Lecture 4: Cholinergic Flashcards
List the drug classes of the Cholinergics
- Direct Acting Cholinomimetics
- Indirect-Acting Cholinomimetics
- Muscarnic Inhibitors
Which drug(s) are Direct acting Cholinomimetics?
- Acetycholine
- Bethanechol
- Nicotine
- Pilocarpine
Which drug(s) are Indirect acting Cholinomimetics?
- Edrophonium
- Physostigmine
- Echothiophate
Which drug(s) are Muscarnic Inhibitors?
- Atropine
- Ipratropium
- Titotopium
Acetylcholine is a _
NT that is released from the nerve from presynaptic terminal to bind to postsynaptic receptor
Explain how ACh is made
What are the ACh receptors?
What terminates the ACh signal?
Receptors:
- Nicotinic (Ion channels)
- Muscarinic (GPCR)
Terminates: acetylcholine esterase
What are the choline ester and alkaloid direct acting acetylcholine receptor agonist?
- Choline Ester: acetylcholine, methacholine, bethanechol, carbachol
- Alkaloid: Muscarine, pilocarpine, nicotine
Does the alkaloid class use AChE metabolism
NO
Does nicotine have muscarinic AChR activity?
Does muscarine have nicrotinic AChr activity?
NO and NO
Which one (choline ester or alkaloid) can cross the membrane
- Alkaloid will distrub throughout the body
- Choline ester is charged so it cannot cross the membrane
What are the different muscarinic receptors?
- M1, M3, M5 (odd): Gq-coupled, PLC activation, ↑ DAG & IP3 production, ↑ Ca2+
* mobilizes calcium to cause contraction and glandular secretion - M2, M4 (even): Gi-coupled, ↓ cAMP, ↓ PKA
* inhibits Adlyl cyclase
Where are the muscarinic receptor location
End organs
- cardiac and smooth muscle, gland cells, nerve terminals
- Sweat glands, skeletal muscle arterioles (sympathetic)
fill in
What is the action of mAChr with muscosal gland
M1
What is the inn, action of mAChR and effect of the heart with muscarinic receptors
- Inn: para
- Action of mAChR: decrease contraction, conduction (M2)
- Effect: decrease BP and bradycardia
What is the inn, action of mAChR and effect of the vasc. endothelium with muscarinic receptors
- Inn: none but can be de/activated by agonist ot antagonist
- ActionL EDRF/NO release, VSM dilation (M3)
- Effect: decrease BP and reflex tachycardia
What is the inn, action of mAChR and effect of the sweat glands with muscarinic receptors
- Inn: symp
- Action: stimulation (M3)-> sym but ACH
- effect: increase secretion
What is the mechanisms of action and pharmacology of Direct-Acting Cholinomimetics?
Acetylcholine, Bethanechol, Pilocarpine
- Activate muscarinic receptors
– Affect all muscarinic receptor subtypes - Mainly evoke parasympathetic effects
- Mild or no desensitization
What does high IOP causes?
How is it caused?
- High IOP causes loss of optic nerve and permanent blindness, open angle glaucoma
- Caused by increase aqueous humor
How can we reduce the ocular hypertension?
- Ocular hypertension can be reduced by increasing aqueous humor flow OUT via Canal of Schlemm
- Contraction of cillary muscle (via activation of M3 receptor) opens the Trabecular meshwork and facilitates aqueous humor outflow
What are drug class+ drug name that can be used to treat glaucoma? Which ones cannot and why?
- Alkaloids (uncharged, lipophilic)-> drug name: pilocarpine can be used to treat
- Choline esters (charged)-> drug name Bathanechol cannot be used to treat becasue unable to penetrate to the eye cillary muscle
What is the AE, contradinication and interactions with Bethanechol, methacholine and pilocarpine?
- AD: Parasympatheitic effects, bronchospasms, hypotension (vasodilation), reflex tachycardia, decrease secretion
- Cont: Asthma, COPD, peptic ulcer, hypotension
- Interactions: B-Blockers
What is the drug class and drug name of direct action nicotinic agonists
- Class: alkaloid-> increase bioav (not charged/lipophilic
- Drug name: Nicotine
- Where is the distribution of nicotinic receptors?
- What type of effect will they cause?
- NMJ
- Autonomic ganglia
- Brain
- Symp and para
Nictonic ace Receptor are what type of receptors
Pentameric cation channels
Does nic ace receptor desensitize?
Yes they can desensitize with ptolonged agonist
Explain what happens at the NMJ
Ach binds to cause Na to come in then cause AP and Ca+Na flow in which causes contraction
Nm=
Nn=
Nm= muscle contraction
Nn=ganglia, ESPS (depolarization)
- Nicotinic agonist activat what?
- What does it stimulate?
- Activate nicotinic receptors
- Stimulate CNS, all peripheral ganglia (and adrenal medulla) and skeletal muscle (NMJ)
* Parasympathetic
* sympathetic
* Catecholamine release
* Skeletal Muscle (somatic NS)
Where do we evoke parasympathomimetic effect?
GI, GU, glands, lungs
Where do we evoke sympathomimetic effect?
CV ( increase cardiac output and blood pressure, sweat glands)
What is the major clinical use of nicotinic agonists
smoking cessation
What do antimuscarinics (muscarinic antagonist) do?
- Inhibit muscarinic receptors
– Drugs available clinically generally act on
all receptor subtypes (limited selectivity) - Evoke parasympatholytic effects
Antagonists only have an effect if there is also an _ present
agonist
Explain what happens to the eye, urinary, gut, muscosal glands and lungs when we give antimuscarinic?
Explain what happens to heart, vasc. endothelium, sweat glands, and CNS when we give an antimuscarinic
What is naturally occurring muscarinic antagonists? Explain the structure
Belladonna alkaloids: atropine
* Tropic acid will bind to receptor
* Base gives bioavibility
What amine (+drugs) are good absorptors and which amines (+drugs) are poor absorptors
Good: Tertary amine
* Tropicamide (eye examination)
* Beztropine (parkinson’s)
Poor: Quaternaty amine
* Ipratropium (asthma)
* Propantheline (gut)
- What drug is used for eye examination?
- What drug is used for parkinson’s?
- What drug is used asthma?
- What drug is used for gut?
- Tropicamide
- Benztropine
- Ipratropium (poor absorption is it good becasue it will stay in lungs)
- Propantheline
Explain what happens in lung repair in asthmas/COPD
- Irritant in lungs-> afferent-> CNS-> parasymp efferent-> contracts smooth muscle-> produce mucous
- uses M3 agonist (ach) for this
What is atropine used for and what is the amine type?
- Bradycardia to increase HR
- 3 degree
What is benztropine used for and what is the amine type?
- Parkinson’s disease, extrapyramidal symptoms
- 3 degree
What is scopolamine used for and what is the amine type?
- Motion Sickness
- 3 degree
What is ipratropium+titropium used for and what is the amine type?
- Bronchospasm in Chronic obstructive pulmonary disease (COPD), and asthma
- 4 degree
quartary stays local
What does ipratropium block
ACh mediated secretion and contraction
autonomatic ganglion
What are the toxic effects of muscarinic antagonist?
- Blurred vision, photsensitivity
- Agitation, hallucination, delirium, coma
- Tachycardia, angina
- Dry mouth, nasal congestion, hot/flush skin, hyperthermia
- Dysuria, retention (no peeing)
- Nausea, distention, cramps, constipation
Abolish parasym
“Dry as a bone, blind as a bat, red as a beet, mad as a hatter, and hot as a hare.”
- What are muscarinic antagonist contradicated for?
- What is an example and how it works?
Open angle glaucoma
Atropine prevents activation of M3
* Causes dilation of cillary muscle
* decreases humor outflow-> increase IOP
Glaucome+atropine=
NOOOOOOOO
What does AChE inhibitors cause?
inhibits the breakdown of ACh therefore increase in Ach for muscarnic receptors
What is the ach signal terminated by?
acetylcholine esterase
What are the key sites on the achE
- Anionic site
- choline subsite
- Acyl pocket
What needs to be down in order for acetyl choline esterase to be active again?
Acetate needs to leave
* This is where drugs target
What does edrophonium do?
- will bind to the choline subsite to get in the way and slow down the breaking down
- Bind to choline subsite and H+ bond to acyl pocket
- short acting (Temporary blocking)
What does neostigmine(4) or Physostigmine (3degree) do?
- It is a carbamate so it will bind to the serine in the acyl pocket to block
- Bind like ACh with covalent bond, decarbamoylation rate slower than deacetylation rate.
- Longer time than edrophonium
What does echothiophate do?
- Organophophates
- Some bind like ACh some only to acyl pocket with covalent bond, dephosphorylation rate slower than decarbamoylation and deacetylation rate.
- Perment so irreversible
Which cholinesterase inhibitors are reversible and which ones are not
reversible:
* Edrophonium (4 degree alcohol)
* Physosostigmine (3) and neostigmine (4)- carbamates
Irr: echothiophate (organophosphates)
What are the effects of cholinesterase inhibition?
- Brain: increase EEG and alertness
- NMJincrease strength
- Parasympathomimetic: bradycardia (dec. HR)
- Stimulation of all automotic ganglia
- decrease IOP, increase motility of bowels and peeing, contriction
- Low dose: indirect dec BP
- Higher dose: increase symp drive (inc BP)
What do we do to test myasthenia gravis and what do we give to fix it (general)
- Looking up eye test shows muscle fatigue
- Fixes it by adding AChE inhibitor-> boosts NMJ function
- What does the NMJ look like in Myasthenia gravis patient compared to a normal patient?
- What do we do to help?
- Less nic receptors and not as dense
- Less Ach release so no ESPS for muscle contraction so loss of muscle contraction
- If we block AChE, then we incre the hald life of Ach so we can have bigger activation of receptors leading to ESPS and better muscle contractions
- What drug do we use to diagnose MG?
- What is the absoprion, fate and excretion?
- MOA?
- Duration?
Edrophonium (alcohols)
* absorbed poorly, destroyed by plasma esterases
* Binds to choline subsite of active center and H+ bond to acyl pocket
* 5-15 min
- What drugs are used to treat MG?
- What is the absoprion, fate and excretion?
- MOA?
- Duration?
Carbamates: Physostigmine (3), Neostigmine (4),
Pyridostigmine (4)
* Physo: Absorbed readily,
destroyed by plasma esterases, enters CNS
* Neo+Py: Absorbed poorly,
destroyed by plasma esterases, excreted in urine, does not enter CNS.
MOA: Bind to acyl pocket of active center via covalent bond and hydrolyzed by enzyme
Other: Donepezil
* Well absorbed, enters CNS, metabolized in liver and kidneys
Besides the activation of M3 receptors, what can help open agle glaucoma?
AChE inhibitors (physostigmine/echothiophate, in eye drops) increase half-life of endogenous ACh → increase cillary contraction → decrease IOP
What are the toxic effects of cholinesterase inhibition
Excess acetylcholine causes desensitization for nicotinic receptors, not muscarinic
* Convulsions-> coma
* Blockage of nic (desensitized)-> diaphragm doesnt work and die
* parasympathomimetic: decrease HR-> block gangion for sympathic but para is not blocked
* depression
* Increase vomit, peeing, pooping, secretions
* decrease BP->hypotesion
Explain the different between MG and cholineesterase crisis
- What is used to treat muscarinic inhibitor poisioning?
- What are the Symptoms?
- What is needed to increase?
- AChE inhibitors: Physostigmine (3)
- Atropine toxicity: Dry as a bone, blind as a bat, red as a beet, mad as a hatter, and hot as a hare
- Need to increase endogenous ACh
- What is used to treat AChE inhibitor poisioning?
- What are the Symptoms?
- What is needed to increase?
- Muscarinic inhibitors: Atropine(3)
- Organophosphate toxicity:
Irreversible AChE inhibition – Paralysis, bronchospasm, diarrhea, hypotension - Need to block actions of endogenous ACh at muscarinic receptors (increase Ach)
