Lecture 11/12 - Cholinergic Agonists Flashcards
What are the direct acting cholinergic agonists? (six)
ACh Muscarine Nicotine Carbachol Bethanechol Pilocarpine
What are the cholinesterase inhibitors? (six)
Edrophonium Neostigmine Pyridostigmine Physostigmine Organophosphates Pralidoxime
What abnormality inhibits ACh release?
Botulism
What can prolong the effects of ACh?
AChE inhibitors
What does ACh stimulate?
M + N
Where are muscarinic receptors located?
PNS effector organs
What is M1+3 linked to?
Gq
What is M2 linked to?
Gi
Where are muscarinic receptors where the PNS is not?
Sweat glands
What do nicotinic receptors respond to?
ACh + Nicotine
What is a special characteristic of nicotinic recptors?
Rapid desensitization
Where are nicotinic receptors found?
Brain
Adrenal medulla
Autonomic ganglia
NMJ
Why can drugs select between NMJ and autonomic nicotinic receptors?
Both have different structures
What is direct action?
Agonist binds and stimulates receptor
What is indirect action?
Molecule binds to enzyme or other part of pathway that leads to a different effect of NT
What will happen with ACh injection/
Slowing of HR - M2
Drop in BP - M3
Why can’t you give ACh orally?
Charged, not absorbed
What does bethanechol stimulate?
M receptors only
What effects predominate with bethanechol?
Bladder + GI
Does bethanechol enter the brain? Why?
No, charged
What does pilocarpine stimulate?
M receptors only
What are the distribution characteristics of pilocarpine?
Not charged, so taken orally
Gets into CNS
What is pilocarpine used for in the eye?
Decrease intraocular pressure (M3)
What is really sensitive to pilocarpine that leads to side effects? what are the effects?
Sweat + Salivary glands
Drooling
What does muscarinic stimulation do to the heart?
Vagal stimulation = Bradycardia (M2)
Atrial-muscarinic receptors
Conduction slowed through AV node
Pre-synaptic decrease NE = Decrease HR (M2)
What does muscarinic stimulation do to the blood vessels?
NO PNS, but M3 is present on endothelium
ACh given IV will cause vasodilation
How does ACh given IV cause vasodilation?
NO
What happens with release of NO from endothelial cells?
cGMP production + Vasodilation
What is the PNS tone like in the GI tract?
High, responsible for digestion
What are the effects of muscarine on the GI tract?
Motility + Peristalsis increase
Tone increases
Salivary + Gastric secretions increase
Sphincters relax
How is carbachol used with horses?
Treatment of colic or impactions
What do you have to watch out for when using carbachol in horses?
If obstruction is present can lead to intestinal rupture
What is carbachol used for in cattle?
Rumen atony and impaction
What does normal PNS activity do to the bladder?
Enhances overall activity
What do muscarinic drugs do to the bladder?
Bladder tone + peristalsis increase Void pressure increase Bladder capacity decrease Detrusor contracts Trigone and sphincter relax
What is the basic end result of muscarinic stimulation of the bladder?
Increased urination
What drug is used for bladder effects?
Bethanechol
What is betahanechol used for?
Urinary atony in cats following urolithiasis
What do you have to watch out for when using betanechol in cats?
That the urethra is patent, so they can control urine output
What are the muscarinic effects in the eye?
Circular muscle contraction = Pupil smaller
Increased AH drainage = Decreased pressure
Ciliary muscle contracts = Near vision
How is pilocarpine used in the eye?
KCS + Glaucoma
What are the side effects of pilocarpine in the eye?
Blurred vision + Brow ache
What are the muscarinic side effects?
Nausea + V/D + Colic Bladder tightness = Increased urination Salivation Bronchoconstriction + increased mucus Blurred vision Constricted pupils
What happens with muscarine toxicity?
Same as side effects just worse
Hypotension + Shock + Bradycardia
What is muscarine toxicity treated with?
Atropine + Albuterol
What are the three main places for nicotinic receptors?
Autonomic ganglia
Skeletal muscle
Brain
What type of channel is nicotinic receptors?
Ligand gated Na+ channel
What movement of ions occurs with an activated nicotinic receptor?
Na/Ca = in K = out
What, in the most general sense, does N activate?
SNS + PNS
What are the SNS effects with nicotinic stimulation?
Hypertension
Tachycardia w/ vagal bradycardia
What are the PNS effects with nicotinic stimulation?
Nausea + Vomiting + Diarrhea + Urination
What happens with desensitization of the NMJ?
Initial muscle twitch/contraction + depolarization blockcade
What is seen with nicotine toxicity?
Vomiting
Convulsion + coma + respiratory arrest
Skeletal muscle depolarization
Hypertension + Cardiac arrythmia
What three things are done to treat nicotine toxicity?
Atropine + Anticonvulsants + Assist respiration
What are the four major drugs that affect AChE? (not toxins)
Neostigmine
Physostigmine
Pryidostigmine
Edrophonium
What are the five examples of Organophostphates?
DFP + Eschothiophate + Soman + Sarin + Malathion
What are the distribution characteristics of neostigmine?
Charged, cant be taken orally + no CNS N
Acts mostly on skeletal muscle
How does pyrdiostigmine compare to neostigmine?
Longer acting
What are the general characteristics of Physostigmine?
Enters CNS
U-shaped response curve
What is Physostigmine used for?
Atropine toxicity
What is the duration of action for Edrophonium?
Very short = 5 to 10 min
What is edrophonium used for?
Diagnosis of myasthenia-like syndrome
What is used to treat myasthenia-like syndrome?
Neostigmine
What is the problem with organophosphates?
Long-lasting effect
Due to aging, becomes irreversible
What can stop oragnophosphate aging?
2-PAM, if given 3 to 4 hours post-exposure
How does aging occur?
Phosphorus-Oxygen bonds breaks
Bond to AChE irreversible
Why does 2-PAM stop the “aging” process”?
Strong nucleophile
Attracts organophosphate away from AChE
What is important to remember when using 2-PAM?
If organophosphate not present it can inhibit AChE itseld
What are the CNS effects of AChE inhibition?
Convulsions + respiratory arrest
What are the effects of AChE inhibition on the eye?
Miosis
Near vision
What are the effects of AChE inhibition on GI/bladder?
V/D + Abdominal cramps + Urination
What are the effects of AChE inhibition on the respiratory system?
Salivation + Secretion + Bronchoconstriction
What are the cardiovascular effects of AChE inhibition?
PNS dominates
Prolonged ACh = M2 stimulation
Bradycardia + Decrease contraction + Decrease CO
What happens with low concentrations of AChE inhibitors at the NMJ?
Skeletal muscle strength increases
What happens with high concentrations of AChE inhibitors at the NMJ?
Twitches + Fasiculation
Blockade
Paralysis
What is myasthenia gravis?
Autoimmune disease
Ab’s to nicotinic receptors
Not enough ACh to stimulate
Weakness and fatigue with excercise
What is physostigmine used for?
Eye = miosis + decrease pressure
Synechia = alternate with atropine
Rumen atony = in cattle
What are the side effects of AChE inhibitor toxicity?
Salivation + Lacrimation + Urination + Defecation + Gastric distress + Emesis
What is the withdrawal time in meat and milk for 2-PAM (pralidoxime)?
28 days for meat
6 days for milk
