Autonomic Nervous System, Cholinergic Agonists and Antagonists Flashcards
(36 cards)
What are the 2 groups of parasympathomimetic drugs?
- direct-acting agents
- cholinesterase inhibitors
What 2 molecules are direct-acting parasympathomimetic agonists? How do they act?
- choline esters (ACh and numerous synthetic esters)
- cholinomimetic alkaloids
act directly on receptors and do not depend upon endogenous ACh for their effects
What are the endogenous agonists at nicotinic and muscarininc cholinergic receptors?
- nicotine
- muscarine
What is the neurotransmitter released at sympathetic and parasympathetic ganglia?
acetylcholine
Effects of direct-acting cholinergic receptor stimulants:
What is the prototypical cholinergic agonist? What are 2 reasons it is not used therapeutically?
acetylcholine
- muscarinic and nicotinic receptors are located at numerous tissues and no selective response can be achieved
- duration of action is short, since it is rapidly inactivated by acetylcholinesterases
Target organ effects of acetylcholine:
How do the pharmacological and physiological effects of primary choline derivatives/esters compare?
PHARMACOLOGICAL: similar to parasympathomimetic effects produced by ACh administration
PHYSIOLOGICAL: not identical and vary in relative selectivity for one organ system to another
There are generally few clinical indications for the use of cholinergic agonists in veterinary medicine, but what 2 are available?
- Bethanechol - resistant to cholinesterase degradation, promotes bladder contraction in paraplegic dogs/cats, and is used to promote detrusor muscle contraction for detrusor sphincter dyssynergia
- Carbachol - topically promotes miosis in ophthalmology, especially after cataract surgery
What are the 3 characteristics of cholinomimetic alkaloids? What 3 are most common in veterinary medicine?
- plant alkaloids
- selective parasympathomimetic agents
- evoke effects by direct activation of muscarinic receptors
Pilocarpine, Muscarine, Arecoline
What are the 3 target organ effects of Pilocarpine?
(cholinomimetic alkaloid)
1. stimulates flow of secretions, like salivary mucous and gastric/digestive secretions, from exocrine glands
2. contraction of GI smooth muscle contraction by increasing smooth muscle tone and peristaltic activity
3. pupillary constriction
What are the 3 targets organs of Arecoline?
(cholinomimetic alkaloid)
1. glands
2. smooth muscles
3. myocardium
How is Pilocarpine typically available as? What are 3 therapeutic uses?
(cholinomimetic alkaloid)
1%, 2%, and 4% ophthalmic solutions
- miosis and decrease in intraocular pressure in glaucoma
- treats keratoconjunctivitis sicca (KCS) in dogs
- dilute solutions (0.125%, 0.25%) can be applied directly to the eye to stimulate tear production
What are 2 possible adverse effects of Pilocarpine?
(cholinomimetic alkaloid)
1. local irritation of inflammation of the uveal tract
2. repeated use can cause systemic effects - vomiting, diarrhea, and increased salivation
How do cholinesterase inhibitors work? What does this cause?
parasympathomimetics that inhibit acetylcholinesterase (AChE)
increases the level of synaptic ACh and enhances the action of ACh at all cholinergic receptors (not just muscarinic, also nicotinic)
What are the 2 groups of cholinesterase inhibitors (indirect parasympathomimetics)?
- REVERSIBLE: physostigmine, neostigmine, pyridostigmine, edrophonium
- IRREVERSIBLE: organophosphates
What are the 3 mechanisms that anticholinersterase agents use to prevent the hydrolysis of acetylcholine?
- reversible AChE inhibition
- carbamylation of AChE
- phosphorylation of AChE
What are the 2 active sites on acetylcholinesterase that recognize acetylcholine? Where do carbamate derivatives act?
- anionic (negative charge) region where electrostatic binding occurs with the cationic nitrogen of the choline moiety
- esteratic site where the carboxyl portion of the acetyl ester binds by covalently
neostigmine and physostigmine interact with the anionic and esteratic sites and are thought to be hydrolyzed in a similar, but slower manner compared to ACh
How do physostigmine and neostigmine act in the GI tract, eyes, skeletal muscle, cardiovascular system, and smooth muscle?
- GI: physostigmine and neostigmine cause smooth muscle contraction, increased frequency and strength of peristaltic waves, and acceleration of intestinal content movement
- EYES: physostigmine causes pupillary constrictions
- SM: neostigmine stimulates nicotinic receptors and have higher effects at lower doses; large dose can cause twitching
- CV: no affects of physostigmine and neostigmine at therapeutic doses; high dose can lead to hypotension and bradycardia
-SM M: smooth muscles of bladder and bronchioles contract
What are the 2 principal uses of indirect acetylcholinesterase inhibitors?
- reverse the effects of nondepolarizing neuromuscular blocking drugs in voluntary muscles
- therapy of dogs with myasthenia gravis (MG)
What is myasthenia gravis? What can be used as an initial screening test for dogs with suspected myasthenia gravis?
congenital absence or acquired autoimmune disease resulting in deficiencies in acetylcholine receptors
Edrophonium
What are the 2 most common acetylcholinesterase inhibitors used for myasthenia gravis? Which is preferred? Why?
neostigmine, pyridostigmine
pyridostigmine - longer duration and lower adverse GI effects
What are the 4 possible adverse effects of acetylcholinesterase inhibitors?
- increased GI motility
- diarrhea
- salivation
- bradycardia
(muscarine effects of excess ACh)
How do organophosphorus compounds work? What are signs of poisoning?
irreversibly phosphorylate the esteratic site of AChE throughout the body —> endogenous ACh is not activated
typical parasympathomimetic actions
- profuse salivation
- vomiting, defecation, urination
- hypermotility in GI tract
- bradycardia
- hypotension
- severe bronchoconstriction
- excess bronchial secretion
