11 - Cholinergics Flashcards
What are the drug classes associates with cholinergics?
Muscarinic receptor agonists Muscarinic receptor antagonists Acetylcholinesterase inhitbiors Ganglionic blocking agents Neuromuscular junction blocking agents
Describe cholinergic neurotramsmission?
AcetylcoA and choline are made into acetylcholine by ChaT.
Ach packaged into vesicles and when the neuron is depolarized, calcium channel release into the presynaptic terminal causes the vesicles to release Ach into the synaptic cleft.
Ash binds to ionotrophic or muscarinic receptors on the effector cell membrane.
Describe the breakdown of the types of cholinergic receptors?
They can be nicotinic or muscarinic.
There are three subtypes of nicotinic: ganglionic, skeletal muscle, and neuronal CNS.
There are 5 subtypes of Muscarinic and they are ALL GPCRs: M1, M3, M5, M2, M4
What are the cardiac effects of muscarinic receptor activation? What about pulmonary effects?
Vasodilation (M3)
Decreased HR and AV nodal conduction (M2)
Bronchoconstriction (mainly M3)
Increased bronchial secretion (mainly M3)
What are the urinary and GI tract effects of muscarinic receptor activation?
Urinary: detrusor muscle contracts, increased voiding pressure, ureter peristalsis (mainly M3)
GI: increase tone/amplitude of contractions and increased secretory activity (mainly M3).
What are the miscellaneous peripheral and CNS effects of muscarinic receptor activation?
Peripheral: increased secretion from glands (mainly M3), miosis and accomodation for near vision (mainly M3). .
CNS: cortical arousal
What drugs are in the choline ester drug class?
Acetylcholine, methacholine, carbachol, and bethanechol.
What drugs are in the alkaloids and their analogs drug class?
Arecoline, pilocarpine, and muscarine.
What are the two muscarinic agonists?
Bethanechol
Pilocarpine
What muscarinic agonist is used orally or subQ for urinary retention (from post op, diabetic neuropathy, or bladder disorders)?
Bethanechol
What muscarinic agonist is used to treat xerostomia, glaucoma, or as a mitotic agent?
Pilocarpine
How do muscarinic agonists such as pilocarpine treat narrow-angle glaucoma?
Causes constriction of the pupillary muscles and opens the angle for drainage of the aqueous humor.
What are common adverse effects that occur with muscarinic agonists?
Diaphoresis (sweating)
Diarrhea, abdominal cramps, nauseas/vomitting, difficulty with accommadatoin (blurred vision), and hypotension.
These are all cholinergic or muscarinic adverse effects.
What are contraindications that muscarinic agents might not be suitable for a patient?
Asthma, COPD, urinary or GI obstruction, acid-peptic disease, CV disease accompanied by bradycardia or hypotension.
What are symptoms of muscarinic agonist toxicity?
SLUDGE: Salivation, Lacrimation, Urination, Defecation, GI upset, Emesis
Also: hypotension, bradycardia, difficulty with accommodation (blurred vision)
These are all cholinergic or muscarinic adverse effects.
What is the action of muscarinic receptor antagonists? What are two ways to do this?
Competitively block muscarinic receptors: antimuscarinic, parasympatholytics.
What are the pharmacological effects of muscarinic receptor antagonists on the CV system?
M2: tachycardia and facilitate AV nodal conduction, block reflex slowing of HR and AV nodal conduction, no direct effect on vascular tone or BP.
What are the Respiratory, Eye, and GI tract effects of muscarinic receptor antagonists?
Resp: Bronchodilation and decreased secretions (mainly M3)
Eye: dilate pupil and paralysis of accommodation (mainly M3)
GI: decrease secretions and motility (mainly M3)
What effects do muscarinic receptor antagonists have on urinary smooth muscles, sweat glands, and the CNS?
Urinary smooth muscle: decrease contractions of ureter and bladder
Sweat glands: decrease sweating and can increase temperature.
CNS: CNS depression and drowsiness.
What are three types of drug classes of muscarinic receptor antagonists? Name the drugs in each class.
Naturally occurring alkaloids: atropine and scopolamine
Semi-synthetic alkaloids: ipratropium
Synthetic antagonists: tropicamide, oxybutynin, darifenacin, glycopyrrolate.
What two muscarinic receptor antagonists are orally bioavailable and non-subtype selective? How are they alike? What is each used to treat?
Atropine and scopolamine:
- both non-subtype selective
- both orally bioavail
Atropine used for bradyarrhythmias, opthalmic uses, during anesthesia, and for anti-cholinesterase or muscarinic toxicity.
Scopolamine has more prominent CNS effects and is used to treat motion sickness and vestibular disease.
Which muscarinic receptor antagonist is non-subtype selective, a quaternary ammonium, and used to treat COPD?
Ipratropium
What is the muscarinic receptor synthetic antagonist tropicamide used for? How long does it take to work?
Mydriatic (pupil dilation) and cycloplegic (paralysis of ciliary muscles causing loss of accommodation)
Fast onset: 20-40 min with a short duration of 4-5 hours.
What are two synthetic muscarinic antagonists that are used for urinary incontinence? How do they differ?
Oxybutynin -has high incidence of muscarinic side effects such as xerostomia, blurred vision, constipation, and drowsiness.
Darifenacin - some selectivity for M3 receptor subtype results in less CNS side effects
What synthetic muscarinic antagonist is used to block parasympathomimetic effects during reversal of neuromuscular blockade with anticholinesterase agents?
Glycopyrrolate - its a quaternary amine so it doesn’t penetrate the CNS.
What are some adverse effects of using muscarinic receptor antagonists?
Xerostomia, blurred vision, dyspepsie (indegestion), constipation, tachy, hyperthermia, cognitive impairment (drowsiness).
These are associated with anticholinergic or antimuscarinic drugs.
When should you use muscarinic receptor antagonists with caution?
If someone has glaucoma, benign prostatic hyperplasia, or conditions worsened by tachy such as angina or arrhythmias
What is a major cause of poisonings related to muscarinic antagonists? What are symptoms of muscarinic antagonist associated toxicity?
Deliberate or accidental ingestion of belladonna alkaloids.
Symptoms of toxicity: hot as a hare, dry as a bone, red as a beet, blind as a bat, mad as a hatter.
What is the function of acetylcholinesterase inhibitors? Why have these gained attention?
Inhibition of acetylcholinesterases causes Ach to accumulate in the vicinity of cholinergic nerve terminals and thus are capable of making effects similar to excessive stim of cholinergic receptors in the periphery and CNS.
As toxic agents in the form of insecticides, pesticides, and chemical warfare “nerve gases”
What are the pharmacological actions of acetylcholinesterase inhibitors?
Stim of muscarinic receptor response at autonomic effector organs.
Stimulation followed by depression and paralysis of all autonomic ganglia and skeletal muscle (nicotinic action)
Stim of cholinergic receptors in the CNS
What are the therapeutic uses of acetylcholinesterase inhibitors?
Atony of smooth muscle of the intestinal tract and urinary bladder.
Glaucoma
Myesthenia gravis
Reversal of paralysis by competitive neuromuscular junction blocking agents
Describe the enzymatic hydrolysis of acetylcholine?
Binding domain contains trp and glu (anionic) that interact with charged ammonium of Ach and a ser, his, glu triad that interacts with the ester group.
upon binding: nucleophilic attach by ser causing hydrolysis of Ach and acetylation of serine
Acetylated ser reapidly hydrolyzed regenerating free enzyme
What is the function and action of non-covalent inhibitors?
Quaternary ammonium so activity limited to periphery and given parenterally. Rapid onset and short duration (minutes)
They are non-covalent inhibitors of AchE because they compete with Ach for the enzymatic cleft.
How do reversible carbamate inhibitors work?
They’re hydrolyzed by AchE but at a slow rate. Carbamateis cleaved making a carbamylated enzyme that is more stable.
This prevents enzyme-catalyzed hydrolysis of ACh.
What two drugs are reversible carbamate inhibitors that work by being degraded by acetylcholinesterase slowly and therefore prevent binding of Ach?
Physostigmine and neostigmine
What reversible carbamate inhibitor is from a calabar bean, is a tertiary amine with CNS effects, and is used to treat chronic wide angle glaucoma and toxicity by antimuscarinic drug poisoning by penetrating the CNS?
physostigmine
Which reversible carbamate inhibitor is a quaternary amine that doesn’t penetrate the CNS and is used to treat myesthenia gravis, treating post-op atony of the gut and bladder, and can reverse paralysis by competitive (non-polarizing_ neuromuscular blocking agents?
Neostigmine
What is myasthenia gravis? How can it be treated?
Nicotinic receptors at the NMJ have been targeted by autoimmune disease causing muscle weakness and rapid fatigue of skeletal muscle.
Blocking acetylcholinesterase will promote cholinergic transmission and prevent muscle fatigue.
What is the action of organophosphorous compounds?
Phosphorylate ser in the substrate-binding domain of acetylcholinesterase.
Regeneration of the enzyme is very slow (hours) and significant regen of active enzyme isn’t usually observed.
Return of activity depends on synthesis of new enzyme.
What are two organophosphorous compounds? What is the action of these?
Nerve gases: sarin, tabun, soman.
Insecticides: parathion (phased out in 2013) and malathion (safer because detoxified in higher organisms)
These are irreversible inhibitors of AchE.
What is the toxicity associated with organophosphorous compounds?
Sympatoms are nicotoinic and muscarinic symptoms.
Most are lipophilic and penetrate CNS.
SLUDGE, hypotension, brady, bad accommodation, medullary resp depression, muscle paralysis due to depolarzing NMJ blockade, death by resp fail.
What is the treatment for organophosphorous compounds toxicity? What are some antidotes?
Remove poisoning, maintain open airway and use artificial respiration.
Treat convulsions and shock.
Antidotes: atropine blocks peripheral and central muscarinic effects. Pralidoxime reactivates acetylcholinesterase peripherally but must be used without 2-3 hours.
How does Pralidoxime work to reverse toxicity of organophosphorous compounds?
It reacts with and removes the AchE inhibitor before the process of aging is complete. This regenerates AchE.
This has to be given rapidly after exposure to be affective.
What is the function of NMJ blocking agents? What are the uses? What are the two classes?
Block neurotransmission at NMJ producing paralysis of skeletal muscle.
Main sue is adjuvant in surgical anesthesia to obtain relaxation of skeletal muscle for operative manipulations. Used for intubation with trach and to control severe muscle spasms.
Classes: competitive non-depolarizing, depolarizing
How do competitive NMJ blocking agents work? What is a cool example?
They are antagonists of nicotinic receptors at hte NMJ (Nm).
Plant alkaloid tubocurare used by S american indians as arrow poison.
Many available, all contain quaternary amine: not orally absorbed, no CNS effects
How do competitive NMJ blocking agents differ?
Duration of action: short, med, and long
Side effects: CV and histamine release
Route of metabolism: metabolized or removed by renal clearance
Describe the adverse effects related to the chemical class of competitive NMJ blocking agents?
Natural alkaloids and congeners - block Nn and/or muscarinic receptors and most cause his release
Ammonio steriods - some (pancuronium) block muscarinic receptors but do NOT cause his release
Benzylisoquinolines - specific for Nm receptors but many cause his release.
How are competitive NMJ blocking agents selected for therapeutic use?
Based on the duration of the procedure and on minimizing CV compromises or other adverse effects with attention to modes of elimination in pts with hepatic or renal failure.
What are the four competitive NMJ blocking agents? How does their duration of action differ?
Recuronium: intermediate, 30-60 min with rapid onset of 1-2 mins
Atracurium: Intermediate, ~45 min. Onset in 3 minutes
Vecuronium: intermediate, 40-45 min, onset of 2-3 min
Pancuronium: long, 85-100 min, onset of 3-4 min.
How is each competitve NMJ blocking agent eliminated? What is the CV effects of each? Which cause histamine release?
Recuronium: hepatic elimination. Minimal CV effects. No His release.
Atracurium: spontaneously degrades in plasma, metabolism by plasma esterases. Minimal CV effects. Slight his release.
Vecuronium: hepatic and renal elimination. Minimal CV effects. No his release.
Pancuronium: renal and hepatic elimination. Slight increase in HR. No his release.
What is the action of depolarizing NMJ blockers?
Activate nicotinic receptors at the NMJ (Nm) maintaining motor end plate depolarization and thus preventing transmission of another action potential.
What is the function of succinylcholine? When is it used?
Quat ammonium with no CNS penetration, not orally absorbed.
Vary rapid onset and ultra-short duration of action because rapidly metabolized by plasma pseudocholinesterase.
Used frequently for trach intubation.
Genetic variation in pseudocholinesterase activity.
What are adverse effects of NMJ junction blocking agents?
Untoward adverse effects inclue prolonged apnea, CV collapse, effects due to his release, anaphylaxis.
Malignant hyperthermia.
Hyperkalemia (depolarizing agents)
What is malignant hyperthermia? What are clinical features? What makes someone susceptible?
Triggered by admin of certain volatile anesthetics and depolarizing NMJ blocking agents.
Contracture, rigidity, heat production from skeletal muscle resulting in severe hyperthermia, metabolic acidosis, tachy.
Genetic susceptibility: mutations of ryanodine receptor on L-calcium channels.
What occurs with overdosage of neuromuscular junction blocking agents? How would you treat it?
Resp paralysis.
Treat by positive pressure artificial ventilation until recovery.
With competitive blocking agents, recovery can be hastened by admin of an acetylcholinesterase inhibitors.
How do surgeons reverse the action of competitive NMJ blockades when a procedure is completed?
By employing an acetylcholinesterase inhibitor.
They may also co-administer a muscarinic receptor antagonist (glycopyrrolate or atropine) to reduce muscarinic actions of bradycardia, GI,GU motility/secretions.
What quaternary ammonium is activated peripherally and is used to diagnose myasthenia gravis and reverse paralysis by competitive neuromuscular blocking agents?
Edrophonium
