Direct Acting Cholinergic Agonist Flashcards
What are muscarinic receptor agonist?
parasympathomimetics
What are parasympathomimetics?
they mimic the parasympathetic response and bind directly to muscarinic receptors to elicit a second messenger-mediated response
What Is the primary use of parasympathomimetics?
primarily for diseases of the eye such as glacoma and accomadation estropia (crossed eyes) and diseases of the GI and urinary tract
What are choline esters?
they are a type of parasympathomimetic
Give an example of the choline esters?
acetylcholine HCl (michol)
bethanecol (urecholine)
carbachol (isopto carbachol, miostat)
methacholine (provaocholine)
What is acetylcholine mostly used for? And what is the formulation?
used in cataract extraction and surgical procedures of the anterior segment of the eye; ophthalmic solultion
What is carbachol used for? And what is the formulation?
used in cataract removal and anterior eye surgery and open angle glaucoma treatment; ophthalmic solution
What is bethanechol used for? And what is the formulation?
treating non-obstructive urinary retention following surgery, postpartum atony and for neurogenic atony
Other uses: post-op atony, megacolon, and gastrointestinal reflux
the administration will be oral and parenterally (SQ)
What is methacholine used for and what is the forumulation?
used for asthma diagnosis and bronchial airway hyperactivity diagnosis
administered as an inhalant with a physician present
but the use of methacholine for this has been discontinued
What is important to remember about methacholine?
the use of it has been discontinued
What is the mechanism of action for choline esters?
stimulation of muscarinic receptor subtypes at the ganglia and effector organs and the central nervous system (if it can get there)
What is important to recall about their molecule structure and how is this beneficial?
all four agents mentioned are permanetly charged quaternary amines and thy are poorly lipid soluble
Which drugs stimulate the nicotinic receptors?
ACh and carbachol
Which of the choline esters are less susceptible to the acetylcholinesterase and why?
carbachol and bethanecol are less susceptible to acetylcholinesterase because of the amine grup
Where are choline esters cleared?
in the kidney
Describe the molecualar structure of acetylcholine?
a quaternary amine (surrounded by four carbons–Ch2- a ester-CH3)
Describe the molecular structure of carbachol?
same a ACh except NH3
Describe the molecular structure of methacholine?
same as ACh except a methyl group attached to the CH group between quanternary amine
Describe the molecular sturce of bethanechol?
same as acetylcholine with both modifications of carbachol and methacholine
What is the cholinesterase susceptibility of acetylcholine chloride ?
very susceptible, the most out of all choline esters
What is the cholinesterase susceptibility of methacholine chloride?
low susceptibility but the second highest out of the group
What is the cholinesterase susceptibility of carbachol chloride?
negliable because of the NH2 group
What is the cholinesterase susceptibility of bethanecol chloride?
negligible because of the NH2 grup
What is the muscarinic action of acetylcholine chloride?
high muscarinic action (+++)
What is the muscarinic action of methacholine chloride?
high muscarinic action (+++)
What is the mucarinic action of carbachol chloride?
lower muscarinic action, average (++)
What is the mucarinic action of bethanecol chloride?
low muscarinic action, average (++)
What is the nicotinic action of acetylcholine chloride?
its fairly high at (+++)
What is the nicotinic action of carbachol chloride?
its fairly high at (+++)
What is the nicotinic action of methachline chloride?
none because of the CH3 group
What is the nicotinic action of bethanecol chloride?
none because of CH3 group
What are the major physiological actions of choline esters with regards to the eye?
the opththamic preparation put in the eye contract the iris sphincter smooth muscle—> cause constriction of pupil (miosis)—>contract the ciliary muscle to cause accommodation for near sight
the contraction of the sphincter pulls the iris away from the angle and contraction of the ciliary muscle stretch the tracecular meshwork to allow aqueous humor to flow out into the canal of schlemnm
What are the major physiological actions of choline esters with regards to glands?
stimulation of M3 receptors causes an increase in secretion of salivary, lachrymal, mucous and sweat glands
What are the major physiological actions of choline esters with regards to the cardiovasculature?
four effects:
- lower heart rate because of M2 receptors which increase K+ conductance and leads to hyperpolarization of atrial cells
- decrease conduction rate in the SA and AV nodes–by decreasing the slow inward Ca2+ current in atrial cells–hyperpolarization
- decrease force of contraction
- no direct cholinergic innervation of blood cells- there are muscarinic receptors on endothelial cells of vesses
endothelial M3 receptors action—> vasodialtion and relaxation as a result of stimulation of NO synthesis in endothelia cells—> NO diffuses into smooth muscle cells and activates production of cGMP—> cGMP activates PKG which increases K+ efflux from smooth muscle cells cause hyperpolarization and preventing Ca2+ influx–resulting in smooth cell relaxation
What are the major physiological actions of choline esters with regards to the GI tract?
all compounds produce an increase in GI tone, secretory activity and motility; GI contraction is due to depolarization of the muscle and an increase in Ca2+ influx
What are major physiological action of choline esters with regards to the urinary tract?
agonist contract he detrosor muscle, which rings the bladder, and relaxes trigone and sphincter muscles with allow voiding; sphincter relaxation is NO and cGMP mediated
What are the side effects of bethanecol?
well bethanecol is the only one that is administered systemically; the others are administered locally, mainly in the eye, and the systemic side effects are generally not a problem
How is bethanecol administered and how is this different thant other choline esters?
its give systemically
What are the side effects of inhalation of choline esters?
wheezing
difficulty breathing
headache
itching
throat irritation
What is the side effects of ophthalmic application of choline esters?
blurred vision
eye pain
irritation
headache
What are the side effects of systemic application of choline esters?
bronchoconstriction:
wheezing
shortness of breath
G.I.- belching
diarrhea and urge to urinate
blurred vision
When are patients contraindicated with the inhaled form of choline esters ?
patients with apparent asthma
wheezing
hayfever
coronary insufficiency and hyperthyroidism
What drugs are contraindicated with the ophthalmic form of choline esters ?
belladona alkaloids (muscarinic antagonist)
cycolpentolate
What conditions are contraindicated with the systemic form of choline esters?
asthma
bradycardia
CAD
occlusions
ulcers
GI obstructions
lesions
recent surgery requiring atony
What are natural alkaloids? Give examples.
muscarine
pilocarpine
oxotremorpine
What is pilocarpine/ where is it found?
in the leaves of Pilocarpus plants in South America
What is muscarine where is it found?
in a variety of mushrooms- Amanita muscaria and species of Clitocybe and Inocybe
What is arecoline/ where is it found?
arecoline is found in betal nuts (Areca catecha) from the East Indies
How is pilocarpine administered and what is important about it?
pilocarpine is the the only alkaloid agent that is give therapeutically;
Uses:
found in ophthalmic solution for open and closed angle glaucoma
secondary glaucoma
induction of miosis for surger
What does pilocarpine do?
its the drug of choice for emergency lowering of intraocular pressure IOP regardless of the cause
extremely effective in opening the trabecular meshwork around Schlemm’s canal—increased drainage and immediate drope in IOP is observed—occurs within a few minutes and last 4 to 8 hours.
How does the body rid itself of pilocarpine?
excretion of the amines is via the kidney
What is the mechanism of action for natural alkaloids?
they have a similar mechanism of action as choline esters
What are the physiological actions of natural alkaloids?
they are essentially the same as the choline esters in the GI tract, eyes, glands, and SM
What are the cardiovascular effects of natural alkaloids?
it depends on the alkaloid:
- muscarine has similar effects as choline esters
- pilocarpine when given IV create hypertension in the long run—>activates the sympathetic NS via stimulation of M1 receptors in the ganglia—>sympathetic post-ganglionic neurons would be depolarized and release NE onto the vessels
What are the side effects and drug interactions when natural alkaloids are give by opthalmic route?
side effects and drug interactions from opthalmic use are the same as those for choline esters
What are the side effects of high levels of muscarine? How can this happen?
high levels of muscarine (known as mycetism or mushroom poisoning)
produce SLUD:
Salivation
Lacrimation
Urination
Defecation
As well as: hallucination (why some people eat!), bronchospasm, bradycardia, and hypotension. Atropine reverses effect.
What will reverse the effects of high levels of muscarine?
Atropine reverses effect
What can lower levels of muscarine still cause?
irritability and restlessness, ataxia, hallucinations and delirium; no atropine needed–support
What are some nicotinic receptor agents?
1) nicotine
2) lobeline
3) dimethylphenylpiperzinium
What is lobeline?
a plant derivative; lower potency than nicotine; with similar spectrum of action
What is dimethylphenylpiperazinium?
a potent synthetic agent; little CNS acess; research tool for selective ganglionic nicotinic receptor stimulation
What is nicotine?
primary stimulant and addictive substance in tobacco
What is the actions of nicotine?
addictive and stimulant properties occur in the CNS; substantial autonomic effects occur via stimulation of nicotinic receptors found in all autonomic ganglia
What is nicotine used for?
used therapeutically to facilitate the cessation of smoking by reducing withdrawals symptoms
What are the products that contain nicotine? Hint about 8 products.
1) nicotine gum (nicorette)
2) transdermal patches (Habitrol RX, NicodremCQ, Nicotrol, and Prostep)
3) lozanges (Commit)
4) oral inhaler (Nicotrol inhaler RX)
5) nasal spray (Nicrotol NS RX)
What are some important structural properties of nicotine and lobeline and why is this important?
nicotine and lobeline are tertiary amines
- both are well absorbed from the lung (as a particulate), the buccal mucosa, and the skin
- not well absorbed from the stomach but more so in the intestine
Where are nicotine agonist metabolized?
first the liver
Where is nicotine removed from the body?
excretion is renal; excreted in the milk of lactating women
What important concept is needed to know about nicotinic blockade?
1) first of course, the nicotinic agonist stimulated the nicotinic receptor causing it to open and allow the flow of Na+ into the postganglionic neuron
2) once the cell is depolarized it must repolarize to fire again
3) failure to repolarize, due to continued presence of the agonist leaves the cell inhibited
4) stimulation is transient; blockade is more persistent; thus initially nicotine is an agonist but in the end it becomes an antagonist
What are the physiological actions of nicotinic agonist such as nicotine and lobeline?
nicotine and lobeline stimulates and inhibits the autonomic ganglia both the SNS and the PSNS
1) activation of the SNS results in an increase in catecholamine release which stimulates the heart and constricts the vasculature
2)
What are the autonomic mediated side effects of nicotinic agonist ?
tachycardia andh hypertension
What happens during acute nicotinic poisoning in the GI, gland, cardiac, CNS, and skeletal muscle?
GI-nausea and vomitting
glands-incred salivation and sweating
cardiac- hypertension and cardia arrhythmias
CNS-stimulation results in convulsions
skeletal muscle-depolarization block which can paralyze the respiratory muscle
What are the contraindications of nicotinic agonist?
1) non-smokers- hypersensitivity to nicotine
2) pregnancy
3) severe angina pectoris
4) life threatening arrhythmias
5) patients who have hypertension: the benefit of nicotine replacement must outweigh the risk of continued cardiovascular insult
What are effects of nicotinic agonist in the eye and what condition is treated?
contraction- ciliary muscle and sphincter muscle of iris
treats glacoma
What are the effects of nicotinic agonist in the GI tract and what condition is treated?
increases peristaltic movement and sphincter relaxation
treats-adynamic ileus
What are the effects of nicotinic agonist in the urinary bladder and what condition is treated?
increases the contraction of detrusor muscle, sphincter relaxation
treats urinary retension
What are the effects of nicotinic agonist in the vascular smooth muscle and what condition is treated?
dilation (minor effects)
What are the effects of nicotinic agonist in the bronchial smooth muscle and what condition is treated?
bronochoconstriction
What are the effects of nicotinic agonist on the body glands and what condition is treated?
secretion
What are effects of nicotinic agonist in the heart and what condition is treated?
1
How is acute nicotinic posioning treated?
with gastic lavage and activated charcoal
