Drugs Affecting The

Autonomic Nervous
System

Israa abdualati
AUTOMATIC NERVOUS SYSTEM
(ANS)
• The ANS is the major involuntary portion of the NS is
responsible for automatic, unconscious bodily function, such
as control of HR and BP and both GIT and GUT functions.
• Nervous System Two main divisions
• I. CNS • Brain & spinal cord
• II. PNS
•Peripheral Nervous System or PNS •
• Includes all the neurons and ganglia found outside the CNS
• 1. Afferent: sensory input to CNS Afferent neurons carry
sensory input from the periphery to the CNS and modify
motor output through the reflex arc.
• 2. Efferent: motor output from CNS Efferent neurons carry
motor signals from the CNS to the peripheral areas of the
body.
• Efferent Neurons
• The efferent portion of the PNS is divided into
• 1. somatic (SNS): one motor neuron innervates the skeletal
muscles and control voluntary (consciously) functions;
movement, respiration and posture.
• 2. automatic nervous system (ANS).
• The ANS is divided into 2 main divisions:
• I. Parasympathetic autonomic nervous system (PANS)
dominates in sleep,
• II. Sympathetic autonomic nervous system (SANS)
Dominates during activity; fight & flight.
• III. Enteric NS located in the GIT, send sensory input to both
PANS & SANS and receive motor output from them -
Myenteric plexus (plexus of aurbach) -Submucous plexus
(plexus of Meissner)
• Location of Ganglia
• Both the PANS and SANS have relay station, or ganglia,
between the CNS and the end organ, but the somatic system
does not;
• The ANS, carries nerve impulses by
• 1. a preganglionic fiber that leaves the CNS,
• 2. a postganglionic fiber that innervates the effector.
• Parasympathetic Division–
• also called the craniosacral division
• The preganglionic fibers arise from the cranial nerve nuclei III,
VII, IX, and X and sacral region (usually S2-S4) of the spinal
cord, and synapse in ganglia close to the effector organ.
• Thus, in contrast to the sympathetic system, the preganglionic
fibers are long, and the postganglionic ones are short.
• Sympathetic Division –
• also called the thoracolumbar division
• The preganglionic fibers arise from the thoracic (T1-T12) and
lumbar (L1- L5) regions of the spinal cord, and they synapse
in paravertebral ganglia close and parallel to the vertebral
column.
• Postganglionic axons lead to an effector organ.
• Adrenal medulla
• the adrenal medulla, like the sympathetic ganglia, receives
preganglionic fibers from the sympathetic system.
• Lacking the axons,
• in response to stimulation by Ach, influences other organs
by secreting the epinephrine and lesser amounts of NEP
into the blood.
• Functions of the Sympathetic Nervous System •
• It is normally active, even at rest; however, it assumes a
dominant role when the body becomes stressed (trauma,
fear, hypoglycemia cold or exercise).
• Fight or Flight – Protective mechanisms designed to help
person cope with the stress or get away from it.
• For example, if you sense danger: Your heart rate increase,
BP rises, eyes dilates, blood sugar rises, bronchioles
expand, and blood flow shift from skin to skeletal muscles.
• Functions of the Parasympathetic Nervous System
1. Rest and digest: maintains essential body functions;
digestive process and elimination of wastes.
2. Save energy.
3. Dilation of blood vessels in skin.
4. Decrease heart rate (bradycardia).
5. Increase secretion of digestive enzymes.
6. Constriction of smooth muscle of bronchi.
7. Increase in sweat glands.
8. Contraction of smooth muscles of urinary bladder.
• Opposite effects between SNS and PSNS
• Myocardium: Sympathetic= tachycardia: Parasympathetic=
bradycardia
• Intestinal smooth muscle: Sympathetic= decreased
motility: Parasympathetic= increased motility
• Pupil muscles of iris: Sympathetic= dilator pupil (radial
muscle) which dilates pupil (mydriasis)
• Parasympathetic= sphincter pupil (circular muscle) which
constricts pupil (miosis)
• Innervated by one division of ANS
• Blood vessels: Sympathetic= Constriction
• Sweat glands: Sympathetic= increased secretion
• Ciliary muscle: Parasympathetic= accommodation reflex
• Pancreas and Stomach: Parasympathetic= increased
Drugs affecting the ANS
• are divided into two groups according to the type
of neuron.
• The cholinergic drugs act on receptors activated by
acetyl choline.
• The adrenergic drugs act on receptors stimulated
by norepinephrine or epinephrine.
The cholinergic neuron
• All preganglionic fibers of both sympathetic and
parasympathetic divisions.
• All parasympathetic postganglionic.
• Few sympathetic postganglionic fibers (sweat gland).
• All Somatic (non autonomic) fibers to skeletal muscle
The adrenergic neuron
• Most sympathetic postganglionic fibers release
norepinephrine; are noradrenergic or simply adrenergic.
• Some peripheral sympathetic fibers release dopamine
(dopaminergic).
• The adrenal medulla, a modified sympathetic ganglion,
receives sympathetic preganglionic fibers and releases
epinephrine (~85%) and to a lesser amount
norepinephrine (15%) into the blood.
• Receptor types
• Parasympathetic – cholinergic receptors: – muscarinic
(M1 to M5) – and nicotinic receptors
• Sympathetic – adrenergic receptors: – alpha (α1, α 2), –
beta (β1 to β 3), – and dopamine (D1 to D5) receptors.
• Locations of muscarinic receptors:
• these receptors have been found on:
• ganglia of the PNS
• the autonomic effector organs: heart, smooth muscle, brain
and exocrine glands.
1. M1 :gastric parietal cells,
2. M2 : cardiac cells and smooth muscle,
3. M3 : bladder, exocrine gland, and smooth muscle. •
Neurons:
• Nicotinic receptors: (NN, NM)
• Locations of nicotinic receptors: nicotinic receptors are
located in the: – CNS, – adrenal medulla, – autonomic
ganglia, – neuromuscular junction.
• Mechanisms of action:
• Ligand-gated ion channel.
• Binding of two Ach molecules elicits a conformational
change that allows the entry of Na+ ions, resulting in
the depolarization of the effector cells.
• Nicotine initially stimulates and then blocks the
receptors
• Cholinergic Transmission –
• Synthesis: •
• Cholinergic neurons contain large numbers of small membrane-
bound vesicles (containing ACh) concentrated near the synaptic
portion of the cell membrane
• ACh is synthesized in the cytoplasm from acetyl-CoA and choline
by the catalytic action of Choline acetyltransferase (ChAT)
• Acetyl-CoA is synthesized in mitochondria, which are present in
large numbers in the nerve ending
• Choline is transported from the extracellular fluid into the
neuron terminal by a Na+- dependent membrane choline
cotransporter (Carrier A).
• This carrier can be blocked by a group of drugs called
hemicholiniums
• The action of the choline transporter is the rate-limiting step in
ACh synthesis
Cholinergic Transmission –
Release:
• Synthesized, ACh is transported from the cytoplasm
into the vesicles by an antiporter that removes
protons (carrier B). This transporter can be blocked
by vesamicol
• Release is dependent on extracellular Ca2+ and occurs
when an action potential reaches the terminal and
triggers sufficient influx of Ca2+ions
• The increased Ca2+concentration "destabilizes" the
storage vesicles by interacting with special proteins
associated with the vesicular membrane (VAMPs and
SNAP- synaptosome associated protein)
Cholinergic Transmission –
Release:
• Fusion of the vesicular membranes with the terminal
membrane results in exocytotic expulsion of ACh into
the synaptic cleft
• The ACh vesicle release process is blocked by
botulinum toxin through the enzymatic removal of
two amino acids from one or more of the fusion
proteins. Black widow spider??
Cholinergic Transmission:
Destruction
•After release - ACh molecules may bind to and activate
an ACh receptor (cholinoceptor)
•Eventually (and usually very rapidly), all of the ACh
released will diffuse within range of an
acetylcholinesterase (AChE) molecule
Cholinergic Transmission:
Destruction
•AChE very efficiently splits ACh into choline
and acetate, neither of which has significant transmitter
effect, and thereby terminates the action of the
transmitter.
•Most cholinergic synapses are richly supplied with
AChE; the half-life of ACh in the synapse is therefore
very short. AChE is also found in other tissues, eg, red
blood cells.
•Another cholinesterase with a lower specificity for ACh,
butyrylcholinesterase [pseudo cholinesterase], is
found in blood plasma, liver, glial, and many other
tissues
 Muscarinic action
3. Smooth Muscles: M3 - All are contracted
Abdominal cramps, diarrhoea – due to increased
peristalsis and relaxed sphincters Voiding of Bladder
Bronchial SM contraction – dyspnoea, attack of asthma
etc.
4.Glands: M3
–
Increased– secretions: sweating, salivation, lacrimation,
tracheobronchial
– tree and gastric glands
Pancratic– and intestinal glands – less prominen
5.Eye: M3
– Contraction of circular fibres of Iris – miosis
– Contraction of Ciliary muscles – spasm of
accommodation, increased outflow and reduction in
IOP
• Ach actions –
• Nicotinic
• 1. Autonomic ganglia:
• –Both Sympathetic and parasympathetic ganglia are
stimulated – After atropine injection ACh causes
tachycardia and rise in BP
• 2. Skeletal muscle – IV injection – no effect – Application
causes contraction of skeletal muscle
• 3. CNS: – Does not penetrate BBB – Local injection in
CNS – complex actions
• (Acetylcholine is not used therapeutically – non specific)
• Bethancol Uses:
• Postoperative and postpartum urinary obstruction,
• neurogenic bladder and GERD (10-40 mg oral),
• Congenital megacolon
Pilocarpine
• Alkaloid from leaves of Jaborandi (Pilocarpus microphyllus)
• Prominent muscarinic actions
• Profuse salivation, lacrimation, sweating
• Dilates blood vessels, causes hypotension
• High doses: Rise in BP and tachycardia (ganglionic action)
• On Eyes: produces miosis and spasm of accommodation
• Lowers intraocular pressure (IOP) in Glaucoma when applied
as eye drops
• Too toxic for systemic use – CNS toxicity
1.Pilocarpine
2.Used as eye drops in treatment of
• narrow angle glaucoma to reduce IOP
2.To reverse mydriatic effect of atropine
• Pilocarpine nitrate eye drops ( 1 to 4% )
• Atropine used as antidote in acute pilocarpine
poisoning ( 1-2 mg IV 8 hrly )
Muscarine
• Alkaloid from mushroom Amanita muscaria
• Only muscarinic actions
• No clinical use
• Mushroom poisoning due to ingestion of poisonous
mushroom
1.Early onset mushroom poisoning (Muscarine type)
2.Late onset mushroom poisoning 3.Hallucinogenic
type
 Cholinergic Drugs – Indirect acting
• Cholinesterase inhibitors or reversible anticholinesterases:
1.Natural: Physostigmine
2. Synthetic: Neostigmine, Pyridostigmine, Distigmine,
Rivastigmine, Donepezil, Gallantamine, Edrophonium,
Ambenonium, Demecarium

Carbamates
3. Acridine: Tacrine
1.Irreversible anticholinesterases:
Organophosphorous Compounds (OPC) – Diisopropyl
fluorophosphate (DFP), Ecothiophate, Parathion,
malathion, diazinon (insecticides and pesticides)

2.Tabun, sarin, soman (nerve gases in war)

3.Carbamate Esters: Carbaryl and Propoxur (Baygon)
 AChEs - Chemistry

• Either esters of Carbamic acid or derivative of

Phosphoric acid
• Carbamates: R1 – Nonpolar tertiary amino N –
physostigmine (lipid soluble); Others – R1
quartenary amino N+ (lipid insoluble)
• Organophosphates: All are highly lipid soluble except
ecothiophate

Carbamates
Organophosphates
 AChEs - MOA
• Normally Acetylcholinesterase (AchE) hydrolyses
Acetylcholine
• The active site of AChE is made up of two subsites –
anionic and esteratic
• The anionic site serves to bind a molecule of ACh to the
enzyme
• Once the ACh is bound, the hydrolytic reaction occurs at a
second region of the active site called the esteratic subsite
• The AChE itself gets acetylated at serine site
• Acetylated enzyme reacts + water = acetic acid and choline
Choline - immediately taken up again by the high affinity
choline uptake system presynaptic membrane
AChEs - MOA

Tryptophan
Glutamate and
histidine
 AChEs - MOA
• Anticholinesterases also react with the enzyme ChEs in
similar fashion like Acetylcholine
• Carbamates – carbamylate the active site of the enzyme
• Phosphates – Phosphorylate the enzyme
• Both react similar fashion covalently with serine
• Carbamylated (reversible inhibitors) reacts with water
slowly and the esteratic site is freed and ready for action
– 30 minutes (less than synthesis of fresh enzyme)

• But, Phosphorylated (irreversible) reacts extremely slowly

or not at all – takes more time than synthesis of fresh
enzyme
 AChEs - MOA
–Sometimes phosphorylated enzyme losses one alkyl group
and become resistant to hydrolysis – aging
Edrophonium and tacrine react only at anionic site – short
acting while
Organophosphates react only at esteratic site
Anticholinesterases –
Pharmacological actions
• 2 (two) important clinically used drugs –
–Physostigmine – Muscarinic and CNS action, lipid
soluble, ganglion acting and less action in skeletal
muscle
• Also organophosphates
Anticholinesterases –
Pharmacological actions
– Neostigmine – lipid insoluble, skeletal muscle acting,
stimulate ganglia, less muscarinic effect
Ganglia: Stimulate ganglia – muscarinic action – less
prominent action
CVS: Complex; Muscarinic – bradycardia and hypotension;
Ganglionic action – stimulation
–increase HR and BP; Medullary centre – stimulation
followed by depression …overall unpredictable
Skeletal Muscle: Ach is not quickly destroyed
– rebinds to same receptors
– repetitive firing
–twitching and fasciculation; increases force of
contraction in muscles
Physostigmine
• Alkaloid from dry ripened seed (Calabar bean) of African
plant Physostigma venenosum
• Tertiary amine, lipid soluble, well absorbed orally and
crosses BBB
• Hydrolyzed in liver and plasma by esterases
• Long lasting action (4-8 hours)
• Penetrates cornea readily on local application in eye -
Muscarinic action on eye causing miosis and spasm of
accommodation on local application
• Salivation, lacrimation, sweating and increased
tracheobronchial secretions
• Increased heart rate & hypotension
Physostigmine - uses
1.Used as miotic drops to decrease IOP in Glaucoma
2.To antagonize mydriatic effect of atropine
3.Belladonna poisoning, TCAs & Phenothiazine
poisoning
4.Alzheimer’s disease- pre-senile or senile dementia
5.Atropine is antidote in physostigmine poisoning.
•ADRs – CNS stimulation followed by depression
Neostigmine
• Synthetic reversible anticholinesterase drug
• Quaternary ammonium compound and lipid insoluble
• Cannot cross BBB
• Hydrolysed by esterases in liver & plasma
• Short duration of action (3-5 hours)
• Direct action on nicotinic (NM) receptors present in
neuromuscular junction (motor end plate) of skeletal muscle
• Antagonises (reverses) skeletal muscle relaxation
(paralysis) caused by tubocurarine competitive
neuromuscular blocker
Neostigmine – Uses
• Used in the treatment of Myasthenia Gravis to increase
muscle strength
• Post-operative reversal of neuromuscular blockade
• Post-operative complications – gastric atony paralytic
ileus, urinary bladder atony
• Cobra snake bite
• Atropine is the antidote in acute neostigmine poisoning
 Other Drugs

• Pyridostigmine: Same as Neostigmine - less potent but

longer acting
• Edrophonium: Same as Neostigmine – shorter duration of
action (1- - 30 minutes) – diagnostic use in MG
Myasthenia gravis (Myo + asthenia)
Symptoms: Weakness and easy fatigability – ptosis to
diaphragmatic paralysis
• Causes: Development of antibodies directed to Nicotinic
receptors in muscle end plate – reduction in number by
1/3rd of NM receptors
Myasthenia gravis – other drugs
• Neostigmine – 15 to 30 mg. orally every 6 hrly
• Adjusted according to the response
• Pyridostigmine – less frequency of dosing
• Other drugs: Corticosteroids (prednisolone 30-60 mg
/day) – immunosuppression
• Inhibits production of NR antibodies and may increase
synthesis or NRs
• Azathioprin and cyclosporine also Plasmapheresis
Overall Therapeutic Uses – cholinergic drugs

1. Myasthenia gravis:
• Edrophonium to diagnose a
• Neostigmine, Pyridostigmine to treat
2. To stimulate bladder & bowel after surgery: –
Bethanechol, Carbachol, Distigmine.
3. To lower IOP in chronic simple glaucoma: – Pilocarpine,
Physostigmine
4. To improve cognitive function in Alzheimer’s disease:
Rivastigmine, Gallantamine, Donepezil.
5. Physostigmine in Belladonna poisoning
• Pharmacotherapy of Organophosphate Poisoning
• Complex effects – Muscarinic, Nicotinic and CNS
• Signs and symptoms:
1. Irritation of eye, lacrmation, salivation, tracheo-
bronchial secretions, colic, blurring of vision,
defaecation and urination
2. Fall in BP, tachy or bradycardia and CVS collapse
3. Muscular fasciculations, weakness, and respiratory
paralysis
4. Irritability, disorientation, ataxia, tremor, convulsins
and coma
• Pharmacotherapy of Organophosphate Poisoning
• Complex effects – Muscarinic, Nicotinic and CNS
• Treatment:
1. Decontamination and termination of further
exposure – gastric lavage if needed
2. Airway maintenance – endotrachial intubation
3. Supportive measures – for BP/fluid and electrolyte
4. Specific antidote – Atropine – 2mg IV every 10
minutes till dryness of mouth or atropinization (upto
200 mg/day)
• Cholinesterase Reactivators – Oximes
• Pralidoxime (2-PAM)
• Oximes have generic formula R-CH=N-OH
• Provides reactive group OH to the enzymes to reactivate the
phosphorylated enzymes – million times faster
• PAM:
– Quaternary Nitrogen of PAM gets attaches to Anionic site
of the enzyme and reacts with Phosphorous atom at
esteratic site
– Forms Oxime-phosphonate complex making esteratic site
free
– Not effective in Carbamate poisoning