Parasympathomimetics (Cholinergic drugs)

The parasympathetic division typically acts in opposition to the sympathetic autonomic nervous system through negative feedback control.
This action is a complementary response, causing a balance of sympathetic and parasympathetic responses.
Overall, the parasympathetic outflow results in the conservation and restoration of energy, reduction in heart rate and blood pressure, facilitation of digestion and absorption of nutrients, and excretion of waste products.
These are drugs that produce actions similar to that of Acetylcholine hence known as parasympathomimetics.
They act either by directly interacting with cholinergic receptors or by increasing the availability of Acetylcholine at these sites.

1. PARASYMPATHOMIMETICS Prof. Amol B. Deore Department of Pharmacology MVP’s Institute of Pharmaceutical Sciences, Nashik

2. Parasympathetic division

3. Parasympathetic division Sympathetic division

4. PARASYMPATHETIC NEUROTRANSMISSION

5. Parasympathetic division synthesize, store and release the neurotransmitter Acetylcholine ( ACh ) hence termed as cholinergic system. Acetylcholine is synthesized locally in the cholinergic nerve endings by the following pathway: Acetyl-CoA + choline choline acetylase Acetylcholine Acetylcholine is produced throughout the neurone, and is stored in inactive form in the synaptic vesicles which are mainly accumulated in nerve endings.

6. Ach biosynthesis

7. Acetylcholine is produced throughout the neurone, and is stored in inactive form in the synaptic vesicles which are mainly accumulated in nerve endings. On arrival of the action potential (nerve impulse) at the nerve endings, in presence of Ca ++ , free Ach molecules are released in to synaptic cleft by the process of exocytosis . The active Ach combines with the cholinergic receptors (muscarinic and nicotinic) on the postsynaptic membrane of innervated target organ.

8. This ACh binds to and activates the cholinergic receptor on the postsynaptic membrane leading to the depolarisation of this membrane. Thus the impulse is transmitted across the synapse. The Ach release in synaptic cleft is rapidly hydrolysed by the enzyme Acetylcholinesterase ( AChE ) within few milliseconds. A part of choline is reabsorbed by nerve endings and later reused in ACh synthesis. A pseudocholinesterase enzyme occurs in the plasma and liver; serves to metabolize ingested esters and Ach.

9. There are two classes of cholinergic receptors – muscarinic and nicotinic. Muscarinic receptors are present in the heart, smooth muscles, secretory glands, eyes and CNS . Three subtypes of muscarinic receptors, M1 to M3. Nicotinic receptors are present in the neuromuscular junction, autonomic ganglia and adrenal medulla. Two subtypes of nicotinic receptors are NM and NN. NM receptors are present at the skeletal muscle end plate and NN receptors at the autonomic ganglia and adrenal medulla. Cholinergic receptors

10. Cholinergic receptors

11. PARASYMPATHOMIMETICS (CHOLINERGICS DRUGS)

12. PARASYMPATHOMIMETICS These are drugs which produce actions similar to that of Acetylcholine hence known as parasympathomimetics . They act either by directly interacting with cholinergic receptors or by increasing availability of Acetylcholine at these sites.

13. Acetylcholine

14. Pharmacological Actions of Acetylcholine

15. RECEPTOR LOCATION PHARMACOLOGICAL ACTION Muscarinic M1 Autonomic ganglia CNS Excitation, memory Muscarinic M2 SA Node AV Node Atrium Ventricle CARDIAC DEPRESSANT ACTION Decreased heart rate Decreased Force of contraction Decreased Excitability of heart Decreased Automaticity of heart Decreased blood pressure Muscarinic M3 Smooth Muscle of Gastrointestinal tract Respiratory tract Urinary tract Eye pupil Urinary sphincter and GIT sphincter   Secretary glands…. Salivary Sweat Lacrimal gland Pancreas Gastric Nasopharyngeal gland   Increased GIT motility, peristalsis Bronchial constriction Bladder and ureter constriction Miosis (pupil constriction) RELAXATION       Increased salivation Increased sweating Increased tears Increased insulin secretion Increased gastric acid secretion Increased mucus secretion

16. Nicotinic N M Neuromuscular junction in Skeletal muscle Skeletal muscle Stimulation Nicotinic N N Autonomic ganglia Adrenal medulla Excitation Release of Adrenaline RECEPTOR LOCATION PHARMACOLOGICAL ACTION

17. Muscarinic action

18. Therapeutic uses of Ach Acetylcholine is not used clinically because- It acts on all muscarinic and nicotinic receptors throughout the body. Thus, overall effect is irrational. On oral administration it is hydrolysed by gastrointestinal enzymes. On intravenous administration, it is metabolised (inactivated) in blood itself by pseudocholine esterase enzyme before reaching site of action. Ach does not cross blood brain barrier hence ineffective for CNS action. Only little fraction of Ach molecules may enter in CNS which get metabolised by acetylcholinesterase enzyme.  

19. DIRECTLY ACTING CHOLINERGICS Choline esters Ex . Acetylcholine, Methacholine , Carbachol Bethanechol , Alkaloids Ex . Muscarine , Arecoline , Pilocarpine

20. Muscarine Arecholine Pilocarpine

21. Mechanism of action These drugs stimulate cholinergic receptors and preganglionic and postganglionic nerve fibers .

22. Therapeutic uses

23. Intestinal obstruction

24. Paralytic ileus

25. INDIRECTLY ACTING CHOLINERGICS Reversible anticholinesterases Ex. Physostigmine , Neostigmine, Pyridostigmine , Rivastigmine , Distigmine , Edrophonium , Galantamine

26. Mechanism of action Reversible anticholinesterases are the drugs that competitively antagonise the acetylcholinesterase ( AchE ) enzyme and prevent the hydrolysis of Acetylcholine . Acetylcholinesterase causes metabolism (hydrolysis) of Ach. Inhibition of AchE enzyme increases both availability and duration of action of acetylcholine.

27. Therapeutic uses

28. Myasthenia gravis

29. Urinary calculi

30. Gallbladder stone

31. Ex . Di-isopropyl flurophosphate (DFP), Tetraethyl pyrophosphate (TEPP), Malathion , Parathion, Ecothiopate , Tabun £ , Sarin £ , Soman £ , Carbaryl * , Propoxur * (*Insecticides, £ Nerve gases for chemical warfare)

32. Organophosphorus compounds never used clinically. They may be used for ophthalmic disorders in minute concentrations.

33. Organophosphorus are easily available and extensively used as agricultural and household insecticides; accidental as well as suicidal poisoning is common.

34. Neostigmine is parasympathomimetic drug which increasing availability of endogenous Acetylcholine at both muscarinic and nicotinic receptor sites. In myasthenia gravis , only nicotinic action is desired hence to suppress muscarinic action (occurring at CNS, heart, blood vessels and eye) atropine ( antimuscarinic ) is administered along with neostigmine.

35. Myasthenia gravis (MG) is a rare autoimmune disorder in which antibodies form against acetylcholine nicotinic postsynaptic receptors at the neuromuscular junction of skeletal muscles. Myasthenia gravis is a neuromuscular disorder that causes progressive weakness and fatigue in the skeletal muscles, which are the muscles your body uses for movement. It occurs when communication between nerve cells and muscles becomes impaired. This impairment prevents crucial muscle contractions from occurring, resulting in muscle weakness.

36. Treatment for Myasthenia Gravis There is no cure for MG. The goal of treatment is to manage symptoms and control the activity of your immune system. Corticosteroids and immunosuppressants can be used to suppress the immune system. These medications help minimize the abnormal immune response that occurs in MG. Additionally, acetylcholinesterase inhibitors, such as physostigmine , neostigmine, pyridostigmine can be used to increase communication between nerves and muscles.