Cholinergic Agonists and Antagonists Flashcards
Direct-acting cholinomimetic Drug list
a) Acetylcholine
b) Bethanechol
c) Carbachol
d) Cevimeline
e) Methacholine
f) Pilocarpine
g) Varenicline (Chantix)
Cholinesterase Inhibitor Drug list
a) Ambenonium
b) Donepezil
c) Echothiophate
d) Edrophonium
e) Galantamine
f) Neostigmine
g) Physostigmine
h) Pyridostigmine
i) Rivastigmine
j) Tacrine
Cholinesterase regenerator drug list
a) Pralidoxime
Antimuscarinic drugs used for motion sickness
i) Scopolamine
antimuscarinic drugs used for gi disorders
i) Atropine
ii) Dicyclomine
iii) Glycopyrrolate
iv) Hyoscyamine
antimuscarinic drugs used in ophthalmology
i) Atropine
ii) Cyclopentolate
iii) Homatropine
iv) Scopolamine
v) Tropicamide
antimuscarinic drugs used for resp disorders
i) Ipratropium
ii) Tiotropium
antimuscarinic drugs used for urinary disorders
i) Darifenacin
ii) Fesoterodine
iii) Oxybutynin
iv) Solifenacin
v) Tolterodine
vi) Trospium
antimuscarinic drugs used for cholinergic poisoning
i) Atropine (+ pralidoxime)
antimuscarinic drugs used for movment disorders
i) Benztropine
ii) Biperiden
iii) Orphenadrine
iv) Procyclidine
v) Trihexyphenidyl
Acetylcholine as a drug
i) Approved for intraocular use during surgery and causes miosis (reduction in pupil size)
ii) Rarely given systemically due to rapid hydrolysis by cholinesterase
methacholine
i) Administered by inhalation for the diagnosis of bronchial airway hyperreactivity in patients who do not have clinically apparent asthma
ii) Rarely used due to need for emergency resuscitation equipment, oxygen, and medications to treat severe bronchospasm (e.g., β2 adrenergic receptor agonists)
bethanechol
i) Can be used to treat patients with urinary retention and heartburn
ii) Selective mAChR agonist
iii) Little cardiovascular stimulation
iv) May produce urinary tract infection if sphincter fails to relax
carbachol
i) Nonspecific cholinergic agonist that is used for the treatment of glaucoma or to produce miosis during surgery or ophthalmic examination
cevimeline
i) Oral tablet used to treat dry mouth (xerostomia) in patients with Sjögren’s syndrome
ii) Metabolized via P450 pathways and eliminated in urine
pilocarpine
i) Approved for xerostomia treatment in patients with Sjögren’s syndrome or head and neck cancer treatment related xerostomia (PO), miosis during ophthalmic procedures (topical), and for glaucoma (topical)
ii) Pure mAChR agonist
Varenicline
i) FDA approved for smoking cessation
ii) Partial agonist that binds with high affinity and selectivity to α4β2 nicotinic ACh receptors located in the brain; stimulates receptor-mediated activity, but at a substantially lower level than nicotine
iii) Stimulation and subsequent moderate, sustained release of mesolimbic dopamine are thought to reduce craving and withdrawal symptoms associated with smoking cessation (reward pathway)
iv) Greater than 90% eliminated in urine as unchanged drug
v) Nausea is most common adverse effect; serious adverse effects include neuropsychiatric symptoms, including changes in behavior, agitation, depressed mood, suicidal ideation, and attempted and completed suicide
vi) Treatment comes with the following warning: If patients, their families, or caregivers notice agitation, depressed mood, or changes in behavior that are not typical for the patient or if the patient has suicidal thoughts or actions, the patient should stop taking varenicline and contact their healthcare professional
ambenonium
quaternary and charged ache inhibitor
donepezil
tertiary uncharged ache inhibitor, dementia
echothiophate
organophosphate - ache inhibitor, this one is charged and not highly lipid soluble (exception), so it doesn’t go cns
edrophonium
alcohol, ache inhibitor, quaternary and charged, reverses paralysis after anesthesia
galantamine
tertiary ucharged ache inhibitor, used for dementia
neostigmine
carbamic ester ache inhibitor, quaternary and charged, effects seen at nmj, reverse paralysis after anesthesia and to block parasympathetic effects during reversal os skeletal muscle relaxation
physostigmine
carbamic ester ache inhibitor, tertiary and uncharged, reverses Intoxication due to anticholinergic agents that can produce cutaneous vasodilation, anhidrosis, anhydrotic hyperthermia, nonreactive mydriasis, delirium, hallucinations, and a reduction or elimination of the desire to urinate, which are generally the result of reduced or blocked mAChR stimulation
iii) Physostigmine can reverse the above mentioned anticholinergic effects and is preferred because it crosses the blood-brain barrier
Also treats overdoeses or Machr antagonists
pyridostigmine
carbamic ester ache inhibitor, quaternary and charged, prophylaxis for ache inhibitor poisoning (nerve gas)
rivastigmine
tertiary unchaged ache inhibitor, used for dementia
tacrine
tertiary uncharged ache inhibitor, used for dementia but not the best one
pralidoxime
cholinesterase regenerator, charged and only at nmj, given with atropine for cholinergic poisoning
scopolamine
has more marked CNS effects producing drowsiness and amnesia (toxic doses of scopolamine can cause excitement, agitation, hallucinations, and coma)
Vestibular disturbances (motion sickness)
oldest agents for seasickness and can be administered by injection, PO, and transdermal patch
useful in preoperative settings to limit increased airway secretions caused by irritant anesthetics
mostion sickness and ophthalmology
atropine
for excess muscarinic stimulation from parasympathetic ganglia and parenteral anticonvulsants (diazepam) for CNS stimulation
antidote recommended for cholinergic poisoning
ineffective against the peripheral neuromuscular stimulation (nAChRs)
therapy for organophosphate exposure
The prototype antimuscarinic compound
tertiary amine that can get into the cns
half life of 2 hours and 60% is unchanged in urine
40% is changed by type 1 and type II and is excreted in urine
Atropine is a reversible antagonist of mAChRs; blockade from a small dose can be overcome by a
larger dose of ACh or equivalent muscarinic agonist
ii) Tissues most sensitive to atropine are salivary,
bronchial, and sweat glands while acid secretion by the
gastric parietal cells is the least sensitive
iii) Antimuscarinic effects generally follow the graph at the
right as doses of atropine increase, but can vary for
other antimuscarinic agents
iv) Atropine antagonizes the actions of all 5 mAChRs and
does not distinguish between receptor types while
other antimuscarinic compounds can be selective for
one or another of these subgroups
minimal stimulant effects on the CNS (particularly the parasympathetic medullary centers) and a slower, longer-lasting sedative effect on the brain
The net CV effects of atropine in patients with normal
hemodynamics are not dramatic: tachycardia may
occur, but there is little effect on blood pressure
Low doses of atropine result in initial bradycardia
before the effects of peripheral vagal block manifest
(see blue line in figure at right between atropine doses
of 0.1 – 1 μg/kg; attributed to the block of presynaptic
M1 receptors on parasympathetic postganglionic nerve
terminals in the SA node, which normally inhibit ACh release)
(4) Moderate to high doses of atropine cause tachycardia by blockade of vagal slowing
Gastric secretion is blocked less effectively than salivary secretion: the volume and amount of acid, pepsin, and mucin are all reduced but large doses of atropine may be required
Atropine suppresses thermoregulatory sweating by inhibiting sympathetic cholinergic nerve fibers (there is no parasympathetic innervation of sweat glands)
In children, ordinary doses of antimuscarinic agents may cause “atropine fever” (body temperature is elevated only if large doses are administered in adults)
Atropine blocks vagal reflexes induced by surgical manipulation of visceral organs
(2) Atropine or glycopyrrolate is paired with neostigmine to block parasympathetic effects during reversal of skeletal muscle relaxation
useful in preoperative settings to limit increased airway secretions caused by irritant anesthetics (e.g., ether)
the first drug of choice for symptomatic bradycardia in an advanced cardiac life support (ACLS) setting
mAChR antagonists may be used in the treatment of common traveler’s diarrhea and other mild or self-limited conditions of hypermotility
ii) Often combined with an opioid antidiarrheal drug to discourage abuse of the opioid agent (classic example is the combination of atropine and diphenoxylate with the trade name Lomotil)
provide symptomatic relief in the treatment of urinary urgency caused by minor inflammatory bladder disorders
Tertiary antimuscarinic agents (preferably atropine) are utilized to treat both CNS and peripheral effects of excessive stimulation of mAChRs due to cholinergic poisoning
In life-threatening situations, as much as 1 gram of atropine per day may be required for as long as 1 month for full control of muscarinic excess
Rapid-onset cholinergic poisoning caused by mushrooms is characterized entirely by signs of muscarinic excess within 15-30 minutes [e.g., nausea, vomiting, diarrhea, urinary urgency, vasodilation, reflex tachycardia (occasionally bradycardia), sweating, salivation, and sometimes bronchoconstriction] and is adequately treated with atropine
Atropine is of no use in delayed-onset mushroom poisoning, which is characterized by vomiting and nausea 6-12 hours after ingestion
Moderate to high doses of atropine in children and infants can cause death due to hyperthermic effects
Nonselective antimuscarinic agents (atropine) should be avoided in patients with acid-peptic disease (potential to slow gastric emptying and increase discomfort)
dicyclomine
not found anywhere in dsa
glycopyrrolate
gi disorders, antimuscuarinic, quaternary and charged, with neostigmine to block parasympathetic effects during reversal of skeletal muscle relaxation
hyoscyamine
gi disorders, antimuscarinic
cyclopentalate
antimuscarinic used for ophthalmology
homatropine
antimuscarinic used in ophthalmology, used to prevent synechia formation (the iris adheres to either the lens or the cornea) in uveitis and iritis
tropicamide
antimuscarinic used in ophthalmology, tertiary amine
ipratroprium
antimuscurinic used in copd and asthma, quaternary
used as an inhalational agent in the treatment of COPD and is currently a first-line therapy (use in asthma is off-label and should be done in combination with a short-acting beta-adrenergic agonist)
tiotropium
antimuscurinic used in copd and asthma
has a longer bronchodilator action than ipratropium (half life 120 hrs vs. 2 hrs) and can be dosed once daily (vs. 3-4 times/day) in patients with COPD
darifenacin
antimuscurinic used to treat urinary urgency, selective for the M3 subtype and are advantageous because of their longer half-lives and reduced incidence of xerostomia and constipation
desoterodine
antimuscurinic used to treat uriary disorders (urgency?)
oxybutynin
antimuscurinic used to treat urinary urgency
The prototype agent used in disorders of the genitourinary tract is oxybutynin, which is somewhat selective for M3 mAChRs with side effects that include dry mouth, dizziness, constipation, blurred vision, dry eyes, and urinary tract infections among others
solifenacin
antimuscurinic used to treat urinary frequency
selective for the M3 subtype and are advantageous because of their longer half-lives and reduced incidence of xerostomia and constipation
tolterodine
antimuscurinic used to treat urinary frequency selective for the M3 subtype and are advantageous because of their longer half-lives and reduced incidence of xerostomia and constipation
trospium
nonselective antagonist that is comparable in efficacy and side effects with oxybutynin
benztropine
antimuscurinic used for movment disorders, tertiary so sued in cns, parkinsons
biperiden
antimuscurinic used for moement disorders
orphenadrine
antimuscurinic used for movment disorders
procyclidine
antimsucurinic sued for movement disorders
trihexyphenidyl
antimuscurinic used in movement disorders, tertiary amine used for parkinsons
mecamylamine
from initial ganglion blockers and has improved GI tract absorption
can cross the blood-brain barrier and cause sedation, tremor, choreiform movements, and mental aberrations
approved for use to treat hypertension and is being investigated for use in smoking cessation therapy
