Lecture 1 - Autonomic Nervous System Flashcards
Breakdown of the nervous system
Nervous system central nervous system + peripheral nervous system
PNS= autonomic +somatic
Autonomic= sympathetic (fight or flight) + parasympathetic (rest and digest)
Identify the major neurotransmitters found in the ANS
PSNS preganglionic neurons release ACh on nicotinic receptors and postganglionic release ACh on muscarinic receptors
SNS preganglionic neurons release ACh on nicotinic receptors and postganglionic release norepinephrine to activate adrenergic receptors on the organ
differentiate sympathetic control of the sweat glands, kidney, and adrenal glands from other areas of the SNS
Sweat glands release ACh on muscarinic postganglionic receptors
renal vascular/kidney release Dopaline on D1 receptor postganglionic
adrenal gland preganglionic receptors release ACh on nicotinic receptors directly into systemic circulation (no postganglionic)
use interchangeably the terms describing drugs affecting the autonomic nervous system (cholinergic vs. parasympathomimetic)
Drugs that mimic ACH in the PNS are cholinergic drugs as well as muscarinic agonists and classified as parasympathomimetic
Drugs that block ACh in the PNS are anticholinergic and muscarinic antagonists and are classified as parasympatholytic
Drugs that mimic NE are adrenergic and are adrenergic agonists and classified as sympathomimetic
Drugs that block NE are antiadrenergic and adrenergic antagonists and are classified as sympatholytic
Contrast the organization and neuron types in the ANS
Parasympathetic neurons on the medulla have a long preganglionic neuron and short postganglionic neuron
pre and post-release ACH
Sympathetic neurons on the spinal cord have a short preganglionic neuron and longer postganglionic neuron
pre-release ACH and post release norepinephrine
organize the major types of neurotransmitter receptors found in the autonomic nervous system based on their structure, signal transduction pathways, tissue distribution, and associated physiologic effects
Cholinoreceptors are ACh receptors
Nicotinic (Na + ion channel) Nm, Nn
-ganglionic, skeletal muscle, neuronal CNS
-5 subunits (Ionotropic a,b,y,s,a)
-ligand-gated Na+ channel, opening leads to depolarization and then opening of voltage-gated Na+ channel to produce an action potential, selectively activated by exogenous nicotine
Muscarinic (GPCR) M1, M2, M3
-M1,M3,M5 are Gq pathway signaling and IP3 is the second messenger to release Ca++ from intracellular storage and DAG activates PKC
-M2, and M4 are Gi (inhibitory) and cAMP is the second messenger where GTP inhibits adenylyl cyclase
Adrenoreceptors are NE+ E receptors
-Alpha a1 uses Gq pathway with IP3 and DAG to activate PKC(vasoconstriction) BUT a2 is Gi inhibitory pathway that inhibits adenylyl cyclase and decreases transmitter release
-Beta B1, B2, B3 signal through Gs pathway that is stimulatory and activates adenylyl cyclase and increases cAMP resulting in phosphorylation of ion channels and other proteins
given a specific drug (agoinst vs antagonist) predict the effects on an organ system or 2nd messenger formation
describe the signal transduction pathways associated with each of the major receptor types found in the ANS
M1,M3,M5, a1(vasoconstriction) signal via Gq pathway in which IP3 mobilizes Ca++ from intracellular stores, DAG activates protein kinase C
M2,M4, a2 signal via Gi inhibitory pathway in which adenylyl cyclase is inhibited by GTP
B1,B2,B3 signal via Gs (stimulatory) pathway in which adenylyl cyclase is activated and cAMP is increased and PKC is activated
describe the major physiological responses under PSNS and SNS control
adrenergic (fight or flight SNS) and the heart rate and force of contraction both increase with B1(and B2) receptors, increases HR, widens bronchial passages, decreases motility of large intestine
cholinergic (rest and digest PSNS) decrease rate and and force of contraction on the heart with M2 receptors, heart rate Is decreases, and metabolism picks up
contrast sympathetic and parasympathetic control of the eye with emphasis on pupillary size, lens, refractive power, and aqueous humor production and flow
pupillary construction (miosis) when the circular muscle is constricted by activation of PSNS nerves (M3) iris gets smaller (pupil shrinks)
M3 agonist PILOCAPRINE ciliary muscle: contraction facilitates outflow of aqueous humor and decreases intraocular pressure
pupillary dilation (mydriasis) when the radial muscle is constricted by activation of sympathetic nerves (a1) iris widens (dilation of the pupil)
a2 agonist BRIMONIDINE on ciliary body inhibits production and increase outflow of aqueous humor
ciliary epithelium NE-Beta secretion of aqueous humor beta antagonist (Timolol) and a decrease in intraocular pressure
glaucoma=increased intraocular pressure (internal eye cancer)
based upon knowledge of the radial and circular muscles predict the effects of a given drug on pupillary size (miosis vs mydriasis)
drugs that are cholinergic/parasympathetic cause pupillary construction by constructing the circular muscle with M3 PSNS nerves
drugs that are adrenergic/sympatheitic will open the eye by pupillary dilation/mydriasis of the radial muscle and a1 SNS nerves
describe the major pharmacologic manipulations of the cholinergic system
QIQ
M1 Gq increase PLC, IP3, DAG, Ca++
M2/4 Gi inhibits aden. cycl,activate K+
M3/5 Gq increase PLC, IP3, DAG, Ca++
acetylcholine has higher affinity for muscarinic receptor than nicotinic
1.choline transported into presynaptic nerve by sodium dependent choline transporter (CHT)
*inhibited by hemicholinium (no clinical use)
2. ACh is made from cholien and acetyl coA by the enzyme choline acetyltransferase (ChAT)
3a. ACh transported into storage vessicle by second carrier “vessicle associated transporter” VAT
*inhibited by vesamicol (no clinical use)
3b. release of transmitter occurs when action potential opens voltage sensitive Ca+ channels and increases intracellular Ca, fusion of vesicles w surface membrane increases ACh
*blocked by botulinum toxin (botox)
4. ACh binds to cholinoreceptors on postsynaptic cell
5. ACh action is terminated by metabolism by the enzyme acetylcholinesterase AChE
6. autoreceptors and receptors on the presynaptic nerve ending modulate transmitter release
examine the structure of a direct-acting cholinergic agonist and identify the major structural features responsible for the drugs activity
direct acting muscarinic receptor agonists activate cholinoreceptors and include choline esters (ACh, methacholine, carbachol and bethanechol) and alkaloids (muscarine, pilocarpine), charge prevents esters from crossing BBB into CNS
COO ester group on end with H3C or H2N, quaternary N with + charge on other end where receptor binds
Explain the molecular basis for the interactions of acetylcholine
and related drugs with muscarinic receptors with particular
emphasis on stereochemical requirements of the drugs
added methyl group makes the neurotransmitter more muscarinic selective
B substitutions reducing nicotinic NT make it more muscarinic selective
the + isomer of methacholine is the better one to be active
Given a chemical modification to the structure of a direct
acting cholinergic agonist, predict the effect on the molecule’s
activity and sensitivity to acetylcholinesterase.
ACh and Carnachol active at both N+M
B substitutions: reduce nicotinic -> muscarinic selectivity, reduce AChE
a substitutions: retain nicotinic, reduce muscarinic
modifications to acetyl group to carbamate-> resistant to AChE
(increase in H is more reduced->M selectivity)
Given a clinical condition, choose an appropriate cholinergic
agonist to treat that condition
PILOCARPINE treats…
-glaucoma, no charge so it can cross through the eye
-Xerostomia (dry mouth/cotton mouth)
-Sjogren’s syndrome (an autoimmune disease in women)
ACh treats…
intraocular for miosis during surgery
CARBACOL treats…
intraocilar for miosis during surgery, glaucoma
BETHANECHOL treats…
urinary retention, post-op ileus
VARENICLINE treats…
smoking cessation
METHACHOLINE
for provocative test for hyperactive airways
Explain why parasympathomimetic drugs should not be used
in asthma, peptic ulcer, or bowel and urinary obstructions
Asthma ane COPD
increases bronchoconstriction
Coronary deficiency
would further lower HR
Peptic ulcer
would increase acid secretion
Bowel/urinary obstructions
if increased contraction does not remove obstruction
Explain the molecular basis for the interactions of acetylcholine
and related drugs with nicotinic receptors.
when 2 ACh bind to a nicotinic receptor, a conformational change is made on the receptor and an ion pore is created where ions flow through
Distinguish the mechanisms of direct and indirect-acting
parasympathomimetic drugs
direct acting are muscarinic receptor agonists while indirect acting are AChE inhibitors
Contrast acetylcholinesterase and plasma cholinesterase
acetylcholinesterase is located in the synapse and has ACh substrate selectivity
plasma cholinesterase is located in the plasma, and is selective for ACh, succinylcholine, and local anesthetics
Define the roles that the amino acids at the esteratic and anionic sites
play in the catalytic steps associated with the actions of
acetylcholinesterase
serine: at the esteric site (off of the C=O bond, serine forms a temporary covalent bond with acetylcholine during the hydrolysis reaction
anionic site is off of the N+ and is important for the enzyme’s specificity and efficiency, this site contains (-) charged amino acids whose reaction with the quaternary amine enhances the enzyme’s substrate specificity, contributing to the high affinity of acetylcholinesterase for acetylcholine (Trp and Phe)
Contrast the structures and molecular interactions of the reversible
cholinesterase inhibitors with acetylcholinesterase
Acetylcholinesterase (AChE) is an enzyme responsible for terminating the action of the neurotransmitter acetylcholine (ACh) by catalyzing its hydrolysis.
Its primary function is to break down acetylcholine into acetate and choline, allowing for the regulation of cholinergic signaling.
AChE has a specific structure with an active site (esteratic site) that includes key amino acids, such as serine, involved in the catalytic hydrolysis of acetylcholine.
The enzyme has an anionic site on its surface, which contributes to substrate specificity by interacting with the positively charged quaternary amine group of acetylcholine.
AChE interacts with acetylcholine through the esteratic and anionic sites.
The interaction involves the formation of a temporary covalent bond between the serine residue at the esteric site and acetylcholine, leading to hydrolysis
Reversible cholinesterase inhibitors are drugs or compounds that temporarily block the activity of acetylcholinesterase, leading to an increase in the concentration of acetylcholine in the synaptic cleft.
These inhibitors often have a functional group (e.g., carbamate or ammonium) that interacts with the esteratic site of acetylcholinesterase
-no ester group
This reversible binding prevents the normal breakdown of acetylcholine, leading to an accumulation of the neurotransmitter in the synaptic cleft and prolonged cholinergic effect
Given a clinical condition, choose an appropriate acetylcholinesterase
inhibitor to treat that condition
EDROPHONIUM
-used to test for myasthenia gravis (MG) which is skeletal muscle weakness due to loss of skeletal muscle nicotinic receptors due to autoimmune disease
PYRIDOSTIGMINE
-treats MG, reversal of nondepolarizing neuromuscular blockade
-pretreatment for potential nerve gas exposure by occupying AChE so nerve gas has nowhere to go
NEOSTIGMINE
-treats MG, reversal of nondepolarizing neuromuscular blockade
-post-op urinary retention
PHYSOSTIGMINE
-can cross BBB, antidote to antimuscarinic poisoning
ECHOATHIOPHATE
(most organophosphates are toxic)
-originally used to treat glaucoma, not used now due to better options
Contrast the mechanism of action of the organophosphates (including
the “aging” effect) and the reversible inhibitors of acetylcholinesterase.
Organophosphates irreversibly inhibit acetylcholinesterase by forming a stable, covalent bond with the enzyme’s active site, the phosphorus atom in organophosphates binds to the serine residue in the esteric site of acetylcholinesterase.
Organophosphates may undergo an “aging” process where the bond between the organophosphate and acetylcholinesterase becomes more stable over time.
Once aging occurs, the inhibition becomes essentially irreversible.
(pralidoxime is an antidote for nerve gas poisoning If used before aging)
Reversible inhibitors like carbamates form non-covalent interactions with AChE and cause a temporary inhibition of acetylcholinesterase.
The inhibition is readily reversible, and enzyme activity can be restored with time as the inhibitor dissociates from the enzyme.
Reversible inhibitors are often used therapeutically to temporarily increase acetylcholine levels, as seen in medications like neostigmine for myasthenia gravis or as a diagnostic agent like edrophonium.
