Autonomic Neurotransmission Flashcards
Synthesis of ACh
acetyl CoA + choline + choline acetyl-transferase enzyme –> ACh
Storage of ACh
transported and stored in nerve terminal vesicles, uptake mediated by H_-ACh antiporter
Release of ACh
AP and depolarization of terminal
influx of Ca, initiate exocytosis
What would inhibit the release of ACh?
Onabotulinumtoxin A
Protein Botulinumtoxin is derived from
clostridium botulinum
Botulinumtoxin A MOA
inactivates synaptic vesicle protein required for vesicle docking
reversible state of cholinergic denervation
How is nerve function restored once being blocked by botulinumtoxin?
sprout new terminals, takes months
Action of Onabotulinumtoxin A
flaccid paralysis of skeletal muscle
Therapeutic uses of botulinumtoxin A
muscle spasms
cosmetic
OAB
axillary hyperhidrosis
Botulinumtoxin A Side Effects
distant spread from injection site, serious dysphagia, breathing difficulties, ptosis
What drug selectively stimulates muscarinic receptors?
Muscarine
What is muscarine derived from?
Amanita muscaria mushroom
What drug selectively blocks muscarinic receptors?
atropine
What is atropine derived from?
atropa belladonna, deadly nightshade
What kind of receptor is a muscarinic receptor?
G-protein-coupled receptors to induce change in cytosolic Ca or cAMP
What kind of receptor are nicotinic receptors?
ligand-gated ion channels, permeability to Na and K increases causing depolarization (EPSP)
What drug stimulates nicotinic neuronal receptor?
nicotine
What does persistent stimulation of the nicotinic neuronal receptor cause?
“Desensitization” (depolarizing blockade)
What drug blocks nicotinic neuronal receptors?
Mecamylamine
What drug competitively antagonizes nicotinic neuromuscular junction receptors?
d-Tubocurarine
Termination of Cholinergic Transmission
- AChE rapidly terminates transmission via hydrolysis
- Inactivation for next depolarization and prevent lateral diffusion
- Butyrylcholinesterase; functions as drug metabolizing enzyme active in plasma, glial cells, and liver
Adrenergic Transmission - Synthesis of Catecholamine NTs
- NE formed in adrenergic postganglionic neurons
- DA formed in basal ganglia of CNS
- NE converted to Epi in adrenal medulla
- Tyrosine hydroxylase is rate limiting step
- Synthesis of epi is increased by GCs
Vesicular Storage of Catecholamines
- vesicles protect NE, Epi, DA from degradation by MAO
2. NTs actively transported into vesicles by vesicular membrane monoamine transporter-2 (VMAT2)
What drug inhibits storage of NE, DA, or Epi into vesicles?
Reserpine
Use for reserpine
oral anti-HTN and antipsychotic
Reserpine MAO
irreversible inhibitor of VMAT2, NTs not stored degraded by MAO, depletes catecholamines from nerve terminal, reduces SNS activity in CNS and peripheral nerves
Reserpine Side Effects
sedation
unopposed cholinergic effects
psychotic depression
Where is NE converted to Epi
cytosol of chromaffin cells
How is epi transported back into vesicles?
VMAT2
Release of Catecholamines
calcium influx –> exocytosis
negative feedback inhibition of NE release
What receptors provide the negative feedback inhibition of NE release?
alpha-2 receptors
What drug stimulates NE release?
Tyramine
What type of foods is tyramine/tyrosine found in?
protein rich foods (cheese, fish, kimchee, meats)
MOA of tyramine
displace NE from vesicle, causing non-vesicular release by reverse transport through NET
What population would be most effected by ingesting tyramine rich foods?
patients taking MAO inhibitors
What can result from an abrupt NE release?
hypertensive crisis
What drug inhibits NE release?
Methyldopa
What is methyldopa used for?
anti-HTN (safe during pregnancy)
Methyldopa MOA
prodrug converted to methyl-NE, which is an alpha-2 selective adrenergic receptor agonist, which reduces “sympathetic outflow” to periphery
Methyldopa Side Effects
sedation, dry mouth, PD, autoimmune hemolytic anemia (Coomb’s test)
Adrenergic Receptor Subtypes
alpha-1 (smooth muscle) - contraction (Gq)
alpha-2 (nerves) - inhibitory (Gi)
beta-1 (heart, kidney) - excitatory/contraction (Gs/cAMP)
beta-2 (lung, skeletal muscle vasculature, uterus) - relaxation (Gs)
Adrenergic Termination
- NE in synapse - reuptake via active NE transporter (NET) & diffusion away from adrenergic receptors
- Circulating NE - ENT in vascular smooth muscle/glands
- Inhibition of reuptake can occur (cocaine)
What drug can inhibit the reuptake of NE?
cocaine
How are catecholamines metabolized?
- MAO - mitochondria
- COMT - cystosolic
VMA - excreted in urine
Responsibility of MAO
clearing catecholamines in nerve terminals
Example of why we would inhibit MAOs
elevate transmitter levels in neurons (SSRIs)
Example of why we would inhibit COMT
treat Parkinsons
What is VMA useful to diagnose?
diseases affecting SNS
Botulinum toxin action and clinical use
Action: inhibit ACh release
Use: cosmetics, muscle paralysis
Reserpine action & clinical use
Action: inhibit vesicular uptake of DA
Clinical Use: anti-HTN
Cocaine Actions & Clinical Use
Actions: inhibit neuronal reuptake of NE
Use: local anesthetic, vasoconstrictor
Tyramine action & clinical use
Action: promote NE release
Use: none, causes hypertensive crisis
Methyldopa action and clinical use
Action: false transmitter/alpha-2 agonist
Use: anti-HTN safe during pregnancy