Cholinergic Drugs Flashcards
2 types of Ach receptors
Muscarinic (heart, smooth muscles, exocrine glands)
Nicotinic (ganglion and skeletal muscles)
What do direct-acting cholinergic drugs affect?
Muscarinic and nicotinic receptors (direct binding)
What do indirect-acting cholinergic drugs affect?
Mainly acetylcholinesterase
Examples of direct-acting cholinergic drugs
Choline esters: acetylcholine, metacholine
Carbamoyl esters: carbachol, bethanechol
Natural alkaloids: pilocarpine, muscarine
Difference between tertiary and quaternary agents
Tertiary: Neutral, therefore lipid soluble, can pass BBB
Quaternary: (+) charge, water soluble, CANNOT cross BBB
Examples of tertiary agents
Alkaloids (pilocarpine), Physostigmine
Examples of quaternary agents
Choline esters, muscarine (??), simple alcohols (edrophonium), carbamates
2 divisions of direct-acting cholinomimetics
Choline esters and Alkaloids
Cholinomimetic choline ester groups
1) Acetic acid esters (Acetylcholine, methacholine)
2) Carbamic acid esters (carbachol, bethanechol)
Acetylcholine profile
Susceptability to AchE: +++ Muscarinic action: +++ Nicotinic action: +++ Antagonized by atropine: +++ Does not cross BBB, very short half-life
Methacholine profile
Susceptability to AchE: + Muscarinic action: +++ Nicotinic action: + Antagonized by atropine: +++ More resistant to hydrolysis NO LONGER USED
Carbachol profile
Susceptability to AchE: - Muscarinic action: ++ Nicotinic action: +++ Antagonized by atropine: + Mitotic drug for glaucoma
Bethanechol profile
Susceptability to AchE: -
Muscarinic action: +++
Nicotinic action: -
Antagonized by atropine: +++
The muscarinic receptor is highly stereoselective. Which isomer of bethanechol does it have more affinity?
S-bethanechol is 1000x more potent than R-bethanechol
Examples of natural cholinomimetic alkaloids
Pilocarpine (tertiary) Muscarine (quaternary) Nicotine Labeline (tertiary) Arecholine
Which is the only cholinomimetic alkaloid with therapeutic use?
Pilocarpine
Examples of synthetic cholinomimetic alkaloids
dimethylphenylpiperazinium (DMPP)
Oxotremorine
**Both used for research
Pharmacologic muscarinic actions of cholinomimetic drugs: CVS
Decrease HR = (-) chronotrophy
Decrease SA & AV node conduction = (-) dromotrophy
(-) ionotrophy
Generalized vasodilation (from NO formation in endothelial walls/blood vessels)
LARGE doses: depressed AV conduction
Pharmacologic muscarinic actions of cholinomimetic drugs: GIT
Stimulation of GI smooth muscles, tone and motility Increased secretions Relaxation of sphincters =DIARRHEA!!!! cha cha cha!!! =D Hi baby!
Pharmacologic muscarinic actions of cholinomimetic drugs: GUT
Contraction of detrussor muscle
Relaxation of trigone and external sphincter
Pharmacologic muscarinic actions of cholinomimetic drugs: Respiratory system
Contraction of bronchial smooth muscles
Increased tracheobronchial secretions
Pharmacologic muscarinic actions of cholinomimetic drugs: Eyes
Miosis - contraction of pupillary sphincter
Cyclospasm - contraction of ciliary muscles
Pharmacologic muscarinic actions of cholinomimetic drugs: Exocrine glands
Increased secretions of ALL glands: lacrimal, salivary, eccrine, sweat, nasopharyngeal, gastric, intestinal
Pharmacologic muscarinic actions of cholinomimetic drugs: CNS
For tertiary only: tremors, hypothermia, locomotor activity, improved cognition
Pharmacologic nicotinic actions of cholinomimetic drugs: NMJ
Disorganized fasiculations or strong contractions of the entire muscle
“depolarization blockade” - stimulation and then flaccid paralysis d/t persistent depolarization at NMJ
Pharmacologic muscarinic actions of cholinomimetic drugs: CNS
High concentrations: emesis, tremor, stimulation of respiratory center
Higher concentration: convulsions to coma
Pharmacologic muscarinic actions of cholinomimetic drugs: Autonomic ganglia
Will depend on the dominant division of that organ
CVS: sympathiomimetic (hypertension, tachycardia, followed by bradycardia)
GIT, GUT: parasympathetic (nausea, emesis, diarrhea, voiding of urine)
Pharmacologic muscarinic actions of cholinomimetic drugs: Adrenal medulla
Increase Epi and Norepi release
Plus Dopa, VIP, Ach
Clinical uses of cholinomimetic drugs: Opthalmology
Glaucoma (pilocarpine, carbachol)
Iritis, keratitis
Accomodative esotropia - strabismus, hyperemetropic accomodative error
Clinical uses of cholinomimetic drugs: GI d/o
To increase GI motility Postop gastric distention, gastric atony Congenital megacolon Ileus **Bethanechol
Clinical uses of cholinomimetic drugs: Xerostomia
In head and neck radiation
Sjogren’s syndrome
**Pilocarpine, bethanechol, Cevimaline (new drug)
Clinical uses of cholinomimetic drugs: CNS
Dementia
**Taclifenasine, Xanomeline
Major Contraindications of cholinomimetic drugs
Asthma Hyperthyroidism Coronary insufficiency Acid Peptic disease GIT obstruction
Adverse effects of cholinomimetic drugs
Flushing Sweating Salivation Abdominal cramps Belching Sensation of tightness in urinary bladder Difficulty in visual accommodation Bronchospasm Hypotension Bradycardia
Cholinomimetic Poisoning and treatment
Exaggeration of parasympathetic effects
Treat with competitive blockers: atropine Epinephrine
Supportive therapy
Treatment of mushroom poisoning: Mycetism
Dependent on species
Fast, without delay
Mushroom species: Inocybe & Clitocybe
High muscarine concentration
Symptoms in 30-60 mins
Treatment: Atropine
Mushroom species: Amantia
Contains muscarine, muscimol, ibotenic acid, etc
S/Sx: irritability, restlesness, ataxia, hallucination, delirium, drowsiness, sedation
Treatment: Mainly supportive, Benzodiazapines (restlessness)
Mushroom species: Psilocybe & Panaeolus
Contains psitocybin and tryptamine derivatives
S/Sx: hallucinations
Mushroom species: Gyromitra
Toxic substance: acetylaldehyde methylformyl hydrazone
S/Sx: GI d/o, delayed hepatotoxicity
Mushroom species: Amantia phalloides, leptiota, galerina
Worst of all the mushrooms (50% of fatal cases)
Toxic substance: Amatoxins
S/Sx: diarrhea, abdominal cramps, symptom free for 24 hours, hepatic/renal malfunction
Treatment: Supportive, penicillin, thioctic acid, silbinin
MOA of indirect acting cholinomimetics
Inhibit hydrolysis of Ach by Acetylcholinesterase (AchE)
What are the steps for degradation of Ach by AchE
1) Ach binds to active site of AchE
2) It is then hydrolyzed to yield free choline and the acetylated enzyme
3) The COVALENT acetyl bond is split by hydration
* *All this in 150 microseconds
What does an indirect acting cholinomimetic do?
It attaches to AchE and is consequently hydrolysed = Ach is spared from being degraded
2 Types of Cholinesterases
Acetylcholinesterase (specific for Ach)
Pseudocholinesterase or Butyrylcholinesterase (non-selective)
Examples of reversible anti-cholinesterases
1) Non-covalent inhibitors: Edrophonium, Tacrine, donepezil
2) Carbamate inhibitors
Examples of carbamate inhibitors
Tertiary: Physostigmine Quaternary: Pyridostigmine Neostigmine Rivastigmine Propoxur (Baygon) Ambenomium Benzpyrinium Demecarium Carbaryl Distigmine
What are the uses of Edophorium?
For diagnosis (not treatment!!!) of Myasthenia Gravis For differential diagnosis between Myasthenia crisis vs cholinergic crisis
Drugs used as anti-curare (for reversal of NM blockade: PANE
Mnemonic: PANE Pyridostigmine Ambenomium Neostigmine Edrophonium
In abdominal surgeries, PANE drugs are given with what anti-muscarinic drug and why is it given?
Atropine, to block muscarinic receptors while reversing the neuromuscular blockade
Use for Rivastigmine
Alzheimer’s
**Cross BBB
Uses for Physostigmine (tertiary)
Atropine intoxication
Use for Neostigmine (quaternary)
Curare intoxication
Use for Pyridostigmine (quaternary)
Chronic management of Myasthenia gravis
Stimulation of bladder and GIT
Has direct action at nicotinic NMJ
Examples of irreversible anticholinesterases:
Organophosphates: Echothiophate (more stable than others) Malathion Parathion Fenthion Chloropyrifos Dimpylate Nerve gas: Sarin, soman, tabun, cyclosarin
What does aging involve? (in organophosphate poisoning)
Breaking of the oxygen-phosphorus bonds of the inhibitor which further strengthens the phosphorus enzyme bond
What are the 2 active sites of AchE and what part of Ach do they bind?
Anionic site (glutamate)- choline (basic) moiety Esteratic site (histidine & serine)
Which active site of AchE do organophosphates bind to? Is it reversible or irreversible?
Only to esteratic sites (via serine residues)
It is irreversible especially after aging
What is the management for organophosphate poisoning? When do they need to be given?
Enzyme regenerators:
Pralidoxime
Obidoxime
Need to be given before aging
Examples of AchE inhibitors that bind to both active sites of AchE
Physostigmine
Neostigmine
Examples of AchE inhibitors that bind to anionic active site of AchE
Edrophorium
Examples of AchE inhibitors that bind to esteratic active site of AchE
Dyflos
What are the 3 steps to Ach degradation
1) Bind to enzyme via electrostatic bond
2) Initial hydrolysis: acetyl group transfer to serine group = acetylated enzyme + free choline
3) Spontaneous hydrolysis of acetylated enzyme
What is the MOA of cholinesterase reactivators
Breaks the phosphorus-enzyme bond formin a phosphoxime
Pharmacologic actions/effects of AchE inhibitors: Eyes
Miosis, contraction of ciliary muscles
Decrease elevated IOP
DRUGS: Physostigmine, Demecarium, Echothiophate
Pharmacologic actions/effects of AchE inhibitors: GIT and GUT
Increased GIT motility and secretions
Increase contraction of detrusor muscle and relaxation of trigone and sphincter
DRUG: Neostigmine
Pharmacologic actions/effects of AchE inhibitors: NMJ
Therapeutic conc: Moderately prolongs actions of released Ach
Higher conc: fasiculations followed by flaccid paralysis
“depolarization block”
Pharmacologic actions/effects of AchE inhibitors: CNS
Initial excitation followed by convulsions and coma and respiratory failure
Can be antagonized by atropine
DRUGS (Alzheimers): Donepezil, Rivastigmine, Galantamine
Pharmacologic actions/effects of AchE inhibitors: CVS
Effects of parasympathetic limb dominate
Mimic vagal nerve activation of the heart
Decreased BP, CO, HR
Large, toxic doses: Marked decrease in HR, CO and BP
Adverse effects of Anticholinesterase drugs
Exaggerated Parasympathetic activity GI distress Salivation and sweating Bradycardia Bronchospasm Difficulty of visual accomodation Flushing
What is DUMBELS in organophosphate poisoning?
Diarrhea Urinary frequency Miosis and muscle weakness Bronchospasm, bradycardia Emesis, excitation Lacrimation Salivation, sweating, seizures
Therapeutic uses of AchE inhibitors: Opthalmology
Glaucoma: Acute angle closure
Direct: Pilocarpine
Indirect: Physostigmine, demecarium, echotiophate
Therapeutic uses of AchE inhibitors: NMJ
Myasthenia gravis (diagnosis (edrophonium) and treatment (pyridostigmine, neostigmine, ambenomium))
Curare or curare-like OD
Adjunct to surgical anesthesia
Therapeutic uses of AchE inhibitors: GIT and GUT
Postop ileus Congenital megacolon Urinary retention DRUGS: bethanechol, neostigmine Xerostomia (pilocarpine, cevimaline)
Therapeutic uses of AchE inhibitors: Antimuscarinic drug intoxication
Physostigmine (only if necessary) of atropine poisoning
Therapeutic uses of AchE inhibitors: CNS
Alzheimer’s
DRUGS: Donepezil, Rivastigmine, Galantamine
Note: Memantine (N-methyl-D-aspertate receptor inhibitor) is still the #1 drug used but it is NOT an anticholinesterase drug
