Flashcards in Cholinergic Agonist Deck (43)
Cholinergic agonists are either direct or indirect acting, what is the difference?
Direct Agonist: bind to and activate muscarinic or nicotinic receptors
Indirect Agonist: act by inhibiting acetylcholinesterase, which hydrolyzes acetylcholine to choline and acetic acid.
ACh has 4 primary direct effects on the cardiovascular system, what are they?
1. Vasodilation (M3)
2. Decrease in heart rate (M2)
3. Decrease in rate of conduction in the SM and AV nodes (M2)
(via decrease in the amount of Ca2+ in the heart)
4. Decrease in force of contraction (M2)
What would happen to a patient if they were injected by a small dose of acetylcholine?
Produces a fall in blood pressure due to generalized vasodilation (M3) accompanied by reflex tachycardia
What would happen to a patient if they were injected by a large dose of acetylcholine?
Produces bradycardia and decrease conduction velocity through the A node (M2) in addition to causing vasodilation and hypotension mediated by M3
There is no actual innervation of the vasculature by the parasympathetic system, so how does M3 cause vasodilation?
there are unninervated M3 muscarinic receptors on the endothelial cells of the vasculature.
--these M3 receptors mediate relaxation of vascular muscle via release of NO from endothelial cells
Each card will list the effects of Acetylcholine on various organ systems, first the vasculature (endothelial cells)
--release of Nitric Oxide and Vasodilation (therefore drop in BP)
--remember you only need a small amount of ACh injected to drop the BP
2nd effect of ACh is on the eye iris?
--miosis (via pupillary sphincter muscle contraction)
3rd effect of ACh is on the ciliary muscle?
--contraction and accommodation of lens to near vision
4th effect of ACh is on the salivary and lacrimal glands
5th effect of ACh is on the bronchi
--Constriction and increased secretions
6th effect of ACh is on the Heart
--bradycardia, decreased conduction velocity, AV block at high doses, and slight decrease in contractility
7th effect of ACh is in the GI tract
--increased tone, increased peristaltic activity, increased secretion and relaxation of sphincters
8th effect of ACh is on the urinary bladder
Contraction of detrusor muscle and relaxation of sphincter
9th effect of ACh is on the sweat glands
Diaphoresis (Remember that sweat glands are an exception to the rule they are sympathetic response not parasympathetic)
10th effect of ACh is on the male reproductive tract
11th effect of ACh is on the uterus
Moving on to the actual drugs. First class of drugs are cholinergic agonists. The first drug is acetylcholine, what would be the use of this drug?
--No systemic therapeutic applications because of its multiplicity of actions and rapid hydrolysis
--use: obtain rapid miosis after delivery of the lens in cataract surgery
The second cholinergic agonists is bethanechol, what is the use?
1. acute postoperative and postpartum non obstructive urinary retention
2. neurogenic atony of the urinary bladder with retention
3. Postoperative ileus or neurogenic ileus
Activates bowel and bladder smooth muscle
Resistant to AChE
In general what are the adverse effects of any cholinergic agonist?
Increased Parasympathetic effects
-sweating (sweat glands)
--low blood pressure (M2)
The third cholinergic agonist is carbachol, what is the use?
Both muscarinic and nicotinic agonist
--constricts pupil (miosis) and relieves intraocular pressure in glaucoma
The fourth cholinergic agonist is methacholine, what is the use?
Mostly muscarinic agonist
--diagnosis of bronchial airway hyperreactivity in subjects who do not have clinically apparent asthma
The last cholinergic agonist is pilocarpine, what is the use?
Partial muscarinic agonist
--second line agent for open angle glaucoma
--management of acute angle-closure glaucoma
--Contracts ciliary muscle of eye (open angle glaucoma) and pupillary sphincter (Closed angle glaucoma)
-resistant to AChE
---potent stimulator of sweat, tears and saliva
The only nicotinic receptor agonist to speak about is Nicotine which is a ganglion stimulant. What are the actions of nicotine?
--Ganglionic stimulation by depolarization
initial response to nicotine therefore resembles simultaneous discharge of both the parasympathetic and sympathetic nervous systems
What are the effects of nicotine in the heart, GI/Urinary tracts and Bronchial tract?
CVS: mainly sympathomimetic therefore increase in HR and blood pressure due to catecholamine release from adrenengic nerve terminals and from the adrenal medulla
GI/Urinary: parasympathetic: nausea, vomiting, diarrhea and voiding of urine
Salivary and Bronchial Secretions: parasympathetic
At high doses nicotine can cause?
ganglionic blockade as a consequence of prolonged depolarization
--also causes a neuromuscular blockade
What are the symptoms of acute nicotine poisoning?
Nausea, salivation, abd pain, vomiting, diarrhea, cold sweat, mental confusion, and weakness
--blood pressure falls, pulse is weak, rapid and irregular.
Nicotine is highly liposoluble, which means what?
Absorption is fast via oral mucosa, lungs, GI mucosa, and skin
--crosses placental membrane and is secreted in milk
What is the use for nicotine?
smoking cessation therapy
Moving on to the indirect acting cholinergic agonists (Anticholinesterases), what is the mechanism of action of these drugs?
Inhibit acetylcholinesterase and thereby increase the concentration of endogenous acetylcholine
Cholinesterase inhibitors have less marked effects on vascular smooth muscle and on blood pressure than direct acting muscarinic agonists, why?
Because indirect acting drugs can modify the tone of only those vessels innervated by cholinergic nerves and because the net effect of vascular tone may reflect activation of both parasympathetic and sympathetic systems.
--therefore since few vascular beds receive cholinergic innervation, the cholinergic effect at vascular smooth muscle is minimal.
The first anticholinesterase is edrophonium, what is the use?
Dx of myasthenia gravis (Causes a rapid but short increase in muscle strength due to the increase in ACh)
The second anticholinesterase is physostigmine, what are the uses?
Tx of overdoses of anticholinergic drugs
--penetrates the blood brain barrier and exerts central cholinergic effects
What are adverse effects of physostigmine?
Lead to convulsions when high doses are used
Inhibition of acetylcholinesterases at the NMJ causes accumulation of acetylcholine and results in paralysis of skeletal muscle.
The third anticholinesterase is neostigmine, what is the use?
1. Reversal of effects of non-depolarizing neuromuscular blockers after surgery
--most commonly used drug for this indication
2. Used for symptomatic treatment of myasthenia gravis
--most commonly used is pyridostigmine though
3. Prevention and tx of postoperative distention and urinary retention
The fourth anticholinesterase is pyridostigmine, what is the use?
1. Indicated for tx of myasthenia gravis
--most commonly used anticholinesterase for this indication
The next set of anticholinesterase drugs are the organophosphates, many are highly liposoluble and extremely toxic. The only one used clinically is echothioophate, what are the uses?
Used for chronic open angle glaucoma, subacute or chronic angle closure glaucoma after iridectomy or where surgery is refused.
The two thiophosphate insecticides are malathion and parathion, what are the effects of each?
Malathion: considered safe enough for sale to the general public
Parathion: not available for general public use due to the danger to humans and livestock
What is the antidote for organophosphate poisoning?
Atropine (competitive inhibitor)
-muscarinic antagonists --- so prevents ACh from binding
What is the pneumonic for organophosphate or any cholinesterase inhibitor poisoning?
E: excitation of the skeletal muscle and CNS
Finally the last organophosphates are the nerve agents, what are they?
Tabun, Sarin and Soman
--among the most potent synthetic toxic agents known
All of the organophosphates, except echothiophate, are fully distributed to all parts of the body, including the CNS.
Finally the last set of drugs in the indirect agonist (Anticholinesterases) are the alzheimer drugs, what is the reasoning behind the use of these drugs in Alzheimers disease?
Donepezil, rivastigmine and galantamine
--patient have reduced cerebral production of choline acetyl transferase -- leads to decrease in acetylcholine synthesis
--these inhibitors attempt to compensate for the depletion of acetylcholine in the cerebral cortex and hippocampus