Cholinergic Agonists and Antagonists (Kruse) Flashcards
Review:
What are the parasympathetic NTMs?
What are the parasympathetic receptors?
NTMs: Ach
Receptors: nAChR, mAchR
Review
What are the sympathetic NTMs>
What are the sympathetic receptors?
NTMs: Ne>Epi (DA); Ach
Receptors: a, B (D), nAchR, mAchR
What are the four events at the cholinergic nerve terminal?
- Ach synthesis
- Ach storage
- Ach release
- Ach destruction
What are the four events at the adrenergic nerve terminal?
- synthesis
- storage
- release
- reuptake
M1 receptors
Location:
Structure:
Mechanism:
Nerves
GPCR, Gq11
IP3, DAG cascade
M2
Location:
Structure:
Mechanism:
heart, nerves, Sm. muscle
GPCR, Gi/o
inhibits cAMP production, activates K channels
M3
Location:
Structure:
Mechanism:
Glands, Sm. muscle, endothelium
GPCR, Gq/11
IP3, DAG
M4
Location
Structure
Mechanism
CNS
GPCR, Gi/o
Inhibits cAMP production
M5
Location
Structure
Mechanism
CNS
GPCR/Gq11
IP3, DAG
Nn
Location
Structure
Mechanism
postganglionic cell body, dendrites, CNS
a and B only
Na, K depolarizing ion channel
In most organs, which receptor type is predominant?
Which receptor type predominates in the heart?
What are the most common receptor types in smooth muscle?
M3
M2
M3 and M2
What is the function of cholinergic agonists?
mimic the actions of Ach on nAchRs and mAchRs
classified based on MOA (direct or indirect)
what are the direct acting cholinergic agonists?
Acetylcholine
Methacholine
Carbachol
Bethanechol
metabolized by AchE
Does Ach display muscarinic or nicotinic action?
Does Methacholine display muscarinic or nicotinic actions?
Does Carbachol display muscarinic or nicotinic actions?
Does Bethanechol display muscarinic or nicotinic actions?
Both equally
Muscarinic only
both, but more nicotinic
Muscarinic only
Which direct cholinergic agonists are uncharged and highly absorbed
muscarine and pilocarpine (chiefly muscarinic acting)
nicotine and lobeline (chiefly nicotinic acting)
Which direct acting cholinergic agonists are charged and poorly absorbed?
Ach
Methacholine
Carbachol
Bethanechol
Indirect cholinergic agonists are also known as?
These come in three flavors. What are they?
AChE Inhibitors
Alcohols (reversible)
Carbamic Acid Esters (reversible, long lasting)
Organophosphates (irreversible, covalent)
Which AchE inhibitors are charged and poorly absorbed?
Neostigmine
Carbaryl
Physostigmine
Edophonium
Which AchE inhibitors are uncharged and highly absorbed?
Echothiophate
Soman
Parathion
Paraoxon
Malathion
Malaoxon
What are some general parasympathetic effects of cholinergic agonists?
Miosis
decreased HR, contraction and conduction velocity
vasodilation in low dose, vasoconstriction in high dose
bronchoconstriction and increased secretions
increased GI motility with sphincter relaxation and increased secretions
contracts detrusor in bladder and relaxes trigone and sphincter
sweat secretions
What are the major uses of direct acting cholinergic agonists?
glaucoma and accomodative esotropia (crossed-eyes)
post-op ileus
congenital megacolon
urinary retention
GERD
xerostomia/Sjogren’s
What are the symptoms of toxicity with direct acting muscarinic stimulants?
N/V/D, urinary urgency
salivation/sweating
vasodilation
bronchoconstirction
SLUDGE (increased gland secretions)
Muscarinic stimulants (direct acting cholinergic agonists) are contraindicated in whom?
pts with asthma, hyperthyroidism, coronary insuffiency and acid peptic disease
What are the symptoms of toxicity in direct-acting nicotinic stimulants?
nicotinic poisoning: from cigarettes or insecticides
causes CNS stimulation, skeletal muscle endplate depolarization, resp. paralysis, hypertension, cardiac arrhythmias
tx with atropine and parenteral anticonvulsants
Ach is used for what issues?
intraocular use during surgery to cause miosis (pupil constriction)
What is bethanechol used for?
Selective mAchR agonist that primarily affects GU tracts
used to treat urinary retention and heartburn
little cardio stimulation
may increase risk for UTIs due to failure of sphincter relaxation
What is carbachol used for?
nonspecific cholinergic agonist used for the treatment of glaucoma or to produce miosis during surgery or eye exam
What is cevimeline used for?
oral tablet used to treat dry mouth in pts with Sjogrens
What is Pilocarpine used for?
xerostomia in pts with Sjogren’s.
induce miosis in eye procedures and glaucoma
it is a pure mAchR agonist
What is Varenicline?
used for smoking cessation
partial agonist that binds with high affinity and selectivity to a4B2 nAChR (Nn)
MOA: stimulates a moderate and sustained release of mesolimbic dopamine to reduce craving and withdrawal from nicotine
may cause nasuea and neuro-psych sx (SI, depression)
How are indirect-acting cholinergic agonists used for glaucoma?
stimulates mAchR on ciliary body to facilitate aq. humor outflow and reduce intraocular pressure
(replaced by B-blockers and prostaglandins)
How are indirect-acting cholinergic agonists used to treat dementia from Alzheimer’s and Parkinson Disease?
AD pts have a deficiency of intact cholinergic neurons
What is used as an antidote for anticholinergic poisoning?
What causes it?
What are the sx of it?
Indirect-acting cholinergic agonists
anticholinergic poisoning can be caused by atropine, antihistamines, TCAs, sleep aids, cold preparations
sx-vasodilation, anhidrosis, anhydrotic hyperthermia, nonreactive mydirasis (dilated pupils), delirium, hallucinations, reduced urine
Indirect-acting cholinergic agonists are also used for what?
reversing neuromuscular paralysis (in surgery)
Myasthenia Gravis
AchE inhibitor toxicity can be treated by what?
indirect-acting cholinergic agonists, specifically atropine, maintaining vitals, decontamination, pralidoxime
causes SLUDGE and NMJ effects
What are the two classes of cholinergic antagonists?
muscarinic and nicotinic
What are the two targets of antinicotinic agents?
neuromuscular junction (ske. muscle relaxants)
ganglia (rarely used)
What are the targets of antimuscarinic agents?
how do they work?
CNS, nerves, heart, smo. muscle, glands, endothelium
block the effects of the parasympathetic autonomic discharge
most clinically used
ex: atropine
Anticholinergics used for motion sickness?
Scopolamine
Anticholinergics used for GI disorders
Atropine
Dicyclomine
Glycopyrroleate
Hysoscyamine
Anticholinergic agents used in ophthalmology
atropine
cyclopentolate
homatropine
scopolamine
tropicamide
anticholinergics used for respiratory disorders
ipratropium
tiotropium
anticholinergic agents used for urinary disorders
darifenacin
oxybutynin
solifenacin
tolterodine
tropspium
anticholinergics used for cholinergic poisoning
atropine (+pralidoxime)
anticholinergics used for movement disorders
benztropine
biperiden
orphenadrine
procyclidine
trihexyphenidyl
What are the general effects of anticholinergics?
incresae sympathetic tone
constrict muscles, tachycardia
bronchodilation and reduced secretions
supresses thermoregulation
sedation/drowsiness
How are anticholinergics used in Parkinson’s Disease?
mAchR antagonists can reduce tremoris
not as effective as dopaminergic therapy, often used in combination
specific drugs: tertiary amines benzotropine, trihyxyphenidyl, procyclidine
Scopolamine for motion sickness can be administered three ways
PO
injection
transdermal
how are anticholinergics used for anesthesia?
atropine is given to block responses to vagal refluxes induced by surgical manipulation of visceral organs
atropine or glycopyrrolate is paired with the cholinesterase inhibitor neostigmine to block its parasympathetic effects
When are mAchR antagonists used in ophthalmologic disorders?
mAchR antagonists are only used when cycloplegia or prolonged mydriasis is required like after LASIK
a-adrenergic receptor agonists are shorter acting and produce less adverse effects and can be used as well/instead
When are homatropine and atropine used in ophthalmogic disorders?
homatropine and atropine are used to prevent synechia formation in uveitis and iritis
long acting agents
mydriasis may last 6 hours to 12 days and cycloplegia persists 10hrs to 14 days
How is ipratropium and tiotropium used for asthma and COPD (anticholinergics)
these are inhaled mAChR antagonists
Tiotropium has a longer bronchodilator action than ipratropium and can be dosed once daily
how are mAchR antagonists used for GI issues?
can be used to treat traveler’s diarrhea and other hypermotility issues, limited use.
May be combined with opioid antidiarrheal
Ex: Lomotil
How are mAchR antagonists used for GU disorders?
treat urinary urgency
agents with selectivity for M3 mAchR work well because of their presence in bladder wall and sphincter muscle
Oxybutinin is an example but causes dry eye/mouth, dizziness, constipation, blurred vision
Darifenacin, solifenacin, and tolterodine also work the same way and have longer half-lives and reduced side effects
What causes cholinergic poisoning?
cholinesterase inhibitor insecticides, wild mushrooms, warfare nerve gases
give Atropine for CNS and pralidoxime for peripheral NS
atropine is useless in delayed onset mushroom poisoining characterized by n/v 6-12 hours after ingestion and causes hepatic/renal damage
High systemic concentrations of anticholinergics can cause the following?
blocked parasympathetic function
dry as a bone, blind as a bat, red as a beet, mad as a hatter, hot as a hare
treat with ACE inhibitors or symptomatically
Contraindicated in people with glaucoma, BPH, acid peptic disease
