cholinergics Flashcards
Muscarinic receptor agonists (parasympathomimetics)
direct agonists of muscarinic receptors
produce effects similar to those observed during stimulation of post ganglionic parasympathetic nerves
Muscarinic receptor antagonists (parasympathlytics, antimuscarinic agents)
completely block muscarinic receptors, interfere with responses that result from parasympathetics stimulation
Acetylcholinesterase inhibitors (Anticholinesterase
agents that enhance the effects of endogenously produced Ach by blocking its natural breakdown by the enzyme acetylcholinesterase
effective at any site where Ach is the NT
Ganglionic blocking agents
neural nicotinic receptor antagonist
competitve antagonists for nicotinic receptors at autonomic ganglia
interfere with ganglionic transmission of both parasympathetic and sympathetic nerves
where are muscarinic receptors located
autonomic effector cells innervated by post gang Parasymp
also located on some cells that have no cholinergic innervation (vascular endothelial cells)
located within CNS
actions are blocked by atropine
properties and subtypes of muscarinic receptors
5 subtypes (all are GPCRs), widely distributed most cells express a few subtypes but one usually predominates
M2s: functionally dominant subtype in heart
M3s: functionally dominant subtype in smooth muscle, secretory glands, eyes and vascular endothelium
effects of muscarinic receptor activation on CV, pulm, UT, GI, misc peripheral effects, CNS effects
CV: Vasodilation (M3 endothelial, M2 decrease HR, M2 decrease AV node)
pulm: bronchoconstriction M3, tracheobronchial secretion M3
UT: detruser muscle contraction M3
GI: increased tone, amp contractions, secretion M3
misc peripheral effects: increase secretion glands M3, miosis and accommodation M3
CNS effects: cortical arousal, all 5 receptors
Choline esters
bethanechol, resistant to hydrolysis by cholinesterases, thus T1/2 is increased compared to Ach
Quaternary amines, low F, does not cross BBB
non-selective
Naturally occuring alkaloids
pilocarpine is a tertiary amine, therefore readily absorbed after oral admin penetrates CNS
non selective
Bethanecole
primary effect: on UT and GI tracts
orally or subQ for urinary retention (post op, diabetic neuropathy, hypoactive bladder)
Pilocarpine
used for treatment of xerostomia (due to head and neck radiation Sjörgren syndrome)
Topically in opthalmology for treatment of glaucoma and as mitotic agent
side effects and contraindications of muscarinic receptor activations
common side effects: diaphoresis, diarrhea, nausea, difficulty with accommodation, and hypotension
contraindications: asthma and COPD, UT or GI obstruction, acid peptic disease, CV disease accompanied by brady cardia or hypotenstion
Toxicology of muscarinic agonists (parasympathomimetics, pilocarpine, bethanecole)
poisoning by ingestion of muscarinic agonists:
SLUDGE (salivation, lacrimation, urination, defecation, gastrointestinal upset, emesis) also hypertension, and bradycardia, and difficulty with accommodation
reversal with atropine
muscarinic receptor antagonists (parasympatholytics, or antimuscarinics) and their effects (CV, resp, eye, GI, smooth muscle, sweat glands, CNS)
competitve inhibitors of muscarinic receptors
CV- tachycardia, Av nodal conduction (M2), block reflex vagal slowing of HR and AV node, no effect on vascular tone or BP
Resp- bronchodilation, dec. tracheobronchial secretions (M3 receptor), dries mucous membranes of resp tract
eyes- dilate pupils (mydriasis) and paralyze accommodation by blocking cholinergic response of the pupillary sphincter muscle and ciliary muscle (M3 - photophbia)
GI: decrease secretions, decrease motility (M3)
sm muscl: decrease in tone of ureter and bladder (M3)
sw gland: inhibit activity of sweat, increases body temp
CNs: depression and drowsiness
naturally occuring alkaloids of muscarinic antagonist
from belladonna plants (atropine, and scopolamine)
semisynthetic of muscarinic antagonist
ipratropium
synthetics of muscarinic antagonist
tropicamide, oxybutynin, darifenacin, glycopyrrolate
atropine
prototypical antagonist
non-subtype selective muscarinic receptor antagonistss, absorbed orally by the GI tract
Therapeutic uses: bradyarrythmias due to high vagal tone
ophthalmic uses (to produce mydriasis and cycloplegia/paralysis of accommodation)
long acting, treats chronic inflammatory disorders
uses during anesthesia (blocks responses to vagal reflexes and reduces tracheobronchial secretions)
anticholinesterase or muscarinic toxicity
scopolamine
non-subtype selective muscarinic receptro antagonist,
greater CNS penetration
major use is to treat motion sickness and vestibular disease
available as a transdermal patch
ipratropium
non-subtype selective muscarinic receptor antagonist
Quaternary ammonium compund used exclusively for respiratory tract (inhalation)
COPD
reduces bronchosecretions and alleviates bronchoconstriction
tropicamide
opthalmic solution to produce mydriasis and cycloplegia
fast acting and short duration
oxybutynin
Urinary incontinence
high incedents of antimuscarinic side effects
darifenacin
urinary incontinence
M3 receptors
less CNS side effects than oxybutinin
glycopyrrolate
blocks parasympathomimetic effects during reversal of NMJ blockade with anti cholinesterase agents
quaternary amine-> no CNS penetration
side effects of muscarinic antagonists, contraindications and toxicity
xerostomia, blurred vision, dyspepsia, constipation, cognitive impairment
contraindications: urniary or GI tract obstruction, uncontrolled glaucoma, benign prostatic hyperplasia, conditions worsened by tachycardia
toxicology: belladonna alkaloids, Hot as hare (no sweating), dry as a bone (dry mouth), red as a beet (excessive heat), blind as a bat (mydriasis), mad as a hatter (ataxia etc)
treat with physostigmine
acetylcholinesterase inhibitors
cause an increase in acetylcholine in the vicinity of cholinergic nerve terminals
aka anticholinesterase agents
insecticides, pesticides, nerve gases
loci: where Ach is released: muscarinic receptors, autonomic ganglia, CNS
therapeutic uses for: atony of smooth muscle of GIT, UT, glaucoma, mg, reversal of competitve NMJ blocking drugs
enzymatic hydrolysis of Acetylcholine
transiently acetylated at numerous loci on the enzyme
non covalent (reverisble) inhibitors of AchE
Edrophonium: quaternary ammonium (no CNS activity), must be IV administered, rapid onset and short durations
Used for diagnosis of MG, and the reversal of paralysis by competitive NM blocking drugs
Reversible carbamate inhibitors of AchE
hydrolyzed by AchE but at a slow rate
Physostigmine: alkaloid from calabar bean, slowly reversible (hrs) tertiary amine (has CNS effects)
uses treatment of chronic wide angle glaucoma, treats toxicity of CNS antimuscarinic agents)
Neostigmine: slow reversible, quat amine no CNS effects), treatment of MG oral, preventation and treatment of post op atony of gut and bladder, reversal of paralysis by competitive NMJ blocking drugs
organophosphorus compounds
phosphorylate the AchE, return of the activity depends on synthesis of new enzymes, lipophilic and penetrate CNS
Nerve gases: sarin
Insecticides: malathion (rapidly detoxed in higher order organisms)
toxicity: SLUDGE +hypotension+bradycardia+difficiuly with eyes
reduced respiration, muscle paralysis, death
antidotes: atropine and with moderate to severe pralidoximine (reactivates AchE, but not effective with aged)
ganglionic blocking drugs
Ach is released from parasympathetics and sympathetic pre ganglionic neurons, activates postganglionic nicotinic receptors (cation influx)
neural nicotinic receptor antagonist - specifically block both the parasympathetic and sympathetic systems
leads to vasodilation
competitive neuromuscular blocking agents
aka non-depolarizing drugs
antagonists of nicotinic receptors at the neuromuscular junction (Nm)
duration of action: short, medium, long duration
side effects: Nn receptor blockade, M receptor blockade, releaase of histamine
route of elimination: inactivated by metabolism or removed by renal excretion
Rocuronium
intermediate duration of action, but rapid onset of action, can be used to facilitate endotracheal intubation, hepatic elimination, no Nn/receptor blocking or histamine releaseing effects
also cisatracurium, vecuronium, pancuronium (long)
depolarizing neuromuscular blockers
activate nicotinic receptors at NMJ maintinging motor end plate depolarization
Succinylcholine: has a quat ammonium, does not enter the CNS, not orally absorbed, allows tracheal intubation (rapid onset, short duration of action
metabolized by pseudocholinesterase
side/adverse effects of nmj block
prolonged apnea, CV collapse (due to histamine release anaphylaxis)
Malignant hyperthermia (succinylcholine) hyperkalemia
toxic effects: (respiratory paralysis, treat with positive pressure, neostigmine.edrophonium) +glycopyrrolate
