Cholinergic Drugs Flashcards
What is the major cholinergic agonist?
Ach- the natural transmitter
What are the major muscarinic agonist drugs?
bethanechol
pilocarpine
What are the major muscarinic antagonists?
atropine
tropicamide
tolterodine
tiotropium
What are the major Achesterase inhibitors?
physostigmine
neostigmine
donepezil
sarin
What is a cholinesterase reactivator?
pralidoxime
What is a nicotinic ganglionic agonist?
nicotine
What is a nicotinic ganglionic antagonist?
trimethaphan
What is the main depolarizing neuromuscular blocker?
succinylcholine
What are the major non-depolarizing neuromuscular blockers?
d-tubocurarine
vecuronium
What is a major Ach Release inhibitor
Onabotulinumtoxin A (Botox)
What type of cholinergic drug is succinylcholine?
a depolarizing neuromuscular blocker
What type of drug is trimethaphan?
a nicotinic ganglionic antagonist
What type of drug is physostigmine or neostigmine?
Acetylcholine esterase inhibitor
What type of drug is nerve gas (sarin)?
acetylcholine esterase inhibitor
If someone has been exposed to sarin, what drug would you give them? Why?
pralidoxime because it reactivates Achesterase
What contributes to the really short clearance time from the synaptic cleft?
the easily cleavable ester bond
What two structural features of Ach also have functional properties?
- easily cleaved ester bond
2. NH4+ quarternary amine which attracts it to its site of action
What receptor is found at all cholinergic AND adrenergic ganglia?
Ng (nicotinic)
What receptor is found at the parasympathetic neuroeffector junctions? What tissue specifically are affected?
Muscarinic on exocrine glands, smooth muscle and viscera
The somatic neuromuscular junction has what type of receptor?
Nm (nicotinic)
The central nervous system has which cholinergic receptors?
M and N
Where would one see non-innervated tissue with AchR? what type of receptor is present?
Muscarinic receptors are present in endothelial cells of blood vessels that cause vasodilation
How does choline enter the nerve terminal?
What drug can block choline transport into the nerve terminal?
It is co-transported with Na+ and is a rate-limiting step.
It can be blocked by hemicholinium
What does hemicholinium do?
It blocks choline from entering the nerve terminal. It is not specific or useful therapeutically
What are the three steps for synthesis and storage of Ach?
- choline enters the nerve terminal (via cotransport with Na+, blocked by hemicholinium)
- Acetyl CoA + choline -(CAT)–> Ach
- Ach is packaged into vesicles
What blocks the release of Ach from vesicles?
What facilitates excessive release?
Botulinum toxin (onabotulinumtoxin A) stops release of Ach A-latrotoxin from black widows cause excessive release of Ach by increasing Ca2+ influx
What are the two receptors for Ach?
What is a natural agonist and antagonist for each?
N agonist- nicotine
N antagonist- d-tubocurarine
M agonist- muscarine
M antagonist- atropine
What are potential effects of Ach binding to receptors?
- excitatory- depolarization of postsynaptic membrane and Ca2+ influx
- inhibitory- hyperpolarization of postsynaptic membrane
What are the two potential mechanisms by which latrotoxin releases Ach vesicles?
- Ca-dependent stimulation of neurotransmitter vesicle fusion with plasma membrane
- Release of cytoplasmic transmitter into nerve junctions via pores induced in the cell membrane by the toxin
What are the symptoms associated with a-latrotoxin?
- severe pain and muscle spasms spreading from site of spider bite
- sweating, stomach cramps. nausea, vomit
- tightness of chest, hard time breathing
- increased BP
How exactly does botulinum toxin prevent the release of Ach?
It is a protease that cleaves SNAP25, VAMP or syntaxin preventing the fusion of the vesicle with the plasma membrane to allow exocytosis
How is onobotulinumtoxinA administered? How long does it last? What happens to the muscles in the area?
It is administered by local injection, lasts weeks, and the muscles atrophy
What are the six things botox are typically used to treat?
- strabismus
- focal dystonia
- chronic blinking (blepharospasm)
- wrinkles
- hyperhidrosis (sweat glands)
- migranes
How are botulinum and tetanus similiar? How are they different?
Botulinum toxin acts on excitatory nerve endings and blocks release of Ach (thus having an inhibitory effect and causing flaccid paralysis)
C. tentani (tetanus toxin) acts on inhibitory nerve endings by the same mechanism of botulinum (prevents vesicle fusion). This inhibits the inhibitory response thus causing tentanic contraction of muscle
What are the two main types of cholinesterases?
Where is each found?
- acetylcholinesterase - at the synaptic cleft
2. butyrylcholinesterase- serum/plasma
Butyrylcholinesterase is of specific interest in the metabolism of what drug?
succinylcholine
What are the two general categories of Achesterase inhibitors? What is an example of each?
Reversible- physostigmine
Irreversible- DFP and organic phosphates (insecticides)
What snake toxin irreversibly inhibits cholinergic receptors?
alpha toxin
What is myasthenia gravis?
an autoimmune disorder where Ab are made against nicotinic receptors
What cholinergic receptor has an
“ALL or NOTHING” response?
Nicotinic receptors have an all or none response. If two Ach bind to the alpha subunits, the channel will allow depolarization and if it is enough depolarization will cause an AP and transmission of a downstream signal
What is “dual response”? What type of receptor is it associated with?
It is when continuous stimulation of a nicotinic receptor leads to:
- failure to repolarize at the postsynaptic junction
- desensitization of the receptors
What preferentially blocks Ng receptors?
Hexamethonium at synapses in autonomic ganglia and adrenal medulla
What preferentially blocks Nm receptors?
Decamethonium at synapses at the neuromuscular junction of somatic systems
Compared to nicotinic receptors, muscarinic have a __________, more _________ response.
Slower more graded response often used to regulate intrinsic activity.
MODULATION NOT CONTROL
M2 and M4 operate through what G protein? What is the result?
Gi - increased K, decreased cAMP, decreased Ca
M135 work through what G protein? What is the result?
Gq- increased PLC->IP3/DAG–> increased Ca
What natural drug blocks all muscarinic receptors?
atropine
What are the two most important things to consider when deciding the utility of a drug?
- what is the SPECIFICITY for the receptor?
2. will it get to the SITE OF ACTION (availability)?
Cholerginc drugs that are _______ amines are more likely to have effects in the CNS whereas ______ amines are largely excluded.
tertiary enter CNS, quarternary are excluded
How does hydrophobicity determine distribution of drugs?
The more hydrophobic a drug, the better it can penetrate, concentrate and provide selective action in the CNS
If 10microg/kg Ach is administered, what happens to:
- the autonomic ganglia firing rate
- HR
- BP
- GI contraction
- nothing because it is not enough to effect Ng receptors
- decreased (but potentially a reflex tachycardia)
- decreased
- increased
What happens if atropine is given with 10mg/kg Ach to:
- ganglion firing rate
- HR
- BP
- GI contractility
There will be no change in anything because this is not enough to influence nicotinic receptors and all the muscarinic receptors are blocked by atropine
If a large dose of Ach (100mg/kg) is given with atropine, what happens to:
- autonomic ganglia firing rate
- HR
- BP
- GI contractility
100mg/kg is enough to excite muscarinic, nicotinic sympathetic ganglia neurons so:
- firing rate increases
- HR increases (bc of sympathetic)
- BP increases (bc of sympathetic)
- nothing happens to GI
If 100mg/kg Ach is given with atropine and a&b blockers, what happens to:
- firing rate
- HR
- BP
- GI contractility
- increases because nicotinic receptors are still being stimulated to fire at ganglia
- normal
- normal
- normal
2-4 because BOTH parasympathetic and sympathetic are blocked
What happens if 100 mg/kg Ach is given with atropine, a&b blocker AND hexamonium to the:
- firing rate
- HR
- BP
- GI contractility
they all are cancelled because:
effector parasympathetics AND sympathetics are blocked as well as Ng by the hexamonium
Where would cholinergic agonists act?
- M receptors at NEJ
- M receptors in non-inervated vasculature
- Mg receptors (depending on penetration)
- Ng and Nm receptors IF THE CONCENTRATION OF DRUG IS HIGH ENOUGH
Why is Ach typically not given as a cholinergic drug?
because it is rapidly degraded
What is bethanechol?
Where is its site of action?
How is it taken?
Why is it better than the prototype drug?
A muscarinic agonist
GI and urinary smooth muscles
Taken orally or subcutaneously
Resistant to BchE and AchE
What is the effect of giving Ach with an AchE inhibitor?
Synergistic effect because it is prolonging Ach life in the synaptic cleft and providing more Ach to act on the effector muscle
How are Ach and bethanechol different in their sites of action?
Ach can have nicotinic effects but bethanechol does not
What would be the relationship if you use bethanechol with AchE inhibitor?
they would have an additive effect because bethanechol is ALREADY resistant to being degraded. You would have extra Ach and bethanechol at receptors then
Why do you take bethanechol orally or s.c.?
So it has good specificity to the site of action (GI and urinary smooth muscle) and decreases the toxicity (action on the vasculature)
What are the four major uses for bethanechol?
- urinary retention- to help release pee
- GI stasis- to get bowels moving post-op
- Diagnosis of atropine intoxication
- Topically for closed angle glaucoma
What are the three major contraindications for using muscarinic agonists?
- Asthma- Ach can bronchoconstrict
- coronary insufficiency- Ach can cause hypotension via vascular dilation
- Peptic ulcers- Ach can stimulate secretion of gastric acid
I have asthma. Why would I be wary of taking a muscarinic agonist?
Muscarinic receptors cause bronchoconstriction
I have been known to get peptic ulcers. What type of drug should I avoid?
I should avoid muscarinic agonists because parasympathetic response is to increase gastric secretion (rest and DIGEST)
I have a history of fainting due to low BP. Why would I not want to take a muscarinic agonist?
They vasodilate which would decrease BP even more causing severe hypotension
What is a cholinomimetic?
A cholinergic agonist
What type of drug is pilocarpine?
a tertiary amine that acts as a cholinergic agonist (mostly muscarinic)
What are the three main clinical uses of pilocarpine?
- Topical application to treat acute glaucoma
- Orally to treat Sjogren’s (inability to form saliva/tears)
- Sweat test for CF
What is Sjogren’s syndrome? What might I use to treat the symptoms?
It is an autoimmune disease that attacks endocrine glands presenting with chronic dry eyes and mouth that can be treated by:
- pilocarpine
- M3 selective agonist
What is the “Belladonna” alkaloids?
What type of amine are they and what do they block?
Atropine and scopolamine which are tertiary amines that competitively block muscarinic receptors
What is tropicamide?
What is advantageous about its half life?
When would you NOT want to use it?
a muscarinic antagonist that helps dilate the eyes for eye exams.
It has a short half life, so the pupils return to normal quickly after the exam.
You would not want to use tropicamide if the person has narrow angle glaucoma because it will block outflow of aq. humor even more and increase intraocular pressure and pain
What is the benefit of using a quarternary amine over a tertiary amine? What would be a drawback?
Quarternary amines have more localized effect and cannot get into the CNS, but they frequently increase blockage of nicotinic receptors too.
What would be the specific instance when you would use atropine as a drug?
If the person had AchE poisoning because atropine would block the receptors from the excess Ach
What would the effect of an antimuscarinic drug be on the eyes?
- mydriasis (pupil dilation)
2. cycopegia (paralysis of ciliary muscles)
What would the effect of an antimuscarinic drug be on the heart? What is controversial about this use?
It would cause tachycardia which is sometimes used:
- in myocardial infarct where bradycardia is prominent
- intraoperative to control bradycardia
What is the effect of antimuscarinic drugs on vasculature?
Not much because dominant tone in the vasculature is sympathetic
What is the effect of antimuscarinic drugs on the GI and urinary tract?
It will decrease motility, secretions, and reduce voiding
What is the major drug used for reducing urge incontinence (uninhibited detrussor contraction)?
Tolterodine an M3 specific blocker which will relax the detrusser
What is tolterodine?
An M3 specific antagonist used for relaxing the detrusser muscle to treat urge incontinence
What is the effect on a muscarinic antagonist on salivation and sweating?
It will decrease salivation and sweating
What is the effect of a muscarinic antagonist on the respiratory tract?
- Bronchodilation
2. reduces secretions
What drug is inhaled to selectively reduce constriction of the bronchioles?
Tiotropium is given as a M blocker in the lungs to remove the parasympathetic contraction
What is the function of tiotropium?
it is a muscarinic antagonist that is inhaled (and Nh4+ so it will stay locally) to relax bronchial constriction
What are the two potential types of drug that could treat asthma and COPD?
- M antagonist (tiotropium)
2. B agonist (albuterol)
What is the effect of atropine on the CNS?
High doses cause restlessness, delirium and hallucinations
What is scopolamine? What does it treat?
It is a muscarinic antagonist that treats car sickness (motion)
What are three potential causes of muscarinic inhibitor overdose?
- accidental (systemic spread of topical application)
- eating berries with alkaloids
- Deliberate (sleeping pills)
What are the symptoms of a cholinergic inhibitor overdose?
They will get sympathetic response so:
- red as a beet- vascular dilation
- Dry as a bone - anhidrosis
- Hot as a hare- can’t sweat so overheat
- Mad as a hatter- dilirium
- Blind as a bat - dilated eyes (mydriasis)
- Full as a flask - urinary retention
What would be the treatment for OD on cholinergic inhibitors?
Physostigmine- an AchE inhibitor which would allow more Ach to act on the few receptors that remain from the anti-muscarinic drugs
What are the two main reasons for using AchE inhibitors?
- therapeutic (myasthenia gravis, Alzheimer’s, opthamology, atony of GI tract)
- Insecticides/chemical warfare
What drugs are reversible inhibitors of AchE?
Donepezil- competitive antagonist
Physostigmine- carbamoylating agent
Neostigmine- carbamoylating agent
Which drugs are carbamoylating agents?
How do they operate?
Physostigmine and Neostigmine covalently carbamoylate the active site of the esterase and then are reversed slowly by hydrolysis (2-6 hours)
What are irreversible inhibitors of AchE? What is their mechanism of action?
Insecticides (DFP) and nerve gases (sarin) and they phosphorylate the active site of the esterase
What are the potential sites of action of AchE inhibitors?
- post-ganglionic parasympathetic muscarinic
- ganglionic nicotinic
- neuromuscular nicotinic
- CNS junction (M and N)
What AchE is selective for NMJ action only? How is this achieved?
Neostigmine because it is a quaternary amine so it can’t penetrate CNS and stays local
At muscarinic sites, AchE will be _________. At nicotinic junctions, the potentiation of Ach will __________.
At muscarinic sites it will be stimulatory
At nicotinic junctions, Ach originally causes facilitation, but then will result in blockage of signal transduction because the receptors will desensitize and the membrane will not be able to repolarize to propogate an AP
What are the effects of AchEI on the eye?
Miosis- pupil constriction (classic pinpoint pupil with organophosphate poisoning)
What is the main AchEI used on the eye? What does it treat?
Physostigmine treats acute angle glaucoma to allow Aq humor to drain by constricting the pupil
What is the role of AchEI on the heart and blood pressure?
Not much
What is the role of AchEI on the GI tract and urinary tract?
It increases gastric contractions and secretions and increasing motility of the bowels
What AchEI is used for the gut and urinary tract?
neostigmine relieves abdominal distension and atony of the bladder
Why can’t AchEI work for gastric atony after a vagotomy?
The source of Ach is gone. So AchE inhibitor would not be able to prolong Ach that isnt there
What would AchEI do for saliva and tears?
It would increase production
What would AchEI do for respiratory tract?
Bronchoconstriction
What drug is used for Alzheimer’s? What class of drug is it and what is the function?
Donepezil is an AchEI which leaves Ach in the synpapses and assist the neurons that are left
What AchEI aids in poisoning by anti-muscarinic drugs?
Physostigmine
What is the classic test to diagnose myasthenia gravis?
Edrophonium test- administration of this AchEI will result in a dramatic (but temporary) improvement in strength bc it leaves Ach to react with the few receptors that haven’t been attacked by autoantibodies
Why is neostigmine given for myasthenia gravis?
- Because it has specificity for NMJ as a quarternary amine
2. it has some direct stimulatory effects on NMJ receptors
What is a myasthenic crisis? How can it be differentiated from a cholinergic crisis?
Myasthenic crisis is muscle weakness due to lack of nicotinic receptors on muscle and brevity of Ach to activate the receptors that are left.
Cholinergic crisis occurs when there is too much AchEI and the Ach remains in the cleft too long overstimulating the receptors so they don’t repolarize and AP can’t propogate
You do the Edrophonium test. If Myasthenia crisis, things will improve. If Cholinergic crisis, things will get worse
When doing the edrophonium test, what should you have on hand in case it is cholinergic crisis and not myasthenic crisis?
atropine (to block muscarinic receptors) and a ventilator (bc bronchoconstriction due to Ach)
AchEI toxicity can occur via accidental exposure to pesticides or suicidal attempts. The effects will be local if the exposure was ________ and will be systemic if the exposure was ________.
Local-dermal
Systemic- respiratory
How would an OD on AchEI appear?
SLUDGE (salivation, lacrimation, urination, defecation, GI effects, emetic)
They will also have muscle weakness and twitching, pinpoint eyes, tightness in the chest
What is the cause of death in a nerve gas poisoning? How long does it take?
How do you recover?
It is respiratory failure bc the excess Ach causes bronchoconstriction
Death can occur between 5min and 24 hrs if pulmonary ingested
You recover by resynthesizing AchE which takes about a day
What treatment is given for an AchE inhibitor poisoning?
- Atropine to reduce muscarinic effects (lungs)
- artificial respiration
- Cholinesterase reactivators (pralidoxime)
What is pralidoxime?
a cholinesterase reactivator that is only effective against phosphorylated AchE
Will pralidoxime help in a physostigmine, neostigmine or doneprezil overdose?
No because it only reactivated phosphorylated AchE. Neo and physo are carbamoylated
What would the physiological effects of nicotine be?
It would stimulate Ng receptors thus triggering parasympathetic, sympathetic and CNS responses because nicotinic receptors are on the post-synaptic neuron at every ganglion
Low doses of nicotine effect stimulation of many organs and excitation of ___________ is especially pronounced. With repeated doses, minor effects dissipate but _________________ effects persist.
Respiration is pronounced Cardiovascular responses (increased rate/BP) persist
Why is nicotine assumed to be addictive?
It affects a4b2 receptor in the nucleus accumbens and prefrontal cortex and is considered to be a “reward” by stimulated release of dopamine
What are the three strategies for quitting smoking?
- give low doses of nicotine (patch, gum, etc) so withdrawal is avoided but harmful tobacco agents are gone
- Partial a4b2R agonist so reward is partially stimulated and withdrawal symptoms are not there. Additionally, bc the receptor will be occupied, continued smoking will not provide the reward it usually does
- Antidepressant enhances noradrenergic and dopaminergic activity by inhibiting reuptake and can antagonize nicotinic receptors
What would cause a toxic overdose of nicotine? What would be the physiological results?
How would you treat toxicity?
Children ingesting cigarettes or insecticide poisoning
First stimulation, but then depression of nerves because of inability to depolarize –>AP leading to respiratory paralysis
Therapy is to do a stomach lavage using charcoal
What drugs inhibit Ng receptors?
What is the physiological effect?
Hexamethonium
Trimethaphan- quarternary sulfonium and preferred method
The drugs are used locally and withdrawal the autonomic tone (so whichever was more prominent)
What is the dominant tone of arterioles? What happens with a Ng inhibitor?
sympathetic is natural tone so with Ng inhibitor you would see a parasympathetic effect–> vasodilation
What is the dominant tone of veins? What would happen with a Ng inhibitor?
Sympathetic so with a Ng inhibitor the veins would dilate and blood would pool
What is the dominant tone of the heart? What would happen with a Ng inhibitor?
Parasympathetic so with Ng inhibitor it would increase HR and contractility
What is the dominant tone of the iris? What would happen with an Ng inhibitor?
PArasympathetic so if that is blocked the pupil will dilate
What is the dominant tone of the GI tract? What would happen with a Ng inhibitor?
Parasympathetic so if it is blocked, the bowels will slow
What are the only situations where an Ng inhibitor is even considered?
- Hypertensive crisis with acute dissecting aortic aneurysm
- To have controlled hypotension in surgery
- To control hyperreflexia with upper spinal cord injuries
What is the desired effect when using a NMJ inhibitor?
flaccid paralysis
What are the two types of NMJ inhibitors that act on the nicotinic receptors?
- Competitive non-depolarizing inhibitors (d-tubocurarine and vecuronium)
- Depolarizing agents (decamethonium and succinylcholine)
What is different molecularly between tubocurarine/vecuronium and succinylcholine/decameconium?
tubo/vecur are bulky, non-flexible
succinylcholine is long and slender
What is the mechanism of action for tubocurarine and vecuronium?
What happens when you use AchEI with these drugs?
They compete with Ach for the receptor binding site and are antagonized by Ach
AchE inhibitors will antagonize these drugs
What is the mechanism of action for succinylcholine and decamethonium?
What happens when you use AchEI with these drugs?
They are agonists for the AchR.
- stimulate the receptors
- Persistent depolarization leads to the inability to have AP transmission
- Receptor desensitization (receptors are endocytosed so they cant be bound)
AchEI will potentiate these drugs because Ach will speed the process of depolarization and desensitization
What is the sequence of paralysis for tubocuranine and vecuronium?
small rapid muscles>limbs/neck> intercostal>diaphragm
What is the sequence of paralysis for succinylcholine?
limbs/neck>small rapid muscles> diaphragm
What NMJ inhibitors can release histamine causing bronchospasm and hypotension?
d-tubocuranine and vecuronium
How does the recovery of phase I and phase II from succinylcholine inhibition of the NMJ compare?
Phase 1 recovery is quick because the membrane will repolarize
Phase 2 is slower because the receptors have to be resensitized
Succinylcholine has a short duration of action (2-5 minutes). Why?
It is rapidly hydrolyzed by butyrylcholinesterase
What are the four major clinical uses of succinylcholine?
- surgical anesthesia- muscular relaxation and reduces risk of respiratory and cardiac depression
- Orthopedic procedures to loosen muscles
- Intubation
- electroshock
What is the drug interaction between succinylcholine and cholinesterase inhibitors?
succinylcholine will be prolonged
tubocurarine and vecuronium will be antagonized because they will have to compete for receptors
What is the drug interaction between NMJ inhibitors and inhalation anesthetics?
The effects of tubocurarine and vecuronium are increased
What antibiotics can increase the blockade of NMJ inhibitors?
Tetracycline, aminoglycoside, peptide antibiotics
What do Ca channel blockers do to the effects of NMJ inhibitors?
enhance the blockade
What are the four disease conditions that can effect NMJ inhibitor actions?
- genetic reduced plasma cholinesterase - will enhance succinylcholine and can lead to prolonged apnea
- genetic mutation to ryanodine receptor leads to widespread rigidity and hyperthermia with succinylcholine
- Tissue damage- succinylcholine can increase hyperkalemia
- myasthenia gravis- less receptors to block so reduce amount of succinylcholine given
What three things are characteristic of a succinylcholine overdose?
- prolonged apnea- treat with artificial respiration and O2
- Cardiovascular collapse
- histamine release
