Far

Eastern University – Nicanor Reyes Medical Foundation

PHARMA A: ANS/PARASYMPATHETICS
Dra. Ona-Cruz, MD
INTRODUCTION TO ANS PHARMACOLOGY

- Some of the preganglionic parasympathetic fibers end in
ganglia located outside the organs innervated such as the
ciliary, pterygopalatine, submandibular, otic, several pelvic
ganglia. However, many parasympathetic preganglionic
fibers actually terminate within ganglion cells diffusely
distributed or in networks in the walls of the organs
AUTONOMIC ANATOMY innervated.
- involuntary body functions - Junctions between autonomic nerve terminals and effector
- sensory (afferent) and motor (efferent) components cells (such as cardiac or smooth muscles or glands) are
- organs and tissues such as smooth muscle, cardiac muscle, different from classical somatic synapses because
and glands transmitters are released not from single boutons (enlarged
- ganglionic synapse in the efferent pathway part of a nerve terminal or axon) but from a chain of
- autonomous (not under conscious control) varicosities of postganglionic cells in the region of the
smooth muscle cells. In addition the autonomic synaptic
Such as visceral functions- CO, blood volume distribution, blood clefts are wider.
pressure, digestion, pupillary response to light, visual focus, o Thus, effects are slower in onset and discharge
excretion from a single motor fiber inactivates or activates
many effectors.
- immune function and seizure discharges (vagus nerve)
- prostate cancer development and progression ORGAN INNERVATION
- With important sensory (afferent) inputs that give - Many organs receive both P and S innervation except for the
information on internal and external environments and ADRENAL MEDULLA, KIDNEYS, PILOMOTEOR MUSCLES, and
modify motor output via reflex arcs the SWEAT GLANDS (sympathetic only)
- The sympathetic innervation to the sweat glands release Ach
DIVISIONS OF THE AUTNOMIC NERVOUS SYSTEM NOT NE and the Ach act on muscarinic receptors.
PARASYMPATHETIC - Ganglia are located close to or in
the innervated organs REGULATION OF NEUROTRANSMITTER RELEASE
- Preganglionic neurons are long, - Autoregulatory presynaptic ⍺2 receptors
postganglionic neurons are short - Heteroreceptors-activated by substances that are released
- Acetylcholine from other nerve endings that synapse in a terminal*
- Muscarinic, Nicotinic receptors LEGEND:
- Homeostatic functions *Myocardial vagal fibers synapse with sympathetic noradrenergic
SYMPATHETIC - Ganglia are located close to the nerves to inhibit NE release
spinal column
- Preganglionic neurons are short THE ENTERIC NERVOUS SYSTEM
and postganglionic neurons are
long
- Epinephrine, Norepinephrine,
Dopamine,
- Alpha, beta, dopaminergic
receptors
- Fight, flight, fright

Sympathetic and parasympathetic are anatomic designations and
do not depend on the type of neurotransmitters released or
whether effect is excitatory or inhibitory.


-

VISION: 20|20 1

 - This system of nerve cells is located in the walls of the inhibited by the agent Botulinium. Clearance of acetylcholine
intestines (esophagus to distant colon) and may be is by the enzymatic action of acetylcholinesterase.
considered as a third division the ANS. - Fusion proteins include the VAMPS and SNAPS.
o It is involved in the motor and secretory activities o VAMPS are vesicle-associated membrane proteins
of the gut especially in the motor activity of the in the vesicular membrane which serve to align the
colon. vesicle to release sites in the inner surface of the
- The ENS includes the myenteric or Auerbach plexus and the cellular membrane.
submucous plexus or Meissner plexus. o These release sites are the SNAPS or synaptosomal
- These are neuronal networks that receive sensory input nerve-associated proteins.
from the walls of the gut and fibers from their nerve cells run o The release of the neurotransmitter is dependent
forward, backward and around the gut musculature to upon enough calcium influx through N-type calcium
control activity and to the secretory glands in the mucosa. channels.
- Sensory fibers transmit information (chemical and o The ion interacts with vamp and triggers fusion and
mechanical) from the mucosa and stretch receptors to motor pore opening into the synapse, and subsequent
neurons in the plexus and postganglionic neurons in the release of the neurotransmitter.
sympathetic ganglia. - Botulinium toxin inhibits this exocytotic process by altering
- The sympathetic and parasympathetic fibers that synapse in the structure of these fusion proteins.
the enteric plexus neurons function for regulation.
- ANS denervation does not abolish GIT activity but appear to ADRENERGIC TRANSMISSION
greatly enhanced motility.
- The ENS is semiautonomous and receives input from motor
outflow to regulate Gut activity and send sensory
information to the CNS.
- The ENS synchronizes impulses so that contents are
propelled forward and sphincters relax when the gut
contracts.

CHOLINERGIC TRANSMISSION

- The catecholamine neurotransmitter precursor tyrosine is
brought into presynaptic nerve cell ending via a sodium-
dependent carrier.
o It is then converted to dopamine by the enzyme
tyrosine kinase.
o The drug metyrosine can inhibit this process.
- Dopamine is transported into the vesicles by VMAT or vesicle
monoamine transporter.
o VMAT action can be inhibited by the agent

- Choline is brought to the presynaptic nerve terminal by the reserpine.
choline transporter, CHT (sodium-dependent). - Norepinephrine(NE) is also brought into the vesicle by
- CHT can be inhibited by the agent Hemicholinium. VMAT.
- In the cytoplasm, acetyCoA is attached to choline to form - Within the vesicle, dopamine is converted into
acetylcholine. norepinephrine by dopamine ß hydroxylase.
o This reaction is catalyzed by choline o Note that in the adrenal medulla and some parts
acetyltransferase or ChAT. of the brain, NE is further converted into
- The neurotransmitter is then stored in the vesicle via vesicle- epinephrine while in dopaminergic nerves,
associated transporter or VAT. synthesis stops in dopamine.
o This transporter is inhibited by the drug Vesamicol. - When action potentials arrive at the nerve endings, voltage-
o Other contents of the vesicle include peptides (P), sensitive calcium channels open and there is influx of
adenosine triphosphate (ATP), and proteoglycans. calcium.
- When an impulse arrives, the voltage-sensitive calcium - Vesicles then fuse with the membrane surface and releases
channels in the terminal membrane opens causing contents into the synapse vis exocytosis.
intracellular influx of calcium. - This event is inhibited by the agents guanethidine and
- This propels fusion of the vesicles with the cell membrane bretyllium.
and exocytosis which releases acetylcholine - Termination of NEaction is by several mechanisms.
neurotransmitters into the synaptic cleft. This process is - It diffuses away from the synaptic cleft. It can also be picked
up by the norepinephrine transporter NET which returns it

VISION: 20|20 2

 into the presynaptic cell.
- This second mechanism is called reuptake 1. AUTONOMIC RECEPTORS
o The action of NET is inhibited by cocaine,
amphetamines, and tricyclic antidepressants.
o To a much lesser extent, termination of NE action is
also accomplished by metabolism by the enzyme
monoamine oxidase (MAO) found in many body
tissues including the brain and GIT.
- Certain drugs can cause elevation of norepinephrine levels
because of inhibition of this enzyme.
o This is exemplified by the class of antidepressants
known as MAO inhibitors.

- Neurotransmitter vesicular release in adrenergic NICOTINIC MUSCARINIC
transmission as described above is similar to that seen in - Bind Nicotine - Bind muscarine
cholinergic transmission. - Blocked by Curare - Blocked by Atropine
- Additional substances released into the cleft are dopamine ß (tubocurarine) -
nd
Linked to 2 messenger
hydroxylase, adenosine triphosphate (ATP), and peptide co- - Linked to ionic channels systems through G-
transmitters. - Response is brief and protein
- Sympathomimetic agents such as tyramine, amphetamine fast - Response is slow and
and ephedrine can cause direct transmitter release from - Located at NMJ, prolonged
noradrenergic endings in a non- calcium dependent process autonomic ganglia and - Found on myocardial
and not via vesicular fusion and exocytosis. to small extent in the muscle, certain smooth
- The above drugs are avidly taken up by NET and upon CNS muscles and in discrete
transport into the presynaptic nerve ending, the VMAT brings - Mediate excitation in CNS regions
them into the vesicles where they rapidly displace target cells - Mediate inhibition and
norepinephrine. - Postsynaptic excitation in target cells
- The expelled NE molecules are then brought out into the - Both pre-and
synaptic cleft by reverse transport of NET. postsynaptic

VISION: 20|20 3

 AUTONOMIC PHARMACOLOGY: CHOLINOMIMETICS TERTIARY - Pilocarpine, Nicotine, Lobeline
DIRECT-ACTING CHOLINOCEPTOR ACTIVATORS OR AGONISTS AMINES - Lipid Soluble
- CHOLINE ESTERS - Well Absorbed
- CHOLINOMIMETIC ALKALOIDS - Renal Excretion
- P-chiefly muscarinic
There are two types of agents which promote parasympathetic - N and L-chiefly nicotinic
transmission and transmission in the autonomic ganglia. QUATERNARY - Muscarine
AMINES - Less Absorbed But When Ingested Can
The direct acting cholinomimetics activate the cholinoceptors Enter CNS Also And Is Poisonous
(Muscarinic or Nicotinic) while the indirect acting agents prolong - Renal Excretion
acetylcholine presence in the synapse by inhibiting - Chiefly muscarinic
acetylcholinesterase.
Chiefly Muscarinic Action: MUSCARINE AND PILOCARPINE
Some cholinesterase inhibitors such as neostigmine can also Chiefly Nicotinic Action: NICOTINE AND LOBELINE
activate nicotinic receptors at the neuromuscular junction.
ACTION OF MUSCARINIC RECEPTORS (2)
CHOLINE ESTERS - Stimulation of muscarinic receptors on effectors by
- Lipid Insoluble-Permanently Charged (Polar) Quaternary acetylcholine OR
Ammonium Group - Inhibition of neurotransmitter release from nerve terminals by
- Hydrophilic acetylcholine
- Not Absorbed Or Distributed In The Cns
- Differ In Susceptibility To Acetylcholinesterase

ACETYLCHOLINE - Highly Susceptible To
Acetylcholinesterase And Is Rapidly
Hydrolyzed
- Acts On Both Muscarinic And
Nicotinic Receptors

METACHOLINE - Less Susceptible To

Acetylcholinesterase
- Acts On Muscarinic Receptors

CARBACHOL - Non Susceptible To

Acetylcholinesterase Cellular Muscarinic Activation
- Acts On Both Receptors But More
On Nicotinic The Cholinoceptor activators act on muscarinic receptors by two
ways to modify organ function.
BETANECHOL - Non Susceptible To - They can either cause direct organ activation via
Acetycholinesterase stimulation of muscarinic receptors on effectors by
- Acts On Muscarinic Receptors acetylcholine, or acetylcholine may bind to muscarinic
nerve terminals to inhibit neurotransmitter release.
Acetylcholine is rapidly hydrolyzed so significant effects can be
achieved only with large IV infusions. There are several cellular events comprising muscarinic
activation.
The systemic effect is brief at only 5-20 seconds after a single - M receptors appear to be of the G protein-coupled type.
large bolus IV injection. - Agonists binding to M1, M3, and M5 lead to activation of
the inositol triphosphate (IP3) diacylglycerol (DAG) cascade.
Only local effects manifest via IM or subcutaneous
administration. DAG activation may lead to opening of the smooth muscle
calcium channels as activation of IP3 causes release of calcium
The other three choline esters especially carbachol and from the endoplasmic and sarcoplasmic reticulum.
betanechol are more resistant to hydrolysis and have longer
duration of action. Cellular cGMP also increases. In cardiac muscles, M2 activation
results to potassium influx leading to hyperpolarization, while this
CHOLINOMIMETIC ALKALOIDS is decreased in ganglion and smooth muscles.
- PILOCARPINE
- NICOTINE M2 and M4 activation causes inhibition of adenylyl cyclase in
- LOBELINE organs such as the heart and intestines.
- MUSCARINE
Muscarinic agonists reduce catecholamine effects on tissues by
weakening the activity of adenylyl cyclase and controlling
increases in cAMP levels induced by these hormones.

VISION: 20|20 4

 ACTION OF NICOTINIC RECEPTORS (nAChR) response when the neurotransmitter is continuously present
- Induces conformational change in nAChR - Continuous exposure: desensitized state , prolonged affinity of
- Opening of ionic channels (K+ and Na+) and cell membrane nAChR to acetylcholine
depolarization - Delays return to resting state and cessation of effector
- Generation of action potentials and accompanying effects on response (e.g. muscular paralysis in NMJ)
effector organs
Nicotinic receptors also modulate their own response to the
neurotransmitter, depending on ACh concentrations.

The response to discrete and brief pulses of acetylcholine is
different than the reaction to a continuous presence of the
neurotransmitter.

For the pulses, nAChR reacts as above- transient opening, rapid
dissociation, and resumption of resting state configuration
because of low affinity to its ligand.

With continuous exposure, on the other hand, the nAChR is said
to undergo a conformational change to a so-called “desensitized
state.”

In this state, the receptor develops a high affinity for
acetylcholine so that the latter remains bound to the receptor for
a longer period.

This delays receptor returns to resting state conformation.
Prolonged receptor occupancy causes cessation of the effector
Nicotinic receptors are ligand-gated ion channels. response- that is, the postganglionic cell stops firing (ganglionic
effect) while the skeletal muscle relaxes (neuromuscular effect).
When two acetylcholine molecules bind to the α subunit of the
nicotinic receptor or nAChR, a conformational change in the This initial event is called depolarizing blockade.
latter takes place resulting to opening potassium- and sodium-
selective channels. With further receptor occupancy however, membrane voltage
eventually returns to resting levels but the receptor becomes
The influx of these cations depolarizes the cell membrane. desensitized or refractory to stimulation.

Simultaneous stimulation of multiple nAChR results to In the neuromuscular junction, this produces muscle paralysis.
generation of action potentials and accompanying effects such as
muscle contraction in neuromuscular junction, firing of post ORGAN SYSTEM EFFECTS OF DIRECT -ACTING CHOLINOMIMETICS
ganglionic neurons, and complex effects in the CNS (e.g. EYES - Miosis
attention, arousal, analgesia). - Contraction Of Ciliary Muscles-
Accommodation
- Opening Of Outflow For Aqueous Humor
CVS - Lowers Peripheral Vascular
Resistance/Vasodilatation (M3)
- Decreases HR (M2)
- Responses Vary With Dose
- Response Of Heart Is Made Complex By
Counter Reflexes Esp For Agents Which
Bind To Ganglionic Receptors (Nachr)

EYE:
- local (topical) instillation of muscarinic agonists produces
iris sphincter contraction producing miosis (small pupils)

- Acetylcholine, however, rapidly dissociated from the nAChR and contraction of ciliary muscles causing accommodation
and is rapidly degraded by acetylcholinesterase. (contraction for near vision).
o So, cellular depolarization lasts only for a very brief - This opens the outflow for aqueous humor into the canal
duration (<10 milliseconds). of Schlemm.

nAChR RESPONSE MODULATION CARDIOVASCULAR SYSTEM:
- nAChR modulate own response to acetylcholine - Main effects are lowering of peripheral vascular resistance
- Response to discrete pulses of acetylcholine differs from and decrease in heart rate. Acetylcholine will illicit different

VISION: 20|20 5

 effects on the heart rate depending on the dose. ORGAN SYSTEM EFFECTS OF DIRECT -ACTING CHOLINOMIMETICS
- At minimum effective doses, IV infusion produces RESPIRATORY - Contraction of smooth muscles of
vasodilatation. SYSTEM bronchial airways
- This induces a reflex increase in heart rate. - Increase in glandular secretions
- With increasing doses however, acetylcholine will also GASTROINTESTINAL - Increase GIT contractions
decrease rate of impulse conduction in the heart and SYSTEM - Increased in gastric and salivary
bradycardia. gland secretions
- Relaxation of sphincter activity
The reduced of firing in the heart’s pacemakers is mediated via - Mediated by M2 and M3
M2 receptors. GENITOURINARY - FAVORS MICTURITION:
- Direct pacemaker effects of muscarinic agonists is SYSTEM - Detrussor stimulation
countered by reflex sympathetic discharge. - Relaxation of trigone and sphincter
- This interaction between sympathetic and parasympathetic - M2 and M3
arms is therefore complex as muscarinic modulation of OTHER GLANDS - Stimulates secretion of
sympathetic effects is achieved via NE release inhibition thermoregulatory sweat, lacrimal
and postganglionic cellular effects. and nasopharyngeal glands
- The overall effect on heart rate is hence dependent on the CNS - Both N and M receptors are present
amount of the agonist present in the heart and blood - Roles of the M receptors have not
vessels and the degree of reflex response. been elucidated in humans
- nACh r present in both pre and post
Compared to the atria, the ventricles have less extensive synaptic cells
parasympathetic innervation and therefore effects are more - Presynaptic nAchr mediates Ach
modest. and N regulation of NTS release*
But during sympathetic stimulation, ventricular effects of - Chronic or prolonged exposure of
muscarinic agonist is noticeable as these agents modulates nAChr to nicotine: DUAL effect (
(antagonizes) said sympathetic influences. initial activation followed by
desensitization)**
- Higher doses of nicotineà tremors,
vomiting, increased RR, seizures and
coma
- nAChr subtype ⍺7 in the CNS and
PNS: cognition and nociception

In animals:
M1: -cognition, M2: tremors, hypothermia, antinociception, M3:
appetite, body fat mass

LEGEND:
* (NTS-GABA, serotonin, glutamate, dopamine, NE) Binding of
Ach to presynaptic nAChr receptors in the hippocampus control
release of NE and also inhibits its own (Ach) release

** initial activation leads to greater release of dopamine from
mesolimbic area hence the potential for addiction. With
desensitization, there is upregulation of the binding sites and
increased affinity for the agonist prolonging the state of
desensitization (nicotine replacement therapy-gums,patches)

PNS - Nicotine has greater affinity for
nAchR in the autonomic ganglia
- When muscarinic agonists are given IV, marked vasodilatation rather than in the NMJ (∝3nAChR)
results and this is due to activation of M3 receptors in the - This receptor subtype α3 as well as
intact endothelium. subtypes β2 and β3 are in these
- Acetylcholine and other muscarinic agonists cause release of ganglia*
endothelium-derived relaxing factor (EDRF) such as nitric - Nicotine has same action on both
oxide (NO). ganglia but the predominant
- NO diffuses to nearby vascular smooth muscle cells, activates response in those in the CVS is
guanylyl cyclase and increasing cGMP and vasodilatation. sympathomimetic whereas the
- An opposite effect is produced when endothelium is absent as predominant response in the GIT
acetylcholine activates M3 receptors to stimulate IP3 and genitourinary systems are
production and release of calcium intracellularly thereby parasympathomimetic
resulting to contraction.

VISION: 20|20 6

 Deletions in these subtypes- autonomic dysfunction- Carbamates are stable in aqueous medium and metabolized by
various esterases including cholinesterase.
Missing α3nAchR in humans- underdeveloped bladder ,
hypoperistalsis GIT, urinary incontinence, bladder distention, The duration of action of these agents depend mainly on the
pupillary dilatation stability of the complexes they form with these hydrolyzing
enzymes.
ORGAN SYSTEM EFFECTS OF DIRECT -ACTING CHOLINOMIMETICS:
AUTONOMIC GANGLIA SIMPLE ALCOHOLS WITH QUARTERNARY AMMONIUM GROUP:
Predominantly - GIT and genitourinary EDROPHONIUM
Parasympathetics - Nausea, vomiting, diarrhea, urination - REVERSIBLE INHIBITOR
Predominantly - CVS - synthetic
Sympathetics - Profound hypertension, tachycardia - Binds to active site of enzyme to prevent attachment of ACh
(INITIAL) - Reflex response: bradycardia via the - Enzyme-receptor complex lasts for 2-10 mins
vagus (parasympathetic regulatory - Short duration of action (5-15 mins
response) - Low lipid solubility
- Uses: MG, ileus, arrhythmias
ORGAN SYSTEM EFFECTS OF DIRECT -ACTING CHOLINOMIMETICS:
NMJ
NMJ - The n AChR in the autonomic ganglion CARBAMIC ESTERS OF ALCOHOL WITH QUARTENARY AMMONIUM
and NMJ both respond similarly to GROUPS: NEOSTIGMINE
ACh and nicotine - REVERSIBLE INHIBITOR
- (differ in their affinity to various - synthetic
cholinoceptor blockers) - Two step hydrolysis
- Forms stronger bond with acetylcholinesterase, more resistant
DEPOLARIZATION BLOCKADE to hydrolysis –TRUE FOR ALL FOUR PROTOTYPES OF
- Rapid Depolarization blockade occurs with agents that are not CARBAMIC ESTERS (N, P,P,C)
rapidly hydrolyzed by acetylcholinesterase (e.g. nicotine) - Complex lasts longer 30 mins to 6 H
- Muscle flaccidity - Lower lipid solubility
- Uses: MG, Ileus

CARBAMIC ESTERS OF ALCOHOL WITH QUARTENARY AMMONIUM
GROUPS: PYRIDOSTIGMINE
- Reversible inhibitor
- Synthetic
- Lower lipid solubility
- Duration of action 4-6 H
- Use: MG




CARBAMIC ESTERS OF ALCOHOL WITH TERTIARY AMINE GROUPS:
PHYSOSTIGMINE, CARBARYL
PHYSOSTIGMINE - NATURALLY OCCURING
INDIRECT-ACTING CHOLINOMIMETICS (CHOLINESTERASE - Greater lipid solubility
INHIBITORS) - Duration of action: 0.5-2H
- SIMPLE ALCOHOLS WITH QUARTERNARY AMMONIUM GROUP - Uses: Glaucoma
- CARBAMIC ESTERS OF ALCOHOL WITH TERTIARY AND CABARYL - HIGHLY LIPID SOLUBLE WITH VERY
QUARTENARY AMMONIUM GROUPS FAST ABSORPTION AND CNS ENTRY
- ORGANIC DERIVATIVES OF PHOSPHATE - LONG duration of action: days to
weeks
The agents bearing permanent quaternary ammonium are lipid - Use: Insecticide
insoluble and therefore poorly absorbed from the intestine, skin,
conjunctiva or lungs. ORGANIC DERIVATIVES OF PHOSPHATE
- Hence the much larger doses required for oral rather than - Irreversible, Long-acting
IV administration. - Mostly Insecticide (EXCEPT FOR ECHOTHIOPATE)
- They do not enter the CNS. - Very lipid soluble (EXCEPT FOR ECHOTHIOPATE) therefore
good absorption in skin, GIT, conjunctivae, lungs, with good
The tertiary amine which is physostigmine, on the other hand, is distribution
well absorbed and is also used as a topical ophthalmic drops. - Can CNS penetration (EXCEPT E)à Neurotoxicity
- It can enter the CNS and is comparatively toxic than the - Shorter half-life in environment compared to other pesticides
quarternary drugs. or insecticides

VISION: 20|20 7


These agents bind to the enzyme and then also hydrolyzed to
become active phosphorylated enzyme-inhibitor complex. This
bond however is very strong and stable.

Cholinesterase inhibitors have effects USUALLY BUT NOT
ALWAYS similar to direct-acting agents. Their main actions will
be on the CVS, GIT, and NMJ

TISSUE EFFECTS
CNS - Low dose- alerting response
- High dose- seizures, coma, death
EYE, - SAME AS DIRECT ACTING
RESPIRATORY
TRACT, GIT,
GENITOURINARY
TRACT

After this initial process, the complex undergoes “aging” in which
CVS - Increase activity in both sympathetic
an oxygen-phosphorus bond of the organophosphate is broken
and parasympathetic ganglia in the
to form an even stronger inhibitor-enzyme binding.
heart and in Ach r in a few cardiac and

vascular smooth muscles which have
Aging rates differ amongst the different inhibitors.
cholinergic innervation
- For example, some chemical warfare agents undergo
- However effects on parasympathetics
aging within ten minutes, some drugs within 48 hours.
predominate in the heart: VAGAL-

LIKE*
When an oxime regenerator compound or cholinesterase
- Minimal effect on blood vessels (most
regenerator such as pralidoxime is given before aging has
do not have cholinergic innervation)
occurred (e.g. in poisoning), the enzyme-inhibitor bond may still
except coronaries
be broken and the enzyme will regain functionality. This is not
- Moderate doses: initial sympathetic
achieved once aging has set in.
effects


ORGANOPHOSPHATES: ECHOTHIOPATE
LEGEND:
- Not as soluble in lipid but soluble in aqueous medium
*decrease HR, decrease conduction, decrease contractile force
- Used in glaucoma as aqueous ophthalmic solution
reduction in CO
- Duration of action: 100H


TISSUE EFFECTS: CVS
ORGANOPHOSPHATES: PARATHION, THIOPHOSPHATES,
MODERATE - Modest bradycardia
MALATION
DOSES - Cardiac output reduction
- Highly soluble and well absorbed via various routes
- Increase in vascular resistance and BP
- Inactive prodrugs converted to active form in insects and
(initiated at level of ganglion)
vertebrates
- Malathion- more rapidly metabolized humans and vertebrates HIGH OR TOXIC - Marked bradycardia
than insects (safer) DOSES - Significant fall in CO
- Parathion- more dangerous for humans as detox is less - Hypotension (due to marked lowering
efficient in HR and CO from para activation)
-

TISSUE EFFECTS: NMJ
- Prolonged action of acetylcholine causes increased muscular
contraction (e.g. in MG, effects of NM blockers)
- Higher levels: depolarization blockade

VISION: 20|20 8

 CLINICAL PHARMACOLOGY S: Salivation D: diaphoresis and diarrhea
Clinical Uses L: Lacrimation U: urination
- Glaucoma U: Urinary Incontinence M: miosis
- Strabismus D: Diarrhea + Diaphoresis B: bradycardia, bronchospasms
- Git-Ileus,Gerd G: GI Upset E: Excess
- Sjogren’s Syndrome E: Emesis L: Lacrimation
- Myasthenia Gravis S: Salivation
- Reversal of Surgically Induced Nm Blockade
- Supraventricular Arrhythmias TOXICITY: DIRECT-ACTING NICOTINIC AGONISTS
- Atropine Intoxication - Extensions of cholinomimetic effects the most dangerous of
- TCA Overdoses which are:
- Alzheimer’s Disease - CNS stimulation (seizures, coma, respiratory arrest)
- Motor end-plate depolarization, depolarization blockade,
These agents reduce intraocular pressure (IOP) by contracting respiratory paralysis
the ciliary body hence opening aqueous humor outflow and - Hypertension and Arrhythmias (ganglionic effects)
reducing its secretion.
Treatment
Gastrointestinal conditions (non-obstructive) such as - ATROPINE and its congeners can reverse effects from
postoperative ileus and congenital megacolon muscarinic excesses in both direct- and indirect acting agents
- e.g. betanechol, neostigmine o For the additional toxicities from acute nicotine toxicity:
Gastroesophageal Reflux Disorder or GERD § seizures- diazepam
- e.g. betanechol (although the preferred agents are the § ventilatory support
proton pump inhibitors) - Nicotine metabolism and excretion is fast so complete
recovery is seen for those who survive the first four hours IF
Sjogren syndrome, postradiation damage to salivary glands- to there is no hypoxic brain damage
increase salivary secretion e.g. pilocarpine
Chronic nicotine toxicity (Drugs of abuse lecture in Pharma B)
EDROPHONIUM: THE TENSIOLON TEST
TOXICITY: INDIRECT-ACTING NICOTINIC AGONISTS (Cholinesterase
Inhibitors)
- Acute effects- extensions of pharmacologic effects
- Most common cause: pesticide/insecticide poisoning-
manifestations rapid or slow, duration of days
- Chemical Warfare (very high levels of exposure)-
manifestations rapid

PROMINENT INITIAL - Miosis
SIGNS - Salivation
- Sweating
- This test utilizing edrophonium can be used to distinguish two - Bronchoconstriction
serious complications in MG. - Vomiting
- Myasthenic crisis is severe myasthenia whereas Cholinergic - Diarrhea
crisis is overdosage of cholinesterase inhibitor treatment.
CNS INVOLVEMENT - Cognitive disturbances
o Both manifests with profound muscle weakness and
- Seizures
places the patient at risk for respiratory depression.
- Coma
- If muscles strength ensues for a brief duration of time - Muscle weakness
immediately after administration of edrophonium, the

condition is more likely myasthenic crisis and an increase in
Muscle weakness-NM blockade
cholinesterase inhibitor is needed.

- If weakness actually worsens after this drug is given, then it is
Treatment:
more of a cholinergic crisis.
- Directed at preservation of vital signs especially respiration
- Such paradoxic weakness is due to nicotinic depolarizing
- Atropine for muscarinic excess
blockade at the NMJ.
- Pralidoxime (enzyme regenerator)
- The MG therapy must then be reduced.


AUTONOMIC PHARMACOLOGY: CHOLINOCEPTOR BLOCKERS
TOXICITIES
- MUSCARINIC RECEPTOR BLOCKERS (ANTIMUSCARINICS,
TOXICITY: DIRECT-ACTING MUSCARINIC AGONISTS (Muscarinic
PARASYMPATHOLYTICS)
Excess)
- GANGLIONIC BLOCKERS
MUSCARINIC SIGNS AND SYMPTOMS (Mnemonics)

- S-L-U-D-G-E
MUSCARINIC RECEPTOR BLOCKERS
- D-U-M-B-E-L-S
NATURAL ALKALOIDS - ATROPINE

- SCOPOLAMINE

VISION: 20|20 9

 SYNTHETIC AND - QUARTERNARY AMINES - Atropine and tertiary amines have good distribution;
SEMISYNTHETIC - TERTIARY AMINES significant CNS levels 30 min to 1 hour after administration*
AGENTS - SCOPOLAMINE has the full distribution and effects on the CNS
- Q agents do NOT have CNS effects at therapeutic doses
LEGEND:
SYNTHETIC AND SEMISYNTHETIC AGENTS AND THEIR USES: * The CNS effects limits the allowable dose when these agents
are used for their peripheral actions
STRUCTURE PROTOTYPE USES

QUARTERNARY PROPANTHELENE, - PEPTIC - ATROPINE has a biphasic
AMINE GLYCOPYRROLATE DISEASE, GIT elimination*
HYPERMOTILITY - 50% of A is excreted unchanged in
TIOTROPIUM - ASTHMA urine, 50% undergoes phases 1 and
2 in the liver before excretion
TERTIARY PIRENZEPINE - PEPTIC DISEASE - Parasympathetic effects of A
AMINE DICYCLOMINE - PEPTIC rapidly diminish except those on
DISEASE, the EYES (at least 72 hours)**
HYPERMOTILITY LEGEND:
TROPICAMIDE - MYDRIATIC, *Rapid phase T1/2= 2H, Slow phase T1/2=13H
CYCLOPLEGIC **ye effects on iris and ciliary muscles-mydriasis and cycloplegia
BENZTROPINE - PARKINSON’S (paralysis of ciliary muscles leading to loss of accommodation)
DISEASE
MOA OF ATROPINE AND OTHER M BLOCKERS
Tertiary amine antimuscarinics (see box) are often utilized for - Cholinomimetic blockade of atropine is reversible and
eye and CNS indication. surmountable
- At low doses, its M effects can be negated by adding more Ach
Because of similarities in the chemical structures, many or M agonists
antihistaminics, antidepressants, and antipsychotics have a lot of - Upon binding to M receptors, Atropine prevents release of IP3
antimuscarinic effects. and prevents inhibition of adenylyl cyclase*
- M blockers upon binding to the receptor converts the
Quaternary amines, because of reduced lipid solubility and constitutively active receptor configuration to inactive forms
therefore less ability to penetrate and affect the CNS have been (inverse agonists)
developed for their peripheral actions. LEGEND:
* In contrast
ATROPINE AND SCOPOLAMINE

- The natural alkaloids are exemplified by atropine and
scopolamine.
- Atropine is a tertiary amine alkaloid ester of tropic acid.
o It is derived from the plant Atropa belladonna (deadly
KINETICS AND DYNAMICS OF MUSCARINIC BLOCKERS
nightshade) and Datura stramonium (thorn apple,
- Salivary, bronchial and sweat glands are the MOST sensitive
Jamestown weed).
and the gastric parietal cells are the LEAST sensitive to
o It has naturally occurring cogeners. Atropine in nature
atropine
exists as l(-)-hyoscyamine but commercially, atropine is
- Antimuscarinics block exogenous cholinoceptor agonists than
available in the racemic mixture of d,l-hyoscamine.
endogenous Acetylcholine
- Scopolamine (hyoscine) is the l (-) isomer derived from
- Atropine binds more to muscarinic rather than nicotinic
Hyoscyamus nigra (henbane).
receptors and non-muscarinic receptors
o The l(-) forms of both agents are 100 times more potent
- Atropine is non selective in binding to all M receptors
than their d(+) forms.
compared to other antimuscarinics

- Q amine blockers are less selective than A in binding to
KINETICS AND DYNAMICS OF MUSCARINIC BLOCKERS
nicotinic and non-muscarinic receptors (e.g. histamine r
- the natural alkaloids and tertiary amines-good GIT and

conjunctival absorption

- Scopolamine- good skin absorption- transdermal patch

- Quaternary amines- low lipid solubility, less orally absorbed

VISION: 20|20 10

 ORGAN SYSTEM EFFECTS OF ANTIMUSCARINICS - Both effects are blocked by atropine.
CNS - A (therapeutic doses)- mild CNS RESPIRATORY - Bronchodilatation
stimulation, sedative effects SYSTEM - Reduction of secretions
- Scopolamine-marked CNS effects- GIT - Reduction of GIT motility and secretions
sedation, drowsiness, amnesia (even at - Mouth dryness
therapeutic doses) - less effects on gastric secretions, no
- High doses of M blockers- excitement, effects on intestinal and pancreatic
hallucinations, agitation, coma secretions
Central acting blockers can control tremors in
Parkinson’s disease Atropine causes some bronchoconstriction and reduction of
- Scopolamine can control motion secretion especially on those with airway diseases such as asthma
sickness or symptoms of vestibular or COPD.
dysfunction - They used for these conditions but may not be as effective
EYES - Mydriasis
as the β agonists. Because of autoregulatory M1 blockade
- Cycloplegia
effect, the dilatation produced by these agents on M3
- Potentially risky for those with narrow
blockade are eventually opposed.
angle glaucoma
- They are also utilized prior to application of inhalation
- Can also cause “sandy eyes”
anesthesis to reduce tracheal secretions and lower risk of
CVS - Effects prominent in SA node: laryngospasm.
o Mod to high doses of A causes
tachycardia (vagal block) Antimuscarinics reduce gut motility and secretions but do not
o Low doses of A causes initial completely abolish these because of the modulatory action from
brief bradycardia before effects the enteric nervous system.
of vagal block appear - Antimuscarinics have more action against exogenous
- A blocks coronary artery dilatation by muscarinic agonists than against endogenous acetylcholine
parasympathetic nerve stimulation and from vagal activity.
skeletal muscle vascular bed dilatation
from sympathetic cholinergic nerves Mouth dryness is an especially prominent effect of
- A blocks endothelial M receptors that antimuscarinic agents because of the sensitivity of the salivary
mediate vasodilatation in blood glands to these agents.
vessels*
- Cutaneous vasodilatation in toxic doses Gastric secretions are not as markedly affected and may require
esp. in upper body (unknown larger doses of atropine.
mechanism)
- A’s net effect on the CVS in the healthy The effect is more on basal secretion rather than on food-,
person is NOT marked- tachycardia nicotine- or alcohol- induced secretions.
possible, little effect on BP
- Antimuscarinics however can prevent New agents such as pirenzepine and telenzepine reduce gastric
or reverse CVS effects of M agonists acid secretion with less side effects because of their selectivity for
* Recall that all BVS contain endothelial M r M1 and possibly M3 receptors.
that mediate vasodilatation
The CVS effect on HR at low dose maybe due Secretions from the small intestines and the pancreas are not
to prejunctional M1 block (autoreceptor) on affected by atropine as they are more under hormonal control.
vagal postganglionic fibers which limits Ach Because antimuscarinics reduce motility and tone of
release for SA node. gastrointestinal smooth muscles, gastric emptying time and
- For the AV node, in high vagal intestinal transit time are prolonged. Hence the utility of these
stimulation, similar events occur as agents as anti-diarrheals especially if the condition is due to use
atropine blocks the muscarinic of cholinomimetics. Anti-motility effects usually dissipate 1-3
receptors in this area, thereby the days after therapy.
reducing the PR interval.
- Effects on the atrial and ventricular
GENITOURINARY - Relaxation of ureteral smooth muscles
muscles are of lesser clinical
SYSTEM and bladder wall
significance.
- Slows voiding

SWEAT GLANDS - Inhibits thermoregulatory sweating
Blood Vessels (except in the thoracic and
(inhibition of eccrine sweat glands)
abdominal viscera) have no parasympathetic
- Atropine fever in children
innervation.

- The coronary arteries however dilate
GENITOURINARY SYSTEM. There is relaxation of ureteral smooth
from parasympathetic nerve
muscles and the bladder wall. Voiding is slowed. Therefore,
stimulation as well as the skeletal
antimuscarinics are used for treatment of spasm due to
muscle vascular bed dilate from
inflammation, surgery or neurologic disorders.
sympathetic cholinergic nerves.

VISION: 20|20 11

 - Urinary retention can however develop in men with benign enzyme regeneration in the NMJ.
prostatic hypertrophy. Effects on the uterus are negligible.
However, PAM and obidoxime are have quaternary ammonium
Thermoregulatory sweating is inhibited by atropine by opposing in their structure and therefore cannot be used to regenerate
stimulatory effects on eccrine sweat glands which contain acetylcholinesterase in the CNS.
muscarinic receptors.
- The consequence of temperature increase occurs only with Diacetylmenoxime is the agent for this purpose as it can cross
large doses among adults. In children however, this may the blood brain barrier. In severe poisoning, administration of
arise even with low doses (atropine fever). PAM for several days have been found to be beneficial. It is not
however recommended for carbamate inhibitors.

CLINICAL PHARMACOLOGY
Therapeutic Uses: MUSHROOM POISONING: RAPID ONSET TYPE
- Parkinson’s Disease - Manifestations within 30m -2H after ingestion
- Motion Sickness - Stomach upset, disulfiram-like reaction, hallucinations,
- Mydriatic nausea, vomiting, diarrhea, urgency, sweating, salivation,
- Preanesthetics bronchoconstriction
- Copd And Asthma - Treatment: IV Atropine 1-2 mg
- Myocardial Infarction
- Neck-Pressure Syncope MUSHROOM POISONING: DELAYED ONSET TYPE
- Parasympathomimetic Effects Of Cardiac Autoantibodies - Manifestations initially appear 6-12 H after ingestion: nausea
- Hypermotility and vomiting
- Urinary Urgency - Then hepatorenal toxicities
- Cholinergic Poisoning - CANNOT be treated by atropine
- Hyperhydrosis - Supportive management

CHOLINERGIC POISONING TOXICITIES FROM CHOLINOCEPTOR BLOCKERS
- Muscarinic effects in CNS and periphery can be reversed by - Therapeutic dose for various indications can elicit undesirable
ATROPINE (tertiary amine) effects in other organs
- Large doses, repeated administration may be needed in - E.g. therapeutic doses for reduction of GIT hypermotility can
chemical warfare poisoning elicit mydriasis, cycloplegia, mouth dryness
- Nicotinic effects of cholinesterase inhibitors cannot be directly - Atropine is safer in adults than children who are prone to
blocked effectively because available agents will prevent develop hyperthermia (atropine fever)
autonomic transmission
TOXICITIES :BLOCKADE OF ALL PARASYMPATHETIC FUNCTIONS
Nicotinic effects of cholinesterase inhibitors cannot be effectively - Dry mouth
blocked directly because available nicotine agonists as well as - Mydriasis
antagonists prevent autonomic transmission. - Cycloplegia
- Tachycardia
Muscarinic effects in the CNS as well as peripheral actions in - Skin flushing
cholinergic toxicity can be reversed by tertiary amides like - Agitation
atropine. In cases of parathion and nerve gases poisoning, large - Delirium
doses of atropine have to be given: 1-2 mg IV every 5-15 minutes - Hallucinations
until dry mouth, reversal of miosis manifest (atropinization). *Treatment is Symptomatic

Repeated administration may be required because effects of Toxic manifestations are managed symptomatically (e.g. cooling
cholinesterase inhibition may last for days. In severe cases, blankets, diazepam etc.) as this is more effective and safer than
treatment duration make be up to a month. administration of cholinesterase inhibitors.

CHOLINERGIC POISONING: CHOLINESTERASE REGENERATORS For the quaternary agents, toxic manifestations are mainly
- Pralidoxime (PAM), Diacetylmenoxime (DAM). Obidoxime peripheral and may cause considerable ganglionic blockade, most
- Must be given before aging prominent of which is orthostatic hypotension. If needed,
- PAM and Obidoxime cannot be given to regenerate neostigmine or other quaternary cholinesterase inhibitors can be
acetylcholinesterase in CNS (Q amines) given to reverse this.
- DAM-DOC for regeneration of acetylcholinesterase in the CNS

Cholinesterase regenerators. Substituted oximes such as
pralidoxime (PAM), diacetylmenoxime (DAM), obidoxime can be
used to hydrolyze phosphorylated cholinesterase and regenerate
its activity from the enzyme-inhibitor complex for as long as they
are given before aging has set in.
- The most common agent used is pralidoxime especially for

VISION: 20|20 12

 RELATIVE CONTRAINDICATIONS TO ANTIMUSCARINICS
- Narrow or Closed angle
glaucoma and patients
with shallow anterior
chamber of the eye
- Prostatic hyperplasia and
benign Prostatic
Hypertrophy
- Acid peptic Disease
- Gastric Ulcers

GANGLIONIC BLOCKING AGENTS
GANGLIONIC BLOCKERS
- INHIBITS ALL AUTONOMIC OUTFLOW
- Many side effects
- Limited clinical utility
- Synthetic agents
- Prototypes-Hexamethonium (C6), Tetraethylammonium (TEA)
- Q amines which are competitive antagonists therefore effects
are surmountable
- Effects depends on blockade of the predominant innervation
of the organ
- Thus usually parasympathetic except in the blood vessels
(sympathetic)





































Notes from Lecture PPT and Manual ONLY

VISION: 20|20 13