Cholinergic agonists and antagonists Flashcards
4 primary direct effects on the CV system
Vasodilation (M3)
Decrease cardiac rate (M2)
Decrease rate of conduction in the SA and AVnodes (M2)
Decrease force of contration (M2)
IV injection of small dose of ACh
fall in blood pressure- vasodilation, reflex tachycardia
IV injection Large dose ACh
brady cardia, decrease through Vnode, vasodilation and hypotension.- CV system
ACh effects on tissue
CV system- bradycardia, decrease in conduction velocity, AV block at high doses, decrease in contrctilty
Eye- contraction and miosis, accomodation of lens to near vision, watery lacrimal secretions
glands- secretions
bronchi- increase in secretions.
GI- increase in tone, peristaltic activity, increased in secretions and relaxation of sphincters.
Urinary- contraction of detrusor muscle, relaxation of sphincter.
sweat glands- diaphoresis
Male reproductive tract- erection
Uterus- varible.
large doses of ACh after atropine administration causes
nicotinic effects, increase in blood pressure due to sympathetic ganglia stimulation and vasoconstriction.
Choline esters-
ACh, carbachol, bethanechol, methacholine
poorly absorved and distributed into CNS
differ in susceptibility to be hydrolyzed by cholinesterase. ACh very rapid. others are more resistant.
quarternary ammonium compounds.
naturally occuring alkaloids
arecholine, muscarine, pilocarpine, nicotine, lobeline.
Acetylcholine uses.
no systemic use.
used to obtain rapid miosis after delivery of lens in cataract surgery, penetrating keratoplsty and iredectomy
Bethanechol
NOT hydrolyzed by AChE, inactivated by other esterases. little or no nicotinic action but
STRONG muscarinc activity
used to treat postop or post partum non obstructive urinary retention and for neruogenic atony of the urinary bladder with retention.
ADVERSE: can cause generalized cholinergic stimulation- sweating salivation, flushing, low BP, nausea, abdominal pain, diarrhea, bronchospasm.
Carbachol
both muscarinic and nicotinc agonist
poorly hydrolized by esterases
used for intraocular miosis during surgery, reduces intraocular pressure after cataract surgery.
Methacholine
hydrolyzed by ACh but slowly, resistant to non specific cholineesterase or butyrylcholinesterase.
predominantly MUSCARINIC, slight nicotinc
used in diagnosis of bronchial airway hyper-reactivity in subjects who do not have clinically apparent asthma
PIlocarpine
tertiary amine,
stable to hydrolysis by AChE
partial muscarinic agonist
used in Glaucoma- second line agent for open angle glaucoma. used to manage acute angle-closure,
you use several drugs to treat glaucoma- timolol, pilocarpine, apraclonidine, acetzolamide and an osmotic agent like glycerol and IV mannitol.
ADVERSE- can enter brain and cause CNS disturbances. stimulates seaeating and salivation.
Nicotine
Tertiary amine. affect NMJ slighlty more. causes ganglionic stimulation which means both para and sympathetic actions.
CVS- mainly sympathomimetic- increased heart rate and blood pressure due to release of adrenergic release.
GI- largely parasympathomimetic- nausea, diarrhea, vomiting, voiding of the urine. causes stimulation of salivary and bronchial secertions.
high doses cause NM blockade.
acute poisoning.- nausea, alsivation, ab pain, vomiting diarrhea, cold sweat, mental confusion, ewakness. low BP, weak pulse, collapse may be followed by convulsions, death may occur from paralysis of respiratory muscles and Central respiratory failure
highly liposoluble, so absorption is fast via oral mucosa, lungs, GI mucosa and skin. corsses placental membrane and is secreted in milk.
Indirect acting cholinergic agonists(anticholinesterases)
simple alcohols bearing a quaternary ammonium group- edropohonium
carbamates- neostigmine, physostigmine, pyridostigmine
Organophosphates- Ecothiophate, parathion, malathion
endrophonium
Quarternary ammonium
binds reversibly to active site of enzyme. short lived- 2-10 minutes.
used to diagnose myasthenia gravis, reverse neuromuscular block produced by non-depolarizing muscular blockers.
Carbamates-
form covalent bond with the enzyme. the carbamate-cholinesterase bond spontaneoulsy hydrolyzes in 30 min-6 hours. clinical recovery in several hours, rarely over 24
organophoshpate-
phosphorylate the active site of the enzyme and the bond is extremely stable. ageing strengthens the bond
pralidoxime can split the bond if it hasn’t undergone ageing
Organ system effects of anticholinesterases
CNS- diffuse activation of EEG, subjective alerting response. high concentration may cause convulsions, coma and respiratory arrest
CVS- increase activation on both sympathetic and parasympathetic ganglia supplying the heart and and at the ACh receptors on cardiac and vascular smooth muscles. in heart, -bradycardia, chronotropic, dromotropic, and inotropic effects are evoked and caridac output falls.due to bradycardia,- M2 receptors
-vasconstriction becasue there aren’t any M3 innervations. large doses cause hypotenstion.
NMJ-low concentrations- increased contraction strength. higher concentrations- fibrillation of muscle fibers.
physostigmine
tertiary amine- can enter CNS- used to treat overdoses of anticholinergic drugs. Do NOT use for TCA overdose becsue of depression of cardiac conduction.
ADVERSE- convulsions with high doses
bradycardia, paralysis of skeletal muscle.
Neostigmine
quarternary ammonium- can’t enter CNS
used to reverse non-depolarizing neuromuscular blockers after surgery.(most common used), used for symptomatic treatment of myasthenia gravis (pyridiostigmine most)
used for prevention and treatment of post op distention and urinary retention.
ADVERSE: salivation- flushing, low blood pressure, nausea, ab pain, diarhea, bronchospasm.
Pyridostimine
quarternary ammonium- doesn’t cross CNS
used for myasthenia gravis
Echothiophate
used for chornic open angle glaucoma, subacute or chronic angle closure galucoma after iridectomy or surgery is refused or contraindicated.
Malathion/Parathion
activated in body by conversion to oxygen analogs
parathion not metabolized
malathion is considered safe for sale to general public
tabun, sarin, soman
synthetic toxic agents. fully distributed to all parts of body.
other inhibitors of AChE
tacrine, donepezil, rivastimne, galantamine- used for alzheimer’s disease.
Pralidoxime
used to reactivate AChE used only for organophosphate unless there is significant carbamate toxicity.
Bella donna alkaloids:
atropine and scopolamine
atropine
binds competitively to muscarinic receptors, preventing acetylcholine from binding tertiary amine. both central and peripheral muscarinc blocker blocker
eye-mydriasis, unresponsivenss to light, cycloplegia. intraocular pressure may rise dangeroulsy
GI- can be used as antispasmodic. Gastric motility is reduced, but HCl production is affected, not effective in promoting healing of peptic ulcers
Urinary system: decreases hypermotlity of urinary bladder
CVS- blockade of atrial M2 receptors and tachycardia. (lower doses, bradycardia. ) at toxic doses, can cause cutaneous vasodilation (atropine flush)
Secertions- salivary, sweat, lacrymal glands blocked, high body temp may result. is an antisialoagogue prior to surgery decreases respiratory secretions
uses: when excessive muscarinc symptoms are severe
- antisiologge, prior to surgery to reduce secretions of respiratory tract
-to increase heart rate or decrease AV-block when bradycardia, or AVblock are hyemodynamically significant and thought to be due to excess vagal tone.
-as an antidote for cholinergic drugs
-as an atidote for amanita muscaria
to alleviate the muscarinic side effects of anticholinesterase.
ready absorbed, patially metabolized by liver, elimnated in urine. half life of 4 hours
adverse effects- dry mouth blurred vision, sandy eys, tachycardia, constipation. restlessness. confusion, halluciantions, delirium, depression. in older indifivdiuals, problems with glaucoma.
Scopoloamine
Belladona alkaloid- tertiary amine Cholinergic antagonist(muscarinic) DOC for motion sickness. Blocks short term memory used for anesthtic procedures.
has a greater and longer duration of action in CNS than atropine
same adverse effects/contraindications as atropine.
Iprotropium/tiotropium
QAC-cholinergic antagonist(muscarinic)
Bronchodilation(M3 antagonist)
used to as inhaltion of treatment for CPD and adjuvant therapy in asthma- same contraindication/adverse effects as atropine.
Homatropine/cyclopentolate/tropicamide
tertiary amine- cholinergic antagonist(muscarinic)
causes mydriasis and cyclopelgia/ preffered over atropine because of shorter duration of action
are able to ender CNS
Benztropine/Trihexyphenidyl
tertiary amines cholinergic antagonist(muscarinic)
restores balance of input after loss of dopaminergic neruons in the nigrostriatal pathway.
used for parkinsonism, extrapyramidal effects(drug induced movement disorders of antypsychotic drugs ( D2)
same contraindications as atropine.
are able to enter CNS
Glycopyrrolate
QAC cholinergic antagonist(muscarinic
-used orally for inhibition of GI motility
Parenteral used to prevent bradycardia during surgery
Tolterodine
tertiary amine cholinergic antagonist(muscarinic
relaxes smooth muscle-
used for overactive bladder
can enter CNS
Mecamylamine/Trimethaphan/Hexamethonium
Cholinergic antagonist- ganglion blocker
antagonize nicotinic receptors on both parasympathetic and sympathetic autonomic ganglia
effects- arterioles and veins are under predominant sympathetic control - so you will have dilation and hypotension (alpha 1
block parasympathetics at the heart and iris and ciliary muscle- will cause tachycardia, mydriasis and cycloplegia(far vision)
gI urinary bladder salivary galnds lose parasympathetics, reduced motility, secertions, urinary retention, zerostomai
sweat galnds lose sympathetics, anhydrosis.
Adverse effects- vasodilation, venodilation, hypotension, tachycardia, mydriasis, decrease in gi urinary motility, xerostoma, anhydrosis,
use to treat hypertension bbeen replaced.
Tubocarpine
structural analog of ACh- non depolarizing neuromuscular blocker/cholinergic antagonist
indications- anesthesia leads to muscle weakness and flaccid paralysis.
actions can be overcome by AChE inhibitors such as neostimine or edrophonium.
minimal oral abosrptoin so it is given Iv. Poor membrane penetartion so no crossing B.
Adverse effects- may cause histamine release and may bind to Muscarinic receptors.
Succinylcholine
structural analogs of ACh–depolarizing neuromuscular blocker/cholinergic antagonists.
activates NM causing depolarization which leads to transient disorganized contraction which leads to desensitization followed by flaccid paralysis.
useful for ET intubation/electroconvulsive therapy.
continuous Iv infusion, rapid hydrolysis by plasma cholinesterase. rapid onset and brief duration. not metabolized effectively at the synapse.
can cause malignant hyperthermia, an AD disorder with excess release of calcium from SR, usually combined with halogenated anesthetic. (Tx dantrolene.
Hemicholinium
Cholinergic Antagonists: Drugs Acting Presynaptically
blocks choline transporter CHT1
still under research
vesamicol
blocks the vesicular ACh H+ antiporter VAChT preventing storage of ACh,
still under research
boulinum toxin
prevents synaptic vesicle fusion inhibiting ACh release (synaptobrevin)
