Cholinergics Flashcards
cholinergic agonist may also be called
Parasympathomimetic
Cholinergic receptors
nicotinic (ganglionic & NMJ; CNS also)
muscarinic (all over; mostly smooth muscle & glands)
Parasympathomimetic vs cholinergic agonists
Parasympathomimetic: primarily at muscarinic
cholinergic agonist: can act at NMJ (nicotinic) as well without being a parasympathomimetic
Anticholinesterase/Cholinesterase antagonist
Cholinesterase: breaks down ACh
increases duration of ACh in synapse
acts as cholinergic agonist/cholinomimetic
ACh is the primary NT in…
the parasymp. NS
Where is ACh found?
post synaptic jxn sites
muscarinic receptors
nicotinic receptors (NM system)
preganglionic sites:
nicotinic & muscarinic receptors of the ganglia
ACh synthesis location
in the cholinergic nerve terminal cytoplasm
ACh synthesis process
Choline Acetyltransferase (ChAT) on the precursors choline (Ch) and acetyl-coenzyme A (acetyl-CoA)
acetylate choline = ACh
Choline is provided mainly through
reuptake
via high-affinity Na co-transport pumps
on nerve terminal membrane
requires energy & Na
Choline that cannot be reuptaken/reused
___% is able to be repackaged
escapes reuptake carriers and is lost
metabolism to lesser extent
80%
De Novo synthesis
De Novo: “from scratch”
makes up for the 20% choline loss
Where do we get the materials for De Novo synthesis?
primarily choline-containing phospholipids
(internal & external membranes of cellular structures; ie terminal)
phosphatidylcholine
stripped from membrane
converted to choline
choline used to make ACh
Acetyl-CoA is synthesized from
pyruvate or acetate
acetylating coenzyme A in mitochondria
Limitations of De Novo synthesis
unable to produce enough Ch to keep up with transmitter needs
only provides enough Ch to make up for amounts lost in the synapse/not brought back via re-uptake
Acetylcholine (ACh) Release
released first on nerve terminal depolarization
non-vesicular released first
then vesicular ACh
Newly synthesized ACh exists in…
the cytoplasm
can be in vesicles, in pools, or in storage attached to other compounds
T/F
Vesicular ACh is the first ACh that can act in the synapse.
False
non-vesicular, as this is released first
Vesicles contain ___ quanta. 1 quanta contains…
1 vesicle = 1 quanta
1 quanta = 5,000 – 50,000 molecules of ACh
other compounds in here as well
vesicles are produced in…
the nerve terminal mainly
Hwo do we package the ACh into vesicles?
ACh is taken from cytoplasm & transported across the neurotransmitter vesicle membrane by a carrier-mediated process
What happens when the action potential reaches the nerve terminal?
Calcium channels open:
depolarizes nerve terminal
calcium into cytoplasm
↓
triggers a much larger calcium release from the sarcoplasm.
↓
vesicles fuse with the inner wall of the nerve terminal
↓
exocytosis
normal amount of ACh released on a single stimulation
several hundred vesicles
aka millions of ACh molecules
(5k – 50k molecules of ACh per vesicle)
can disrupt ACh release
Hemicholinium-3 (HC-3): eventually depletes ACh
Vesamicol: cannot package ACh
Botulinium Toxin (BoTox): irreversible inhibition of ACh release
Black Widow Spider Venom: overstimulates → depletion
Hemicholinium-3 (HC-3)
inhibits high-affinity uptake carriers of Ch
eventual depletion of ACh in terminal
-Ch will be metabolized more
-De Novo synthesis cannot keep up
What happens if ACh is depleted?
cannot pass signal
Vesamicol
inhibits ACh transport system on the vesicles
↓
decreased amount of ACh in vesicles
↓
decreasing available ACh for transmission
cannot package ACh
Botulinium Toxin (BoTox)
a toxin produced by Clostridium sp.
-binds to nerve terminal
-blocks ACh vesicles from fusing with internal terminal cell wall & exocytosis
-irreversible inhibition of ACh release from terminal
Botox cosmetic use
decrease facial fine wrinkles
relaxes the muscles around the wrinkle
Small amount injected around the wrinkle, which leaves the muscles unable to contract.
Black Widow Spider Venom
binds to nerve terminal (similar to BoTox)
but
instead of blocking release, triggers exocytosis of ACh vesicles
initial overstimulation via cholinergic transmission
↓
blockade (ACh depletion)
-early severe stomach cramping
-potential fatality d/t respiratory paralysis.
T/F
the GIT has a large [ ] of muscarinic receptors.
True
GI motility is stimulated by muscarinic receptors
Where can AChase be found?
-in synapse
-bound into postsynaptic membrane
-surface of postsynaptic membrane
-pre-synaptic membrane
True AChase is found…
-postsynaptic membrane of cholinergic neurons
-on RBCs
Vmax
maximum velocity
how quickly the enzyme can produce
True AChase when acting on ACh will…
break 10s of thousands of ACh per second
HIGH VMAX
How do we increase ACh activity at the post syn membrane?
fire neuron frequently
multiple pulses of ACh
can more constantly stimulate pst syn receptor.
T/F
As soon as we stop firing the pre-synaptic neuron, the post-synaptic activity of ACh stops.
True
ACh is broken down into __ & __. Which are used for…
ACh → choline + acetic acid
choline: reuptake by nerve terminal, re-acetylated to make more ACh
acetic acid: can enter Krebbs cycle
T/F
Choline can interact act an ACh receptor but has less activity than ACh.
True
produces practically no post-synaptic activity
Ch vs. ACh
potency
Ch approximately 10,000 times less than ACh
T/F
Choline can be obtained through other places than phosphatidylcholine of the membrane.
True
carriers can take Ch into nerve terminal
T/F
Intake of supplemental choline can increase transmission and alleviate certain disorders.
False
not very effective
A cholinoreceptor could be…
(means its a cholinergic receptor)
could be nicotinic or muscarinic
A2 adrenoceptor
norepi
heteroreceptor
(innervated by separate neuron that releases the compound this receptor reacts to)
stimulates cell to block further release
autoreceptor vs heteroreceptor
autoreceptor: reacts w/ compound released from nerve terminal
heteroreceptor: on nerve terminal but responds to NT released from elsewhere
The presynaptic A2 adrenoceptor acts as a (autoreceptor/heteroreceptor). This allows…
heteroreceptor
sympathetic system can shut off parasymp. so both are not firing at once
The receptor allowing the release of ACh is a (nicotinic/muscarinic) (hetero/auto)receptor.
muscarinic
autoreceptor
Components of the ACh structure
ester
(rapid hydrolysis by esterases)
quat amine
(permanent + charge; covalent bond)
2 C spacer between these groups
Natural components that the muscarinic and nicotinic receptors react to
-Muscarinic – Muscarine – from mushroom Amanita muscaria
-Nicotinic – Nicotine – from tobacco plant
T/F
Nicotine cannot stimulate muscarinic receptors well & muscarine cannot stimulate nicotinic receptors well.
True
react properly only to their respective compounds they’re based on
Muscarinic Receptor family
(M1 – M5)
M1: autonomic ganglia & CNS
M2: supraventricular heart region
M3: smooth muscles, glands, vascular endothelial cells
T/F
Even when referring to the same receptor (ie: M1), it will not be identical across humans.
True
very similar but not identical
Role of M1 receptor
autonomic ganglia
modulate signal
Role of M2 receptor
supraventricular regions of heart
(control regions: SA & AV nodes)
controls heart rate
Which muscarinic receptor controls heart rate?
M2
95% of muscarinic receptors
M3
Muscarinic Receptors
M 1, 3 & 5
coupled to phospholipase C via G protein
activation:
splits phosphatidylinositol polyphosphates
(from cell membrane)
↓
inositol 1, 4, 5 triphosphate (IP3) & Diacylglycerol (DAG)
IP3
(inositol 1, 4, 5 triphosphate)
water soluble
in cytoplasm: acts on IP3 receptors on the SR, increasing Ca++ release which can then act in cell
Diacylglycerol (DAG)
(lipid soluble)
stays in cell membrane
along with increased Ca++, activates protein kinase C (PKC) which can then control many other enzyme activities
kinase fxn
cleaves proteins, activating enzymes
T/F
M1 and M3 normally mediate inhibtory responses.
False
excitatory
ACh action on most blood vessels causes ___ via ___ receptors
vasodilation
M3
Why is vasodilation considered an excitatory effect?
via M3r
increased Ca++
↓
activates Nitric Oxide Synthetase
↓
increases Nitric Oxide
(diffuses from endothelial cells to smooth muscles of vasculature)
↓
activates guanylate cyclase (in cytoplasm)
↓
increase cGMP
↓
relaxation of vascular smooth muscles
M2 & M4 receptors mediate mainly ____ effects via ____.
inhibitory
G proteins
M2 & M4
MoA
(mainly inhibitory)
-inhibit adenyl cyclase (decreased cAMP)
-trigger membrane K+ channels = hyperpolarization = inhibits SA node automaticity = ↓HR
Which M receptors decrease cAMP?
M2 M4
Stimulation of which M receptor would decrease HR?
M2 & M4
M1
Late EPSP in ganglia
blocked by Atropine
N2 vs M1
in ganglia
N2 is inital stimulation
M1 modulates that stimulation; slower, more consistent, and longer duration
both together = longer overall stimulation
M2
Cardiac mainly
↓ SA automaticity
↓ AV nodal conduction
result: ↓HR
blocked by Atropine (like M1)
Atropine blocks which M receptors?
M1 M2 M3
may block 4 & 5 but still unclear
M3
mainly at neuroeffector junctions
(glands, smooth muscles)
salivation, urination, defecation, pupillary constriction, bronchoconstriction
blocked by Atropine (like M1)
M4
mainly in CNS (striatum)
? mainly inhibitory autoreceptors
M5
salivary glands
some CNS (substantia nigra)
Exact importance unclear.
Nicotinic Receptors
Endogenous ligand (neurotransmitter)
ACh
Nicotinic Receptors
Two primary types (several subtypes)
Nm (N1): NMJ
Nn (N2): autonomic ganglia & neurons
Nm (N1)
neuromuscular (NMJ)
Blocked by d-tubocurarine (non-depolarizing)
& decamethonium (depolarizing)
Nn (N2)
“neuronal”
autonomic ganglia & neurons
Blocked by hexamethonium (non-depolarizing)
unlike muscarinic receptors, the nicotinic receptors are…
ion channels; pentameric; ligand gated ionophore
muscarinic: tied to phospholipase C & enzyme control systems
T/F
Nm (N1) receptors are voltage-gated, while Nn (N2) receptors are ligand-gated.
False
Nm (N1) & Nn (N2) are both ligand-gated, pentameric ionphores
Nicotinic Receptors
ACh sites & requirements
Simultaneous binding of TWO molecules of ACH is required to open channel.
Binding sites in pockets between certain subunits.
Nm (N1) & Nn (N2)
are ionophores that allow passage of which ion(s)?
Na+ (or Ca++)
What the hell am I looking at
shows similarities between subunits and other ionphores
structures are almost identical
-amine
-disulfide bridge
-M1,2,3,4 receptor
-Carbox. acid attached to M4
A1 subunit: has extra disulfide bridge
all probably came from 1 ionophore
Ganglionic receptors are (nicotinic/muscarinic)
nicotinic
Ganglionic receptors
location
symp NS
parasymp NS
neuromuscular junctions
Ganglionic nicotinic receptor antagonist
Trimethaphan (Arfonad)
Neuromuscular Nicotinic receptors are stimulated by
Nicotine and ACh
D-tubocurarine (Tubarine)
non-depolarizing nicotinic antagonist
almost irreversible antagonist of nicotinic receptors
α-bungarotoxin (from snake venom)
initially stimulate receptor, then block
Neuromuscular depolarizing blockers (Decamethonium and Succinylcholine (Anectine)
Autoreceptors
-shuts off further release of ACh
-pre synaptic membrane
-mainly muscarinic (M1, M2, M4,??)
-nicotinic autoreceptors increase rather than inhibit ACh release (feed forward)
Heteroreceptors
innervation on nerve terminal by another type of receptor (A2r on cholinegic nerve terminals)
controls release via another system
receptor may not be innervated but can react to circulating neurotransmitter
How does the symp NS control the eye?
contracts radial muscles
iris is pulled open
more light into eyes
see better in the dark
dilates the eye
(Sympathetic NS)
Dilation of eye
physiologic effects
obstructs canal of schlemm
(outflow channel for aqueous humor which is cont. produced in eye)
block trabecular network
(group of BV vessels)
↑IOP
happens in glaucoma
Aqueous humor
continuously produced in eye
canal of schlemm:
allows it to flow out of eye
picked up by BV
reabsorbed back into body
Parasymp. NS
Eye effects
thru CN 3, a branch goes to ciliary muscle (ciliary body)
sphincter muscle with circular-shaped fibers
PNS stimulation contracts fibers, which constrict the eye opening
suspensory ligaments
suspend the lens so it stays behind pupil
tied onto ciliary muscle
ciliary muscle tightens = shpincter draws inward
releases tension on suspensory ligaments
lens is not pulled as tight
becomes more spherical
Parasymp stimulation gives the lens which shape?
more spherical; lose tension = can bend light more (can focus in oncloser objects)
(vs. disc shape)
sympathetic stimulation of eye
blocks ciliary muscle from contracting
loosen ciliary muscle & it dilates
pulls on suspensory ligaments
lens assumes flatter shape
flatter lens is good for bending light at longer distance = see farther
ability to focus your eyes
accommodation
Choline esters
Acetylcholine (Miochol-E)
Methacholine (Provocholine)
Carbachol (Miostat)
Bethanechol
Choline esters
Acetylcholine (Miochol-E)
short t½ (secs in blood; d/t plasma AChase).
ophthalmic for glaucoma or surgery i.e., cataracts, or for eye exam
causes miosis
moA:
-contractions sphincter muscles of the iris & ciliary muscles → accommodation for near vision
-stimulate ciliary muscles, opening traebeclear network and increasing aqueous humor outflow.
T/F
Plasma cholinesterase is as equally active as true acetylcholinesterase.
False
less active
Choline esters
Methacholine (Provocholine)
-β-methyl group gives more muscarinic activity
-longer duration than ACh (less well hydrolyzed by AChE)
given by inhalational route
diagnose airway hyperreactivity in asymptomatic asthmatics
adverse reactions – headache, dizziness, pruritus
NOTE: - keep emergency meds and equipment ready due to asthmatic type reaction
Choline esters
Methacholine (Provocholine)
considerations
keep emergency meds and equipment ready due to asthmatic type reaction
Choline esters
Carbachol (Miostat)
resistant to AChE hydrolysis due to carbamyl group
nicotinic & muscarinic effects
antiglaucomic, miosis induction for surgery/exam
much longer duration than ACh (6 – 8 hours in eye)
adverse reactions:
stinging/burning of eye, corneal clouding
may cause systemic effects
(salivation, GI cramps, N/V in sensitive persons)
carbamyl group
provides esters w/ resistance to hydrolysis by normal esterases
T/F
Ophthalmic medications can cause systemic effects
True
esp if they are not metabolized right away
Choline esters
Bethanechol
structure & metab
β-methyl group + carbamyl group
further enhances doA
muscarinic mainly
slow hydrolysis
Not destroyed by AChE (at least very slowly)
bad PO absorption
Onset 30-90 min
DoA: 1H PO, 2H subQ
Choline esters
Bethanechol
uses
Tx:
-urinary retention (primary use)
-stimulate GI motility
-counteract anticholinergic fx of tricyclic antidepressants.
-paraplegics (direct acting & CNS pathway not needed)
-Drug of choice for post partum & post op urinary retention
Choline esters
Bethanechol
moA & SEs
-Minimal CV effects
-bladder: stimulates detrusor muscle, which decreases bladder capacity and triggers urination
-relaxes urinary sphincters (urination)
-GIT: ↑ peristalsis, motility
↑ peristalsis & ↓ sphincter tone = poop
Alkaloids
Pilocarpine (Isopto Carpine) (Salagen tabs)
Muscarine
Arecholine
Alkaloids
Pilocarpine (Isopto Carpine) (Salagen tabs)
use
alkaloid from Pilocarpus microphyllus
ESP sweat glands & eyes – glaucoma
miotic for exam/surgery
Occusert: ocular slow-release system for glaucoma
Salagen Tabs: Sjogren’s syndrome Sx
(AI Dz; exocrine glands; dry eyes, mouth, skin; fatigue, aching joints).
Alkaloids
Pilocarpine (Isopto Carpine) (Salagen tabs)
moA & doA
directly stimulates muscarinic receptors
open-angle glaucoma: contracts ciliary muscle, increasing outflow of aqueous humor
closed angle glaucoma: miosis opens angle of anterior chamber – allowing aqueous humor to exit
PO: stimulates glandular secretions, including salivary flow
Duration:
PO: 3-5H
(ophthalmic)
solution: 4 – 14H
gel: 18 – 24H
Alkaloids
Muscarine
from Amanita muscaria
muscarinic agonist only
poisoning treated with Atropine
(poisoning rare; not very potent)
Alkaloids
Arecholine
from Betel nut, which is chewed by many populations in Africa and East Indies
no therapeutic use
CNS effects similar to nicotine and habit forming
Acetylcholinesterase Inhibitors
primary forms
-True acetylcholinesterase
(primarily RBCs, pre & post-synaptic)
-Pseudocholinesterase/plasma cholinesterase/butyrylcholinesterase
(plasma & many other sites)
ACh vs butyrylcholinesterase
structure
ACh: 2 C ester
butyrylcholinesterase: 4 C ester
T/F
butyrylcholinesterase and acetylcholinesterase are equally active towards ACh.
False
butyrylcholinesterase is less active (still very active tho)
function of AChE in the synapse
destroy acetylcholine and prevent overstimulation of cholinergic receptors
AChE Structure
multiple forms
-simple chains (oligomers, dimers or tetramers)
-multiple chains that form a more complex structure
anionic site: attract & hold ACh’s (+) quat amine
esteratic site: serine group; splits ACh into choline and acetic acid
Acetylcholinesterase is a member of the large group of enzymes in the body known as ____
esterases
true AChE is bound to…
outer surface of the plasma membrane
or
basement membrane of the synapse
Which part of AChE’s structure cleaves the ester on ACh?
esteratic site
lines up thanks to spacing & the anionic site, which holds the quat amine group (+)
AChE
has a anionic site that attracts & holds the ____ of ACh in place so that the ester group is directed to a ____ site.
anionic site holds quaternary amine group of ACh
ACh ester group → esteratic site on AChE
AChE
esteratic site contains a ___ group which provides….
serine
the site’s esteratic functions; splits ACh → choline & acetic acid.
The ___ site on AChE splits ACh into __ & __.
esteratic site (has serine group)
choline
acetic acid
Acetylcholinesterase Inhibitors (AChE-I’s)
fxn
block enzymatic degradation of ACh by AChE
allows released ACh to act longer at the cholinergic receptor sites
AChE-I’s
act as ____ in the autonomic system
act as _____ in the somatic system
parasympathomimetics (increase ACh doA)
neuromuscular stimulants
Besides their potential clinical uses, specific AChE-I’s have been widely used as ….
insecticides
(i.e. clorpyrifos (Dursban), diazinon (Spectracide), carbaryl (Sevin)
“war gas”
(i.e. sarin, soman, tabun)
Soman
AChE-I
so toxic that <1 drop on the skin is fatal
How does war gas work?
irreversible bonding
overstimulates cholinergic system
produce too much secretions
“drown”
What gives the anionic site its negative charge?
various AAs
serine hydroxy group (OH) reacts with O on esteratic group
How acetic acid and choline are formed
acetic acid
1) serine hydroxy group (OH) reacts with O on esteratic group
2) bond breaks & no longer tightly held to AChE
3) ester bonded to serine; water places OH back on serine
4) releases acetic acid
choline
water molecules knock mlcl off anionic site
Water is also known as a
nulceophile
Acetylcholinesterase Inhibitors
Which AChEI has tautomer forms?
Physostigmine
double bond will move
can be Quat amine at times
Which is attached to AChE longer?
ACh
AChEIs
AChEIs
not as quickly broken down (vs ACh)
Which AChEI is a true competitive inhibitor?
Edrophonium
only acts on anionic site
doesnt interact at esteratic site
Edrophonium vs the other girls
only acts on anionic site
does not form carbamate group (N + ester) which bonds to esteratic site
they will leave this structure at the serine site
(they dont come off easily)
true competitive inhibitor
‘edro is not like the ester girls”
AChE-I’s
2 classifications based on their AChE binding
Reversible agents
Irreversible agents
AChE-I Reversible agents
MoA
example
do not permanently bind to AChE
A) simple H or ionic binding at the site
B) longer & stronger inhibition d/t covalent bond at serine/esteratic site
i.e. the carbamate types: neostigmine (Bloxiverz)
slowly removed by nucleophilic attack of water molecules (rejuvenates AChE)
carbamylated enzyme
enzyme attached to carmabae w/ a serine OH group
water can break but needs higher energy
reversible but takes longer
T/F
the reaction that created a carbamylated enzyme cannot be reversed.
False
takes longer but is reversible
AChE is rejuvinated once….
carbamate group removed
H reattached to serine group
done by nucleophilic attack by water
Organophosphates are….
Irreversible Acetylcholinesterase Inhibitors
Irreversible Acetylcholinesterase Inhibitors
drug class/types examples
organophosphates, insecticides, war gas
Irreversible Acetylcholinesterase Inhibitors
MoA
long-term or permanent covalent bonds to serine esteratic site
strong!
nucleophilic attack by water ineffective
‘aging’: covalent bond of OPs is further strengthened with time
“Aging”
what this program is doing to me…lol
irreversible AChEIs: OPs
-covalent bond of OPs is further strengthened with time
-‘R’ group on the phosphoryl group splits off
half-aging times
varies per OP
most toxic = minutes
less toxic = days
T/F
In order for a AChEI to render AChE incapable, it must “age” the enzyme.
False
‘aged’ or not, the enzyme is incapable of further hydrolysis of ACh
Once ‘aged’ the only way to restore normal function is to ______ (which takes up to ____).
re-synthesize the enzyme
six weeks for complete regeneration
Treatment for OP poisoning
anticholinergic agent, Atropinem
(block overstimulation by excess ACh)
Pralidoxime (2-PAM, Protopam)
enzyme reactivator
only works if OP has not ‘aged’
T/F
Pralidoxime cannot restore the phosphorylated enzyme to normal if the attached OP is ‘aged’.
True
Once ‘aged’, even its strong nucleophilic attack cannot restore
Symptomology of AChE-I toxicity
salivation, lacrimation, urination, defecation (SLUDGE)
sweating
miosis
(cholinergic crisis)
T/F
reversible AChEIs don’t have to interact with the anionic site
False
this applies to irreversible
When reacting with AChE,
reversible AChEIs form ____
irrereversible AChEIs form ____
reversible carbamylated enzyme
phosphorylated enzyme
Why can’t Pralidoxime rejuvenate AChE after the OP ages it?
the way the bond breaks does not leave an OH group to allow its nucleophile attack
the structure is now “locked”
must resynthesize (6 weeks)
(AChEI Irreversible Agents)
Echothiophate (Phospholine)
miotic used for glaucoma & diagnosis
organophosphate class
⚠️ asthmatic & cardiac pts
Ophthalmic: initial stinging/burning
Long-term use: cataract risk
(AChEI Irreversible Agents)
Malathion
topical (lotion, shampoo)
external parasites (head lice)
OP class
one of the least toxic of the OPs
very potent insecticide
Must be converted to malaoxon (active)
faster in insects
humans eliminate a lot before its converted
poisoning only on ingestion or aspiration
Advantage: kills the eggs (nits) (vs pyrethroid agents)
Potential poisoning Tx: atropine + pralidoxime.
(AChEI Reversible Agents)
Physostigmine (Eserine) (Antilirium)
Isolated from the Calabar bean
(poison in West African natives in witchcraft trials)
ophthalmic & IV
mainly open-angle glaucoma
Alzheimer’s disease (limited success)
tertiary compound
crosses BBB better than Neostigmine (a quat)
(AChEI Reversible Agents)
Neostigmine (Bloxiverz)
uses
PO & IV
IV:
-MG acute episodes & diagnosis
-antagonize Non-DNMB (tubocurarine)
-post-op urinary retention & abdominal distention (but bethanechol is better)
(AChEI Reversible Agents)
Neostigmine
moA
Action at different muscle groups depends on:
-sensitivity of the muscle group
-distributes to that site
some direct NM nicotinic stimulation
Physostigmine use in TCA OD
(occasionally)
treat toxic anticholinergic effects i
not recommended d/t seizure potential
Physostigmine MoA
Potentiates the effects of ACh at:
peripheral nicotinic & muscarinic sites
CNS mainly muscarinic
Physostigmine
normal response to IV
↑ skeletal muscle tone
↑ GI tone & motility
bradycardia
↑ sweat & salivary gland
bronchoconstriction
miosis
↓IOP (widens trabecular network =↑ outflow aq. humor)
Physostigmine @ high doses
acts directly at neuromuscular & ganglionic nicotinic receptors as a depolarizing blocker.
Physostigmine
metab & doA
Rapidly hydrolyzed by cholinesterase
IV doA: 1-2H
ophthalmic doA: 12 – 36H
Neostigmine (Bloxiverz) vs pyridostigmine
both quats
neo has shorter HL
preferred agent for MG diagnosis
edrophonium
due to its extremely short half-life
T/F
Neostigmine & physostigmine have the same moA & ultimate effect
False
same moA
but
Neo is a quat., so no CNS effects.
Neostigmine
absorption
onset
metab
PO: 1% – 2% absorbed
onset: 2 – 4H
IV Onset:10 – 30 min
Elimination: primarily liver microsomal enzymes
some excreted unchanged in the urine
Reversible Agents
Pyridostigmine (Mestinon)
routes and use
regular & SR PO
Myasthenia Gravis Tx
Reversible Agents
Pyridostigmine (Mestinon)
absorption
PO: poor
very variable person to person
Reversible Agents
Pyridostigmine (Mestinon)
Excretion
mainly unchanged via kidneys
some liver microsomal enzymes & cholinesterases
Pyridostigmine vs Neostigmine
both quats
pyridostigmine:
-longer doA & onset
-fewer muscarinic effects (more specific to NMJ)
Reversible Agents
Edrophonium (Enlon)
onset & duration
rapid onset: 30 – 60 seconds
short doA: 5 – 10 minutes
IM
onset: 2 – 10 min
duration: 5 – 30 min
Available in parenteral form only since it has a very short duration in the body
Edrophonium (Enlon)
Edrophonium (Enlon)
structure
moA
Structurally different! not a carbamate
Binds to anionic site by ionic & H bonding
bond easily broken = short duration
rapid renal elimination (unchanged)
Treating OP poisoning
“treat until full atropinized”
eyes cannot dilate any more
10 mg Q30-60 min
Edrophonium
for reversal
- NDNMB reversal: risky d/t short duration
-with atropine: treat resp depression from curare
Edrophonium
uses
-drug of choice for MG diagnosis
(not treatment b/c short half-life)
-allows potential benefits/risks of AChE-I therapy
T/F
Edrophonium is the drug of choice for MG diagnosis and treatment.
False
drug of choice for MG diagnosis
(not treatment b/c short half-life)
T/F
Edrophonium
Few nicotinic effects are seen in challenge dosing with this drug due to the short duration of action
False
muscarinic effects (salivation, bradycardia)
AChEIs Reversible Agents
Donepezil (Aricept)
piperidine-type reversible ChE-I
mild-moderate Alzheimer’s
(only improves earlier stages)
binds by H bonding (easily reversed)
memories are tied to…
ACh release in certain areas of the brain
(Alzheimers drugs)
Donepezil (Aricept) vs Tacrine
Donepezil:
-doesnt have hepatotoxicity risk
-fewer peripheral effects (greater affinity for CNS cholinesterase)
-longer HL (higher CNS affinity & slower elimination)
T/F
Most of the AChE-I’s show little selectivity between true AChE and pseudo ChE
True
exception is donepazil (more selective for true AChE)
Donepezil (Aricept)
absorption
almost 100%
Donepezil (Aricept)
metab
P450 system
donepezil → 2 active + 2 inactive metabolites
HLoE: parent + active metabolites = 70 Hrs
Rivastigmine (Exelon)
reversible AChEI
improve thinking & memory in Alzheimer’s
Galantamine (Razadyne)
reversible AChEI
cognitive loss d/t Alzheimer’s
acts as a reversible, competitive antagonist of AChE
acts as a reversible, competitive antagonist of AChE
Galantamine (Razadyne)
Cholinergic Antagonists
block ACh at muscarinic receptors
can be tertiary or quat
compounds penetrate different tissues at different concentrations (compound’s effect varies at therapeutic doses)
Advantage of blocking true AChE and not pseudoChE
maintain many normal metabolic pathways
Quats have higher ___________ ratio
ganglionic blocking to antimuscarinic activity
CNS penetration of
Atropine
Scopolamine
Ipratropium
Atropine (tert): poor CNS penetration
Scopolamine (tert): penetrates CNS better than Atropine
Ipratropium (Quat): little, if any, CNS activity
other drug classes w/ anticholinergic effects
H1-blockers
phenothiazines
TCA’s
carbamazepine (Tegretol)
watch for anticholinergic SEs with these!
Anticholinergics were a mainstay for ulcer therapy until
cimetidine (70’s)
Anticholinergic toxicity symptoms
hot as a hare (hyperthermia d/t decreased sweating)
blind as a bat (mydriasis & cycloplegia)
mad as a hatter (CNS stimulation)
dry as a bone (xerostomia)
tachycardia
constipation
confusion
urinary retention
Some nicotinic activity seen with some compounds, but not a major concern
Cholinergic Antagonists
Tertiary Agents
Atropine (USP)
Scopolamine (Transderm Scop)
Benztropine mesylate (Cogentin)
Dicyclomine (Bentyl)
Darifenicin (Enablex)
Tolterodine (Detrol)
Homatropine
Cyclopentolate (Cyclogyl)
Tropicamide (Mydriacyl)
Cholinergic Antagonists
Quaternary Agents
Glycopyrrolate (Robinul)
Ipratropium (Atrovent HFA)
Tiotropium (Spiriva)
Cholinergic Antagonists
Atropine
derived from…
which forms are in/active
belladonna plant
(l-hyoscyamine is active, d form is not)
Cholinergic Antagonists
Atropine
uses
Prototype of its class
-brady🩷
-pre-op decrease secretions
-mydriatic for eye exam
-No longer for Parkinson’s disease
☆ Important in AChE-I toxicity to counteract excessive ACh (ex. Reversal of neuromuscular blockade)
Cholinergic Antagonists
Atropine
moA
-competitive inhibitor & autonomic postganglionic cholinergic receptors (muscarinic)
-in SNS at sweat glands
Cholinergic Antagonists
Atropine
dose dependent effects
therapeutic doses: Does not block at NMJ
-Low doses: paradoxical ↓HR
-higher doses: restlessness, hallucinations (abuse potential), disorientation
Sites most/least receptive to atropine
most= Salivary, bronchiole, sweat glands
eye & heart
GI tract
Which causes greater CNS depression?
atropine
scopolamine
scopolamine
drowsiness, euphoria, etc
T/F
Atropine is a potent bronchodilator & decreases bronchial secretions, making it useful for asthmatics.
False
side effects limit this use
(although it is a potent bronchodilator & decreases bronchial secretions)
Atropine HL
~12H
Scopolamine (Transderm Scop)
uses
-motion sickness (blocks output from vestibular nuclei in inner ear → vomiting center)
-Parkinsonism
-Truth drug in WWII (twilight sleep & lowers inhibitions)
-preop ↓ bronchial secretions
⚠️High incidence CNS depression @ therapeutic doses
Atropine vs Scop
potentcy
Scop: More potent on iris, ciliary body, secretions
atropine: more potent at heart, bronchial and GI smooth muscles
Scopolamine (Transderm Scop)
8H
Scopolamine (Transderm Scop)
be cautious of ____ at therapeutic doses
⚠️High incidence CNS depression @ therapeutic doses
Scopolamine (Transderm Scop)
derived from
Naturally occurring alkaloid (belladonna plant)
(Cholinergic Antag; Tert)
Benztropine mesylate (Cogentin)
Oral and parenteral forms available
(Cholinergic Antag; Tert)
Benztropine mesylate (Cogentin)
uses
Parkinsonian syndromes, including antipsychotic induced extrapyramidal symptoms
(M1 antagosim)
(Cholinergic Antag; Tert)
Benztropine mesylate (Cogentin)
structure
Synthetic muscarinic antagonists (structure similar to atropine)
(Cholinergic Antag; Tert)
Benztropine mesylate (Cogentin)
moA
Synthetic muscarinic antagonist
-antihistamine & LA effects
-Blocks CNS muscarinic receptors (M1)
(↓ excessive cholinergic activity seen in Parkinsonism)
-blocks dopamine reuptake (prolongs dopamine activity)
-direct smooth muscle antispasmodic action
Do we expect to see CNS stimulation from Benztropine mesylate (Cogentin)?
crosses BBB, but minimal CNS stimulation
(Cholinergic Antag; Tert)
Benztropine mesylate (Cogentin)
DD effects
small doses: minor CNS depressant
larger doses: atropine-like CNS stimulation
Tolerance to effects in prolonged use (especially in Parkinson’s disease)
Therapeutic effects ~ 2 - 3 days
Benztropine mesylate (Cogentin)
how long until we see the therapeutic effects?
2 - 3 days
(Cholinergic Antag; Tert)
Dicyclomine (Bentyl)
(little CNS activity)
-antispasmodic in IBS (antimuscarinic effects and direct action on smooth muscles in GI tract)
-Limited effects on salivary glands, sweat glands, or cardiovascular system
(Cholinergic Antag; Tert)
Darifenicin (Enablex)
moA & use
-overactive bladder & urgency
-Competitive agent
-More potent at M3 receptors
(Cholinergic Antag; Tert)
Darifenicin (Enablex)
metab & SEs
-98% protein bound (mostly alpha-1-acid)
-P-450 metabolism 97% (CYP2D6 and CYP3A4)
⚠️ hepatic insufficiency & P-450 inhibitors (clarithromycin)
Major SE’s: dry mouth, dry eyes, constipation, UTI’s
(Cholinergic Antag; Tert)
Tolterodine (Detrol)
-overactive bladder
SE’s: blurred vision, dry mouth, dizziness, constipation
Metab: CYP3A4 (interacts w/ Ketaconazole, macrolide antibiotics, cyclosporine (3A4 inhibitors) requiring dosage reduction)
Meds metab by CYP3A4 interacts w/ …
Ketaconazole, macrolide antibiotics, cyclosporine (3A4 inhibitors)
reduce dose
for Overactive Bladder (OAB)
Tolterodine (Detrol)
Darifenicin (Enablex)
fesoterodine (Toviaz)
flavoxate
oxybutynin (Ditropan XL)
solifenacin (Vesicare)
(Cholinergic Antag; Tert)
Homatropine
Cyclopentolate (Cyclogyl)
Tropicamide (Mydriacyl)
Structurally similar to atropine
-ophthalmic: mydriasis & cycloplegia for diagnosis
- temporary stinging/burning
~increase intraocular pressure
❌ glaucoma or a sensitivity to anticholinergics
Contraindicated in patients with glaucoma or a sensitivity to anticholinergics
Homatropine
Cyclopentolate (Cyclogyl)
Tropicamide (Mydriacyl)
(cholinergic antag; Quat)
Glycopyrrolate (Robinul)
uses
-GI antispasmotic
-treat bronchospasms
-pre-op: decrease salivary, GI, pulmon secretions
-decrease risk of acid aspiration
-block the effects of surgical vagal stimulation
-block muscarinic effects of reversal
No CNS effects- can’t treat OP toxicity
(cholinergic antag; Quat)
Ipratropium (Atrovent HFA)
uses
Structurally similar to atropine, but is a quat
-oral inhalation or nasal spray
-bronchodialator (COPD better than albuterol, but not other β2 adrenergic agonists)
-acute asthma attacks
-Nasal spray: rhinorrhea d/t colds/allergies
(cholinergic antag; Quat)
Tiotropium (Spiriva)
Structurally similar to atropine, but is a quat
-oral inhalation (powder)
-bronchodialator (better than albuterol in COPD)
