PPT 7/8 Cholinomimetics Flashcards
exam 2
What do cholinomimetic agents do?
ACh receptor stimulants and cholinesterase inhibitors - mimic the effect of ACh
What are the classifications of cholinomimetic agents?
Muscarinic and nicotinic - based on which receptor activated
Differentiate between direct and indirect-acting cholinoceptor stimulants
Direct-acting - agonists of receptors (choline esters and alkaloids)
Indirect-acting - cholinesterase inhibitors, prolonging ACh in the synapse (reversible and irreversible)
Where are muscarinic receptors found?
Nerve, heart and smooth muscle, and glands and endothelium
Where are nicotinic receptors found?
Neuromuscular end plate, skeletal muscle, and autonomic ganglion cells
Muscarine mimics the effect of what?
Parasympathetic nerve discharge
- Parasympathomimetic
Where does the action of muscarinic drugs take place?
Effector cells, not those in the ganglia
What is given to treat muscarinic excess? Why?
Atropine 1-2mg IM - blocks muscarinic receptors
Where does the action of nicotinuc drugs take place?
Stimulates autonomic ganglia and skeletal muscle NMJ, not effector cells
Differentiate between transmembrane signaling in the cholinoceptors
Muscarinic - G-protein linked
Nicotinic - Ion channel
Which drugs are esters of choline?
Ach, Methacholine, Succinylcholine (Sux), Carbachol, and Bethanechol
Which drugs are alkaloids?
Muscarinic: Muscarine, Pilocarpine (betel nut)
Nicotinic: Nicotine, Lobeline
Esters of choline solubility
Permanently charged – insoluble in lipids (don’t cross barriers easily, can use patch)
Indication for administration of ACh
used primarily for pupilary constriction
Indication for administration of Methacholine
diagnosis of asthma
Indication for administration of Carbachol
Decreases IOP
Indication for administration of Bethanechol
Bladder dysfunction, reflux disease
What are the pharmacokinetics for esters of choline drugs?
- A: Poor
- D: Poor in CNS (hydrophilic)
- M: Varies
ACh: Rapid (5-20 seconds)
Methacholine: 3x longer
Carbachol/Bethanechol – resistant to hydrolysis
What are the pharmacokinetics for alkaloid drugs?
A: Pilocarpine, Nicotine, Lobeline = well
Nicotine is lipid soluble – transdermal delivery
Muscarine is less completely absorbed - charged
E: Kidneys – enhanced by acidification of urine
How do cholinomimetics affect the eye?
Muscarinic agonists – cause contraction of the pupil - PNS stimulus
Increase intraocular drainage
Differentiate between the types of glaucoma
Glaucoma = excessive amount of intraocular fluid, increased IOP
- Open-angle: Poor drainage in the eye’s drainage canals, but can still drain
- Angle-closure: Mechanical obstruction in the eye’s drainage system, iris has bulged forward to narrow and partially block the drainage angle
How do cholinomimetics affect the CV system?
Reduction in peripheral vascular resistance
Vasodilation – reduction in BP – reflexive increase in HR
- Large doses (overdose) - bradycardia
Which type of glaucoma is atropine contraindicated for? Why?
Angle-closure - atropine relaxes the ciliary muscle, causing complete obstruction of the drainage of the aqueous humor (medical emergency - blindness)
How do cholinomimetics affect the respiratory system?
Smooth muscle of bronchial tree contracted (better airway tone)
Tracheobronchial mucosa secretion increased
How do cholinomimetics affect the GI system?
Increased secretory and motor activity in gut - can treat post-operative ileus
Salivary and gastric glands stimulated
Sphincters relax
How do cholinomimetics affect the brain in the CNS?
Mainly muscarinic sites - muscarine doesn’t cross barrier easily
Nicotine
Mild alerting action (smoking) - release of dopamine, serotonin, GABA, NE
- Larger doses: tremor, emesis, stimulates respiratory center, convulsions, fatal coma
How do cholinomimetics affect the neuromuscular junction?
- Immediate depolarization of endplate
- Increased permeability to Na and K
- Muscle contraction
- If not readily hydrolyzed = depolarization blockade (flaccid paralysis) - Succinylcholine
How do cholinomimetics affect the spinal cord in the CNS?
Mainly nicotinic sites
What are the types of indirect-acting cholinomimetics?
Simple alcohols, carbamic acid esters of alcohols, and organic derivatives of phosphoric acid (organophosphates)
Why do organophosphates last for a long time?
Can form covalent bonds with AChE, somewhat irreversible
What are the indirect-acting cholinomimetics that we need to know?
Alcohols - edrophonium
Carbamates - neostigmine and pyridostigmine
Organophosphates - echothiophate
What is echothiophate used for and how long does it last?
Glaucoma, 100 hours
What is edrophonium used for and how long does it last?
MG (dx), ileus, and arrhythmias; 5-15 min
What is neostigmine used for and how long does it last?
MG, ileus; 0.5-2 hrs
What is pyridostigmine used for and how long does it last?
MG, 3-6 hours
What is the mechanism of indirect-acting cholinomimetics?
Targets ACh esterase (AChE), preventing the breakdown of ACh
How can an organophosphate covalent bond be broken?
Need a strong nucleophile - Pralidoxime
Why does Pralidoxime need to be given in the first few hours of organophosphate poisoning?
Aging
Breaks oxygen-phosphorous bond
Makes phosphorous-active site bond even stronger
Nucleophiles no longer effective
What are the 4 major therapeutic uses of indirect-acting cholinomimetics?
- Disease of the eye - glaucoma
- GI and urinary tracts - ileus
- Neuromuscular junction - MG and anesthesia
- Atropine overdose
MG is treated by which drug class?
Cholinesterase inhibitors
Which drug is used to diagnose MG?
Edrophonium - can also be used to assess whether longer-lasting AChE inhibitors will work
What is the pathophysiology of MG?
ACh receptors are internalized and degraded, leading to impaired muscle contraction
Weakness, fatigue, worsens with exercise
How are indirect-acting cholinomimetics used in surgical anesthesia?
Neuromuscular blockades are frequently produced as an adjunct (pancuronium)
Relaxants - AChE inhibitors useful to reverse effects after surgery (neostigmine)
How can atropine overdose be treated?
Overcome by increasing ACh present at NMJ; Competitive ACh receptor blockade - Physostigmine
What are the symptoms of overdose of direct-acting muscarinic stimulants?
SLUDGE-M: Need atropine
Salivation, lacrimation, urination, defecation, GI motility, emesis, myosis
What are the symptoms of overdose of cholinesterase inhibitors?
SLUDGE-M - need atropine and pralidoxime (organophosphate poisoning)
How do you treat an overdose of cholinesterase inhibitors?
- Vital sign maintenance
- Decontamination
- Atropine
- Pralidoxime (organophosphates only) - pesticides
What are the symptoms of overdose of direct-acting nicotinic stimulants?
Nicotine acute toxicity - fatal dose is 40mg
Ingestion (children) is usually followed by vomiting
HA, N/V, dizziness, breathlessness, collapse, loss of consciousness
What are the 4 antimuscarinic drugs?
Tropicamide
Ipatromine
Scopolamine
Atropine
What are the 2 kinds of antinicotinic drugs?
Ganglion blockers and NMJ blockers
Atropine is a competitive inhibitor to ____
ACh
What are the indications for the use of atropine?
Blocks the parasympathetic response
- Bradycardia
- Poisonous mushrooms and organophosphate poisoning
Why is atropine used preoperatively?
- To help prevent vagal stimulation and potential bradycardia
- Reduce respiratory secretions
- Block unwanted GI activity
What are the respiratory effects of atropine?
Blocks parasympathetic response of constricting airways → opens airway
Can treat asthma or COPD, but atrovent more useful
What are the effects of atropine on the eyes?
- Dilator
- Cycloplegia – paralysis of the ciliary muscle (can’t switch from near/far vision (accommodation))
- Decreased watering
- Tropicamide - used for eye exams to dilate
What are the effects of atropine on the heart?
Increases the heart rate after a transient bradycardia at the low dose
Why can you see an initial dip in HR after giving atropine?
The theory is that it is due to atropine affecting muscarinic receptors on presynaptic cells more than on the ACh receptors of the effector cells
What are the effects of atropine on salivary glands?
Diminishes gland excretory function
What are the effects of atropine on urination?
Decreases micturition speed, or the speed of urination
Summary of atropine effects
- Decreases urine production, salivation, accommodation
- Increases HR
What are the contraindications to atropine?
- Glaucoma patients - especially closed-angle
- Elderly men (known prostatic hyperplasia) - swelling in the prostate gland because it decreases urination → urinary retention
What are the signs and symptoms of atropine overdose?
BRAND - blindness, redness, absent bowel sounds, nuts (CNS), dilated pupils
What is the treatment for atropine overdose?
Physostigmine - can produce dangerous CNS effects
How do ganglion blockers work? Why aren’t they used anymore?
- Block ACh at nicotinic receptors
- Not used anymore because of lack of specificity - both sympathetic and parasympathetic (because ACh released in all ganglion)
What are the two types of NMJ blockers?
Depolarizing muscle relaxant
Nondepolarizing muscle relaxants (Competitive blockers)
What kind of NMJ blocker is succinylcholine?
Depolarizing muscle relaxant
What are the clinical uses of succinylcholine?
- Most often used to facilitate intubation
- Electroconvulsive therapy
What are the side effects of succinylcholine?
Fasciculation
Muscle pain
Hyperkalemia
Malignant hyperthermia
Apnea
Why does succinylcholine have prolonged effects?
Not metabolized locally at NMJ - Metabolized by cholinesterase in plasma
How does succinylcholine work?
Binds to ACh-R, causing continuous end-plate depolarization and muscle relaxation; works for 5-10 min
Differentiate between phase I and phase II blocks
Phase I: depolarization and lack of repolarization
Phase II: longer-term, end plate repolarizes over time, muscle no longer reacting to succinylcholine; deeper block
How do nondepolarizing muscle relaxants work?
Competitive antagonists: compete with ACh at binding site (ACh-R), but do not depolarize the motor end plate; curare derivatives
What are the 3 examples of nondepolarizing muscle relaxants?
- Long acting
- Pancuronium
- Intermediate acting
- Atracurium
- Short acting
- Mivacurium
What are the medications that reverse NMJ blockers?
Neostigmine (increases ACh at the synapse) and Sugammadex (for rocuronium and vecuronium)
