PARASYMPATHMIMETICS

1. PARASYMPATHMIMETICS PARASYMPATHMIMETICS PARASYMPATHMIMETICS

2. CHOLINOMIMETICS, MUSCARINIC AGONISTS, CHOLINOCEPTIVE AGONISTS A) Direct Parasympathomimetics: • 1-Choline Esters: a- Acetylcholine b- Methacholine. c-Carbachol. d-Bethanechol. 2-Cholinomimetic Alkaloids: a- Pilocarpine. b-Muscarine. c-Arecoline. d. oxotremorine

3. B) Indirect Parasympathomimetic (Anti-Cholinesterases): • They inhibit cholinesterase enzymes ( and include both TRUE and Pseudocholinesterasea). • They causes an accumulation of the endogenous A.Ch. leading to the stimulation of both the Muscarinic and Nicotinic receptors to provide the corresponding actions.

4. 1-Reversible Anti-Cholinesterasees: a- Quaternary Alcohols : Edrophonium. It is not a substrate for the Enzyme. b- Carbamate Derivatives. Are Substrate for the Enzyme. -Physostigmine. -Neostigmine. - Pyridostigmine .

5. 2-Irreversible Anti-Cholinesterases (Organophosphorus Compounds): Non-competitive Irreversible inhibition of enzyme. a. Di- isopropyl flurophosphate (DFP ) b. Echothiophate, used as eye drops in the treatment of glaucoma

6. c. Tetraethyl pyrophosphate (TEPP) d. Nerve gases ( Tabun, Sarin & Soman ) e. Agricultural Insecticides ( Parathion, Malathion & Fenthion) f. Metrifonate used in treatment of urinary bilhaziasis

7. A- Choline Esters: 1- Acetylcholine : Synthesis: a- Active Uptake of Choline by Cholinergic Varicosity (Rate Limiting Step) N.B. hemicholinium Inhibits Neuronal Uptake of Choline. b- In Mitochondria of Cholinergic Nerve Terminal (Varicosity): Acetate + Co. A + ATP Acetyl Co. A + ADP c-In Cytoplasm of cholinergic Nerve Ending (Varicosity): Choline + Acetyl Co.A Acetylcholine + Co.A 

8. Absorption and Fate : a. ACh is ineffective orally and be given parenterally. b. Rapidly hydrolyzed in the blood and tissues to choline and acetic acid by the enzyme cholinesterase.

9. Types of cholinesterase : There are two types of cholinesterase : a. True cholinesterase: - occurs in the CNS , red blood cells and in all cholinergic structures. - it is responsible for the hydrolysis of ACh released at the cholinergic sites.

10. b. Pseudocholinesterase: • It occurs in the liver and plasma. • It hydrolyzes drugs with structural similarity to Ach. - The enzyme has two active sites, the anionic site ( containing glutamate ) and the estratic site which contains serine amino acid

11. Properties of Ach: • Very short duration of action because of its rapid hydrolysis by both enzymes. • Not used as a drug. • Not be given orally.

12. PharmacologicalActionsofAcetylcholine There are two main actions called: 1- Muscarinic actions 2- Nicotinic actions.

13. Muscarinic actions

14. 1 - Actions on The Cardiovascular System: A- On the heart : a- Negative Chronotropic SAN  decreases The heart rate (Bradycardia). b- Negativeinotropic on Atrium (decreases the force of contraction). c- Negative Dromotropic (  A-V Conduction).This will reduce the cardiac output

15. B- On the blood vessels: A.Ch. + Non - innervated muscarinic receptors on Intact Endothelium  releases Endothelium Derived Relaxing Factor (EDRF, Nitric Oxide)  increases the cGMP levels vasodilatation. C. Blood pressure: Caues fall in blood pressure as a result of the bradycardia and vasodilatation.

16. The induced vasodilatation of both peripheral and systemic blood vessels leads to; a- Reduction of the systemic ABP b- Reduction of the PVR c- Reduction of the blood flow to some organs e.g. kidney and the liver

17. 2- Actions on Gastrointestinal tract: a- Motility : Stimulation b- Sphincters : Relaxation c- Secretions : Increase

19. 3- Urinary bladder: (Evacuation) a-Detrusor Muscle : Contraction ( urination) b- Sphincters : Relaxation ( urination)

21. 4- Eye : a- Circular Muscles ( M3) : Contraction ( Miosis) b- Ciliary Muscles (M3) : Contraction for near vision ( to see the near objects)

27. 5- Glands: Sweat, salivary and lacrymal : Stimulation to increase secretions. 6- Lung : a- Bronchial Muscles: Contraction ( Bronchoconstriction) b- Bronchal glands : Stimulation ( Increased secretions)

31. Nicotinic Actions

32. 1-Stimulation of Autonomic Ganglia and Adrenal Medulla (Nn) a. Acetylcholine stimulates the autonomic ganglia, resulting the release of noradrenaline from the sympathetic nerve endings .

33. b. Stimulation of the adrenal medulla release of adrenaline and noradrenaline . This effect is blocked by the ganglionic blockers, hexamethonium

34. 2- Motor end plate (Nm): Acetylcholine induces muscle twitching. This effect is blocked by the neuromuscular junction blocker decamethonium and flaxedil.

35. Acetylcholine reversal:In presence of atropine; high doses of acetylcholine produce an increase in blood pressure instead of a decrease.

36. Therapeutic uses of Ach: Not used therapeutically because of: a. Its multiplicity in action, b. Its rapid inactivation by cholinesterase enzymes. c. Being ineffective orally. • Except during cataract , it produces immediate brief miosis

37. 2- Synthetic Cholinomimetic esters : They are characterized by 1. More stable than ACh 2. More selective than Ach 3. Have longer duration of action 4. Active orally and parentrally

38. They can be prepared either by 1. B-methylation, increases the muscarinic activity. 2. Addition of carbamate increases the stability and resist the enzymatic hydrolysis.

39. Properties: 1- ALL are quaternary ammonium compounds 2- Morespecific. 3- Lessmetabolised: Hence have longer duration of action and Effective Orally. 4- NEVER be injected I.V. or I.M. toxicity is abolished by ATROPINE.

40. Contraindicated in: a- Bronchial asthma(Bronchospasm and increased secretion). b- PepticUlcer (Gastric Acid Secretions). c- AnginaPectoris (Hypotension  reduction of coronary blood Flow). d- Thyrotoxicosis (Atrial Fibrillation).

41. Therapeutic Uses of methacholine 1. Paroxysmal atrial tachycardia 2. Raynaud's disease 3.Diagnosis of atropine (Belladonna) toxicity How? BecauseNormally when injected, It causes colics, salivation, lacrimation, sweating. These symptoms do not appear in case of atropine toxicity

42. Uses of carbachol: Used for treatment of Glaucoma and cataract extraction. Uses of Bethanechol ( Urecholine ) 1. Paralytic ileus 2. Post operative retention of urine, in absence of mechanical obstruction 3. Gastric atony 4. Glaucoma

43. A- Methacholine : a- Its nicotinc actions are not clear b- It has longer duration of action c- Its muscarinic actions are more prodominent on the cardiovascular system than on GIT and urinary bladder.

44. B- Carbamylcholine ( Carbachol): a- It has a longer duration of action b- Its nicotinc action is nearly similar to Ach c- Its muscarinic actions are more prodominent on the eye , urinary bladder and GIT. C-Bethanechol ( Urecholine) : It is completely similar to that of carbachol , but the main difference is that it does not have nicotinic actions.

45. II- Cholinomimetic Alkaloides

46. II- Cholinomimetic Alkaloides : Pilocarpine Pilocarpine is a direct prasympathomimetic tertiary amine. a. It is a naturally occurring alkaloid obtained from Pilocarpus jaborandi leaf. b. It is readily absorbed from the GIT. c. Inactivated by cholinesterase enzyme .

47. d. It has longer duration of action. e- Passes the B.B.B (Avoids in Parkinsonism). f- Excreted in urine.

48. Pharmacological actions A. Eye: Locally in the eye as eye drops, it produces: a. Miosis b. Contraction of the ciliary muscle leading to accomodation for near objects c. Decreases the intra-ocular pressure.

49. B. Exocrine glands Increases the secretion of the exocrine glands especially salivary (sialagogue action) and sweat (diaphoretic action) Smooth muscles. C It increases the tone and motility of the GIT, urinary bladder and bronchoconstriction.

50. Therapeutic uses : 1. Treatment of glaucoma, the drug of choice in the emergency of the increased IOP in both open and closed angel glaucoma. 2. To counteract the mydriaticeffect of atropine, homatropine and eucatropine .