The document discusses autonomic drugs and the autonomic nervous system. It notes that autonomic drugs are clinically relevant and used to treat conditions like angina, heart failure, and high blood pressure. The autonomic nervous system maintains homeostasis through the sympathetic and parasympathetic nervous systems. Cholinergic transmission occurs through the release and binding of acetylcholine to nicotinic and muscarinic receptors.

1. Autonomic Nervous System -
“Autonomic Pharmacology”
Dr. D. K. Brahma
Department of Pharmacology
NEIGRIHMS, Shillong

2. Autonomic Drugs are very much
Clinically Relevant

3. Goal !
To Learn about the drugs affecting the
autonomic nervous system
Be prepared to link mechanism of drug action
with knowledge mainly of cardiovascular anatomy,
physiology and neurobiology
to predict effects of drugs

4. Autonomic drugs are used
for the
treatment of Angina

5. Autonomic drugs are used
for the
treatment of Heart
Failure

6. Autonomic drugs are used for
the
treatment of High Blood
Pressure
• Autonomic drugs also used for
treatment of
- Anaphylactic shock
- Septic shock
- Benign prostatic hypertrophy
- Alzheimer’s disease
- Asthma

7. +
Drug A increases
activity of
organ O
Autonomic Pharmacology is Practical
Nerves to organ O
release neurotransmitter N,
and N increases
the activity of organ O
Mimic transmitters
Drug A enhances release
of neurotransmitter N by
acting on receptors of N

8. +
Drug A decreases
activity of
organ O
Autonomic Pharmacology
Nerves to organ O
release neurotransmitter N,
and N increases
the activity of organ O
Block transmitters
Drug A blocks
receptors for
neurotransmitter N

9. +
Atropine blocks Ach receptors (muscarinic)
and decreases intestinal motility
Atropine blocks
muscarinic cholinergic
receptors
that respond to ACh
Understanding actions of drugs that influence the
autonomic nervous system allows prediction of
their effects!
Parasympathetic nerves
release Acetylcholine (Ach)
and increase
intestinal motility

10. For a definite clinical outcome!
Sympathetic nerves
release Noradrenaline (NA)
and increase
Blood Pressure
Propranolol blocks
Receptors (β-adrenergic)
that respond to NA
Propranolol blocks β-adrenergic receptors
and decreases Blood Pressure
+

11. The autonomic nervous system maintains the
internal environment of the body –
HOMEOSTASIS
• Role of ANS in homeostasis links to specific target
organs - (Circulation, respiration, digestion,
temperature regulation and some endocrine
secretion)
• In contrast – endocrine system is more generalized
• ANS in periphery – nerve, ganglia and plexuses
innervates heart, glands, other smooth muscles and
visceral organs

12. Organization of
Nervous System - Recall
Central Nervous System
“Brain and spinal cord”
Peripheral Nervous System
Autonomic Nervous System Somatic Nervous System
Afferent Division Efferent Division
Sympathetic
“thoracolumbar”
Parasympathetic
“craniosacral”

13. AUTONOMIC NERVOUS SYSTEM
• SYMPATHETIC
– Fight or Flight
• PARASYMPATHETIC
– Rest and Digest

14. Controls
skeletal
muscle
Controls
cardiac
muscle &
glands
Peripheral Nervous System
Somatic
Nervous
System
Autonomic
Nervous
System
One
Neuron
Efferent
Limb
Two
Neuron
Efferent
LimbPostganglionic
Preganglionic
smooth &

15. Somatic Vs
Autonomic
Somatic Autonomic
1. Organ supplied Skeletal Muscle All other organs
2. Distal most synapse Within CNS Outside CNS in ganglia
3. Nerve fibres Myelinated Preganglionic – Myelinated
Postganglionic – Non-myelinated
4. Peripheral plexus
formation
Absent Present
5. Efferent Transmitter Acetylcholine Acetylcholine and Noradrenaline
6. Effect of Nerve
section
Paralysis and
atrophy
Activity maintained – no atrophy

16. ANS Organization –
Autonomic afferents
• Afferent fibers from visceral structures – are the first link in the reflex arcs of the
autonomic system
• Most visceral reflexes are mediated through the central nervous system (CNS)
• Information on the status of the visceral organs is transmitted to the CNS through
the cranial nerve (parasympathetic) visceral sensory system and the spinal
(sympathetic) visceral afferent system
• Cell bodies are located in the sensory ganglia of Cranial Nerves and the dorsal root
ganglion of Spinal Nerves - mixed and nonmyelinated Nerves
• The cranial visceral sensory - mechanoreceptor and chemosensory information
– 4 cranial nerves - V, VII, IX and X
– Carries from face, head, toungue, palate, carotid body, oesophagus, thoracic and abdominal
visceral organs except pelvic
• The spinal visceral system - temperature and tissue injury of mechanical, chemical,
or thermal origin:
– Sensory afferents from all viscera at thoracic level
– Muscle chemosensations – at all spinal level
• Pelvic sensory responses at S2-S4 level

17. ANS –
Central connections
• No Exclusive autonomic area in CNS
• Intermixing - somatic responses always are accompanied by visceral
responses, and vice versa
• Autonomic reflexes can be elicited at the level of the spinal cord -
sweating, blood pressure alterations, vasomotor responses to
temperature changes, and reflex emptying of the urinary bladder,
rectum, and seminal vesicles.
• Hypothalamus and STN - is the organ to regulate
– Highly integrated pattern of responses are organized in hypothalumus
• Many autonomic centres are located in mid brain, medulla – limited
pattern responses
• Sympathetic – Lateral and Posterior nuclei; Parasympathetic –
Anterior and Medial nuclei

18. ANS –
Efferent fibres
• Motor limb – Sympathetic and Parasympathetic
• Most organs receive both innervations
• Functionally antagonistic of each other
• EXCEPTIONS:
– Most Blood vessels, sweat glands, spleen and hair follicles –
Sympathetic
– Gastric and pancreatic glands, cilliary muscles – Parasympathetic
• Overall – depends on the tone at particular moment (summation)
• Exception: Atrial fibres – ERP reduced by both

19. Sympathetic
Nervous
System
(Thoracolumb
ar Outflow) -
paravertebr
al,
prevertebral
and terminal
Parasympathetic:
Craniosacral
outflow

20. Transmitters and Receptors - General
• Neurotransmitter
– All preganglionic and postganglionic Parasympathetic – Acetylcholine
(Ach)
– Postganglionic sympathetics – norepinephrine (NE, noradrenaline)
• Somatic: Nicotinic (NM) ACh type of receptor
– NM: musculoskeletal junction
• Autonomic:
1. Parasympathetic:
• Preganglionic: Nicotinic (NN) Ach
• Postganglionic: Muscarininic (M)
2. Sympathetic:
• Preganglionic: Nicotinic (NN) Ach
• Postganglionic : Noradrenergic (NA) - ɑ and ß (alpha and beta)
• Adrenal medulla (NN) Preganglionic and Postganglionic - Adrenaline in
blood stream

21. Enteric Nervous System
• Considered 3rd Division of ANS
– Control activities of the GI tract are controlled locally
– Afferent sensory neurons and a number of motor nerves
and interneurons
– Organized by Auerbach`s plexus or myenteric plexus and
Meissner`s plexus or submucous plexus
• Myenteric plexus – contraction and relaxation
• submucous plexus – secretory and absorptive function
• Parasympathetic as a whole is excitatory (pre and post
ACH) while sympathetic is relaxant (preganglionic Ach
inhibition)
• Stimulation of these neurones causes release of – ACh,
NE, VIP, ATP, Substance P, 5-HT etc.

22. Enteric Nervous System

23. Neurotransmission
• Understanding the steps of chemical mediation of nerve
impulses is important – exploited pharmacologically
• Conduction refers to the passage of an impulse along an
axon or muscle fiber
• Transmission (Neurohumoral) transmission means the
transmission of message across synapse and neuroeffector
junctions by release of humoral (chemical) messages
• Initially junctional transmission was thought to be Electrical
• But, Dale (1914) and Otto Loewi (1921) provided direct proof of
humoral transmission – vagusstoff and acceleranstoff
• Many Neurohumoral transmitters identified: Acetylcholine,
noradrenalin, Dopamine, 5-HT, GABA, Purines, Peptides etc.

24. Axonal Conduction
• At rest, the interior of the typical
mammalian axon is ~70 mV negative to the
exterior
• Essentially a K+ Nernst potential based
• These ionic gradients are maintained by the Na+,
K+-ATPase
• In response to depolarization to a threshold
level, an action potential (AP) is initiated
locally
• The AP consists of two phases:
• rapid increase in the permeability of
Na+
• rapid inactivation of the Na+ channel
and the delayed opening of a K+ channel
• Tetrodotoxn, Saxitoxin and Batrachotoxin

25. Junctional Transmission - Steps
• Arrival of the AP at the axonal terminals initiates a series of
events that trigger – transmission of excitatory or
inhibitory:
1. Release of stored Transmitter (prejunctional regulation) –
• Cotransmission: enzymes, other proteins, and cotransmitters
(e.g.,ATP, NPY)
• autoreceptors and heteroreceptors - M2 and M4 and ɑ2A, ɑ2B
and ɑ2C
2. Combination of the transmitter with postjunctional
receptors and production of the postjunctional potential
• EPSP and IPSP
3. Initiation of postjunctional activity
4. Termination of transmitter action
– NET, SERT, DT

26. Junctional Transmission Steps - Image

28. Sites of Cholinergic Transmission
Acetylcholine (Ach) is major neurohumoral transmitter
at autonomic, somatic and central nervous system:
1. All preganglionic sites (Both Parasympathetic and
sympathetic)
2. All Postganglionic Parasympathetic sites and
sympathetic to sweat gland and some blood vessels
3. Skeletal Muscles
4. CNS: Cortex Basal ganglia, spinal chord and others
Parasympathetic Stimulation – Acetylcholine (Ach) release at neuroeffector
junction - biological effects
Sympathetic stimulation – Noradrenaline (NA) at neuroeffector junction -
biological effects

29. 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 sodium-dependent membrane carrier
(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
1000-50000 and 300000

30. 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)
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??

31. 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
• 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

32. True Vs Pseudo AChE
True AChE Pseudo AChE
Distribution All cholinergic sites,
RBCs, gray matter
Plasma, liver,
Intestine and
white matter
Action on:
Acetycholine
Methacholine
Very Fast
Slower
Slow
Not hydrolyzed
Function Termination of Ach
action
Hydrolysis of
Ingested Esters
Inhibition More sensitive to
Physostigmine
More sensitive to
Organophosphates

33. Cholinergic receptors - 2 types
• Muscarinic (M) and Nicotinic (N):
Muscarinic
(M) - GPCR
Nicotinic (N) –
ligand gated

34. Muscarinic Receptors ??
1. Selectively stimulated by Muscarine and blocked by
Atropine – all are G-protein coupled receptors
2. Primarily located in heart, eye, smooth muscles and
glands of GIT
3. Subsidiary M receptors are also present in ganglia for
modulation – long lasting late EPSP
4. Autoreceptors (M type) are present in prejunctional
cholinergic Nerve endings
– also in adrenergic nerve terminals leading to vasodilatation
when Ach is injected
5. Blood vessels: All blood vessels have muscarninc receptors
although no cholinergic innervations

35. Muscarinic Receptors - Subtypes
• Pharmacologically - M1, M2, M3, M4 and M5
• M4 and M5 are present in certain areas of Brain and
regulate other neurotransmitters
• M1, M3 and M5 fall in one class, while M2 and M4 in
another class
• However - M1, M2 and M3 are major ones and present
in effector cell and prejunctional nerve endings in CNS
• All subtypes have little agonist selectivity but selective
antagonist selectivity
• Most organs usually have more than one subtype but
one subtype predominates in a tissue

36. Muscarinic Receptors - Location
• M1: Ganglion Cells and Central Neurons (cortex,
hippocampus, corpus striatum)
– Physiological Role: Mediation of Gastric acid secretion and
relaxation of LES (vagal)
• Learning, memory and motor functions
• M2: Cardiac Muscarinic receptors
– Mediate vagal bradycardia
– Also auto receptors in cholinergic nerve endings
• M3: Visceral smooth muscles, glands and vascular
endothelium. Also Iris and Ciliary muscles

37. Muscarinic Receptor Subtypes
M1 M2 M3
Location Autonomic ganglia,
Gastric glands and
CNS
Heart and CNS SMs of Viscera,
Eye, exocrine
glands and
endothelium
Functions EPSP & Histamine
release & acid
secretion with CNS
learning and motor
functions
Less impulse
generation, less velocity
of conduction,
decreased contractility,
less Ach release
Visceral SM
contraction,
Constriction of
pupil, contraction
of Cilliary muscle
and vasodilatation
Agonists Oxotremorine Methacholine Bethanechol
Antagonists Pirenzepine Methoctramine &
Triptramine
Darifenacin
Transducer IP3/DAG and PLA2
increase – Ca++ and
PG
K+ channel opening and
decresed cAMP
IP3/DAG and PLA2
increase – Ca++
and PG

38. Acetylcholine (cholinergic receptors)
– Muscarinic Receptors
• Selectively stimulated by Muscarine and
blocked by Atropine
M1 M2 M3
Ganglia
and CNS
Heart Glands and
Smooth Muscles

39. Nicotinic (N) Receptors
• Nicotinic receptors: nicotinic actions of ACh are
those that can be reproduced by the injection of
Nicotine (Nicotiana tabacum)
– Can be blocked by tubocurarine and
hexamethonium
• ligand-gated ion channels
– activation results in a rapid increase in cellular
permeability to Na+ and Ca++ resulting -
depolarization and initiation of action potential

40. Nicotinic Receptors - NM Vs NN
NM (Muscle type)
1. Location: Skeletal Muscle
end plates
2. Function: Stimulate skeletal
muscle (contraction)
3. MOA: Postsynaptic and
Excitatory (increases Na+ and
K+ permeability)
4. Agonists: ACh, carbachol
(CCh), suxamethonium
– Selective stimulation by phenyl
trimethyl ammonium (PTMA)
5. Antagonists: tubocurarine,
Atracurium, vecuronium and
pancuronium
NN (Ganglion type)
1. Location: In autonomic ganglia of
all type (ganglion type) –
Sympathetic, Parasympathetic and
also Adrenal Medulla
2. Function: Depolarization and
postganglionic impulse – stimulate
all autonomic ganglia
3. MOA: Excitatory – Na+, K+ and
Ca+ channel opening
4. Agonists: ACh, CCh, nicotine
– Selectively stimulated by
Dimethyl phenyl piperazinium
(DMPP)
5. Antagonists: Trimethaphan,
Mecamylamine and
Hexamethonium

41. Cholinergic Drugs or
Cholinomimetic or
Parasympathomimetics
Drugs producing actions similar to Acetylcholine by –
1) interacting with Cholinergic receptors or 2)
increasing availability of Acetylcholine at these sites

42. Question…?
• What side effects might you expect to see in a
patient taking a cholinergic drug?
• Hint… Cholinergic = “Colon-Urgent”

43. Classifiction - Direct-acting (receptor
agonists)
• Choline Esters
– Natural: Acetylcholine (Ach)
– Synthetic: Methacholine, Carbachol and
Bethanechol
• Alkaloids: Pilocarpine, Muscarine, Arecholine
– Synthetic: Oxotremorine

44. Cholinergic Drugs – Indirect acting
• Cholinesterase inhibitors or reversible
anticholinesterases:
1. Natural: Physostigmine
2. Synthetic: Neostigmine, Pyridostigmine, Distigmine,
Rivastigmine, Donepezil, Gallantamine, Edrophonium,
Ambenonium, Demecarium
• Irreversible anticholinesterases:
1. 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)

45. ACh actions –
Muscarinic
1. Heart: M2
– SA node hyperpolarization (decrease in rate of diastolic
depolarizaton) - reduction in impulse generation and Bradycardia
– AVN and PF – RP is increased – slowing of conduction –
partial/complete heart block
– Atrial fibres: Reduction in force of contraction and RP in fibers
abbreviated
– Atrial fibrillation and flutter – nonuniform vagal innervations and
variation in intensity of effect on RP in diferent atrial fibres
– Decrease in ventricular contractility (less prominent)
2. Blood Vessels: M3
– Cholinergic innervations is limited – skin of face and neck
– But, M3 present in all type blood vessel – Vasodilatation by Nitric
oxide (NO) release – fall in BP and flushing
– Penile erection

46. Muscarinic action
– contd.
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

47. 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)
Bethanecol Uses: Postoperative and postpartum urinary
obstruction, neurogenic bladder and GERD (10-40 mg oral)

48. 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
• Diaphoretic (?), xerostomia and Sjögren’s syndrome

49. Pilocarpine – contd.
1. Used as eye drops in
treatment of wide angle
glaucoma to reduce IOP
2. To reverse mydriatic
effect of atropine
3. To break adhesion
between iris and
cornea/lens alternated
with mydriatic
• Pilocarpine nitrate eye
drops ( 1 to 4% )
• Atropine used as
antidote in acute
pilocarpine poisoning ( 1-
2 mg IV 8 hrly )

50. Pilocarpine in Glaucoma
• Constriction of circular muscle of Iris
• Contraction of ciliary muscle
• Spasm of accomodation – fixed at near vision

51. 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

52. Mushroom Poisoning
• Early Onset Mushroom Poisoning: Occurs ½ to 1 hour
– Symptoms are characteristic of Muscarinic actions
– Inocybe or Clitocybe – severe cholinergic symptoms like
vomiting, salivation, lacrimation, headache,
bronchospasm, diarrhoea bradycardia, dyspnoea,
hypotension, weakness, cardiovascular collapse,
convulsions and coma
– Antidote is Atropine sulphate ( 2-3 mg IM every hrly till
improvement)
• Hallucinogenic type: due to Muscimol or ibotenic acid
present in A. muscria. Blocks muscarinic receptors in
brain and activate amino acid receptors. No specific
treatment – Atropine is contraindicated.

53. Late Onset Mushroom
Poisoning
• Occurs within 6 - 15 hours
• Amanita phylloides (deadly nightcap)– due to peptide
toxins – Inhibit RNA polymerase II and therefore mRNA
synthesis
• Irritability, restlessness, nausea, vomiting, bloody diarrhoea
ataxia, hallucination, delirium, sedation, drowsiness and
sleep – Kidney, liver and GIT mucosal damage
• Maintain blood pressure, respiration
• Inj. Diazepam 5 mg IM
• Atropine contraindicated as it may cause convulsions and
death - penicillin, thioctic acid and silibinin (antidote?)
• Gastric lavage and activated charcoal

54. Cholinergic Drugs – Indirect acting
• Cholinesterase inhibitors or reversible
anticholinesterases:
1. Natural: Physostigmine
2. Synthetic: Neostigmine, Pyridostigmine, Distigmine,
Rivastigmine, Donepezil, Gallantamine, Edrophonium,
Ambenonium, Demecarium
Tertiary amine N (lipid soluble) and quartenary N+ (lipid
insoluble)
• Irreversible anticholinesterases:
1. 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)

55. 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
Glutamate and
histidine
Tryptophan

56. AChEs - MOA
• Anticholinesterases also react with the enzyme ChEs in
similar fashion like Acetylcholine
• Carbamates – carbamoylates the active site of the enzyme
• Phosphates – Phosphorylates 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
– Sometimes phosphorylated enzyme losses one alkyl group and
become resistant to hydrolysis – aging
• Edrophonium and tacrine reacts only at anionic site – short
acting while Organophosphates reacts only at esteratic site

57. Anticholinesterases – Individual Drugs
• 2 (two) important clinically used drugs –
– Physostigmine – lipid soluble, ganglion acting and
less action in skeletal muscle
• Also organophosphates
– Neostigmine – lipid insoluble, skeletal muscle
acting

58. Physostigmine
• Alkaloid from dried ripe 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)
• It indirectly prevents destruction of acetylcholine
released from cholinergic nerve endings and causes
ACh accumulation
• Muscarinic action on eye causing miosis and spasm of
accommodation on local application
• Salivation, lacrimation, sweating and increased
tracheobronchial secretions
• Increased heart rate & hypotension

59. Physostigmine - uses
1. Used as miotic drops to decrease IOP in
Glaucoma
2. To antagonize mydriatic effect of atropine
3. To break adhesions between iris and cornea
alternating with mydriatic drops
4. Belladonna poisoning, TCAs & Phenothiazine
poisoning
5. Alzheimer’s disease- pre-senile or senile
dementia
6. Atropine is antidote in physostigmine poisoning.
ADRs – CNS stimulation followed by depression

60. 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 and other
competitive neuromuscular blockers
• Stimulates autonomic ganglia in small doses - Large
doses block ganglionic transmission
• No CNS effects

61. Neostigmine – Uses and ADRs
• 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
• Produces twitchings & fasciculations of muscles
leading to weakness
• Atropine is the antidote in acute neostigmine
poisoning

62. Physostigmine Vs Neostigmine
Physostigmine Neostigmine
Source Natural Synthetic
Chemistry Tertiary amine Quaternary ammonium
compound
Oral absorption Good Poor
CNS action Present Absent
Eye Penetrates cornea Poor penetration
Effect Ganglia Muscle
Uses Miotic Mysthenia gravis
Dose 0.5-1 mg
oral/parenteral
0.1-1% eye drop
0.5-2.5 mg IM/SC
15-30 mg orally
Duration of action 4-6 Hrs 3-4 Hrs

63. Myasthenia gravis (Myo + asthenia)
• Autoimmune disorder affecting 1 in 10,000 population
(?) – reduction in number of NM receptors
• Causes: Development of antibodies directed to
Nicotinic receptors in muscle end plate – reduction in
number by 1/3rd of NM receptors
– Structural damage to NM junction
• Symptoms: Weakness and easy fatigability – ptosis to
diaphragmatic paralysis
• Treatment:
– 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)
• Azathioprin and cyclosporin also Plasmapheresis

64. Myasthenic crisis
• Acute weakness and respiratory paralysis
– Tracheobronchial intubation and mechnical ventilation
– Methylprednisolone IV with withdrawal of AChE
– Gradual reintroduction of AChE
– Thymectomy
• The problem – overtreatment Vs actual disease
(opposite treatments)
– Diagnosis by various tests – Tensilon Test
– Injection of Edrophonium – 2 mg (observe) – after half a
minute 8 mg (observe)
• In MG – symptoms will improve
• In overtreatment – symptoms worsen

65. Overall Therapeutic Uses – cholinergic
drugs
1. Myasthenia gravis: Edrophonium to diagnose
and Neostigmine, Pyridostigmine & Distigmine
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
6. Cobra Bite

66. Pharmacotherapy of Organo[hosphate
Poisoning
• Signs and symptoms:
1. Irritationof 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. Excitement, tremor, convulsins and coma
• Treatment:
– Decontamination – gastric lavage if needed
– Airway maintenance
– Supportive measures – for BP/fluid and electrolyte
– Specifc antidote – Atropine – 2mg IV every 10 minutes till
dryness of mouth or atropinization (upto 200 mg/day)

67. Cholinesterase Reactivators - Oximes
• Pralidoxime (2-PAM) and Obidoxime Diacetyl
monoxime (DAM)
• 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
– Dose: 1-2 gm IV slowly maximum 12 gms/24 hrs

68. Summary
• Biosynthesis of Acetylcholine
• Distribution of Muscarinic and Nicotinic receptors
• Classification of Anticholinesterases
• Mechanism of action of Anticholinesterases and Aging
• Action of cholinomimetics on eye
• Physostigmine Vs Neostigmine
• Myasthenia gravis
• Neostigmine and its uses
• Use of Edrophonium
• Oximes
• Alzheimer`s disease drug names

69. Khublei Shibun/Thank you