Introduction to Cholinergic agonists and antagonists - through slide 39 - SRS Flashcards
Describe cholinergic transmission from synthesis to termination
- CHT transporter brings in hemicholiniums
- ChAT synthesizes ACh from choline and AcCoA
- ACh is packaged in vesicles by VAT
- VAMPS engage synaptic vesicles and lead to exocytosis of the ACh
- ACh interacts with muscarinic (G proteins) and nicotinic receptors
- ACh destroyed by AChE
Describe adrenergic transmission from synthesis to termination
- Tyrosine hydroxylase converts tyrosine to dopa to dopamine to NE
- VMAT packages the NE in synaptic vesicles
- CA++ channels open and lead VAMPS to engage vesicles, exocytosing NE
- NET takes up NE from the synaptic cleft
What is the parasympathetic NT?
ACh
What are the parasympathetic receptors?
•nAChR, mAChR
What are the sympathetic NTs?
•NE > Epi (DA); ACh
What are the receptors for the sympathetic system?
•α, β, (D), nAChR, mAChR
What type of receptors are the muscarinics?
GPCRs
Which muscarinic receptors are what kind of G’s (s, i, q)?
Odds are Stimulatory via Gq (M1,3,5)
Evens are inhibitory via Gi (G2,4)
Where are M1s?
CNS and ganglia
Where are M2s?
Heart, nerves, smooth muscle
Where are M3s?
Glands, smooth muscle, endothelium
In most organs what mAChR are predominant?
M3
What muscarinic receptor predominates in the heart?
M2
What muscarinic receptors are predominant in smooth muscle?
M3, M2
What are the types of agonists for cholinergic drugs?
Direct-acting
indirect-acting`
What is the class of indirect-acting cholinergic drugs?
AChE inhibitors
What are the types of cholinergic antagonists?
Antinicotinic agents
antimuscarinic agents
What types of antinicotinic agents are there? What is the problem with these?
Neuromuscular blockers
ganglion blockers
Tend to have many side effects due to the abundance of nicotinic receptors through the body.
What is the prototype antimuscarinic agent?
Atropine
What are the impacts of cholinergic agonists on the following:
Eye
Salivary gland
bronchi
heart
GI tract
Bladder
- Eye - pupil constriction, near vision
- Salivary gland - salivation
- bronchi - constriction and secretion
- heart - slowing
- GI tract - gastric secretion increased, colic, diarrhea
- Bladder - Void urine
What are direct-acting cholinergic drugs?
Choline esters, alkaloids
What are the problems for the direct acting cholinergic agonists?
What is the typical approach to using these drugs?
Poor absorption, susceptible to AChE
Used locally, such as topical application - eye drops
What are the four choline esters we covered?
Acetylcholine
methacholine
carbachol
bethanechol
What are the cholinomimetic alkaloids we covered?
Muscarinic - Muscarine and pilocarpine
Nicotinic - nicotine and lobeline
Muscarine is charged, but capable of…
Crossing BBB, thus highly toxic when ingested
What are the two major uses for direct-acting cholinergics?
Diseases of the eye
- glaucoma
- accomodative esotropia
GI/GU disorders
- Postoperative ileus
- Congenital megacolon
- Urinary retention
- Esophageal reflux
- Xerostomia, Sjögren syndrome
Name 6 direct acting cholinergic agonists
- Acetylcholine
- bethanechol
- carbachol
- cevimeline
- methacholine
- pilocarpine
What is the approved use for acetylcholine we covered?
•Approved for intraocular use during surgery and causes miosis (reduction in pupil size)
Bethanechol is a selective mAChR agonist that primarily affects what systems?
What can it be used for?
Risk associated with this?
Urinary and GU tracts
treats urinary retention and heartburn
UTI if sphincter fails to relax
Carbachol is a nonspecific cholinergic agonist that is used for treatment of?
Glaucoma
produce miosis during surgery or opthalmic exam
What is cevimeline used for?
Treat xerostomia in Sjogrens patients`
What is methacholine used for?
Used in diagnosis of bronchial airway hyperreactivity
What is pilocarpine useful for?
Xerostomia, miosis
What is the trade name of varenicline?
Chantix
What is varenicline used for?
What is its target?
Smoking cessation
binds with high affinity and selectivity to α4β2 nAChRs (NN)
What type of drug is varenicline?
Partial agonist -
•stimulation and subsequent moderate, sustained release of mesolimbic dopamine are thought to reduce craving and withdrawal symptoms associated with smoking cessation
Who should not have varenicline?
People with a history of depression or suicidal ideation
Muscarinic stimulants produce the slude toxicity effects, what is the approach to mitigating this?
Atropine used for muscarinic effects
Nicotine poisoning can occur via cigarettes and insecticides, what are the toxiticy effects? (5)
- CNS stimulation,
- skeletal muscle end plate depolarization,
- respiratory paralysis,
- hypertension,
- cardiac arrhythmias
What are the three chemical groups of AChE inhibitors?
Alcohols
carbamates
organophosphates
What are some clinical uses of AChE inhibitors?
(6)
- Mysathenia gravis
- reversal of neuromuscular blockade during anesthesia
- alzheimers
- parkinsons
- antidote for anticholinergic poisioning
- Sarin gas
What are the effects of AChE inhibitor toxicity?
SLUDGEM
- Salivation, Lacrimation, Urination, Defecation, Gastrointestinal, Emesis
- Also NMJ effects: muscle fasciculations followed by paralysis
If treating alzheimers or parkinsons would you use a charged or uncharged AChE inhibitors?
Uncharged
What is the alcohol AChE inhibitor? What are its lipid solubility and charge profiles?
Edrophonium
lipid sol - low
Charged
What are the carbamates we looked at?
What are their lipid solubilities and charges like?
neostigmine, low lipid sol. and charged
pyridostigmine, low lipid sol. and charged
physostigmine, high lipid sol. and uncharged
What is the organophosphate AChE inhibitor we covered? Lipid sol? Charge?
Echotiophate - low lipid sol. and charged
What are the cholinergic antagonist subgroups?
Antinicotinic
antimuscarinic
What are the antinicotinic agents?
neuromuscular junction - skeletal m.
ganglia (rarely used)
What organs are the antimuscarinics used for?
CNS, nerves, heart, s. muscle, glands, endothelium
block autonomic discharge
What drug is used for motion sickness? What type of drug is it?
Scopolamine - antimuscarinic
What antimuscarinics are used for respiratory disorders?
Ipratropium
Tiotropium
What are the antimuscarinic agents used for GI disorders?
Atropine
dicyclomine
glycopyrrolate
hyoscyamine
What antimuscarinic drugs are used for movement disorders?
Are these likely charged or uncharged?
- Benztropine
- Biperiden
- Orphenadrine
- Procyclidine
- Trihexyphenidyl
likely uncharged so as to reach CNS
What are the antimuscarinics used in opthalmology?
- Atropine
- Cyclopentolate
- Homatropine
- Scopolamine
- Tropicamide
What antimuscarinics are used for urinary disorders?
- Darifenacin
- Oxybutynin
- Solifenacin
- Tolterodine
- Trospium
What drugs are used for cholinergic poisoning?
Atropine + pralidoxime
What are the effects of antimuscarinics on the CNS?
- Sedation
- drowsiness
- amnesia
- hallucinations
- tremor reduction
What are the effects of antimuscarinics on the eye?
- Pupil dilation
- cycloplegia (ciliary muscle paralysis)
- Loss of accomodation
- Secretion reduction
What are the effects of antimuscarinics on the cardiovascular system?
Tachycardia
(small effect on blood pressure)
What would an antimuscarinic do to the respiratory system?
Bronchodilation
secretion reduction
What are the effects of antimuscarinics on the GI tract?
- Reduction in salivation
- gastric secretion
- prolonged gastric emptying time
What effects do antimuscarinics have on the GU tract?
urinary retention
What effect do antimuscarinics have on sweat glands?
Suppression of thermoregulatory sweating by inhibiting sympathetic cholinergic nerve fibers (no parasympathetic innervation of sweat glands)
What is the target for anticholinergic treatment for Parkinsons? What are the drugs we covered for this?
mAChR antagonists can reduce tremors
Tertiary amines:
- benztropine
- trihexyphenidyl
- procycline
Scopolamine is used for motion sickness, what are the routes of administration?
PO, injection, transdermal
Atropine can be used for anesthesia, how/when?
- Given to block responses to vagal reflexes induced by surgical manipulation of visceral organs.
- Atropine (or glycopyrrolate) is paired with the cholinesterase inhibitor neostigmine, to block its parasympathetic effects during reversal of neuromuscular blockade.
When performing eye surgery what kinds of drugs would you want?
mAChR antagonists - to induce cycloplegia or mydriasis
•α-adrenergic receptor agonists are shorter-acting and produce less adverse effects
What are two drugs used to prevent synechia formation in uveitis and iritis?
homatropine and atropine
(produce long lasting mydriasis and cycloplegia)
Asthma and COPD can be treated with anticholinergics, what are they? Which can be used once a day?
Ipratropium
Tiotropium - longer bronchodilation = 1 dose per day
anticholinergics can be used to treat GI disorders, what are these often combined with and why?
- Often combined with an opioid antidiarrheal drug to discourage abuse of the opioid agent
- Example: Lomotil - combination of atropine and diphenoxylate
Anticholinergics can be used to treat GU disorders, what receptor do we want these to be selective for?
What are four drugs that are options for this?
Selectivity to M3 subtype of of mAChr - predominate in bladder wall and sphincter smooth muscle
- Darifenacin
- silifenacin
- tolterodine
- Oxybutynin - not preferred d/t short half life and significant side effects (xerostomia, dizziness, constipation, blurred vision)
What are examples of poisoning events that anticholinergics are useful for?
- AChE inhibitor overdose
- Sarin gas
- Organophosphate insecticides
What are two examples of poisonings that anticholinergics are not good for?
- Poisoning at the nAChR - must use plaidoxime to regenerate the nAChRs
- Delayed-onset mushroom poisoning
What are three contraindications for anticholinergics?
- Glaucoma
- Prostatic hyperplasia
- Acid-peptic disease
