Lecture 1 - Autonomic Nervous System

Question 1

Breakdown of the nervous system

Answer 1

Nervous system central nervous system + peripheral nervous system

PNS= autonomic +somatic

Autonomic= sympathetic (fight or flight) + parasympathetic (rest and digest)

Question 2

Identify the major neurotransmitters found in the ANS

Answer 2

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

Question 3

differentiate sympathetic control of the sweat glands, kidney, and adrenal glands from other areas of the SNS

Answer 3

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)

Question 4

use interchangeably the terms describing drugs affecting the autonomic nervous system (cholinergic vs. parasympathomimetic)

Answer 4

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

Question 5

Contrast the organization and neuron types in the ANS

Answer 5

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

Question 6

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

Answer 6

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

Question 7

given a specific drug (agoinst vs antagonist) predict the effects on an organ system or 2nd messenger formation

Question 8

describe the signal transduction pathways associated with each of the major receptor types found in the ANS

Answer 8

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

Question 9

describe the major physiological responses under PSNS and SNS control

Answer 9

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

Question 10

contrast sympathetic and parasympathetic control of the eye with emphasis on pupillary size, lens, refractive power, and aqueous humor production and flow

Answer 10

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)

Question 11

based upon knowledge of the radial and circular muscles predict the effects of a given drug on pupillary size (miosis vs mydriasis)

Answer 11

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

Question 12

describe the major pharmacologic manipulations of the cholinergic system

Answer 12

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

Question 13

examine the structure of a direct-acting cholinergic agonist and identify the major structural features responsible for the drugs activity

Answer 13

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

Question 14

Explain the molecular basis for the interactions of acetylcholine
and related drugs with muscarinic receptors with particular
emphasis on stereochemical requirements of the drugs

Answer 14

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

Question 15

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.

Answer 15

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)

Question 16

Given a clinical condition, choose an appropriate cholinergic
agonist to treat that condition

Answer 16

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

Question 17

Explain why parasympathomimetic drugs should not be used
in asthma, peptic ulcer, or bowel and urinary obstructions

Answer 17

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

Question 18

Explain the molecular basis for the interactions of acetylcholine
and related drugs with nicotinic receptors.

Answer 18

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

Question 19

Distinguish the mechanisms of direct and indirect-acting
parasympathomimetic drugs

Answer 19

direct acting are muscarinic receptor agonists while indirect acting are AChE inhibitors

Question 20

Contrast acetylcholinesterase and plasma cholinesterase

Answer 20

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

Question 21

Define the roles that the amino acids at the esteratic and anionic sites
play in the catalytic steps associated with the actions of
acetylcholinesterase

Answer 21

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)

Question 22

Contrast the structures and molecular interactions of the reversible
cholinesterase inhibitors with acetylcholinesterase

Answer 22

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

Question 23

Given a clinical condition, choose an appropriate acetylcholinesterase
inhibitor to treat that condition

Answer 23

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

Question 24

Contrast the mechanism of action of the organophosphates (including
the “aging” effect) and the reversible inhibitors of acetylcholinesterase.

Answer 24

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.

Question 25

Compare the toxicity of Malathion and Diazinon in mammals and
insects

Answer 25

organophosphates are man made chemicals used as insectisides

Malathion is converted to the active MALAOXON in insects by CYP450

Malathion converted to inactive form by carboxyesterase in mammals and birds

Question 26

Understand the pharmacologic aspects of cholinergic agents used to treat Alzheimer’s dementia, and their effects on progression of disease

Answer 26

Dementia is atrophy of the brain (decrease in size) and loss of cholinergic neurons in the brain

DONEPEZIL(aricept)
-binds to anionic site and blocks ACh binding, non covalent and reversible, enhances cognitive ability, does not slow progression of disease, treats all stages of Alzheimers

RIVASTIGMINE(exelon)
-reversible carbamate AChE inhibitor, enhances cognitive ability by increasing cholinergic function, loses effectiveness as disease progresses

GALANTAMINE(razadyne)
-reversible competitive AChE inhibitor, extract from daffodil, loses effectiveness as disease progresses, maybe a nicotinic receptor agonist, CYP450 inhibitors increase bioavailability

MEMANTINE(namenda)
-N-methyl-D-aspartate receptor antagoinst, NMDA receptors activated by glutamate in CNS in areas assoc. with cognition and memory, may slow progression of disease, approved for moderate to severe cases, DONEZEPIL and MEMANTINE as combination drug for moderate to severe alzheimers

Question 27

Recognize the symptoms of parasympathomimetic side effects

Answer 27

DUMBBELS
diarrhea urination miosis bradycardia bronchoconstriction emesis lacrimation sweat and salivation
SLUD
salivation lacrimation urination defecation
OTHER
increase sweating, decreased HR, constricted pupils, CNS activation

Question 28

Recognize the signs and symptoms of parasympathomimetic toxicity
and choose an appropriate treatment.

Answer 28

ATROPINE
cholinergic receptor antagonist

PRALIDOXIME
if irreversible AChE inhibitor, 2PAM

Question 29

Interpret clinical and functional outcomes of antimuscarinic drugs
acting on M1, M2, and M3 muscarinic receptors

Answer 29

muscarinic receptor blockade, competitive antagoinsm at the muscarinic receptor mediated actions of ACh on autonomic effectors innervated by postganglionic cholinergic nerves and smooth muscles that lack choinergic innervation

little effect on actions of ACh at nicotinic receptor

widespread distribution of muscarinic receptors throughout brain, therapeutic doses are attributable to their central muscarinic blockade
ATROPINE can produce partial block (M1) only at a relatively high dose
ANTIMUSCARINICS are competitive antagonists for muscarinic receptors (M1, M2, M3) smooth and cardiac muscle and exocrine glands

Question 30

Recognize the pharmacophore characteristic of antimuscarinic drugs

Answer 30

antimuscarinic drugs competitively and reversibly inhibit muscarine receptor activation by preventing the binding of ACH
-Tertiary amines (N with 3C) good access to CNS, long lasting, M1M2M3 nonselective
-Quaternary amine (N with 4C) Have + charge

Question 31

Describe the various clinical uses of antimuscarinic drugs, and
recognize examples of drugs used for each clinical purpose

Question 32

Understand how the clinical use of an antimuscarinic drug
depends on the drug’s duration of action

Question 33

Explain why antimuscarinic drugs with a quaternary amine group
are suitable for some clinical purposes but not others

Question 34

Recognize the anticholinergic effects of drugs that were not
designed to target muscarinic receptors.

Question 35

Recognize the key structural features of anti-muscarinic drugs as
well as ganglionic and neuromuscular blockers