1. Drugs acting on the autonomic nervous system
ph. rawan ghazwi
Dept. of Pharmacology
Second semester 2015

2. 1-Review of the ANS. 2- Cholinergic drugs 3- Adrenergic drugs
Agonists.
Antagonists.
3- Adrenergic drugs

3. Divisions of the Nervous System

5. autonomic nervous system
The autonomic nervous system is that part of the nervous system that controls the involuntary activities of the body (maintaining the internal environment of the body i.e homeostasis)
Arterial pressure, gastrointestinal motility and secretion, urinary bladder emptying, sweating, body temperature, and many other activities.

6. There are two major subdivisions in the autonomic nervous system:
a) Sympathetic nervous system.
b) Parasympathetic nervous system.
Drugs acting on the autonomic nervous system are those that produce their effect either by :
Mimicking
Altering
The function of this system.

7. Neurotransmitters (NTs)
Receptors
Chemical signals to communicate between nerve cells & nerve cell & effector organs.
Ex:
Acetylcholine (Ach) .
Norepinephrine (NE).
Neurons naming by NTs :
Neurons which secret Ach are cholinergic neurons.
Neurons which secret NE are adrenergic neurons.
Are structures which receive NTs from the axonal terminals of neurons.
1- Cholinergic receptors
Muscarinic receptors
Nicotinic receptors
2- Adrenergic receptors
Alpha receptors
Beta receptors

9. Within the ANS, two neurons are required to reach a target organ , a preganglionic neuron & a postganglionic neuron.
All preganglionic neurons (end in the ganglia) release Ach as their transmitter.
The Ach binds to nicotinic receptors on the postganglionic cell (the receptors are Nicotinic).

10. All of the parasympathetic postganglionic fibers release Ach.
At the target organ Ach interacts with muscarinic receptors.
MOST of the sympathetic postganglionic fibers release NE.
At the target organ NE interacts with a variety of receptors (alpha & beta).

11. Postganglionic fibers
Sympathetic
Parasympathetic
Arises from
Thoracolumbar
Craniosacral
Function
Adjusting response to stressful situations.
‘’Fight or Flight’’
Activation of these nerves is sometimes called (‘’ Rest and Digest response’’)
Maintain essential body functions.
Preganglionic fibers
Short
Long
Ganglia
Close to midline
Close to or within effector organ
Postganglionic fibers
Neurotransmitter
Norepinephrine (mainly)
Acetylcholine
Receptors
(effector organs)
α receptors β receptors
(Adrenergic receptor )
Muscarinic and nicotinic receptors (cholinergic)

12. Fibers and Neurotransmitters of ANS
the somatic system; there is NO ganglia here but the fibers that come from the CNS to the skeletal muscles forming neuromuscular junctions that release acetylcholine as neurotransmitter & stimulate receptors which are referred to as Nicotinic receptors.

13. Fibers and Neurotransmitters of ANS
The adrenal medulla is also regarded as a Ganglia so it has a sympathetic supply, epinephrine (80%) is the neurotransmitter.

14. Where we can find nicotinic receptors. So, 1. Adrenal medulla. 2
Where we can find nicotinic receptors??? So, 1. Adrenal medulla. 2. sympathetic ganglia. 3. Parasympathetic ganglia. 4. NMJ. all have NICOTINIC receptors and the neurotransmitter is ACETYLCOHLOINE

15. Remember that the nicotinic receptors at the neuromuscular junctions are NOT exactly the same as the nicotinic receptors in the ganglia, because drugs that block these receptors at the neuromuscular junctions are NOT the same as those which block the nicotinic receptors at the ganglia.

16. The neurotransmitter of the sympathetic system is MAINLY norepinephrine in the effector cells,
EXCEPT sweat glands, its ACETYLCHOLINE .
The neurotransmitter of the parasympathetic system is ALWAYS acetylcholine.

18. Hypertension & Tachycardia :
The effects of sympathetic & parasympathetic systems are -in most cases- opposing each other,ex : -
Hypertension & Tachycardia :
Due to sympathetic stimulation.
While in:
Hypotension & Bradycardia.
Due to parasympathetic stimulation.

19. Q) What is the effect of ANS on saliva?
The one exception to the opposite- effect rule is the salivary gland.
Both sympathetic and parasympathetic systems increase secretion in salivary gland , but the secretions are of different types.
sympathetic its very thick leads to having dry mouth.
parasympathetic its very thin & plenty leads to running nose ,lacrimation & salivation (Exocrine gland)

20. Effects of the ANS on the effector organ

21. Parasympathetic Response
Body Tissue/Organ
Sympathetic Response
Parasympathetic Response
Eye
(mydriasis)
(miosis)
Lungs
Dilates bronchioles and reduce secretion
Constricts bronchioles and increase secretions
Heart
Increases heart rate and contractility.
Decreases heart rate and contractility.
Blood vessels
Constricts (skin,mucous memb)
Dilates GI
-Relaxes smooth muscles.
-decrease peristalsis (constipation) and tone
-Contraction of smooth muscle
-Increases peristalsis (diarrhea) and increase tone.
Bladder
Relaxes bladder muscle /contraction of sphincter.
Constricts bladder/relax of sphincter (urination)
Uterus
Relaxes uterine muscles
___________
Salivary gland
Increases salivation (thick and viscous)
Increases salivation (thin and watery secretion)

22. Genitalia
Stimulates ejaculation
Stimulates erection.
Kidney
Secretion of renin
Adrenal medulla
Secreted NE & epinephrine (EP)

23. There are two type of muscle in the iris: 1- The radial muscle: which supplied by the sympathetic system. Mydriasis (dilate of pupil) contraction of the radial muscle 2- The iris sphincter (circular ) muscle : which supplied by the parasympathetic system. Miosis (constrict of pupil) contraction of the iris sphincter (circular) muscle.

24. Ciliary muscle is responsible for accommodation
Supply by parasympathetic fibers
-Ciliary muscles
-Suspensory ligaments
Suspended the lens of the eyes

25. Anti- Cholinergic drugs:
Ciliary muscle (relax )
Suspensory muscle (contract)
mydriasis
Ciliary muscle (contract ) Suspensory muscle (relax) miosis
Lens become more flattened
Lens become more convex and spherical
Cycloplagia
Pts unable to (loss of) Accommodate (far vision)
Blurred vision
Ex. u can’t read at normal distance need for further distance to read well.
Fixed accommodate
Near vision
Ex. Bring the book closer to ur eyes.

27. Q) Which one of the following is characteristic of parasympathetic stimulation? A. Decrease in intestinal motility. B. Inhibition of bronchial secretion. C. Contraction of sphincter muscle in the iris of the eye (miosis). D. Contraction of sphincter of urinary bladder. E. Increase in heart rate.

28. Drugs affecting the autonomic nervous system are divided into :
The cholinergic drugs: act on receptors that are activated by acetylcholine.
The adrenergic drugs :act on receptors that are stimulated by norepinephrine or epinephrine.
Cholinergic and adrenergic drugs both act by either stimulating or blocking receptors of the ANS.

29. Parasympathetic division

30. Cholinergic Agonists

31. or parasympathomimetics agents.
Cholinergic agonists
cholinomimetics
or parasympathomimetics agents.
Cholinergic drugs are drugs that produce effects that mimic the effects of the endogenous Acetylcholine (ACh).

32. Synthesis, Storage and Release of ACh

33. Synthesis, Storage and Release of ACh

34. Cholinergic receptors (cholinoceptor)
Muscarinic receptors
Stimulate smooth muscle
Nicotinic receptors
Stimulate skeletal muscle
M1.
Neurons and Parietal cells
Nm or N1.
Neuromuscular Junction
M2.
Heart.
Presynaptic neurons
Nn or N2.
CNS
Autonomic Ganglia
Adrenal Medulla
M3.
Bladder,.
Exocrine glands (salivary,bronchial,sweat).
Smooth muscles (vascular) M4 M5

36. General Effects of Cholinergic Drugs

37. * Very short duration of action. *Non-selective (affected all organs)
Ach : is the substance that transmits nerve impulses a cross the parasympathetic branch of the ANS .
Acetylcholine (Ach) is rapidly broken down by cholinesterase so not used therapeutically???
Ach choline + acetate.
* Very short duration of action.
*Non-selective (affected all organs)

38. Classification of Cholinergic Drugs
Direct-Acting Cholinergic Agonists
Have a direct action on the receptor for ACH .some drugs are specific & selective for the muscarinic receptor; others are specific for the nicotinic receptor; other on both.
Ex,
Bethanechol
Pilocarpine

39. (cholinesterase inhibitors)
II) Indirect-Acting Cholinergic Agonists
(cholinesterase inhibitors)
Act by blocking the metabolism of ACH by *acetylcholinesterase (AchE) , they compete with ACH for the active site on the cholinesterase enzyme. These drugs effectively increase the concentration of ACH at all cholinergic synapses.
Reversible Anticholinesterases
Irreversible Anticholinesterases
*enzyme destroys Ach

41. Mushrooms of Amanita species
contain muscarine, which if ingested can cause intoxication

42. I- Direct-Acting Cholinergic Agonists

43. 1- Bethanechol :
1-Treatment of urinary retention ???
2- paralysis of intestine.
3- Stimulate GI motility
should not be given if there is mechanical obstruction of intestine or urine flow.

44. 2- Pilocarpine:
Uses:
as eye drop: The drug of choice in the emergency lowering of intraocular pressure of Glaucoma
causes miosis.

46. S/Es:
Salivation
↓ BP
Bronchospasm
Colic, Diarrhea.
Bradycardia

47. (II) Indirect-Acting Cholinergic Agonists
These drugs produce their effect by inactivating the enzyme Acetylcholinesterase, thus increasing ACh level at the receptors (non-selective)
Also called Anticholinesterases
They affect
muscarinic and nicotinic receptors of the ANS
nicotinic receptors of the neuromuscular junction and they also affect the brain

48. II) Indirect-Acting Cholinergic Agonists Cholinesterase inhibitors
1. Reversible Anticholinesterases

49. treatment of Myasthenia Gravis(ORALLY) Paralytic ileus Bladder a tony
Neostigmine
Its effect on NMJ of voluntary muscles.
Can be given orally, I.M., S.C.
treatment of Myasthenia Gravis(ORALLY)
Paralytic ileus
Bladder a tony
it is used as an antidote for competitive neuromuscular blocking agents(IV). (At end of operation).
Edrophonium
Is very short duration (10-20 mins) .
Used in the diagnosis of Myasthenia Gravis (MG) given as (IV)….. why??
If they have MG  dramatically improve muscle strength.
Pyridostigmine
Their durations of action are 3 – 6 hours.
It is used in the chronic management of myasthenia gravis.

50. Myasthenia Gravis
Is an autoimmune disease that involves rapid fatigue of skeletal muscle and weakness .
caused by circulating antibodies against the nicotinic receptors at the postsynaptic neuromuscular junction( lack of ACh released at the nerve endings of parasympathetic)
Using indirect cholinergic drugs will inhibit the activity of AchE &promote muscle contraction.

51. 2. Irreversible Anticholinesterases Organophosphate compounds
Lipid soluble(cross BBB) will abs from skin,lung,gut & conjunctiva.
They form a covalent bond with acetylcholinesterase
thus irreversibly inactivating it.
- They are used as nerve agents in the military
Some of them are used in insecticides
Ex, Echothiophate is used in the management of
glaucoma

52. Organophosphates: – Insecticides – Nerve gases • Malathion • Parathion
• Sarin
• Tabun
• Soman

53. Organophosphates poisoning
Toxicity will produce (All cholinergic effects)
DUMBLESS
-- Runny nose, chest tightness, constricted pupil -- Excessive salivation, urination ,diarrhea and defecation -- Muscle weakness and paralysis -cough, wheezing, bronchoconstriction. -- Coma, convulsions -- Death
D:diarrhea
U:urination
M:miosis
B:bronchial constriction ,bradycardia
L:lacrimation
E:excitation (convulsions)
S:salivation
S: sweating

54. Antidote: Decontamination of clothing Atropine (2mg every 15-60 mins)
Mechanical ventilation.
Diazepam.
Pralidoxime (PAM) enzyme reactivation  Active AchE.

55. Cholinergic Crisis
A condition in which there’s severe cholinergic effects
Caused by excessive intake of irreversible Anticholinesterases inhibitors
Features:
- All the usual cholinergic effects
- Muscle paralysis
Treatment : withdrawal drug and we can used atropine.

56. Major uses of the cholinergic drugs in the treatment of : 1- Urinary retention. 2- Myasthenia gravis. 3- Glaucoma. 4- Paralytic ileus. 5- Bladder a tony