Test 1: 14-16 Flashcards
where is ACh released
muscarine is considered to be a –
‘parasympathomimetic’
will cause vagal stimulation to the heart (decrease HR?)
how to make ACh
Choline synthesized from — supplied by diet and protein metabolism
serine
how is ACh made inside the nerve ending?
choline is brought into cell transporter (rate limiting step)
choline + Acetyle CoA (choline acetytransferase) = ACh
ACh moved into vesicle by VaCht(Vesicular acetylcholine transporter)
ACh is then moved out of nerve
there are no intracellular breakdown of ACh (unline NE)
what does botulinus toxin do?
blocks release of ACh into synapse
leads to flaccid paralysis
clostridium botulinum: cleaves synaptobrevin subunit to prevent export
how is ACh broken down
within the synaptic cleft
very fast reaction
water and acetylcholineterase(AChE)
will cleave/hydrolyze into acetic acid and choline
choline is then brought back into the nerve to be used again (this is rate limiting step)
how is NE vs ACh broken down in the synaptic cleft
NE: most NE will be taken back into the nerve to be recycled or broken down by MAO, anything left in the synaptic cleft will get eaten by COMT, bind to postsynaptic receptor, or bind to presynaptic autoreceptor(that stops reaction)
ACh: only gets broken down in the synapse, very fast hydrolization by AChE
— is not specific for ACh, but will hydrolyze it
Pseudocholinesterase (pseudo-/butyro-ChE)
non specific or serum cholinesterase
made by the liver and found in blood plasma
what is the rate limiting step of making ACh
choline reuptake into the nerve
where are nicotinic sites in PNS?
neuromuscular junctions(skeletal)
all preganglionic fibers (ANS and adrenal medulla)
where are the muscarinic sites in the PNS
where ACh is released at postganglionic fiber
all parasympathetics and sympathetic to the sweat gland
Muscarine is considered to be ‘parasympathomimetic’
nicotinic: both sympathetic and parasympathetic ganglia
what type of receptors are nicotinic?
ligand-gated ion channels
(ionotropic receptors)
what kind of receptors are muscarinic
GRCP
(metabotropic receptors)
Nicotinic — receptors are ligand-gated, nonselective cation ion channels
ACh
nicotinic ACh receptors will stimulate both the — and —
synpathetic and parasympathetic postganglionic neurons
ACh released all all pregranglionic site
4 effects of Nicotinic ACh receptors
stimulates ANS: sym and para postganglionic neurons
stimulate release of EPI/NE from adrenal medulla
cause contraction of skeletal muscle (Nm)
cause CNS effects: tremor, anxiety, respiratory and circulatory center effects
how does nicotinic receptor work?
5 subunits: 2⍺, 1 β𝛾δ
2 ACh binds to ⍺, pore opens, Na moves in and K moved out
— receptor works by Binding of 2 molecules of ACh causes opening of central pore allowing the flow of ions through the pore according to their concentration gradients (Na+ and K+)
nicotinic ACh
Muscarinic activation will cause:
— secretion
— contraction
relaxation of —
— of the heart
gland: sweat, salivary, tear, mucous
smooth muscle and pupillary constriction
sphincters: GI tract, urinary tract, biliary tract
slowing (bradycardia)
GPCR receptors
accronym to remember muscarinic activation
SLUMD
Salivation, Lacrimation, Urination, Miosis(pupils contract), Defecation,
M2 muscarinic receptors are found —
heart, smooth muscle, autonomic ganglia
where are M3 muscarinic receptors found
Exocrine glands, smooth muscle, blood vessels (endothelium)
Activation of M2 receptors are — in cardiac muscle
INHIBITORY
due to inhibition of adenylate cyclase (decrease cAMP in the cell) and activation of K+ channels (moves K out of cell)
Activation of M3 receptors are — in smooth muscle
EXCITATORY
due to the opening of plasma membrane and intracellular Ca2+ channels
how do M2 receptors cause inhibition of cardiac muscle
M2 will ativate K channels, this will cause K to leave making cell less negative (decreasing action potential)
M2 will also inhibit adenylate cyclase which leads to decrease in cAMP (cAMP used throughout the cell)
how does M3 receptors excitatory to smooth muscle?
M3 will open Ca channels, (Ca will come into cell, more positive= easier to cause impulse/contraction)
M3 will also open plasma membrane channel→ allow IP3 in which triggers more Ca into cell → contraction of cardiac muscle
what are some parasympathomimetics drugs
ACh
methacholine
carbachol
bethanecol
what happens when you give acetylcholine
No significant therapeutic applications
will trigger both nicotinic and muscarinic sites
poorly absorbed by GI or skin
if IV, rapidly hydrolyzed by plasma cholinesterase
no CNS effect, can’t get past BBB because it is + charged
— is a synthetic analog of acetylcholine that is more selective for Muscarinic vs Nicotinic receptor activity
methacholine (provocholine)
less susceptibile to getting hydrolyzed by AChE
used to diagnose asthma: will cause bronchial constriction
can cause bradycardia and hypotension
methacholine (provocholine) is more selective for — receptor activity
Muscarinic vs Nicotinic (M»N)
muscarinic ACh receptors: SLUMD
M2: inhibitory to cardiac muscle
M3: excitatory to smooth muscle
methacholine (provocholine) is used for
Used for diagnosis of asthma.
* Look for exaggerated bronchial constriction after methacholine administration
Cardiovascular side effects have limited its clinical use
* Potential for somewhat unpredictable bradycardia and hypotension
Muscarinic»_space; Nicotinic
muscarinic ACh receptors: SLUMD
M2: inhibitory to cardiac muscle
M3: excitatory to smooth muscle
— are synthetic ACh that are Resistant to acetylcholinesterase (AChE) action
carbachol (carbamylcholine)
bethanecol (myotonachol)
what receptors do carbachol work on
Muscarinic and Nicotinic activity (M = N)
synthetic of ACh, that is resistant to AChE degredation
what is carbachol used for
- Selectively stimulates smooth muscle in the urinary and gastrointestinal tracts
- Limited clinical use due to ganglionic stimulation (activates both para- and sympathetic side)
- Used to induce miosis (pupil constriction)
- Used in treatment of glaucoma to increase the outflow of aqueous humor from the eye
resistant to AChE
M=N
bethanecol works on what receptors?
Muscarinic vs Nicotinic receptor activity (M»_space; N)
what is bethanecol used for
test pancreatic function since it increases secretions
Used to treat urinary retention by stimulating contraction of bladder
muscarinic: M3: found in exocrine glands, smooth muscle and blood vessels: is excitatory for smooth muscle
— is a Naturally Occurring Cholinergic Alkaloid from a south american shrub
pilocarpine
100x more potent then ACh
M>N
will cause sweating and increased salivation
will cause miosis, decreases intracoluclar pressuer by increasing drainage, increases BP and causes tachycardia
pilocarpine will cause
(muscarinic effect) will cause sweating and increased salivation
will cause miosis
decreases intracoluclar pressuer by increasing drainage
(nictotinic effect) increases BP and causes tachycardia
south american shrub that acts as parasympathomimetic that is 100 x more potent then ACh with M>N activity
— is made from the betel nut and turns teeth black
arecoline
M=N effect
previously used to treat tapeworm cause it increased GI movement
arecoline is used for
no current uses
previously used to treat tapeworm infections
can be addictive and turn teeth black
made from betel nut
M=N receptors
muscarine is made from —
mushroom amanita muscaria
poisonous from M»>N response
- marked lacrimation, salivation, sweating, miosis
- severe abdominal pain
- frequent watery and painful bowel evacuations
- cardiovascular collapse
- vertigo, weakness, confusion, coma, convulsions
- death in few hours
antidote atropine
muscarine acts on what receptors?
M»>N
cause: marked lacrimation, salivation, sweating, miosis - severe abdominal pain - frequent watery and painful bowel evacuations - cardiovascular collapse - vertigo, weakness, confusion, coma, convulsions - death in few hours
poisionous mushroom
what does muscarine cause
- marked lacrimation, salivation, sweating, miosis
- severe abdominal pain
- frequent watery and painful bowel evacuations
- cardiovascular collapse
- vertigo, weakness, confusion, coma, convulsions
- death in few hours
antidote for muscarine
muscarinic receptor antagonist
atropine
muscarine is from poisonous mushroom
side effects of atropine
Tachycardia
- Decreased intestinal contraction and motility
- Drying of airway and sinuses and brochodilation
- Pupillary dilation (mydriasis)
- Tremor
- CNS delusion ,excitement, life-like dreams
atropine is an anticholinergic with M»>N effects
what receptors does atropine work on?
M»>N
with nonselective M1-6 activation
— is made from deadly nightshade
atropine
what are some therapeutic uses for atropine
atropine is a antimuscarinic agent:
decrease respiratory secretions after intubation
used in cold medications: decreases lacrimal and nasal gland secretions
antiasthmatic (blocks ACh mediated bronchoconstriction
scopolamine is used for
motion sickness
sedate mentally ill patients
antimuscarinic agent
tropicamide is used for
causes mydriasis (dilates pupil for very short time)
synthetic antimuscarinic agent: stops ACh receptors
contraction of radial iris muscles causes
dilation (mydriasis)
innervated by SYM only
contraction of the circular iris muscles will cause
constriction of pupil (miosis)
innervated by the PARA
the iris is under both para and sym control, which one is stronger?
para
para controls circulear muscle (keeps eye slightly contricted at all times→ miosis)
to cause miosis what kind of drug
muscarinic agonists
miosis/constriction controlled by PARA
to cause mydriasis what type of drug
muscarinic antagonist
mydriasis/dilation controlled by SYM
tropicamide will cause short term dilation of the eye
cililary muscle is controlled by —
PARA
muscle is always slightly contracted
contraction of the ciliary muscle causes
lens to bulge, used for near vision
controlled by PARA: always slightly contracted
relaxation of the ciliary muscle will cause the lens to —
flatten
used for far vision
under control of PARA
— is paralysis of the ciliary muscles
cycloplegia
can be from to little or too much ACh
lens shape is controlled by contraction of ciliary muscle which is under PARA control and always slightly contracted
paralysis of accommodation of the cililary muscle is caused by —
muscarinic antagonist= too little ACh
ciliary muscles kept slightly contracted by PARA, if you block this muscle relax and lens flattens= farsighted
spasm of accomodation of the ciliary muscle is cause by
muscarinic agonist or AChE inhibtors or too much ACh
ciliary muscle under control of PARA, kept slightly contracted, if you increase stimulation will lead to constant state of max contraction= nearsighted
farsightedness is caused by — of accommodation
paralysis
too littel Ach= relaxation and flat lens
nearsightedness is caused by — of accomodation of the ciliary muscle
spasm
too much ACh= max contraction and lens bulges
Inducing miosis with — and — drugs can increase drainage
pilocarpine (miosis= contraction controlled by PARA)
physostigmine
β antagonist (—) decrease aqueous humor production
timolol
nicotine causes —
a bunch of stuff- No significant therapeutic uses for nicotine
hard to determine cause nicotinic receptors( NM > NN) on PARA and SYM
nicotinic receptors also desensitize with increased dose
— Specifically blocks ganglionic Nicotinic receptors (NN) not as active against NM
hexamethonium (C6)
Use is limited since it blocks both sympathetic and parasympathetic ganglia
— is a ganglionic blocker of nictonic agents and Has been used in veterinary medicine to lower blood pressure during surgery
trimethaphan (arfonad)
what will AChE inhibitors do
increase effect of ACh throughout, will have sym, somatic and para effects
AChE inhibtors block the breakdown of ACh and are —
parasympathomimetics
will have more ACh activation of both muscarinic and nicotinic receptors
— type of anti-AChE with Quaternary nitrogen that binds reversibly to the anionic site on AChE
reversible inhibitor
— type of anti-AChE with Substrate for AChE and occupy active site for extended time
carbamylating inhibitor
— type of anti-AChE that Covalently binds to and irreversibly inactivates AChE
phosphorylating inhibitors
edrophonim (tensiolon) works as a reversible anti AcHE by —
competitive inhibitor for binding sites
no covalent attachment means rapidly reversible
used to diagnose myasthenia gravis
edrophonium (tensilon) is used to diagnosis —
myasthenia gravis
reversible Anti- AChE- simple competitive inhibitor
Myasthenia Gravis is a neuromuscular disease characterized by weakness of skeletal muscle contraction as a result of a decrease in ACh receptor density at the neuromuscular junction
how is edrophonium/tensilon used to diagnose myasthenia gravis
MG→ autoantibodies cause ACh receptors to be internalized
edrophonium will block the degrade of ACh allowing for a greater chance of ACh to bind to the receptor that are left
will have short response →transient improvement
increase ACh= increase muscle contraction
how does carbamylated inhibitors of AChE work?
this drug will bind to same enzyme that breaks down ACh, but it will get stuck for 30 minutes
substrate will sit in active site of AChE for extended time
how does physostigmine(eserine) work?
carbamylated inhibitor of AChE
will sit in AChE binding site and prevent it from working for 30 minutes
made from West African plant Physostigma venenosum
physostigmine (eserine) was originally used to treat MG, — and — poisoning.
glaucoma
atropine
increases ACh available
physostigmine is a carbamylated inhibtor of AChE that sits in AChE binding site for extended period
how does DFP work
phosphorylating inhibitor of AChE
will bind to AChE but will not let go, inactivating the enzyme → increases ACh avialable
how to overcome phosphorylating inhibitors of AChE
these drugs break AChE by binding and never letting go
body needs to make new AChE enzymes which could take weeks.
toxic exposure when 80-90% of all AChE is inactivated
nerve gas, sarin and VX gas work by
Phosphorylating Inhibitors of AChE
permently inactivate AChE
leads to overflow of ACh in the body →SLUMD and then paralysis and respiratory failure
2-PA M does not work against — inhibitors
carbamylating AChE (PNPD)
does not cross BBB, only works on non-aged complex
will give atropine after to prevent extra ACh in mus. recp
