Cholinergic Pharm

Question 1

Basic Anatomy of Parasympathetic NS

Answer 1

• Pre-ganglionic synapse - release acetylcholine - bind NICOTINIC receptor (same as sympathetic)
• Post-ganglionic @ organ innervated - release acetylcholine - bind MUSCARINIC receptor

Question 2

Muscarinic Receptors (+ 3 subtypes)

Answer 2

• Location - peripheral parasympathetic effector cells
• GPCR - 7 transmembrane subunits
• M1 - nerves - IP3/DAG to inc Ca++
• M2- heart,nerves, smooth muscle - inhibit cAMP which activate K+ channels to dec HR
• M3- glands, smooth muscle, endothelium - IP3/DAG to inc Ca++ (contraction)

Question 3

Nicotinic Receptors (+ 2 subtypes)

Answer 3

• Location - NMJ or ganglia
• Pentamer w/ channel; must have at least 2 alpha subunits b/c these bind the acetylcholine and must bind 2 acetylcholine to open channel
• Nm - 2 alpha, beta, delta, gamma - at NMJ
• Nn- only alpha and beta subunits - post-ganglionic cell bodies

Question 4

What do muscarinic receptors regulate?

Answer 4

• CNS- cognition, memory, sleep, motion detection, seizure activity, regulation of apatite, thermoregulation, suppression of pain
• Eye - Contract pupillary sphincter and ciliary muscles to close/let less light in (mitosis) and flatten lens to enhance near vision (myopia) and stimulate lacrimal gland
• Heart - Primary - slow heart rate
  
  • Dec atrial contractility, shorten AP duration, slow AV node
  • Done by inc K+ channels —> hyper polarization AND dec slow inward Ca++ current
• ***NO DIRECT PARASYMPATHETIC INNERVATION OF BLOOD VESSELS
• Lungs - Bronchial smooth muscle contraction and inc mucus secretion
• Gut- Contraction of both circular and longitudinal muscles for peristalsis
• Bladder- Stim micturition and urination

Question 5

Nicotinic Receptors of NMJ

Answer 5

• One axon right from ventral horn to NMJ - multiple branches - motor unit
• Release acetycholine - then nicotinic receptors on muscle itself —> depolarization (EPP - end plate potential) —> muscle contracts
• Tonic release of acetylcholine maintains muscle tone

Question 6

Acetylcholine at Ganglia (4 fates)

Answer 6

• 1- EPSP via nicotinic receptors on post-synaptic membrane
• 2- IPSP via muscarinic receptors on post-synaptic membrane (M1)
• 3- secondary slow EPSP via muscarinic receptors (M2)
• 4- late, slow EPSP via myraid peptides

Question 7

Direct Muscarinic Agonists

Answer 7

• Eye - acetycholine, carbachol, pilocarpine
• Gut - bethanecol (not used now)
• Lungs - methacholine challenge to diagnose airway hypersensitivity

Question 8

Toxicity of Direct Muscarinic Agonists

Answer 8

• Salivation, sweating, lacrimation
• Nausea, vomiting diarrhea
• Miosis and myopia (near-soghted) and small eyes
• Headache, visual disturbances
• Bronchospasm and bronchial congestion
• Bradycardia
• Hypotension and shock

Question 9

Direct Nicotinic Agonists

Answer 9

Succinylcholine and nicotine (addictive)

Question 10

Indirect Cholinergic Agonists

Answer 10

Cholinesterase Inhibitors

• Endrophonium - for myasthenia graves diagnosis
• Organophosphates - irreversibly age cholinesterase (in insectisides, nerve gases and drug DFP)
• Physostigmine, pyridostigmine, neostigmine - reversibly bind enzyme
  
  • MG treatment
  • Used in surgery - reverse paralysis of neuromuscular block, reverse anti-muscarinic agents used to inc HR in surgery and reverse surgery-induced paralysis of GGI or urinary bladder
  • Or used in central antimuscarinic toxicity (OD)

Question 11

Toxicity of Cholinesterase Inhibitors

Answer 11

• DUMBELS (products of muscarinic stimulation)
  
  • Diarrhea, urination, miosis, bronchospasm, emesis, lacrimation, salivation and sweating
• Products of nicotinic stimulation
  
  • muscle paralysis, sweating, hypertension, tachycardia

Question 12

How to treat muscarinic agonist toxicity

Answer 12

Atropine

Question 13

How to treat cholinesterase inhibitor toxicity

Answer 13

**Treat w/ pralidoxamine, 2-PAM and atropine for muscarinic effects + respirator and treat seizures if present w/ diazepam

Question 14

Muscarinic Antagonists

Answer 14

• Atropine
• Hycosamine, scopolamine (motion sickness)
• Synthetic - homatropine, tropicamide (shorter duration of action- used by eye Dr to dilate but cannot see near)
• Ipratropium - treat COPD (does not cross BBB) **Atrovent
• Totlerodine - partial receptor selectivity; synthetic derivation used to treat urinary incontinence (only for neuronal/urge problem NOT stress incontinence)
• Antihistamines - dec secretions but side effects b/c CNS drowsiness

Question 15

Anti-muscarinic Toxicity

Answer 15

“Red as a beet, dry as a bone, blind as a bat, mad as a hatter”

Question 16

Depolarizing v Non-depolarizing Neuromuscular Blocks

Answer 16

• Non-depolarizing/ competitive
  
  • Bind at same site as acetylcholine - only need to bind one of two alpha sites
  • Dec frequency of channel opening
• Depolarizing/ noncompetitive
  
  • Succinylcholine (only one clinically used)
  • Phase I -extend duration of channel opening —> motor end plate remains depolarized so unresponsive to subsequent impulses hat maintain muscle tension -> paralysis
  • Phase II - after prolonged exposure the membrane depolarizes but no EPP b/c receptor no desensitized
    
    • Usually does not happen b/c succinylcholine rapidly degraded by cholinesterase BUT may happen if on cholinesterase inhibitor
    • Purpose = quick, short muscle relaxation (ex - to put in tube)

Question 17

Adverse Effects/Contraindications of Neuromuscular Blocks (7)

Answer 17

• Cause histamine release —> bronchospasm, hypotension, excessive bronchial and salivary secretion)
• At high doses, can work on sympathetic ganglia —> tachycardia; Also possible dysrhythmias
• Hyperthermia (ONLY DEPOLARIZING)
• Myalgia (muscle pain) - probably from muscle fasciculations during depolarizing blockade
• Inc intraocular pressure
• Should not be used if pt has low temp or electrolyte imbalance due to soft tissue injury
• CHF patients - because these blockers can inc K+ release (serve hyperkalemia)

Question 18

Drugs that Interact w/ Neuromuscular Blocks (4)

Answer 18

• Potentiated by inhaled or local anesthetics so may have to dec dose
  
  • Succinylcholine w/ halogenated anesthetics —> life-threatening hyperthermia
• Antibiotics that reduce Ca ++ can lead to less acetylcholine so inc potency
• Same w/ Ca-channel blockers
• Cholinesterase inhibitors reverse non-depolarizing blockade BUT enhance depolarizing blockade (b/c cholinesterase normally degrade succinylcholine)