Cholinergic agonists and antagonists-Kruse Flashcards
These direct-acting cholinergic agonists contain permanently charged quaternary NH4 groups that result in their poor absorption and distribution into the CNS
choline esters
List the ranking of direct-acting cholinergic agonists, choline esters, from most rapid to least rapid in terms of cholinesterase metabolism
ach > methacholine > carbachol = bethanechol
These direct-acting cholinergic agonists are uncharged tertiary amine that are well absorbed from most sites of administration
Alkaloids
Which choline ester has the greatest muscarinic action? Nicotinic action?
Muscarinic: Methacholine
Nicotinic: Ach and Carbachol
List the location, Structural features (2nd messenger), and mechanism of M1 receptors
location=nerves
Structural=Gq/11
Mechanism: IP3, DAG
List the location, Structural features (2nd messenger), and mechanism of M2 receptors
location=heart, nerves, smooth m
structural=Gi/0
Mechanism=inhibition of cAMP, activate K channels
List the location, Structural features (2nd messenger), and mechanism of M3 receptors
location=glands, smooth m., endothelium
structural=Gq/11
Mechanism=IP3, DAG
List the location, Structural features (2nd messenger), and mechanism of M4 receptors
location=CNS
structural=Gi/0
mechanism=inhibit cAMP
List the location, Structural features (2nd messenger), and mechanism of M5 receptors
location=CNS
structural=Gq/11
mechanism=IP3, DAG
List the location, Structural features (2nd messenger), and mechanism of Nn receptors
location=postganglionic cell body, dendrites, CNS
structural=alpha and beta only
mechanism=Na, K depolarizing ion channel
Nicotine has a greater affinity for __ nAChRs
Nicotine itself has a greater affinity for neuronal nAChRs than skeletal muscle nAChRs
list the parasympathetic effects of the following:
- Sphincter muscle of iris: ___
- Ciliary muscle of eye: ___
- Heart: ___
- Blood vessels: ___
- Bronchial muscle: ___
- Bronchial glands: ___
- GI motility: ___
- GI sphincters: ___
- GI secretion: ___
- Urinary detrusor muscle: ___
- Urinary trigone and sphincter: ___
- Sweat, salivary, lacrimal, nasopharyngeal glands: ___
iris-contraction (miosis) ciliary m.-contraction for near vision heart-decrease rate/contractile strength/conduction velocity blood vessels-dilation (via EDRF) bronchial muscle-contraction (bronchoconstriction) bronchial glands-stimulation gi motility-increase gi sphincters-relax gi secretion-stimulation detrusor-contract trigone and sphincter-relax glands-secretion
the major clinical uses of the direct-acting cholinomimetics are for ___
diseases of the eye (glaucoma, accommodative esotropia), and the GI/GU tracts (post-operative atony, neurogenic bladder)
describe the effects of muscarinic stimulants and glaucoma
cause contraction of ciliary body, which facilitates outflow of aq humor and reduces intraocular pressure
___ is the most widely used choline ester for GI/GU disorders, including postoperative ileus, congenital megacolon, urinary retention, esophageal reflux
bethanechol
___ are used to increase salivary secretion (eg dry mouth associated with Sjorgren syndrome
pilocarpine and cevimeline
overdoses of pilocarpine and the choline esters cause predictable muscarinic effects (nausea, vomiting, diarrhea, urinary urgency, salivation, sweating, cutaneous vasodilation, bronchial constriction) and are blocked by antimuscarinic compounds such as __-
atropine
what are some major contraindications to the use of mAChR agonists that are distributed systemically?
asthma
hyperthyroidism
coronary insufficiency
acid-peptic disease
what drug combination can be used in the case of acute nicotine toxicity?
atropine –> for excess muscarinic stimulation from parasympathetic ganglia
diazepam –> parenteral anticonvultant for CNS stimulation
__- is approved for intraocular use during surgery and causes miosis; rarely given systemically
acetylcholine
__- is rarely used but adminstered by inhalation for the diagnosis of bronchial airway hyperreactiviy in pts who do not have clinically apparent asthma
methacholine
___ can be used to treat pts with urinary retention and heartburn, is a selective mAChR agonist with little CV stimulation, and may produce UTI if sphincter fails to relax
bethanechol
___ is a nonspecific cholinergic agonist that is used for tx of glaucoma or to produce miosis during surgery or ophthalmic examination
carbachol
___ is an oral table used to treat dry mouth (xerostomia) in pts with Sjorgren syndrome. It is metabolized via P450 pathways and eliminated in urine
cevimeline
___ is a pure mAChR agonist that is approved for xerostomia tx in pts with Sjogrens syndrome or head and neck cancer tx related xerostomia (PO), miosis during opthalmic procedures (topical), and for glaucoma (topical)
pilocarpine
Varenicline (Chantix) is a partial agonist that binds with high affinity and selectivity to what receptor? What is the most common adverse effect? The serious side effects?
alpha4beta2 (a4b2) nAChR’s
most common –> nausea
serious –> neuropsychiatric symptoms, changes in behavior, agitation, depressed mood, suicide ideation
this drug is an indirect-acting cholinergic agonist that has an alcohol group
edrophonium
these drugs are indirect-acting cholinergic agonists that are carbamic acid esters
neostigmine, pyridostigmine, physostigmine, and cabaryl
echothiophate, parathion and malathion (insecticides), and sarin, soman, and tabun (nerve gases) are examples of what?
organophosphates–> indirect-acting cholinergic agonists
binding to AChE is covalent and irreversible
Describe the effects on the CNS with low concentrations of AChE inhibitors:
diffuse activation on EEC and a subjective alerting response
Describe the effects on the CNS with high concentrations of AChE inhibitors:
generalized convulsions d/t neuronal hyperstimulation (may be followed by coma or resp. arrest)
Describe the effects on the eye, resp tract, gi tract, and urinary tract with AChE inhibitors:
similar to the direct acting cholinomimetics (bethanechol, carbachol, pilocarpine); these organs are innervated by mAChRs and stimulation results in parasympathetic responses
describe the net cardiovascular effects with moderate doses of AChE inhibitors
modest bradycardia, a fall in CO (due to bradycardia, decreased atrial contractility, and some reduction in ventricular contractility), and a modest increase in BP
toxic doses of AChE inhibitors cause more marked bradycardia, occasionally tachycardia, and hypotension
These AChE inhibitors can reverse the paralysis induced by neuromuscular blocking drugs during surgical anesthesia
Neostigmine and edrophonium are preferred
Donepezil, rivastigmine, galantamine, and physostigmine are preferred for treatment of this neurological disorder
Progressive dementia of the alzheimer type
List some effects of intoxication d/t anticholinergic agents and name a drug that can reverse these effects:
Cutaneous vasodilation Anhidrosis Anhydrotic hyperthermia Nonreactive mydriasis Delirium Hallucinations Reduction or elimination of desire to urinate
-Physostigmine can reverse the above mentioned anticholinergic effects and is preferred because it crosses the BBB
Nondepolarizing neuromuscular blocking agents in combination with AChE inhibitors will diminish neuromuscular blockade. One exception is the drug ___ (metabolized by AChE), where neuromuscular blockade is prolonged
Mivacurium
This drug in combination with AChE inhibitors will enhance phase 1 block and antagonize phase 2 block
Succinylcholine
Describe the interaction between direct-acting cholinergic agonists and AChE inhibitors:
Combination will enhance the effects of cholinergic agonists
Describe the effects of beta-blockers in combination with AChE inhibitors:
Combination may enhance the bradycardic effects
Describe the effects of the combination of AChE inhibitors and systemic corticosteroids:
Coadministration with AChE inhibitors may enhance muscle weakness seen in pts with myasthenia gravis
This mAChR antagonist is the antidote recommended for cholinergic poisoning in combination with maintenance of vital signs (respiratory in particular)
Atropine
Atropine is ineffective against peripheral neuromuscular stimulation (nAChRs)
List an example of a cholinesterase regenerator and describe the current antidotal therapy for organophosphate exposure resulting from warfare or terrorism:
- Pralidoxime
- Atropine, an oxime (pralidoxime), and a benzodiazepine as an anticonvulsant
Animal studies have shown that pretreatment with ___ reduces the incapacitation and mortality associated with nerve agent poisoning, especially with agents such as soman that show rapid aging. It has been approved for combat use in US military personnel
Pyridostigmine
-should be discontinued at 1st sign of nerve gas exposure
___ drugs elicit their effects at the NMJ and on nAChRs in the ganglia
Antinicotinic
The prototype antimuscarinic compound is ___
Atropine
What are some mAChR antagonists that can be used to reduce the tremor associated with PD?
Benztropine and trihexyphenidyl
This drug can be useful in treating motion sickness and is one of the oldest agents for seasickness and can be administered by injection, PO, and transdermal patch
Scopolamine
This long-lasting mAChR antagonist is used to prevent synechia formation in uveitis and iritis
Homatropine
Which antimuscarinic agents can be used to treat asthma and COPD?
Ipratropium and Tiotropium
___ is used as an inhalational agent in the tx of asthma and COPD and is currently a first line therapy
Ipratropium
THe recently approved agent ___ has a longer bronchodilator action than ipratropium and can be dosed once daily in pts with COPD
Tiotropium
This mAChR antagonist is used in the tx of common travelers diarrhea. It is a combo of atropine and diphenoxylate.
Lomotil
What is the prototypical antimuscarinic agent used in disorders of the GU tract?
Oxybutynin
___ is a nonselective antagonist that is comparable in efficacy and side effects with oxybutynin
Trospium
List some antimuscarinic agents for urinary disorders that are more selective and may produce less adverse effects
Darifenacin, solifenacin, and tolterodine
What are some contraindications for antimuscarinic agents?
Pts with glaucoma (reduced secretions) and used with caution in elderly men with a history of prostatic hyperplasia
