Introduction to ANS (Autonomous Nervous System) & Cholinergic drugs

1. .

2. Introduction to ANS
 Neurons = A cell that received & send electrical signal
over long distance.
 Nervous system = Brain + Spinal Cord + Ganglia +
Receptor organ.
 CNS = Brain + Spinal Cord.
 PNS = Other then Brain + Spinal Cord
 ANS = Heart muscles, smooth muscles.
 Sympathetic nerves system = adjust stress & prepare
the body for fight or flight.
 Parasympathetic nerves system = adjust stress free,
rest and digest. 2

3. Introduction to ANS Con..
 Somatic = ( voluntary ) neuron association with skittle
muscle influence voluntary movement.
 Involuntary nerves = that control muscles of internal
organs- heart, blood vessels, exocrine glands, lungs,
stomach, viscera
 Reflex = muscles contraction in response to stretching.
 Hypothalamus = control – 1. Body temperature 2.
Hunger 3. Thirst 4. Body equilibrium.
 Maintains homeostasis
 Endocrinal, metabolic, immunological, emotional
activities, somatomotor, Integrates sensory. 3

4. Introduction to ANS Con..
 Afferent nerves = nerve that care impulse toward
CNS.
 Efferent nerves = nerve that care impulse away from
CNS.
 Pre-ganglionic neuron = myelinated
 Post-ganglionic neurons = non-myelinated
 Ganglion = junction b/w pre & postganglionic fibers.
 Nerve conduction = generate nerve impulse
 Nerve transmission = transfer impulse one nerve to
another nerve or muscles.
4

5. 5

7. Neurotransmitters
 Sympathetic: ADRENERGIC
 Central: EPINEPHRINE
 Peripheral: NOREPINEPHRINE
• Parasympathetic: CHOLINERGIC
 Acetylcholine
7

8. .

9. Cholinergic system
 Acetylcholine is the principal NT at nm junction.
 Synthesize, store, release ACh
 Sites of ACh release
 Ganglia: pre-ganglionic fibres of ANS (both sympathetic
& para-sympathetic)
 Post-ganglionic parasympathetic nerve endings
 Sweat glands
 Skeletal muscles
 Adrenal medulla
 CNS: brain, spinal cord
9

10. 10

11. Synthesis of acetylcholine
11

12. Steps in Cholinergic transmission
 Synthesis
 Storage of NT
 Release
 Post junctional effects
 Termination of action
12

13. Cholinesterases
 ACh is hydrolyzed to choline & acetic acid by
cholinesterases
 2 types
 True cholinesterases
 At neurons, ganglia, nm junction
 Pseudocholinesterases/ Butyryl cholinesterases
 In plasma, liver
13

14. Cholinergic Receptors
 2 types
 Muscarinic
 Present in heart, smooth muscles, glands, eyes, CNS
 GPCRs
 M1-M5
 Agonist – Muscarine; Antagonist – Atropine
 Nicotinic
 Present in nm junction, autonomic ganglia, adrenal medulla
 Ion channels
 5 subunits
 NM (on NM junction of skeletal muscles), NN (on autonomic
ganglia, adrenal medulla)
 Agonist – Nicotine, Antagonist – Curare
14

15. Cholinergic receptors
Receptor Location
M1 Ganglia; Gland; CNS, Parietal cell of stomach
M2 Heart; Pre-synaptic; CNS
M3 Glands; Smooth ms; CNS, Eyes
M4 CNS
M5 CNS
NM Skeletal muscle NM junction
NN Autonomic ganglia
Adrenal medulla
CNS
15

16. CHOLINERGIC RECEPTORS
 G-Protein coupled Receptors
MUSCARINIC NICOTINIC
 Ligand gated ion Channels

17. Cholinomimetic Agents
i. Choline esters
 Acetylcholine
 Methacholine
 Bethanechol
 Carbachol
ii. Alkaloids & related drugs
Muscarine
Pilocarpine
Arecholine
17
Parasympathomimetic drugs/ agonists
A.Directly acting (ACh like) agents

18. Cholinomimetic Agents
i. Reversible AntiChEs
a) Tertiary
 Physostigmine
 Tacrine
b) Quarternary
 Neostigmine
 Pyridostigmine
 Edrophonium
ii. Irreversible anticholinesterases
a) Organophosphates
 Miotics
Dyflos (DFP)
Ecothiophate
 Insecticides
Malathion (Licel), Parathion
Diazinon (Tik-20)
 War gases: Sarin, Soman, Tabun
b) Carbamates: Propoxur (Bagyon)
18
B. Indirectly acting agents (ACh enhancers/amplifiers)

19. Cholinergic drugs
 Chemicals that act at the same site as ACh
 Mimic actions of ACh
Acetylcholine
 Muscarinic actions
 Heart (M2): Depress SA, reduces heart rate, force
of contraction, decrease conduction velocity
 Blood vessels: relax vascular smooth muscles,
dilates blood vessels of skin & mucous membrane,
BP
19

20. Acetylcholine
 Smooth muscle: tone of all other non-vascular smooth
muscles
 GIT: peristalsis (M3)
 Urinary bladder (M3): contract detrussor, relax trigone of
bladder, promotes voiding of urine
 Bronchus (M3): contraction: Bronchospasm
 Secretory glands:
 Enhance secretions (GI secretions-M1)
 Eye (M3): miosis (circular muscles of iris), accommodation,
drainage of aqueous humor, ciliary muscle contraction
20

21. Acetylcholine
Nicotinic actions:
 NMJ
 Contraction of skeletal muscles
 Autonomic ganglia
 Stimulation of symp & parasymp ganglia, adrenal
medulla
 CNS
 Neurotransmitter
 Produce alerting response
21

22. Acetylcholine
Uses
 PO: Destroyed in GIT
 Not used therapeutically
 Esters of ACh
 Carbachol: longer DOA
 Used in glaucoma
 Bethanechol: hypotonia of bladder & GI smooth
muscles, post op paralytic ileus, urinary retention
 Adverse effects
 Diarrhea, flushing, salivation, sweating, bradycardia,
hypotension, Bronchospasm, syncope
22

23. Alkaloids
Pilocarpine
 Natural source:
 Stimulates cholinergic receptors
 Tertiary amine (crosses BBB)
 Miosis, spasm of accommodation, IOP
  Sweat, salivary secretions
 Adverse effects:
 burning sensation, painful spasm of accommodation, brow
ache, corneal edema
 Uses: glaucoma, break adhesions between iris & lens,
counter dryness of mouth.
23

24. Glaucoma
 Increased IOP
 Causes
 Blockage of drainage of aqueous humor
 Increased formation of aqueous humor
 Management
 Decrease formation of aqueous humor
 Timolol, betaxolol, levobunolol
 Adrenaline, acetazolamide, Apraclonidine, brimonidine.
 Increase drainage of aq humor
 Carbachol, pilocarpine, physostigmine, latanoprost
24

25. Alkaloids
Arecoline
– Chief alkaloid of areca or betel nuts
– Muscarinic & nicotinic receptors
– Enhances salivary secretion
– No therapeutic indication
Muscarine
– Quaternary amine
– Muscarinic receptors
– Found in mushrooms (Amanita muscaria)
– Small amounts  edible
– Large amounts  poisonous
– Effects: fall in BP, temporary pause of heart beat,
Antidote: ATROPINE
25

26. Anticholinesterases
 The agents inhibiting the action of
acetylcholinesterase are called anti
acetylcholinesterase (AntiCHEs) or
 Cholinesterase inhibitors
26

27. Anticholinesterases
i. Reversible AntiChEs
a) Tertiary
 Physostigmine
 Tacrine
b) Quarternary
 Neostigmine
 Pyridostigmine
 Edrophonium
ii. Irreversible anticholinesterases
a) Organophosphates
 Miotics
Dyflos (DFP)
Ecothiophate
 Insecticides
Malathion (Licel), Parathion
Diazinon (Tik-20)
 War gases: Sarin, Soman, Tabun
b) Carbamates: Propoxur (Bagyon)
27

28. Action of anticholinesterases
28

29. • Physostigmine - only anticholinesterase capable
of crossing the blood brain barrier. Is more lipid
soluble.
• Used as an antidote for overdosage of
anticholinergics such as:
atropine, antihistamines, TCA, phenothiazines.
• Glaucoma.
• Pyridostigmine - drug of choice for patients
with Myasthenia gravis.

30. • Neostigmine - prototype anticholinesterase agent.
Used for long-term treatment of myasthenia gravis
and as an antidote for tubocurarine and other non-
depolarizing agents in surgery.
• Donepezil -
• Used in the treatment of mild to moderate
Alzheimer’s disease.
• Helps to increase or maintain memory and
learning capabilities.

31. • Cobra bite – edrophonium (prevent respiratory
paralysis.
• atropine poisoning – Physostigmine
(antogonizes both central and peripheral effects).
• Alzheimer’s Disease – Donepezil,
galantamine, tacrine, rivastigmine.

32. Myasthenia Gravis (Myo + asthenia)
Autoimmune disorder
Reduction in number of free NM
receptors
Causes: Development of
antibodies directed to Nicotinic
receptors at muscle end plate
 Reduction in number by 1/3rd of NM
receptors
 Structural damage to NM junction
 Weakness & easy fatigability on
repeated activity, with recovery after
rest
32

34. Myasthenia gravis – Treatment
Neostigmine: improve muscle contraction by allowing ACh
released fromprejunctional endings to accumulate.
Neostigmine – 15to 30mg. orally every 6 hrly
Dose frequency is Adjusted according to the response
Pyridostigmine – less frequency of dosing

35. Other drugs: Corticosteroids (prednisolone 30-60 mg
/day induces remission and 10mg daily or on
alternate days can be used for maintenance therapy. )
– immunosuppression
 Inhibits production of NRantibodies .
 Both azathioprine and cyclosporine also inhibitNR-
antibody synthesis by affecting T-cells.
 Removal of antibodies by plasmapheresis (plasma
exchange) is another therapeutic approach.

36. Anticholinesterases
 Uses
 Glaucoma
 Reverse effects of mydriatic
 To prevent/break adhesions between iris & lens
 Myasthenia gravis
 Reverse effects of muscle relaxants
 Post op paralytic ileus/ urinary retention
 Belladona (atropine) poisoning: Physostigmine DOC
 Alzheimer’s disease
36

37. Cholinergic Agents: Adverse Effects
 Adverse effects are a result of overstimulation of the PNS.
 Cardiovascular: – Bradycardia, hypotension, conduction
abnormalities (AV block and cardiac arrest)
 CNS: – Headache, dizziness, convulsions
 Gastrointestinal: – Abdominal cramps, increased
secretions, nausea, vomiting
 Respiratory: Increased bronchial secretions, bronchospasm
 Other: Lacrimation, sweating, salivation, miosis
37

38. Drug Adverse Effects of Cholinergic Agents
“MSLUBDD”
Many Smart Ladies Ultimately Bring Disaster for Dudes!
Miosis
Salivation
Lacrimation
Urination
Bronchoconstriction
Defaecation
Decreased heart rate

39. Acute toxic effects of irreversible
cholinesterase inhibitors (OP poisoning )
• These agents are lipid soluble
• Can enter the body by the eye,skin, respiratory system and GI
tract.
• organophosphate insecticides (malathion, parathion) or nerve
gases (sarin, tabun, soman)
• These agents cause excessive cholinergic
stimulation (muscarinic) and neuromuscular blockade

40. • Cholinergic crisis occurs because the
irreversible anticholinesterase poison binds to
the enzyme acetylcholinesterase and
inactivates it.
• Thus, acetylcholine remains in cholinergic
synapses causing excessive stimulation of
muscarinic and nicotinic receptors.

41. Treatment of OP poisoning
Emergency treatment includes:
• Decontamination of clothing
• Flushing poison from skin and eyes
• Activated charcoal and lavage for GI
ingestion
• Atropine to counteract the muscarinic
effects (2mg IV every 10 min till pupil
dilates, max 50-100 mg)

42. • To relieve the neuromuscular blockade by
nicotinic effects, give pralidoxime, a
cholinesterase reactivator.
• Pralidoxime causes the anticholinesterase
poison to release the enzyme
acetylcholinesterase.
• Give Pralidoxime as soon as possible as if too
much time passes, the poison bond becomes
too strong (aging) for the pralidoxime to work.
• Other oximes- obidoxime, diacetylmonoxime