Cholinergic Agents Flashcards
muscarine
a poisonous substance found a a mushroom that mimics the effects of ACh
results in smooth muscle contractions, secretion, decreased heart rate, fall in blood pressure
atropine
blocks muscarinic response to ligand
nicotine
increases heart rate and blood pressure, mimics the effects of ACh in large doses or when injected with atropine, which blocks the muscarinic receptors
tubocurarine
blocks nicotinic receptors
structure-activity relationship (SAR) for acetylcholine
has nicotinic and muscarinic sides
the more substituents added to the molecule, the more muscarinic it becomes
acetylcholine as a direct-acting parasympathomimetic agent
mimics the effects of parasympathetic stimulation
slows heartrate through SA node
G-protein receptors opens potassium channels and generates the outward potassium currents to hyperpolarize the membrane
SA node pacemaker
driven by the funny current (pacemaker potential)
calcium channels activated by hyperpolarization and a potassium curve repolarizes the cells
three ways that vagal stimulation can decrease the heart rate
activation of potassium channels
inhibition of funny current
inhibition of L-type calcium currents
parasympathetic function at the AV node
ACh decreases AV conduction by an increase in gK (potassium conductance)
effect of ACh on blood vessels
even though there is no parasympathetic innervation on blood vessels, ACh can cause dilation through receptors that are in the endothelium
results in EDRF (NO) release and relaxation of smooth muscle
effect of a low dose of ACh alone
produces vasodilation and a reflex tachycardia in response to the decrease in blood pressure when injected IV
effect of ACh and neostigmine
much larger fall in blood pressure due to vasodilation and decrease in heart rate when injected IV
high doses in the vicinity of muscarinic receptors may be able to overcome the reflex
effects of ACh and neostigmine and atropine (a muscarinic blocker)
only increases blood pressure and heart rate are observed
removal of the muscarinic link leaves only the sympathetic division, which is then activated by the direct action of ACh on sympathetic ganglia
sustained effects eventually are produced from epinephrine after norepinephrine effects terminate
Why isn’t acetylcholine used clinically?
non-specific
rapid hydrolysis
methacholine
methyl group on beta carbon atom of ACh, making it more resistant to ACh and more specific for muscarinic receptors
metacholine challenge used to detect bronchial asthma
bethanechol
combines structural features of methacholine and carbachol
specific for muscarinic receptors and resistant to hydrolysis by esterases
therapeutic uses - treatment with disorders of low bowel tone (adynamic ileus) and urinary retention problems
contraindications - effect on heart can produce shock, asthmatics, hyperhtroid patients susceptible to arrhythmias, peptic ulcers, intestinal or bladder obstruction
adynamic ileus
absence of motility due to decreased activity of the autonomic nervous system - GI tract
pilocarpine
mimics the effects of acetylcholine - muscarinic activator
tertiary amine with the important part of its structure following the structure-activity relationship (SAR) for muscarainic receptors
natural alkaloid and not hydrolyzed by cholinesterases
therapeutic use - glaucoma therapy, dry mouth - sjogren’s syndrome (autoimmune disease of exocrine glands)
cevimeline
acetylcholine mimic
newer agent with more efficacy than pilocarpine to treat symptoms of Sjogren’s syndrome
glaucoma
disease associated with increased intraocular pressure resulting in blindness
increased pressure can be caused by increased synthesis and/or decreased outflow of aqueous humor
AH synthesis in ciliary body -> AH in anterior chamber -> AH to trabecular meshwork to canal of Schlemm -? AH out of the eye through the venous system
narrow angle glaucoma
acute, congestive
filtration angle is markedly reduced, impairing the exit of AH, drug pretreatment is required prior to surgery
pilocarpine contracts circular muscle fibers, pulls iris toward the center of the eye and uncrowds the angle
other agents prior to surgery are anti-cholinesterases, acetazolamide or methazolamide or dichlorphenamide, mannitol
open angle glaucoma
no physical obstructrion, but the trabecular meshwork has poor tone and is misaligned
tone is improved by pilocarpine and helps add tone and open the pores
surgical treatments for glaucoma
narrow angle - laser iridotomy
open angle - laser trabeculoplasty
anti-cholinesterases
indirect-acting parasympathomimetic agents (drugs which potentiate the action of endogenous ACh at muscarinic receptors)
two types of cholinesterases
true, specific or acetylcholinesterase - localized to cholinergic synapses and red blood cells
pseudo, non-specific or butyryl cholinesterases - all over
general symptoms of poisoning with anticholinesterase agents
Salivation
Lacrimation
Urination
Defecation
“SLUD syndrome”
toxicity of irreversible cholinesterase inhibitors
ACh is released in unphysioligically high amounts due to activation of presynaptic nicotinics - high calcium permeability
this causes the nerve to fire and increase the ACh concentration even more
CNS symptoms of cholinesterase poisoning
anxiety, headache, tremors, conusion, violent activity, convulsions, coma, depression of respiratory and CV centers, cyanosis, fall in blood pressure
-stigmine
reversible cholinesterase inhibitor
physiostigmine
reversible cholinesterase inhibitor
tertiary amine, can cross the blood brain barrier
duration about 1-2 hours
oral or parenteral administration
therapeutic uses - glaucoma therapy, as an antidote
neostigmine
reversible cholinesterase inhibitor
quaternary so no CNS effects
duration 2-4 hours
oral or parenteral administration
therapeutic uses of neostigmine
treat myasthenia gravis
reverse non-depolarizing block at the end of surgery
miotic
glaucoma therapy
treat urinary retention
treat GI stasis, most common autonomic use
pyridostigmine bromide
reversible cholinesterase inhibitor
same as neostigmine except available in slow release form for long-lasting 4-12 hour oral effect, useful at bedtime
edrophonium
duration only 5-15 minutes
generally IV but you can give IM
therapeutic uses - to test for MG and distinguish from cholinergic chrisis
contraindications of reversible cholinesterase inhibitors
asthma, hyperthyroid patients, ulcers, GI or bladder obstruction similar to those of bethanecol
other features - all are hydrolyzed by liver cholinesterase
quaternary agents have direct stimulatory action on the ACh receptor in addition to inhibiting cholinesterase
mechanism of ACh hydrolysis by ChE
ACh anchors at the anionic site of ChE, enzyme activity is at the esteratic site
interaction of ACh with the esteratic site causes a rearrangement of the complex leaving an acetylated enzyme and a free choline
the acetylated enzyme then reacts with water to free the acetic acid and regenerate the enzyme
mechanism of reversible icholinesterase inhibitorsn
molecules have slower hydrolysis after the conformational change of the enzyme to cleave the molecule
usually leaves the enzyme carbamylated and is hydrolyzed very slowly
mechanism of edrophonium
combines electrstatically at theanionic site of ChE and hydrogen bonds to the imidazole of histidine at the esteradic site
transient inhibition
DFP mechanism
reacts only with the serine residue of the steratic site to fomr a phosphorylated enzyme which does not hydrolyze at all
resynthesis of the enzyme is necessary to restore ChE, a process which takes 3-6 weeks
DFP
diisopropyl phosphorofluroidate
prototype agent used as nerve gas by British and Americans in WWII
oily liquid that is absorbed by every route, including skin
effects similar to those of physostigmine
Tabun and Sarin
both synthetic nerve gasses made in Germany during WWII as insecticides
SARIN is structurally DFP minus one isopropyl group
irreversible inhibition of cholinesterases
parathion
agricultural insecticide
metabolized to paraoxon, the toxic form that inhibits ChE
responsible for many poisonings and deaths
malathion
insecticide
slightly safer than parathion because higher animals can metabolize this faster than parathion
chlorpyrifos
extremely popular insectiside in garden products and in pet flea collars for many years
VX
the deadliest of nerve gases, 2.5 million tons in Newport still being cleared, terrorism in Japan, Gulf War, etc.
treatment of toxicity
1) decontaminate (remove from skin)
2) block excess muscarinic activity with atropine (a lot is needed)
3) treat skeletal muscle effects through artificial respiration or reactivation of the enzyme
4) yridostigmine (not good!)
5) anticonvulsants if severe (diazepam)
2-PAM and mechanism
aka pralidoxime
designed on theoretical bases, reactivates ChE by first attaching to anionic site and then binding to the P atom of the inhibitor and removing the inhibitor from the esteratic site
predominant effect is at skeletal neuromuscular junction with much less effect occurring at muscarinic neuro-effector sites
anticholinergic agents
muscarinic antagonists - agents that block actions of ACh at cholinergic neuro-effector sites
ganglionic blockers - block nicotinic receptors on autonomic ganglia
atropine
a belladonna alkalid from deadly nightshade
prototype drug
acts as a competitive inhibitor at muscarinic receptors
effects are opposite to those of parasympathetic stimulation
causes pupillary dilation, bronchiolar dilation, constipation, urinary retention, decreased secretions, etc.
decreased sweating as well, increases heartrate at clinical doses
therapeutic uses for atropine
- mydriatic and cycloplegic for eye exam
- COPD treatment
- GI and urinary bladder spasms
- blockade of secretions
- increase heart rate
- antidote for cholinesterase poisoning
- Parkinsonium
effect of atropine is generally too long to be practical and other derivatives are employed instead
may precipitate an attack of narrow angle glaucoma
accommodation
object moves toward eye -> CNS reflex -> parasympathetic firing is increased -> lens is allowed to round into its natural shape to focus on the approaching object
cycloplegia
paralysis of accommodation, lens fixed for distant vision
cyclospasm
spasm of ciliary muscle and blurred vision
atropine treatment of bronchioles
treat COPD
can also treat asthma with atropine-like agents such as ipratropium and tiotropium
atropine treatment of GI spasms
spasms of smooth muscle cause pain known as cholic, relieved by atropine
current drug of choice
can also treat enuresis in children
atropine treatment of blockade of secretions
respiratory secretions
acid secretions, may be used synergeistically with antibiotics and proton pump inhibitors
adjunct to surgical procedures such as intubation
atropine to increase heart rate
during stage 2 of anesthesia
during spinal anesthesia
Parkinsonism
atropine was a popular treatment in the past, superseded by L-dopa
symptoms of parkinsonism can be alleviated by blocking the ACh effects or increasing hte effects of dopamine
homatropine
derivative of atropine with a shorter duration of action
scopolamine
similar to atropine but has an additional oxygen on one of the rings, more CNS depressant effects at usual therapeutic doses
has been used int he past for sedative hypnotic effects in conjunction with opiod analgesics
not effective when severe pain is present
very effective against motion sickness
effects of muscarinic receptor blockers
anti-emetic - targets muscarinic receptors in the vestibular nucleus and the vomiting center
seadation - blocks the muscarinic receptors int he cholinergic basal forebraine and mesopontine cholinergic nuclei associated with the reticular activating system
amnesia - blocks muscarinic receptors in the septo-hippocampal projection
symptoms of belladonna toxicity from atropine and scopolamine
Dry as a bone -decreased secretions, urinary retention
Red as a beet - cutaneous vasodilation due to histamine and/or compensatory effect due to increased body temeprature
Mad as a hatter - delierium, hallucinations, eventually coma
Hot as a stove - increased body temperature (decreased sweating)
Blind as a bat - mydriasis, cycloplegia
treatment of atropine toxicity
emesis if mental status is not severely impaired
gastric lavage even as late as 24-48 hours after ingestion
activated charcoal after gastric emptying
if anticholinergic effects are severe use an antidote - physostigmine
drugs for overactive bladder
tolterodine
fesoterodine
oxybutynin
solifenacin
darifenacin
drugs for ocular defects
cyclopentolate
tropicamide
homatropine
drugs for Parkinson’s disease
benztropine
trihexyphenidyl
drugs for bronchiolar dilation in asthmatics and COPD
ipratropium - quaternary, blocks ganglia, produces effective bronchiolar dilation without impairing mucilliary clearance
tiotropium - treats COPD, superior to ipratropium because it does not block presynaptic inhibitory muscarinic receptors as ipratropium does
drugs for spasms of GI tract
atropine
lomotil
glycopyrrolate
ganglionic blocking drugs
basic processes involved are essentialyl the same as the processes for skeletal neuromuscular junctions
block the action of ACh at autonimc ganglia
both sympatetic and parasympathetics are blocked
particular effect observed depedns on whcih system controls ther esting tone of a particular organ
predominatn tone is muscarinic cholinergic, mediated largely by the parasympathetic division
ganglionic blocking drugs
