Mechanisms
Located in Heart, Nerves, and SM
Gi Potein Linked
Inhibition of cAMP production and activation of K+ Channels
Action of M2 and M3 receptors in the gut Smooth Muscle cells
#M3 receptors in gut >> #M2 receptors
M3 activation gets Gq to activate Phospholipase C and cleave IP3 and DAG and IP3 opens Calcium channels in SR for direct muscle contraction
M2 activation inhibits relaxation by blocking Adenylate Cyclase and therefore decreasing cAMP levels (cAMP inhibits contraction) therefore blocks relaxation
Activation of Muscarinic Receptors in Endothelium of BV
No parasympathetic nerve stimulation there, but circulating agonists can activate M3 receptors in blood vessels and cause release of NO which causes vascular Dilation
Activation of Sphinctors!
Predominant tone in sphinctors is adrenergic but pre-ganglionic parasympathetic neurons synapse on cholinergic neurons in the spinctor that activate inhibitory interneurons and lead to relaxation
Activation of M1 through intermediate neuron causes relaxation
What are the names of the Muscarinic Agonists?
Carbamylcholine (Carbachol ... more Nicotinic than Muscarinic)
Describe general characteristics of the synthetic muscarinic agonists?
ALL are CHARGED and so do NOT cross BBB or membranes
Non-descriminatory and non-selective
What is the only non-charged Muscarinic Agonist?
Pilocarpine!!! Natural Alkaloid made by plants that is non-charged and can penetrate BBB
What are the symptoms of Parasympathetic Overstimulation?
SLUDGE Salivation, Lacrimation, Urination, Deffecation, Increased GI motility, Emesis DUMBELS - better bc includes B which is Bradycardia and Broncorrhea (most pts die from Broncorrhea)
Also Miosis and constricted pupils, ataxia, slurred speech and restlessness
What are clinical uses for Cholinomimetic Agonists?
Eyes - use Pilocarpine or Carbachol to constrict sphinctor muscles in narrow angle glaucoma
GI - Bethanechol used for post-operative ileus, congenital megacolon, Esophageal reflux disease
GU - used to increase urinary retention and tone of Detrussor
Salivary gland - use pilocarpine topically to treat xerostomia
What are the contraindications for Muscarinic Agonists?
Ashtma and COPD
Hyperthyroidism (dont want to compromise rhythmicity of heart)
Coronary Insufficiency (M2 receptors leads to Bradycardia)
Peptic Ulcer (M1 for gastric secretions)
Mechanical Obstruction of GI or GU
What are the muscarinic Antagonists?
ATROPINE!! - naturally occurring alkaloid Cyclopentolate and Tropicamide
Glycopyrrolate Scopolamine Pirenzepine
Urinary - tolterodine and Darifenacin
Which Muscarinic Antagonists are un-charged?
Scopolamine - crosses BBB!!! Atropine is also uncharged but crosses BBB slowly
Which Muscarinic Antagonists have Receptor Specificity - what is it and how is it used?
Pirenzepine - M1 affinity and used to treat peptic ulcers
Tiotropium is M1/M3 specific used as an aerosolized spray in the lung
Tolterodine and Darifenacin are M3 specific and used for detrussor muscle in bladder
What are the symptoms of Muscarinic Receptor Blockade?
Opposite of SLUDGE Tachycardia, Atropine Flush and vasodilation, improved respiration bc bronchiole dilation and decreased secretions reduced GI motility and glandular secretions dilation and cycloplegia
Effects of Scopolamine?
Uncharged and Lipophillic so can cause Amnesia, Euphoria and dreamless sleep at low doses
Prevents motion sickness
What are Muscarinic Antagonists used for in the pulmonary system?
Ipratropium Bromide can be used in cold to open bronchi
Rhinitis can be relieved (but really just use anti-histamines)
***Tiotropium Bromide aerosolized and M1/3 selective to dilate bronchioles and reduce secretions WITHOUT THICKENING THEM - used for chronic bronchitis and emphysema!!!
What / how are muscarinic antagonists clinically used in GU and GI systems?
Used to stop intestinal hypermotility and non-infectious diarrhea = Glycopyrrolate
M3 selective Darifenacin (Enablex) or Tolterodine (Detrol) used for Overactive Bladder
How are Muscarinic Antagonists used in Anesthesia?
Pre-anesthesia give Glycopyrrolate (charged) or Atropine (uncharged) to stop salivation/resp tract secretions for intubation
Recover from Anasthesia used to recover paralyzed muscle function (ex. Pancuronium non-depolarizing Nicotinic block reversed with Neostigmine anti-cholinesterase but need to balance parasympathetic with an antimuscarinic!) so give glycopyrrolate)
Scopolamine gives amnesia
What antimuscarinics are used in the eye?
Tropicamide! Shortest acting anti-muscarinic to cause dilation
Next is cyclopentolate
Prophylactically give Transdermal patch of Scopolamine!!!
Contraindications for use of Muscarinic Antagonists?
Narrow-Angle Glaucoma Cardiac Arrhythmias Chronic Lung Disease
Mushroom Poisoning and Cholinergic OD?
Treat with Atropine!! Treat SLUDGE with Atropine!