ANS Cholinergic Flashcards
parasympathetic effect on the eye
M3 - Miosis (contraction of sphincter muscle)
M3 - accomodation cyclospasm (near vision contraction of ciliary muscle)
used in opthalmic exams/glaucoma
long term use may lead to cataracts/retinal detachment
Muscarinic Antagonism effect on the eye
M3 - Mydriasis (dilation)
M3 - accomodation to far vision leading to cycloplegia
Hemicholinium
inhibit choline active transport pp to presynaptic nerve endings.
Botulinum Toxin
inhibits Ach exocytosis by interaction with
“clostridum botulinum”
bacterial entersthru recycling vessicle reuptake
synaptobrevin. degrades SNAP-25 preventing vessicle fusion to membrane (protease prevents SNARE complex)
Rx. blepharospasm, strabismus, hyperhydrosis, dystonia, and cosmetics
Acetylcholinesterase inhibitors
indirect acting cholinomimetics
Reversible: edrophonium, physostigmine, neostigmine
Irreversible: echothiophate, malathion, parathion
Muscarinic effect on the heart
M2 - SA node negative chronotropy
M2 - AV node negative dromotrophy
used in supraventricular tachycardia (SA node M2 receptors via vagus nerve)
Muscarinic effect on the Lungs
M3 - bronchioles contraction (bronchospasm)
M3 - gland secretions
Muscarinic effect on the GI tract
M3 - increased motility and cramping
M1 - increase secretions
M3 - contraction. diarrhea/involuntary defecation
Muscarinic effect on the Bladder
M3 - contraction of detrussor
relaxation of the trigone/sphincter
voiding/urinary incontinence
muscarinic effect on the sphincters
M3 - relaxation
lower esophageal contracts!
muscarinic effect on the glands
M3 - secretion. sweat thermoregulation, salivation, lacrimation
muscarinic effect blood vessel endothelium
M3 - dilation (NO/endothelial derived relaxing factor NO innervation (no effect indirect agonists AchE inhibitors)
Cholinergic receptor mechanism
M1 and 3 (Gq) phospholipase C (IP3/Dag/Ca+)
M2 (Gi) decrease adenylyl cyclase, cAMP
Nn and Nm are both ionic Na/K channels
AcetylCholine
M and N choline ester direct agonist
short half life, no clinical use
quickly metabolized by AchE
intraoccular use for cataract surgery to stimulate rapid miosis
Bethanechol
M choline ester direct agonist
no AchE hydrolysis, no CNS
DoA ~2hrs
Rx. ileus (postop/postpardum/neurogenic), urinary retention
Methacholine
M>N direct agonist
some AchE hydrolysis (unpredictable magnitude)
Dx bronchial hyperreactivity (asthma)
Pilocarpine
M direct agonist
no AchE hydrolysis. uncharged (CNS)
Doa ~2hrs. less potent than Ach itself.
Rx. glaucoma (topical), xerostomia
Edrophonium
indirect cholinomimetic - AChE Inhibitor
short acting
Diagnosis Myasthenia gravis from cholinergic crisis
Myasthinia Gravis
“autoimmune HSR type II disease acting on the nicotinic cholinergic Ach Receptors (muscular end plates fast inotropic inhibited by curare).
Muscle weakness with prolonged activity, worsening over the day, ptosis, double vision, difficulting swallowing/chewing/speaking,
Tx. With long DoA AChE inhibitor (…stigmine)
DD. Lambert-Eaton wiich is worse in morning when Ca+ is lowest
Cholinergic crisis
Organophosphates/carbamates etc.
Rx. with atropine (effects) and pralidoxime (AchE regenerator)
DUMBBELSS
diarrhea, urination, miosis, bradycardia, bronchoconstriction, excitation (CNS/ nicotinic muscle excitation then paralysis), lacrimation, salivation, sweating.
nicotinic effects: skeletal excitation followed by paralysis, CNS stimulation
lambert-Eaton
autoimmune disease HSR type II acting on the presynaptic voltage-gated Ca+2 channels preventing excocytosis of Ach to act on nAchR of the motor end plate.
Muscle weakness worst in the morning when Ca+ is lowest.
dd. Myasthenia Gravis that acts on the AchR themselves and worsens at night with use.”
Physostigmine
indirect cholinomimetic- AchE inhibitor enters CNS DoA ~3hrs (intermediate) Rx. Glaucoma Rx. Atropine overdose +/- symptomatic (and antidepressant OD)
Neostigmine
indirect cholinomimetic- AchE inhibitor
NO CNS
DoA short acting more potent than physostigmine. Contraction before paralysis.
Rx. Ileus
Rx. urinary retention
Rx. myasthenia
Rx. reversal of nondepolarizing NMJ blockers (curare)
pyridostigmine
indirect cholinomimetic- AchE inhibitor NO CNS DoA ~4hrs Rx. Ileus Rx. urinary retention Rx. myasthenia Rx. reversal of nondepolarizing NMJ blockers (curare)
Indirect acting cholinomimetics
AChE inhibitors: -endrophonium (short acting diagnostic) -physostigmine (CNS - atropine antidote) -neostigmine and pyridostigmine (rx ileus, urine ret, myast, reverse NMJ blockes) -donepezil (CNS -Alz) -tacrine (CN - Als with hepatic effects) Irreversible: organophosphates ( toxin rx glaucoma detox with paralidoxime) - echothiophate, parathion, malathion
Alzheimers
late onset dementia with progressive memory loss ad cognitive decline. Neurropathology includes neurofibrillary tangles, amylid plaques, and loss of Ach neurons in the Meynert’s necleus rational for clinical use of AchE inhibitors.
degeneration of neurons in specific regions of cerebral cortex and hippocampus. Most common cause of dementia, incraease with age. Sporatic/ rarely familial. Increased risk in patients with Downs syndrome (ch21) often by 40YOA
4 genes are associated: 9amyloid precursor protein) APP encoding betaAPP, PSEN1 and 2 coding for presenilin.
APOE is not associated with monogenic alzhymers but increases susceptability to nonfamilial (most common form) and influences the age of onset of some monogenetic forms.
* Deposition of two fibrillary proteins (intracellular): Beta-amyloid and Tau (neurofibrillay tangles extracellular) [hirano bodies]
- amyloid/senile plaques which contain amyloid and APOE lipoproteins form in the extracellular spaces
- Tau proteins are microtubule-associated axon structural support proteins abundant in the brain, hyperphosphorylations of which compose the intracellular neurofibrillary tangles found within neurons. Although accumulation of tau fibrillary tangles is one cause of neuro degeneration in alheimers, the actual Tau protein mutations are associated with other neurodegenative deseases such as AD demenia, frontotemporal dimentia.
- The beta-APP amyloid presursor protein (21q21.3) proteolytically cleaved by Alpha, beta, (both cell surface) and gamma (atypical) secretases. 90% betaAPP are cleaved by alpha protease which cleaves within the beta-amyloid (Abeta) domain precluding its formation. The remaining 10% cleaved by beta and gamma protease into Abeta40 and very little Abeta42. Mutations are seen to increase the production of Abeta42 a neurotoxin. Diagnostically Abeta42 elevated in plasma serum. Presenilin 1 and 2 also increase production of Abeta42 as they are critical cofactors for gamma protease. Mutation in PSE1 has earlier onset of symptons than mutations in PSEN2. APOE is a component of the alzhymer amyloid plaques by binding to the Abeta proteins. Three common allleles for APOE gene Echo2,3 and 4. APOEecho4 homozygots have onset before 70yrs, heterozygots after 70yrs. Those with APOEecho2 are shown to have later onset. Carriers of the APOE echo4 allele are also shown to have poorer outcomes of head injury.
* final stages are primive reflexs and death by malnutrition, secondary infections, heart disease.
Parathion
indirect cholinomimetic - irreversible AChE inhibitor
Organophospates insecticide/military weapons
DUMBBELSS
diarrhea, urination, miosis, bradycardia, bronchoconstriction, excitation (CNS/ nicotinic muscle excitation then paralysis), lacrimation, salivation, sweating.
RX. atropine/pralidoxime
Malathion
indirect cholinomimetic - irreversible AChE inhibitor
Organophospates - degraded by UV light.
tx head lice
DUMBBELSS
diarrhea, urination, miosis, bradycardia, bronchoconstriction, excitation (CNS/ nicotinic muscle excitation then paralysis muscle), lacrimation, salivation, sweating.
RX. atropine/pralidoxime
Pralidoxime
regeneration of AchE
rx in cholinergic crisis due to AChE Inhibitor overdose
functions by reversing the phosphorylation of AchE and by aging of the organophosphate by cleaving it.
Atropine used for muscarinic management effect.
Atropine
muscarinic receptor antagonist (prototype) CNS activity management of AchE inhibitor overdose antisecretory mydriasis/cycloplegia (short acting) hyperthermia (vasodilate) tachycardia sedation urinary retention and antidiarrheal behavioral excitation and hallucinations (antispasmolitic) C/I narrow anlge glaucoma,
Drugs with antimuscarinic effects
antihistamines tricyclic antidepressants quinidine amantadine meperidine C/I narrow anlge glaucoma,
Tropicamide
direct muscarinic blocker
opthalmology (topical)
scopolamine
direct muscarinic blocker
rx motion sickness
sedation
short term memory block
Benztropine
direct muscarinic blocker
lipid soluble (CNS)
Rx Parkinsonism
Rx acute extra pyramidal symptoms induced by antipsychotics
trihexyphenidyl
direct muscarinic blocker
lipid soluble (CNS)
Rx Parkinsonism
Rx acute extra pyramidal symptoms induced by antipsychotics
ipratropium
direct muscarinic blocker
asthma and COPD (inhalation)
NO CNS
no change in mucus viscosity
Donepezil
indirect cholinomimetic- AchE inhibitor lipid soluble (CNS) Rx. alzheimers (oral bioavail 100% long DoA)
Tacrine
indirect cholinomimetic- AchE inhibitor
lipid soluble (CNS)
Rx. alzheimers
no longer used due to liver toxic
Organophophates and carbamates
indirect cholinomimetic- AchE inhibitor irreversible toxin, lipid soluble (CNS) rx glaucoma detox with paralidoxime DUMBBELSS diarrhea, urination, miosis, bradycardia, bronchoconstriction, excitation (CNS/ nicotinic muscle excitation then paralysis), lacrimation, salivation, sweating.
echothiophate
indirect cholinomimetic- AchE inhibitor
irreversible toxin, lipid soluble (CNS)
rx glaucoma
detox with paralidoxime
Chronic AchE inhibitor toxicity
peripheral neuropathy causing muscle weakness and sensory loss.
demyelination not due to AchE inhibition
Parkinsons
loss of pigmented dopamine secreting dopaminergic neuronal cells of the substantia nigra. Associated with somatic deletion of mtDNA and subsequent clonal expansion of the deletions in each cell.
Treat with L-dopa (but acts globaly acting on the affect, motivation,and reward center of the brain which can lead to psychosys)
Lewy Bodies
ANS pharm on dually innervated tissue
PANS dominates in dual innervation SA and AV nodes- bradycardia pupil (miosis constriction/accomodation near vision cyclospasm) salivation GI and GU muscles sphincters
SANS is only dominant in vascular tone (veins and arterioles) and thermoreg sweat glands.
hexamethonium
Nn nicotinic receptor antagonist (ganglion block SANS or PANS)
reduce predominant autonomic tone (basal)
prevent baroreceptor reflex in HR
toxicity - rarely used
mecamylamine
Nn nicotinic receptor antagonist (ganglion block SANS or PANS)
reduce predominant autonomic tone (basal)
prevent baroreceptor reflex in HR
toxicity - rarely used
Baroreflex
increase MAP - increase APs (rate of change)
* Aortic arch thru Vagus (X)
* Carotid Sinuses thru glossopharyngeal (IX)
nucleus tractus solitarius of the medulla
* efferent PANS vagus X to SA node (M2)
* efferent SANS to SA, AV, muscle, Artierioles, Veins. (B1 and a2)
vasodilate (B2)
Charbachol
M choline ester direct agonist
doa ~1 hr, poor AchE substrate
tx glaucoma
Muscarine
M direct agonist
Toxic mushroom
DUMBBELSS
diarrhea, urination, miosis, bradycardia, bronchoconstriction, excitation (CNS/ nicotinic muscle excitation then paralysis), lacrimation, salivation, sweating.
Cevimeline
M natural alkaloid direct agonist
M1/M3 agonist (M2 is cardio)
tx xerostomia (used with pilocarpine)
Rivastigmine
indirect cholinomimetic- AchE inhibitor
transdermal patch
tx Alzheimers, dimentia, parkinsons
Galantamine
indirect cholinomimetic- AchE inhibitor
tx alzeimers. natural OTC sleep aid.
propantheline
direct muscarinic blocker
rx urge incontinence
terodiline
direct muscarinic blocker
rx urge incontinence
darifenacin
direct muscarinic blocker
M3 selective
rx urge incontinence
solifenacin
direct muscarinic blocker
M3 selective
rx urge incontinence
fesoterodine
direct muscarinic blocker
rx urge incontinence
tolterodine
direct muscarinic blocker
rx urge incontinence
trospium
direct muscarinic blocker
rx urge incontinence
cyclopentolate
direct muscarinic blocker
opthalmologic produce myadriasis and cycloplegia prior to refraction
tiotropium
direct muscarinic blocker
NO CNS
DoA long, inhaled solutions
Tx Asthma/COPD, xerostomia nasal spray
trimethaphan
Nn nicotinic receptor antagonist (ganglion block SANS or PANS)
reduce predominant autonomic tone (basal)
prevent baroreceptor reflex in HR
toxicity - rarely used
Oral, CNS, DoA ~10hrs
Tx Aortic dissection decrease BP in emergency
