1. Pharmacology of the autonomic nervous system
Pharmacology of the autonomic nervous system. Drugs affecting cholinergic nervous system
Anton Kohút

5. Steps of neurotransmission

6. Steps of cholinergic neurotransmission

11. Transduction system

12. Cholinergic neurotransmission
Transduction system
Agonist (acetylcholine)
Receptor (M)
G-protein (Gs, Gi)
Effector enzyme (phospholipase C, PLC)
Second messenger (IP3, DAG)
Drug action

13. Muskarínový receptor

15. Interaction with receptors

16. Receptors:
- adrenergic: α - α1, α2
β – β1, β2
- cholinergic: M (M1-M-3) N

17. Cholinergic receptors - muskarinic - nicotinic

18. Nicotinic receptors

19. Nicotinic receptors Muscular typ Ganglionic typ CNS typ Localization
Muscular typ
Ganglionic typ
CNS typ
Localization
Neuromuscular junction
Vegetative ganglions
Brain
membrane effects
Excitation increase of permeability for Na/K
Excitation: increase of permeability for Ca++
agonists
Acetylcholine
Nicotine
antagonists
Tubocurarine
Dimecamine
Mecamylamíne
Mecamylamine
 - conotoxine

20. Characteristic of muscarinic receptors
Typ
M1 (neural)
M2 (cardial)
M3 (glandular)
Localization
CNS, cortex, hipokampus,
Parietal cells
Heart,
Smooth muscle (GIT)
CNS
Exocrine glands
Effects
Excitation CNS,
Increase of HCL
Cardial inhibition,
neural inhibition,
Increase of secretion, contraction GIT, vasodilatation miosis
Antagonists
Atropine
Dicycloverine
Ipratropium
Pyrenzepine

25. Functions of the autonomic nervous system
1. Sympathetic: activated in response to stressful situations (trauma,
fear, hypoglycemia, cold, or exercise).
I "fight or flight
2. Parasympathetic system
Dominant over the sympathetic system in
"rest or digest" situations.

31. Groups of drugs influencing vegetative system

32. Muscarinic agonists Parasympathomimetics Representative: acetylcholine

33. Effects of parasympathomimetics
Cardiovascular effets (M2):
 cardiac slowing and (reduced automaticity)
 decreased force of contraction (mainly in atria)
 inhibition of AV conduction
Smooth muscle (except vascular smooth muscle
 contracts in response to muscarinic agonists
 peristaltic activity of GIT increase
 bladder and bronchial smooth muscle also contract
Vascular smooth muscle
 acetylcholine produces vasodilatation - mediator is NO
Exocrinne glands
 stimulation of gastric acid secretion (M1)
 sweating, lacrimation, salivation, bronchial secretion (M3)
Effects on eye
 lower the intraocular pressure, myosis

34. Mechanismof vasodilatation after ACH

35. Groups of parasympathomimetics
Indirectly acting
Reversible anticholinesterases
- short-acting drugs (edrophonium, ambenonium)
- medium-duration anticholinesterases
(neostigmine, pyridostigmine, physostigmine)
b. Irreversible anticholinesterases (organophosphates)
tabun, sarin. soman
pesticides, as well as war gases:
-are usually high lipid-soluble
compounds and are rapidly
absorbed through mucous membrane, unbroken skin
Directly acting
a. Acetylcholine -  rapid destruction
 nonselective effect (M and N)
b. More stable derivates of Ach:
Metacholine, Betanechol, Carbachol
Alkaloids:
muscarine (Amanita muscaria), pilocarpine (Pilocarpus jaborandi)
They have no significant nicotinic effect
muscarine - toxicologic interest only

37. Clinical uses and side effects of parasympathomimetics
 myasthenia gravis - (neostigmine, pyridostigmine,)
 glaucoma (physostigmine),
 antidote
- in atropine poisoning (physostigmine)
- in curare-like drug-induced muscle paralysis (neostigmine),
 urinary tract stimulant (neostigmine)
 GIT postoperative abdominal distension (neostigmine)
Side effects
flush, - salivation,- nausea, -vomiting, -diarrhea, -hypotension –bronchoconstriction - asthmatic attack

39. Intoxication by organophosphates
Symptoms
a. Effects on autonomic cholinergic synapses (M)
Glands, GIT, bronchoconstriction
Bradycardia, hypotension, disturbancies in vision
b. Effects on the neuromuscular junction (N)
Muscle contraction, in large doses (poisoning)  depolarisation of membrane 
neuromuscular block
c. Effects on the CNS
Excitation,- convulsion - depresion - respiratory failure
Treatment
1. first step - remove the source to prevent further exposure,
2. most muscarinic symptoms are blocked by atropine,
3. to restore acetylcholinesterase activity  oximes
 pralidoxime, trimedoxime, obidoxime.

40. Muscarinic antagonists (parasympatholitics) Representative: atropine

41. Atroppa belladona

42. Groups of muscarinic antagonists (parasympatholitics)
1. Tertiary ammonium compounds:
- Alkaloids - atropine and scopolamine,
atropine - (Atropa belladonna), scopolamine (Datura stramonium)
Semisynthetic derivate of atropine - homatrapine
- Selective M1 - pirenzepine and dicyclomine -
benztropine and trihexyphenidyl – (CNS- antiparkinsonic drugs)
2. Quarternary synthetic deivates of atropine
- Atropine methonitrate - peripheraly very similar to atropine but it dos not cross blood-brain barrier - lacks central actions
Propantheline - methscopolamine, ipratropium

43. Effects of muscarinic antagonists
Inhibition of secretion
Effects on heart rate
Effects on the eye – mydriasis, paralysis of accomodation, cycloplegia)  disturbances of near vision, -intraocular pressure may rise
Effects on the GIT – inhibition of motility
Effects on other smooth muscle
-bronchial, biliary and urinary tract smooth muscle are all relaxed
Effects on CNS
-atropine produced mainly excitatory effects on CNS
(low doses - mild restlessness

44. Clinical uses of muscarinic antagonists
Premedication for anesthesia
-inhibition of bronchial and salivary secretion, inhibition of reflex bronchoconstriction
-reduced bradycardia after some anesthetics
GI disorders
- to reduce gastric acid secretion (pirenzepine),
to reduce gastrointestinal motility (dicyclomine)
Ophthalmology
-pupilary dilatation - homatropine is often used

45. Clinical uses of muscarinic antagonists (cont.)
Bronchial disorders
- ipratropium bromide is useful in treatment of asthma
Motion sickness
- scopolamine is used in preventing motion sickness
Other
- Parkinson´s disease (benztropine),antidote, diarrhea

46. Side effects Atropine like effect
-blurred vision,
-tachycardia,
-dry mouth,
-constipation,
-urinary retention, -
-mydriasis

47. Atropine poisoning
 mainly in youg children who eat deadly nightshade berries
 excitement and irritability  hyperactivity and rise body temperature  result of blocking muscarinic receptors in the brain
 they are opposed by anticholinesterase drugs (physostigmine)

48. Myorelaxants

50. Classification of myorelaxants
I. drugs that act presynaptically
 by inhibiting of ACH synthesis: hemicholinium
 by inhibiting ACH release: botulinum toxin, bungarotoxin (venom of various snakes (cobra family)
 by inhibiting of calcium entry (magnesium ion, aminoglycoside ATB),
II. drugs that act postsynaptically
interfering with the postsynaptic action of ACH:
 non-depolarising agents tubocurarine, pancuronium, gallamine
 depolarising agents succinylcholine

52. Non-depolarising agents - tubocurarine
Effects
Paralysis
small muscles of the face and eye are paralyzed first,
 limb, neck and trunk  then intercostal muscles are affected  diaphragm muscles.
Other effects
- release of histamine vasodilatation  fall in blood pressure,
- bronchospasm consequence of histamine release   asthma,
- neuromuscular blockade last from 20 min to 1 hour.

53. Non-depolarising agents – tubocurarine (cont.)
Terapeutic uses
 are used therapeutically as adjuvant in surgical anesthesia,
 strychnine intoxication,
 tetanus,
 diagnosis of myasthenia gravis,
 adjunct relaxation during maximal electroshock therapy.

54. Depolarizing agents - succinylcholine
Effects
 muscular fasciculation last only a few minutes (3 – 5 min),
 paralysis is slightly different than in non-depolarising drugs, but paralysis of respiratory muscles is the last,
 does not produce ganglionic block,
 has weak histamine-releasing action,
 Unwanted effects
 bradycardia
 increased intraocular pressure
 prolonged paralysis by genetic differences of cholinesterase activity
 malignat hyperthermia - sudden rise in body temperature
 usually treated by dantrolene (prevention of calcium release from sarcoplasmatic reticulum) + rapid cooling