Autonomic Neurotransmission- Cholinergic transmission Flashcards
How is the nervous system divided?
the Nervous system is divided into - CNS and PNS
- PNS -> sensory neurons and motor neurons
- Motor neurons -> autonomic and somatic
- Autonomic - sympathetic and Parasympathetic
- ANS: independent, activities are not under conscious control, concerned with visceral functions such as cardiac output, blood flow distribution, and digestion.
- Somatic: voluntary functions such as movement, respiration, and posture
- Parasympathetic - rest and digest
- Sympathetic- fight or flight
What is the morphology of the nerves in the ANS?
2 neurons:
- Preganglionic -> cellular bodies in the CNS
- Postganglionic ->cellular bodies in the autonomic ganglia
What is the function of the nerves in the ANS?
control of heart, smooth muscles, and exocrine glands
Compare sympathetic and parasympathetic nerves.
Sympathetic: - site of origin: thoracolumbar (thoracic and lumbar region of the spinal cord) - length of fibers: Short preganglionic Long postganglionic
Parasympathetic: - site of origin: Craniosacral (brain and sacral area of teh spinal cord) - length of fibers Long preganglionic Short postganglionic
How do the neurotransmitters and motor nerves function in the ANS?
What are the neurotransmitters involved:
- Acetylcholine
- Norepinephrine
- Dopamine
Acetylcholine:
- all preganglionic nerve fibers (S and PS)
- Postganglionic parasympathetic fibers
- postganglionic sympathetic fibers to the sweat glands
- voluntary motor fibers
Norepinephrine:
- Postganglionic sympathetic fibers
- Adrenal medulla (+epinephrine)
Dopamine:
- Postganglionic sympathetic fibers to the renal vascular smooth muscle
What are the different types of cholinergic receptors?
Which is a cholinergic receptor?
Cholinergic receptors are receptors on the surface of cells that get activated when they bind a type of neurotransmitter called acetylcholine.
- Nicotinic (Nn, Nm)
- Muscarinic (M1-5)
Where are M1 receptors localized and what type of cellular response do they elicit?
M1 = ‘neural’
Localized:
- Cerebral cortex
- Autonomic ganglia
- glands: gastric, salivary, lacrimal, etc.
Cellular response:
- GPCR (Gq)
increase IP3, DAG, Excitation
Where are M2 receptors localized and what type of cellular response do they elicit?
M2 = ‘cardiac’
Localized:
- heart - atria
- CNS: widely distributed
Cellular response:
- GPCR (Gi)
- inhibition of AC (adenylyl cyclase), lower cAMP, inhibition
where are M3 receptors localized and what type of cell response do they elicit?
M3 = ‘glandular/ smooth muscle’
Localized:
- Exocrine glands: gastric, salivary, etc.
- Smooth muscle: gastrointestinal tract, eye, airways, bladder
- Blood vessels: endothelium
Cellular response:
- GPCR (Gq)
- increase IP3, DAG, Excitation
Where are M4 receptors localized and what type of cell response do they elicit?
M4
Localized:
- CNS
cellular response:
- GPCR (Gi)
- inhibition of AC (adenylyl cyclase), lower cAMP, inhibition
Where are M5 receptors localized and what type of cell response do they elicit?
M5
Localized:
- CNS
Cellular response:
- GPCR (Gq)
- increase IP3, DAG, Excitation
where are Nn receptors localized and what type of cellular response do they elicit?
Nn
Localization:
- Autonomic ganglia: mainly postsynaptic
- adrenal medulla
- CNS
Cellular response:
- Ionotropic (α,β-pentamer)
Excitatory
Increased cation permeability (mainly Na+, K+)
where are Nm receptors localized and what type of cellular response do they elicit?
Nm
Localization:
- Skeletal neuromuscular junction: mainly postsynaptic
Cellular response:
- Ionotropic (α,β,γ,δ-pentamer)
Excitatory
Increased cation permeability (mainly Na+, K+)
What are the effects of stimulation of cholinergic receptors on the Eye? Which receptors are found here?
Receptor = M3
Eye:
- pupil
- Ciliary muscle
- Lacrimal secretion
Effect:
- Contraction (miosis)
- Contraction (accomodation)
- Increase
What are the effects of stimulation of cholinergic receptors on the heart? Which receptors are found here?
Receptor = M2
Heart:
- SA nose
- AV node
Effect:
- decrease excitation (negative bathmotropic effect)
- decrease conductance (negative dromotropic effect)
What are the effects of stimulation of cholinergic receptors on the GIT? Which receptors are found here?
Receptor= M1 (stomach) & M2 (Intestines)
Stomach:
HCl -> increase secretion
Intestines:
- longitudinal muscles -> contraction
- Sphincter muscles -> relaxation
- intestinal glands _> increased secretion
What are the effects of stimulation of cholinergic receptors on the genitourinary tract? Which receptors are found here?
Receptor = M3
Effect: Genitourinary tract: - Bladder Detrusor: contraction Sphincter: relaxation
What are the effects of stimulation of cholinergic receptors on the Bronchi? Which receptors are found here?
Receptor = M3
Effect:
Bronchi:
smooth muscles -> contraction
Glands -> increase secretion
What are the effects of stimulation of cholinergic receptors on the glands? Which receptors are found here?
Receptor = M3 (salivary glands) & M (sweat glands)
Effect:
Salivary glands -> increase secretion
Sweat glands (thermoregulatory, S fibers) -> increase secretion
What are the effects of stimulation of cholinergic receptors on the skeletal muscles? Which receptors are found here?
Receptors = Nm
Effect:
Skeletal muscle -> contraction
What are the effects of stimulation of cholinergic receptors on the autonomic ganglia? Which receptors are found here?
Receptors = Nn
Effect:
Autonomic ganglia -> Excitation (S & PS)
How does cholinergic transmission occur?
- ACh synthesis:
- > ACetyl CoA + choline
- ACh is stored in synaptic vesicles
- release of ACh (exocytosis) with the participation of Ca2+
- Binding to and activation of postsynaptic receptors: Nicotinic receptors (Nn + Nm) Muscarinic receptors (M1-5)
- Inactivation of ACh
acetylcholinesterase - regulation of Ach release
Presynaptic heteroreceptors
postsynaptic heteroreceptors
What are the possible ways to affect cholinergic transmission?
- Hemicholiniums
= inhibit choline transporter (stop formation of ACh) - Vesamicol
= inhibit vesicle-associated transporter (VAT) - Botulinum toxin
= blocks acetylcholine vesicle release process through the enzymatic removal of two amino acids from one or more of the fusion proteins) - Receptor agonists and antagonists
- Inhibitors of acetylcholine esterase (acetylcholine is not inhibited)
How are the different cholinergic drugs classified?
- Drugs affecting muscarinic (mAChR) and nicotinic (nAChR) receptors:
~ Choline esters (directly acting)
~ Anticholinestertase drugs (indirectly acting) - Drugs affecting muscarinic receptors (mAChR):
• Muscarinic agonists
• Muscarinic antagonists - Drugs affecting nicotinic receptors (nAChR):
• Nicotinic agonists
• Nicotinic antagonists (neuromuscular-blocking drugs, muscle relaxants) - Drugs inhibiting acetylcholine release
What drugs can be used to treat glaucoma?
- Cholinoreceptor-activating drugs
= carbachol
(more possibilities)
How are the cholinesterase inhibitors (ChEI) classified?
1) With a quaternary ammonium group (N+)
- Neostigmine
- Pyridostigmine
- Poor absorption:
◦ Much higher doses are required for oral
administration than for parenteral injection - Do not cross the BBB
2)With a tertiary ammonium group • Galantamine • Donepezil • Rivastigmine - Good absorption - Cross the BBB
• Organophosphates (insecticides, chemical warfare “nerve gases”) - Good absorption from the GIT, lungs, skin, and conjunctiva - Heavy poisoning
What is the pharmacokinetics of cholinesterase inhibitors- with a quaternary ammonium group?
1) With a quaternary ammonium group (N+)
- Neostigmine
- Pyridostigmine
- Poor absorption:
◦ Much higher doses are required for oral
administration than for parenteral injection - Do not cross the BBB
What is the pharmacokinetics of cholinesterase inhibitors- with a tertiary ammonium group?
2)With a tertiary ammonium group • Galantamine • Donepezil • Rivastigmine - Good absorption - Cross the BBB
• Organophosphates (insecticides, chemical warfare “nerve gases”) - Good absorption from the GIT, lungs, skin, and conjunctiva - Heavy poisoning
What is the mechanism of action of ChEIs?
- potentiate the actions of the endogenous ACh
What are the M-cholinomimetic effects of ChEIs?
•M-cholinomimetic (muscarinic) effects:
◦ Eye: myosis, accommodation, ↓IOP
◦ Heart: bradycardia, ↓ AV conductance
◦ RS: Contraction of the smooth muscle of the bronchial
tree and increased secretion of bronchial glands
◦ GIT: stimulation of salivary glands, increased acid secretion, increased
secretion of intestinal glands, increased motor activity of the gut, sphincter relaxation
◦ Urinary bladder: stimulation of the detrusor muscle,
relaxation of the sphincter, thus promotion of voiding
What are the N-cholinomimetic effects of ChEIs?
◦ Depolarization of the endplates – increased contraction of the
skeletal muscle
What are the CNS effects of ChEIs?
only the lipid-soluble part
◦ In low concentrations – Activation of the EEG
◦ In higher concentrations – Generalized convulsions ->
coma and respiratory arrest
What are the clinical uses of ChEIs?
- Glaucoma
- Postoperative ileus (atony and paralysis of the stomach and bowel
following surgical manipulation) - Urinary retention
◦ Postoperative atony
◦ Postpartum
◦ Secondary to spinal cord injury - Myasthenia gravis
- Curare-induced neuromuscular paralysis (overdose of nondepolarizing neuromuscular junction blockers)
- Atropine intoxication (Galantamine)
- Alzheimer’s disease (Donepezil, Rivastigmine)
What are the contraindications and toxicity of ChEIs?
Contraindications
◦ Ulcer disease
◦ Bronchial asthma
◦ Obstructive ileus
Toxicity
◦ Eye: myosis
◦ Glands: sweating
◦ GIT: salivation, vomiting, diarrhea
◦ CVS: bradycardia, AV block, hypotension
◦ RS: bronchoconstriction
◦ Depolarizing neuromuscular blockade: paralysis
Treatment of the intoxication:
◦ Atropine
◦ Obidoxime
What are muscarinic agonists, what is their mechanism of action, and clinical use?
Drug:
◦ Pilocarpine – plant
alkaloid
Mechanism of action:
◦ Agonist of М receptors (direct
interaction)
Clinical use:
◦ For decrease of IOP
What are muscarinic antagonists?
Natural alcaloids:
◦ Atropine (from Atropa belladonna)
◦ Scopolamine (Hyoscine) (from Datura stramonium)
Drugs:
Natural
◦ Atropine
◦ Scopolamine
Semi-synthetic
◦ Butylscopolamine
Synthetic
◦ Mydriatics
Cyclopentolate
◦ Bronchospasmolytics
Ipratropium
Tiotropium
◦ Urospasmolytics
Oxybutynin
Solifenacin
Darifenacin (selective for M3 receptors)
What is the pharmacokinetics of atropine?
Good oral absorption and absorption through the conjunctiva
Good tissue distribution
Short t1/2 ~ 2 h
Renal excretion ~ 60% unchanged
Effect in the eye >72 h
What are the effects of atropine on the eye, heart, RS, and digestive system?
Eye:
• Mydriasis (duration: days)
• Cycloplegia (paralysis of the ciliary muscle resulting in a loss of accommodation)
• ↑ IOP (dangerous in glaucoma)
• Reduction of lacrimal secretion (dry or “sandy” eyes)
Heart:
• SA node: tachycardia
• Improvement of AV conductance
RS:
• Bronchial muscle: relaxation
• Bronchial glands: ↓ secretion
Digestive system:
• Stomach and intestines: ↓ motility, spasmolytic effect
• Gallbladder and biliary ducts: spasmolytic effect
• Glands: ↓ secretion of salivary glands (xerostomia, dry mouth) > intestinal glands >
gastric glands
What are the effects of atropine on the genitourinary tract, CNS, and sweat glands?
Genitourinary tract:
- Urinary bladder: relaxation of the bladder wall – slow
- Ureters: relaxation of the smooth muscle, spasmolytic effect
What are the indications for atropine?
In ophthalmology:
◦ For pupil dilation (mydriasis)
◦ For accurate measurement of refractive error in
young children (loss of accommodation)
For treatment of sinus bradycardia, e.g. acute MI
As a spasmolytic agent for gastro-intestinal, biliary and
renal colics
As a premedication in general surgery (↓ bronchial
secretion)
For the treatment of poisoning with: ◦ Organophosphates (large doses!) ◦ Mushrooms: ◦ Amanita muscaria ◦ Amanita phalloides
What are the adverse effects, toxic effects, and contraindications of atropine?
Adverse effects: ◦ Dry mouth (xerostomia) ◦ Constipation ◦ Blurred vision ◦ Tachycardia
Тoxic effects: ◦ CNS: agitation, delirium ◦ Hot and flushed skin ◦ Elevated body temperature “dry as a bone, blind as a bat, red as a beet, mad as a hatter”
Contraindications:
◦ Glaucoma
◦ Benign prostatic hyperplasia
What is scopolamine?
Muscarinic antagonist - plant origin Scopolamine (hyoscine) ◦ Sedation ◦ Antiemetic effect (М-rec. in the vestibular apparatus and in the vomiting center) ◦ For motion sickness (kinetosis)
What are Ipratropium and Tiotropium?
Muscarinic antagonist - synthetic drugs -> bronchospasmolytics
Ipratropium, Tiotropium ◦ Bronchodilatatory effect, for inhalation ◦ Treatment of bronchial asthma and COPD
What is Butylscopolamine?
Muscarinic antagonist - semi-synthetic drug
Butylscopolamine ◦ A derivative of scopolamine with a quaternary ammonium group ◦ Spasmolytic action ◦ For gastrointestinal, biliary and renal colics
What is cyclopentolate?
Muscarinic antagonist - mydriatics
causes Mydriasis
What are oxybutynin, solifenacin, and darifenacin?
Muscarinic antagonists - urospasmolytics
Oxybutynin, Solifenacin, Darifenacin ◦ Relaxation of the urinary bladder ◦ For the treatment of urinary incontinence in adults
What are the drugs affecting nicotinic receptors (nAChR)?
Agonists of nicotinic receptors
◦ Nicotine, Cytisine
◦ Usage:
◦ For smoking cessation
What are neuromuscular blocking drugs? - Non-depolarizing
Antagonists of nicotinic receptors ◦ Ganglion-blocking drugs ◦ Not used nowadays in Bulgaria ◦ Neuromuscular blocking drugs ◦ Non-depolarizing Pipecuronium Atracurium
What are neuromuscular blocking drugs? - Depolarizing
Antagonists of nicotinic receptors
◦ Ganglion-blocking drugs
◦ Not used nowadays in Bulgaria
Depolarizing
Suxamethonium
