Exam II: Cholinergic Agonists Flashcards
Cycle of ACh (All 6 steps)
- ACh made from acetyl-CoA and choline
- ACh stored in neurons (“quanta”)
- Release of ACh when neurons stimulated by an action potential
- ACh binds to ACh-R
- AChE breaks down ACh
- Acetyl-CoA and choline recycled
What are the two types of cholinergic receptors?
Muscarinic
Nicotinic
Are muscarinic receptors found in the sympathetic or parasympathetic nervous system…or both?
Parasympathetic
Where are nicotinic receptors found ( in terms of nervous system…not specific organ )
Ganglionic level of both parasympathetic and sympathetic sides of ANS
Do nicotinic receptors have inhibitory capabilities?
No. They only relay the efferent message sent from CNS
If a cholinomimetic agent acts to stimulate it is an ______. In contrast, if an cholinomimetic agent acts to inhibit it is an ______.
Direct agonist
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Indirect agonist
by preventing breakdown of ACh
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What are the two groups of direct-acting cholinomimetics?
- Esters of Choline
2. Alkaloids
List 4 examples of choline esters
- ACh
- Bethanechol
- Carbachol
- Methacholine
List 4 examples of alkaloids
- Lobeline
- Muscarine
- Nicotine
- Pilocarpine
What are the characteristics of choline esters?
- Hydrophillic
(they poorly penetrate BBB b/c of their methyl groups pulling electrons and causing a positive charge - Hydrolized by AChE
- Above properties vary on chemical structure
All alkaloids are _______ except for _____ which is a ___________.
Tertiary amines
Muscarine
quartenary amine
All choline esters are ________.
Quarternary ammoniums
What are the characteristics of direct acting alkaloids?
- Well absorbed after oral administration
- Lipid soluble –> allows for a larger VD
- NOT susceptible to AChE
What are the three types of AChE inhibitors?
- Simple alcohols
- Carbamate Esters
- Organophosphates
Contrast the three AChE inhibitor’s binding effects
Simple alcohols = bind weakly and reversibly
–> half life is very short (< 10 min)
Carbamate Esters = bind reversibly but stronger than simple alcohols
–> half life from 30 min to 6 hours
Organophosphates = covalent bonds make it nearly irreversible
–> half-life lasts hundreds of hours
Describe the effects cholinomimetics have on the eye and what these effects facilitate.
- Iris sphincter smooth muscle - contraction, causing miosis (pupil constriction)
- Ciliary muscle –> contraction (accomodation)
These facilitate aqueous humor flow from the anterior chamber and alter the amount and focus of light reaching the retina
What drugs are used to treat glaucoma? Describe the type of these drugs.
Pilocarpine (muscarine agonist)
Physostigmine (carbamate ester…AChE inhibitor)
Describe the effects cholinomimetics have on the respiratory system.
Do we use cholinomimetics to treat respiratory conditions?
Cause contraction of bronchiole muscles and stimulate secretion of bronchiole glands (inc. mucous)
We do not use cholinomimetics to tx respiratory conditions
Describe the effects cholinomimetics have on the GI system
Increase motility (peristalsis), increase secretion, and relax sphincter muscles
What is a GI disorder in which you would use a cholinomimetic to tx
Post-operative ileus –> use neostigmine (AChE inhibitor)
Describe the effects of cholinomimetics on the GU system
Detrusor muscle –> contraction
Trigone and sphincter –> relaxation
What are cholinomimetics can be used to treat urinary retention?
Bethanecol (Choine ester…direct acting)
Neostigmine (Carbamate ester…indirect acting)
What secretory glands do muscarine agonists stimulate?
- Sweat glands –> diaphoresis
- Salivary glands
- Lacrimal glands
- Nasopharyngeal glands –> snot
Muscarinic receptors in the CNS are found to:
- Induce tremor
- Cause hypothermia
- Interfer w/ nocieption (ability to sense stimuli)
Nicotinic receptors in the CNS are found to:
- Induce tremor
- Stimulate emesis (vomitting)
- Stimulate respiratory center
Indirect cholinomimetics in the CNS can cause:
- convusions
- coma
- respiratory arrest
How are cholinomimetics used to threat Alzheimer’s Disease?
AChE inhibitors slow progression (do not cure)
Name 4 AChE inhibitors used to treat Alzheimer’s Dz
- Tacrine
- Donepezil
- Galatamine
- Rivastigmine
What drugs is used to treat smoking cessation? What does it do?
Varenicline
A direct nicotnic agonist that decreases cravings and pleasurable effects of cigarettes
Describe how ACh acts at the neuromuscular junction
- ACh released from presynaptic neurons
- ACh binds to nicotinic receptors on muscle fiber
- This results in depolarization of muscle fiber
- Causes contraction of skeletal muscle
Contrast the effects of low, medium, and high doses of indirect cholinomimetics at the neuromuscular junction
LOW DOSE: prolongs effects of ACh, increasing the strength of muscle contraction
MEDIUM DOSE: may cause muscles to fibrillate - muscles not effective
HIGH DOSE: block depolarization causing muscle paralysis
Myasthenia Gravis
An autoimmune process of antibodies targeting nicotinic receptors. These antibodies block binding of ACh to receptors
What are some symptoms of myasthenia gravis?
Ptosis
Difficulty speaking
Weakness
What drugs are used to treat Myasthenia Gravis?
AChE inhibitors
What cholinomimetic is used to reverse neuromuscular paralysis (usually following surgery)
Neostigmine (an indirect acting carbamate ester)
What do you use to treat an excessive amount of anticholinergic action in the body?
AChE inhibitors (physostigmine) because you want to inc. the amount of ACh at receptor sites
Jack eats a mushroom of the genus Inocybe (containing muscarinic alkaloids). What kind of cholinomimetic toxicity does Jack have and what can be done to treat him.
Toxicity of Direct muscarinic agonists
Tx: Atropine
What is the fatal dose of nicotine?
40 mg or 1 drop of pure liquid.
2 ciagrettes has this much, but fortunately most gets destroyed by burning
Acute nicotine toxicity can cause:
- CNS stimulation (convusions, resp. arrest, coma)
- Skeletal muscle depolarization –> leads to blockage and resp. paralysis
- Hypertension and cardiac arrhythmias
How do you treat acute nicotine toxicity?
Supportive until drug is metabolized within a few hours
What causes cholineresterase inhibitor toxicity?
Organophosphates and carbamate cholineresterase inhibitors
What symptoms are displayed when one has toxicity of cholineresterase inhibitors?
Muscarinic excess
How do you treat someone with cholineresterase inhibitor toxicity?
- Monitor V/S
- Decontaminate if possible
- Antidote w/ parenteral atropine or pralidoxime
