muscurinic Flashcards
cholinergic synapse overview
Ach is like the carrier of choline goes into the synapse and the vesicle holds it until it is released by a NT autoreceptors reside on the synapse (M2 off switch) on the post synaptic cell there are cholinesterase inhibitors, cholinoceptors (G protein coupled M)
what is ach hydrolyzed by at the synapse
AChE
why can’t you give Ach as a drug
- rapidly hydrolyzed - bad absorption because of the positive charge - buteryl cholinesterase (rapidly broken down int he plasma to hydrolyze)
heteroreceptor and autoreceptor
hetero- alpha 2 auto - M2 they both cause an effect on parasymp activity (chlonidine causes dry mouth)
BuChE
Ach and other choline-based esters can by hydrolyzed by plasma esterase such as butylrylcholinesterase - important for drugs who are based on Ach
muscurinic recptors
G-protien coupled receptors - contains an ester and a charge like Ach
nicotinic
ligand gated cation channels (primarily sodium)
M1 location
CNS, gastric, salivary, autonomic ganglia, enteric nerves
M1 G protein
Gq
M1 response
inc IP3, inc DAG, inc Ca- depolarization and excitation, inc AA
M1 function
inc cognitive function, inc siezure activity, inc secretions, inc autonomic ganglia depolarization, dec dopamine release and locomotion (alzehiemers not enough Ach)
M2 G protien
Gi
M2 location
autonomic nerve terminals, CNS, heart, smooth muscle
M2 cellular response
inhibition of cAMP and VGCC
M2 function
dec heart rate, inc smooth muscle contraction via auto/hetero receptors, inc tremors, hypothermia, and analgesia,
M3 G protein
Gq
M3 tissue location
CNS, smooth muscle, glands, heart
M3 cellular response
same as M1
M3 function
increased smooth muscle contraction (bladder), inc salivary gland, inc food intake, body fat deposits inhibit dopamine release, synthesis of NO
structure of muscurinic agonists - ammonium group
- ammonium group: nitrogen capable of bearing a positive charge (quat amine), can have no charge (tertiary amine), can’t be a secondary amine - biggest sub on nitrogen can be a methyl (if ethyl the activity dec on agonist)
structure of muscurinic agonists (3)
- ammonium 2. ethylene 3. acyloxy group do not want drugs to be too big! made after ach 2 molecules between N and ester
structure of muscurinic agonists- ethylene bridge
2 carbon atoms between nitrogen and oxygen INGs rule of 5 - longer or shorter than 5 atoms between N and C terminal will not work
structure of muscurinic agonists- acyloxy group
ester, ether, or ketone - really only needs to be an oxygen!
methacholine
M>>N methyl on the beta carbon which makes it much better M than N - slows down the metabolism hydrolysis by AchE and has some nicotinic activity
carbachol
no methyl group on B carbon (not selective for M and can activate M or N) has a carbamate that can be broken down by acetyl cholenesterase much less - increases resistance to hydrolysis - lots of nicotinic activity because no methyl
adding a methyl group on the B carbon of a muscurinic agonist
increases the selectivity for M over N and slows down the metabolism - survives the cholinesterase better
carbamate on the end of the muscurinic agonist
N + ester broken down by AchE much less - increases resistance to hydrolysis
bethanechol
like methacholine and carbachol having a baby ! has a carbamate and a methyl group! hydrolysis resistant AChE, no nicotinic activity
pilocarpine
plant derived alkaloid - would eat it for dry mouth doesnt fit the mold - has a lactone ring but it still works! hydrolysis resistant AChE, no nicotinic activity
cevimeline
pharmacologically muscurinic agonist- does not look like it would fit the mold hydrolysis resistant by AChE, no nicotinic activity
INGs rule of 5
5 atoms starting from the alpha carbon (C right next to N) all the way to the terminal
off-label uses of muscurinic agonists
- acute urinary retention (non-obstructive) - treatment of disabling anticholinergic side effects from meds such as tricyclic antidepressent - bronchial airway hyper-reactivity (no asthma) - lowering of intraocular pressure in glaucoma (mydriasis in symp and constrict in parasymp) - miosis induction after opthalmoscopic exam -xerostomia and sjogren’s syndrome - COPD - bradycardia
CNS (M,N)
stimulatory, N small doses elevation of mood, alerting, addiction (nausea), large doses, seizures; coma; convulsions
sphincter muscle of iris (M)
contraction (miosis)
ciliary muscle of eye (M)
contraction, accommodation for near vision
heart (M)
decrease in heart rate
bronchi (M)
contraction
blood vessel (M)
dilation and release of EDRF from endothelium
motility in GI (M)
inc perstalisis
sphincters in GI (M)
dec tone, relaxation (exception: contracts the gastroesophageal sphincter)
urinary bladder (M)
inc contraction and inc secretion
skeletal muscle (N)
activation of NM end plates, contraction
glands (M)
inc secretion
what do muscurinic antagonists violate to not make them agonists
- attached to nitrogen a lot bigger than methyl group - not 5 molecules between N and ester
muscurinic antagonist- N
nitrogen is either a tertiary amine or quaternary ammonium- can’t get into the brain if it is charged
muscurinic antagonist- R1, R2
R1 and R2 are carbocyclic or heterocyclic rings
muscurinic antagonist- R1, R2
R1 and R2 are carbocyclic or heterocyclic rings the other is usually saturated (but not required) sometimes these rings fuse together, rings can’t be too large or else the drug can’t bind
R3 on muscurinic antagonists
usually a hydrogen, hydroxyl, or component of R1 or R2 - or can be other small groups
“X” on muscurinic antagonists
usually an ester but this is not required- can also be an ether or even absent altogether - just part of the aliphatic chain
length between ring-substituted carbon and the nitrogen on muscurinic antagonists
usually 2-4 atoms - more potent agents have 2 methylene units in this chain
muscurinic antagonists used for the following disease states
COPD, parkinson’s disease, overactive bladder, mydriatics/cycloplegics (opthalmic exams), IBS-D
peripheral M antag adverse effects
xerostomia, dry eyes, blurred visions, dry skin, tachycardia
central M antag adverse effects
confusion, hallucinations (jimson weed), delerium, coma
what structural features would limit the CNS effects on an antimuscurinic drug
ionized nitrogen on a quaternary ammonium - can’t pass the BBB
what are potential drug interactions with antimuscurinic
cautious when using with other antimuscurinics benydryl + amitryptiline
relaxation of sphincter muscle of the iris
mydriasis- dialating
relaxation of ciliary muscle of the iris
loss of accommodation and blurred vision “paralyze” cycloplegia - accommodates for long range of vision
pilocarpine
glaucoma - need to find a different way to dilate, stimulates the alpha 1 instead
drugs for opthalmic
atropine, tropicamide, cyclopentolate
drugs for COPD
Tiotropium (Spiriva), Ipratropium (Atrovent), Glycopyrrolate (Seebri), Aclidinium (Tudorza), Umeclidinium (Incruse Ellipta)
COPD SAR M antagonists
all quaternary ammonium - little central effects - bad for oral absorption - all have an ester and aromatic rings
parkinsons disease - MOA
deficiency of dopamine in the nigrostriatal tract - leads to an imbalance between dopamine and ach in motor control areas - treated with drugs that can reduce ach activity
would a quat ammonium be good for drugs to fight parkinsons?
NO, they do not want a charge so they can get in the brain
parkinsons drugs
benztropine (cogentin), trihexphenydil (artane)
IBS drugs have the potential for adverse CNS effects
no, they do not
IBS drugs
dicyclomine (bentyl)
muscurinic receptors and nausea / vomiting
M1 mainly participate in vestibular nasea/vomiting aka motion sickness, M1 also on the nucleus of tractus solitarius (vomiting center)
what drug is given for motion sickness
scopolamine
sudden urge to urinate
miturition- stretch on receptor, parasymp fire and motor neuron stop firing, smooth muscle contracts, internal sphincter passively pulled open, external sphincter relaxes, higher CNS input facilitates or inhibits reflexes
why does oxytrol have less side effects
antimuscurinic drugs - less side effects because it has a greater AUC- used to treat over active bladder
what do all quat ammoniums have in common?
they all end i n -ium
advantage of M3 selectivity
no cardiovascular effects - cardioselective for M3, still get constipation/ dry mouth, dec in CNS effects
functional tissue selectivity M3 for urinary
“functional” means we do not know why- may be a different subtype, slight differences of the receptor, environment may cause 1 receptor over another and may be pH environment
how does this metabolize
p450 because of the ester - it is an ium because of the + charge
functional tissue selectivity for bladder M3 - solifenacin- CYP 314 metabolized
Darifenacin- 2d6 and 3a4- cause dry mouth and selective m3
oxybutinin-
Most lipophilic of all agents for OAB - goes into brain so do not use for elderly
phase 2 conjunction, replace functional group with OH
Refer to previous page for discussion of formulation-
dependent ADR profiles.
Active metabolite: desethyloxybutynin
What side effects would you predict in
someone who was a CYP2D6 poor metabolizer
when compared to an ultra-rapid metabolizer?
more parent drug and less metabolite,
Tolterodine and Fesoterodine
fesoterone- prodrug of 5-HMT, more predictable and much cleaner
tolerodine- no esterase, less predictable
