4_5900139072940153266pharmacotherapy.pptx

Therapy

1. Lecture on Drugs acting on the ANS: Cholinergics (for B.Pharm. II-yr.) By:- Niguse M . 1

2. Learning objectives At the end of this session learners are expected to To explain the function and organization of ANS Describe the process of Neurotransmission at Cholinergic neurons Describe the types and distribution of cholinergic receptors Identify the different class of cholinergic agonists T heir SARs and T herapeutic purpose. 2

3. Introduction… The nervous system comprises The brain and spinal cord(CNS) Various types of nerves Afferent nerves Carry sensory impulses from all parts of the body to the brain Efferent nerves Through which messages are conducted to the muscles & all organs of the body Somatic nerves Has sensory components which convey sensations from The eye , nose & other sensory organs to the brain The autonomic nervous system Has an important function in maintaining the internal environment of the human body in a steady state Role is vital in returning the body to a homeostatic state Conveys sensory impulses from The blood vessels The heart and All of the organs in the chest, abdomen & pelvis Through nerves to the brain, mainly the medulla, pons & hypothalamus 3

4. Introduction…. Organization of the Nervous System 4

5. Introduction…. The autonomic nervous system Works generally without voluntary control (below the conscious level) Autonomic = self governing We do not consciously direct Rate of the heart beat / heart rate Diameter of the blood vessels Blood pressure Digestion Respiration Blood pH The need to stimulate salivary glands to produce saliva etc.. Impulses often do not reach our consciousness but elicit largely Automatic or reflex responses through the efferent autonomic nerves Thereby eliciting appropriate reactions of the heart, vascular system, etc 5

6. Introduction…. Autonomic Nervous System Based on the anatomic origin of out flow Divided in to two Sympathetic division Come from thoracic and lumber regions of the spinal cord Preganglionic nerves are short & synapse in paired ganglia adjacent to spinal cord Is the “ Fight or Flight” branch of the ANS Increases Cardiac output and Pulmonary ventilation Directs blood to muscles Raises blood glucose Slows down digestion, kidney filtration & other functions not needed during emergencies Whole sympathetic system tends to “go off” together Sympathetic system not required in controlled environment 6

7. Introduction… Autonomic Nervous System Parasympathetic divisions Comes from cranial & sacral regions of the CNS Have long preganglionic nerves which synapse at ganglia near or on the organ innervated Is the “ Rest & Digest” branch of the ANS Promotes normal maintenance of the body Acquires building blocks and energy from food Involved in urination, defecation & getting rid of the wastes Promotes secretion & mobility of different parts of the digestive tract Does not “go off” together; activities initiated when appropriate Sympathetic & Parasympathetic systems often function in antagonistic ways 7

8. Introduction… Autonomic Nervous System In the ANS there are two nerves between the CNS and the organ The nerve cell bodies for the second nerve are organized into ganglia CNS  Preganglionic nerve  Ganglion  Postganglionic nerve  Organ At each junction neurotransmitters are released to carry the signal to the next nerve or organ Neurons in these systems classified Based on chemical neurotransmitters they release to mediate a nerve impulse 8

9. Motor nerves of peripheral nervous system 9

10. Introduction……. Drugs affecting the autonomic nervous system (ANS) are divided into two sub-groups According to the type of neuron involved in their mechanism of action. The 1 st group, called the cholinergic drugs , They act on receptors that are activated by acetylcholine ( ACh ). The 2 nd group, called the adrenergic drugs , They act on receptors that are stimulated by norepinephrine or epinephrine. Both the cholinergic and adrenergic drugs act either by stimulating or blocking neurons of the ANS.

11. Introduction ….... T he cholinergic neuron The preganglionic fibers terminating I n the adrenal medulla, T he autonomic ganglia ( both parasympathetic and sympathetic ), and T he post-ganglionic fibers of the parasympathetic division They use acetylcholine ( ACh ) as a neurotransmitter. Cholinergic neurons also innervate voluntary muscles of the somatic system and are also found in the CNS . 11

12. Introduction contd... Neurotransmission at Cholinergic neurons Neurotransmission in cholinergic neurons involves 6 steps. Synthesis of acetylcholine (ACh) Uptake into storage vesicles Release of neurotransmitter Binding to receptor Degradation of ACh Recycling of Choline 12

13. Introduction contd... Neurotransmission at Cholinergic neurons contd... The 1 st four, synthesis, storage, release and binding of the ACh to a receptor, A re followed by the 5 th step, degradation of the neurotransmitter in the synaptic gap (ie., the space between the nerve endings and adjacent receptors located on nerves or effector organs), A nd the 6 th step, the recycling of choline. 13

14. Introduction contd... Neurotransmission at Cholinergic neurons contd... 14

15. Introduction contd... Neurotransmission at Cholinergic neurons contd... Synthesis of ACh Choline is transported from the extracellular fluid into the cytoplasm of the cholinergic neuron by a carrier system that cotransports Na and can be inhibited by the drug hemicholinium . Choline acetyltransferase (CAT) catalyzes the reaction of choline with acetyl CoA to form ACh in the cytosol. 15

16. Introduction contd... Neurotransmission at Cholinergic neurons contd... Storage of ACh in vesicles The ACh is packaged into vesicles by an active transport process coupled to the efflux of protons. The mature vesicle not only contains ACh but also ATP and proteoglycan. 16

17. Introduction contd... Neurotransmission at Cholinergic neurons contd... Release of ACh When an action potential propagated by the action of voltage-sensitive Na channels arrives at a nerve ending, voltage-sensitive Ca channels in the presynaptic membrane open, causing an increase in the conc. of intracellular Ca. Elevated Ca levels promote the fusion of synaptic vesicles with the cell membrane and release of ACh into the synapse. This release is blocked by botulinum toxin. 17

18. Introduction contd... Neurotransmission at Cholinergic neurons contd... Binding to receptor ACh released from the synaptic vesicles diffuses across the synaptic space and binds to either post-synaptic receptors on the target cell or to pre-synaptic receptors in the membrane of the neuron that released the ACh. Binding to the receptor leads to a biological response within the cell such as the initiation of a nerve impulse in a postganglionic fiber or activation of specific enzymes in effector cells as mediated by 2 nd messenger molecules. 18

19. Introduction contd... Neurotransmission at Cholinergic neurons contd... Degradation of Ach The signal at the post-junctional effector site is rapidly terminated. This occurs in the synaptic cleft where acetylcholinesterase cleaves ACh to choline and acetate. 19

20. Introduction contd... Neurotransmission at Cholinergic neurons contd... Recycling of Choline Choline may be captured by a Na-couped high affinity uptake system that transports the molecule back into the neuron, where it is acetylated and stored until released by a subsequent action potential. 20

21. Introduction contd... C holinergic receptors ( cholinoceptors ) Two families of cholinoceptors are – Muscarinic receptors Nicotinic receptors They can be distinguished from each other on the basis of their different affinities for agents that mimic the action of ACh (cholinomimetic agents). 21

22. Introduction contd... MUSCARINIC RECEPTORS These receptors, in addition to binding ACh, also recognize muscarine, an alkaloid that is present in certain poisonous mushrooms . By contrast, the muscarinic receptors show only a weak affinity for nicotine. 22

23. Introduction contd... MUSCARINIC RECEPTORS contd... several sub-classes of muscarinic receptors have been p’cologically distinguished as M 1 , M 2 , M 3 , M 4 , and M 5 . Locations of muscarinic receptors These receptors have been found on ganglia of the peripheral nervous system and on the autonomic effector organs, such as heart, smooth muscle, brain and exocrine glands . Although all 5 sub-types have been found on neurons, M 1 receptors are also found on gastric parietal cells, M 2 receptors on cardiac cells and smooth muscle, and M 3 receptors on exocrine glands and smooth muscle . 23

24. Introduction contd... MUSCARINIC RECEPTORS contd... Mechanisms of ACh signal transduction A no. of different molecular mechs. transmit the signal generated by ACh occupation of the receptor. For ex., when the M 1 or M 3 receptors are activated, the receptor undergoes a conformational change and interacts with a G protein, which in turn activates phospholipase C . This leads to the hydrolysis of phosphadylinositol-(4,5)-biP to yield diacylglycerol and inositol, which cause an increase in intracellular Ca ++ . This cation can then interact to stimulate or inhibit enzymes, or cause hyperpolarization, secretion or contraction . 24

25. Introduction contd... MUSCARINIC RECEPTORS contd... Mechanisms of ACh signal transduction contd... In contrast, activation of the M 2 sub-type on the cardiac muscle stimulates a G protein that inhibits adenylyl cyclase and increases K + conductance, to which the heart responds with a decrease in rate and force of contraction . 25

26. Introduction contd... MUSCARINIC RECEPTORS contd... Muscarinic agonists and antagonists Attempts are currently underway to develop muscarinic agonists and antagonists that are directed against specific receptor subtypes. For ex., Pirenzepine, a tricyclic anticholinergic drug, selectively inhibits M 1 muscarinic receptors, such as in the gastric mucosa. At therapeutic doses, Pirenzepine does not cause many of the side effects seen with the non-subtype-specific drugs. Therefore , Pirenzepine may be useful in the treatment of gastric and duodenal ulcers. 26 pirenzepine

27. Introduction contd... NICOTINIC RECEPTORS Nicotine initially stimulates and then blocks the receptor. Nicotinic receptors are located in the CNS , adrenal medulla, autonomic ganglia, and the neuromuscular junction . Drugs with nicotinic action stimulate the nicotinic receptors located on these tissues. The nicotinic recepts of autonomic ganglia differ from those of the neuromuscular junction. For ex., ganglionic receptors are selectively blocked by hexamethonium , whereas neuromuscular junction receptors are specifically blocked by tubocurarine. 27

28. Introduction contd... NICOTINIC RECEPTORS contd... These receptors, in addition to binding ACh, also recognize nicotine but show only a weak affinity for muscarine . 28

29. CLASSIFICATION Indirect acting (reversible) Cholinergic agonists Direct acting Indirect acting (irreversible) Acetylcholine Bethanechol Carbachol Pilocarpine Edrophonium Neostigmine Physostigmine Pyridostigmine Echothiopate Isoflurophate 29

30. Classification contd... PARASYMPATHOMIMETIC AGENTS The term Cholinergic and parasympathomimetic are not equivalent but are generally considered as synonyms. Compds . that mimic the action of ACH at parasympathetic system are called as cholinergic parasympathomimetic agents. Thus , these drugs stimulate the effect of cells innervated by post-ganglionic parasympathetic nerves . They are classified as direct-acting and indirect acting cholinergics. 30

31. Classification contd... Direct-acting cholinergic agonists Cholinergic agonists mimic the effects of ACh by binding directly cholinoceptors . These agents are The esters of choline Cholinomimetic alkaloids All these drugs have longer duration of action than ACh . Some of the more therapeutically useful drugs ( pilocarpine and bethanechol) preferentially bind to muscarinic receptors and are sometimes referred to as muscarinic agents . 31

32. Classification contd... Direct-acting cholinergic agonists contd... Choline esters Choline esters are synthetic derivatives of choline. They stimulate muscarinic receptors affecting the cardiac muscle, smooth muscle, exocrine glands and the eye. They are lipid-insoluble and do not readily enter the CNS (effects occur primarily in the periphery ). They are highly resistant to being destroyed by AChEs . The choline esters differ in their relative sensitivity to hydrolysis and in their relative nicotinic and muscarinic effects. 32

33. Classification contd... Direct-acting cholinergic agonists contd... Choline esters contd... Thus, methacholine , while still susceptible to hydrolysis, is much more stable than ACh , and Carbachol and Bethanechol are resistant to hydrolysis by AChE . Carbachol has a high level of nicotinic activity, Methacholine with little nicotinic activity, and Bethanechol essentially of no nicotinic activity . 33

34. Classification contd... Direct-acting cholinergic agonists contd... Choline esters contd... SAR Ach is the acetyl ester of choline, and is a quaternary ammonium compd. which possesses a cationic (positively charged) head joined by a two carbon chain to an ester group. 34

35. Classification contd... Direct-acting cholinergic agonists contd... Choline esters contd... SAR contd... 35

36. Classification contd... Direct-acting cholinergic agonists contd... Choline esters contd... SAR contd... These drugs may differ from ACh in any of 3 ways – Relative muscarinic activity Relative nitonic activity Resistance to enzymatic hydrolysis The degree of muscarinic activity decreases by replacement of acetyl group, however, some substitutions result in resistance to hydrolysis. 36

37. Classification contd... Direct-acting cholinergic agonists contd... Choline esters contd... SAR contd... Carbachol , where the acetyl group is replaced by a carbamyl, has both muscarinic and nicotinic properties, but is almost entirely resistant to hydrolysis by AChE or BuChE. Bethanechol is similarly resistant to hydrolysis; however, it possesses mainly muscarinic activity as Methacholine, due to the β -methyl substitution. 37

38. Classification contd... Direct-acting cholinergic agonists contd... Choline esters contd... SAR contd... Although both Carbachol and Bethanechol possess muscarinic activity, their effects on the heart are minimal and their GIT effects predominate. Methacholine, conversely, has its effects predominantly on the heart. 38

39. Summary Acetylcholine—structure, SAR, and Receptor binding The positively charged nitrogen atom is essential to activity. Replacing it With a neutral carbon atom eliminates activity. The distance from the nitrogen to the ester group is important. The ester functional group is important. The overall size of the molecule cannot be altered greatly. Bigger molecules have poorer activity. The ethylene bridge between the ester and the nitrogen atom cannot be extended. There must be two methyl groups on the nitrogen. A larger, third alkyl group is tolerated, but more than one large alkyl group leads to loss of activity. Bigger ester groups lead to a loss of activity . 39

40. 40 Modification of the ethylene group There should be no more than five atoms Between the nitrogen & the terminal hydrogen atom for maximal activity Replacement of hydrogen atoms of the ethylene bridge By alkyl groups larger than methyl Affords compounds much less active than ACH Introduction of a methyl group on the carbon  to the 4 nitrogen Affords acetyl- -methylcholine (methacholine) Is selective for muscarinic receptors Has muscarinic potency equivalent to that of ACH Possesses much greater muscarinic potency than nicotinic potency A methyl group on the carbon -to the 4 nitrogen Affords acetyl -methylcholine Relative to ACH, activity is reduced at both muscarinic & nicotinic receptors It exhibits greater nicotinic than muscarinic potency

41. 41 Modification of the acyloxy group The ester functional group is essential Replacing the acetyl group by higher homologue (propionyl or butyryl) The resulting ester is less potent than ACH Choline esters of Aromatic or high mol. wt. acids Possess cholinergic antagonist activity Chemical instability of ACH can be solved by Replacing the acetyloxy group with a functional group resistant to hydrolysis Lead to the synthesis of carbamic acid ester of choline A potent cholinergic agonist - Carbachol Possessing both muscarinic & nicotinic activity Less readily hydrolyzed in the GIT or by AChE Can be administered orally

42. Classification contd... Direct-acting cholinergic agonists contd... Choline esters contd... Therapeutic uses Methacholine was used to control supraventricular tachycardia. Bethanechol is used as a GIT stimulant to relieve urinary retention. ACh is used to produce brief periods of miosis during extraction of cataracts. Methacholine is also used for diagnosis of belladonna poisoning, familial dysautonomia , and bronchial hyperreactivity . 42

43. Classification contd... Direct-acting cholinergic agonists contd... Cholinomimetic alkaloids Muscarine, Arecoline, Pilocarpine are natural alkaloids; Oxotremorine and Aceclidine are of synthetic . 43

44. Classification contd... Direct-acting cholinergic agonists contd... Cholinomimetic alkaloids Pilocarpine, Muscarine, and Oxotremorine are relatively specific for muscarinic ACh receptors, while Arecoline can activate nicotinic receptors. The p‘cological actions of the alkaloids are similar to that of the choline esters: miosis, increased tone and motility of GI and urinary tract, increased secretion of the exocrine glands, hypotension and bradycardia. Unlike the choline esters, these drugs cross the BBB and therefore have profound CNS side effects. 44

45. Classification contd... Direct-acting cholinergic agonists contd... Cholinomimetic alkaloids Therapeutic uses These drugs (essentially only Pilocarpine) is in the treatment of glaucoma. 45

46. Classification contd... Direct-acting cholinergic agonists contd... 46

47. Classification contd... Anticholinesterases (Indirect-acting) Acetylcholinesterase (AChE) is an enzyme (tetrameric protein) that cleaves acetylcholine to acetate and choline. AChE has two important sites. The anionic site and esteratic site. The anionic site possesses a glutamate residue, and in esteratic site histidine imidazole ring and a serine hydroxyl group are present. 47

48. Classification contd... Anticholinesterases (Indirect-acting) contd... AChE inhibitors have been used clinically in the treatment of myasthenia gravis. They are also employed to treat glaucoma and more recently in Alzheimer’s disease . In addition, cholinesterase inhibitors are widely utilized as pesticides and , if misused, can produce toxic responses in mammals and man. 48

49. Classification contd... Anticholinesterases (Indirect-acting) contd... Reversible ( Carbamates ) All these drugs are structurally resemble to cholinesterase enzyme and have greater affinity for the active sites which results into a temporary inhibition of the enzyme. Hence they are termed as “ Reversible anticholinesterases ”. 49

50. Classification contd... Anticholinesterases (Indirect-acting) contd... Reversible 50

51. Classification contd... Anticholinesterases (Indirect-acting) contd... Reversible contd... Physostigmine Structure-activity relationships (SAR): The carbamate group is essential to activity. The benzene ring is important. The pyrrolidine nitrogen (which is ionized at blood pH) is important . 51

52. Anticholinesterases (Indirect-acting) contd... Analogues of physostigmine Physostigmine has limited medicinal use since it has serious side-effects, and as a result it has only been used in the treatment of glaucoma. However, simpler analogues have been made and have been used in the treatment of myasthenia gravis and as an antidote to curare. These analogues retain the important features mentioned above . Miotine :- still has the necessary carbamate, aromatic, and tertiary aliphatic nitrogen groups. It is active as an antagonist but suffers from the following Disadvantages:- It is susceptible to chemical hydrolysis. It can cross the blood-brain barrier as the free base . This results in side-effects due to its action in the CNS. 52

53. Neostigmine: - was designed to deal with both the problems described above. First of all, a quaternary nitrogen atom is present so that there is no chance of the free base being formed. Since the molecule is permanently charged , it cannot cross the blood-brain barrier and cause CNS side-effects. Anticholinesterases (Indirect-acting) contd... Miotine 53

54. Classification contd... Anticholinesterases (Indirect-acting, Irreversible) A no. of synthetic organophosphate compds . have the capacity to bind covalently to acetylcholinesterase . The result is a long lasting increase in ACh at all sites where it is released. Many of these drugs are extremely toxic and were by the military as nerve agents. Related compds. such as Parathion are employed as insecticides. 54

55. Classification contd... 3. Anticholinesterases contd... Irreversible (SAR) 55

56. SPECIFIC DRUGS…Summary Acetylcholine ( ACh ) It is a quarternary ammonium compd. Ach is the most widespread autonomic transmitter present in the body. ACh virtually has no therapeutic effect b’coz of its differences of action and susceptability to hydrolysis by acetylcholinesterase and plasma butyryl -cholinesterase . ACh has both muscarinic and nicotinic activity. 56

57. Specific drugs contd... Synthesis of Ach The synthesis of ACh involves the reaction of choline with active acetyl (CoA ). The active acetyl CoA being formed by the combination of acetate with CoA. The reaction between acetylCoA and choline is catalyzed by the enzyme cholineacetylase . 57

58. Specific drugs contd... Carbacho l It is an ester of carbamic acid. In carbachol, the terminal methyl (-CH 3 ) group of ACh is replaced by amino (–NH 2 ) group. It is a poor substrate for acetylcholinesterase and  is not readily hydrolyzed than ACh . It has both muscarinic and nicotinic actions. It is used to reduce intraocular pressure and also to induce miosis (pupil constriction) and relieves intraocular pressure of glaucoma. 58

59. Uses of Cholinergic drugs For myasthenia gravis, both to diagnose (edrophonium) and to treat (neostigmine, pyridostigmine, distigmine ). To stimulate the bladder the bowel after surgery (bethanechol, carbachol, distigmine ). To lower intraocular pressure in chronic glaucoma ( pilocarpine ). To bronchodilate patients with airflow obstruction (ipratropium, oxitropium ). To improve cognitive functive in Alzheimer’s disease (rivastigmine, donepezil). 59

60. End of lecture on “Cholinergic drugs” 60