Drugs affecting the autonomic Nervous system.pptx

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1. Drugs affecting the autonomic Nervous system Unit two pharmacology I Bon Voyage

2. PHARMACOLOGY OF AUTONOMIC nervous system ANATOMY AND PHYSIOLOGY Nervous system controls center of the body divided into Central Nervous System (CNS) includes: Brain and spinal cord The peripheral nervous system (PNS) includes: SNS and ANS PNS includes: Somatic nervous systems - controls voluntary functions [skeletal muscle function] Autonomic nervous systems - controls involuntary functions like circulation, respiration, digestion and the maintenance of body temperature 2

3. Autonomic Nervous System The ANS is part of the peripheral nervous system and it controls many organs and muscles within the body. In most situations, we are unaware of the workings of the ANS because it functions in an involuntary, reflexive manner.

4. Introduction Some Important Terms ANS: The system of nerves and ganglia that innervates the blood vessels,heart,smooth muscle,viscera and glands Controls their involuntary functions Consisting of sympathetic and parasympathetic. Neurones involved in the ANS pathway Preganglionic Postganglionic Ganglia Sympathetic trunk ganglia Preventral ganglia Terminal ganglia

5. Comparison of Somatic and Autonomic Systems

6. ANS is most important In non emergencies In emergencies Fight or Flight Rest and Digest

7. Sympathethic & Parasympathetic Nervous system Two have opposite actions in many cases One activates physiological response and other inhibits it According to older simplifications one is “excitory”(SNS) and other(PSNS) is “inhibitory”. But overturned due to many exceptions Modern characterizations: SNS (quick response mobilizing system) & PSNS(more slowly activated dampening system)

8. Neurotransmiters CHOLINERGIC:- Neurons which sectrets achtylcholamine ADRENERGIC:- Neurons which secrets norepinephrin

9. Neurotransmiters All preganglionic and postganglionic parasympathetic neurons secret acetylcholine 2% of postganglionic sympathetic secret acetylcholine These are termed as CHOLINERGIC 98% of postganglionic sympathetic neurons secret norepinephrin These neurons termed as ADRENERGIC.

10. CHOLINERGIC RECEPTORS Two types of receptors that bind Ach Nicotinic and muscarinic. Named after drugs that bind to them and mimic ACh effects Responses in parasympathetic and sympathetic ganglia, as well as skeletal muscle are nicotinic The response of most autonomic effector cells in peripheral visceral organs is typically muscarinic Muscarinic (M): M1- Stomach(Increase motility and secretion) M2 – Heart(reduce heart rate) M3 - Smooth muscle (GI, bronchi, Genito-urinary, some BV), Exocrine glands Nicotinic (N): Nn - Autonomic ganglia (N-I) Nm - Skeletal muscle (N-II) 10

11. Adrenergic neurotransmitters and receptors Receptors for the sympathetic neurotransmitters Alpha-adrenergic receptors Beta-adrenergic receptors Alpha-adrenergic Receptors: Divided into α 1 and α 2 receptors Differentiated by their location on nerves α 1 located on postsynaptic effector cells (the cell, muscle, or organ that the nerve stimulates) α 2 located on presynaptic nerve terminals and control the release of neurotransmitters The predominant α 1 -adrenergic agonist responses are: Vasoconstriction and CNS stimulation 11

12. Beta-Adrenergic Receptors All are located on postsynaptic effector cells β 1 -adrenergic receptors—located primarily in the heart β 2 -adrenergic receptors—located in smooth muscle of the bronchioles, arterioles and visceral organs The beta-adrenergic agonist response results in: Glycogenolysis Bronchial, GI and uterine smooth muscle relaxation Cardiac stimulation 12

13. Fate of Released catecholamine's Catecholamine's are removed through Neuronal reuptake (uptake 1) Diffusion into circulation Active transport (uptake 2) into postjunctional cells. Metabolism Metabolism Monoamine Oxidase ( MAO) located in both neurons and post- junctional cells. Deaminates catecholamines Catechol -O- methyltransferase ( COMT): located in post- junctional cells. Catalyzes the O- methylation of catecholamines 13

14. Fate and metabolism of acetylcholine Removal by ACETYLCHOLINESTERASE (AChE) AChE Found in cholinergic neurons and neuromuscular junction. Butyrylcholinesterase (pseudocholinesterase) Found in liver and plasma 14

15. Sympathetic and Parasympathetic Effects [summary] 15

16. CLASSIFICATION OF AUTONOMIC DRUGS 1. Drugs acting on the parasympathetic NS 2. Drugs acting on the sympathetic NS Parasympathomimetics or cholinergic drugs: Mimic acetylcholine or the effects of parasympathetic nerve stimulation 2. Parasympatholytics : Inhibit parasympathetic nervous system activity or that of cholinergic drugs Sympathomimetics or adrenergic drugs Mimic the effects of sympathetic nerve stimulation 2. Sympatholytics: Inhibit the activity of sympathetic nerve or that of sympathomimetics 16

17. CHOLINERGIC DRUGS (PARASYMPATHOMIMETICS) There are two groups of cholinergic drugs: Direct acting Indirect acting Direct-acting: Bind to and activate muscarinic or nicotinic receptors and include the following subgroups: a. Esters of choline: Methacholine Carbachol Betanechol b. Cholinergic alkaloids: Pilocarpine Muscarine Nicotine 17

18. PARASYMPATHOMIMETICS ACHE destroys acetylcholine and shorten its half life . Inhibition of acetylcholinesterase enzyme delays destruction of acetylcholine, thereby prolonging its effect. Due to inhibition more ACh is available at the receptors ACE inhibitors are classified Reversible Irreversible 18 Indirect-acting cholinergics Inhibition of acetylcholinesterase (ACHE) enzyme

19. Pharmacological action of cholinergic drugs Increased body secretion : Salivation, lacrimation, and increased bronchial, gastric, intestinal and sweat gland secretion. Increased GI motility: Diarrhea, Gastrointestinal cramps, Emesis. Increase tone and motility of bladder and relaxation of bladder sphincter Contraction of gallbladder and ducts: urinary urgency Bronchoconstriction Constriction of the iris to produce meiosis: Reduced IOP Decreases heart rate, Vasodilatation At recommended doses, the cholinergics primarily affect the Muscarinic receptors. At high doses, cholinergics stimulate the Nicotinic receptors. Desired effects: from muscarinic receptor and many undesirable effects are due to nicotinic receptors 19

20. Direct-acting cholinergic drugs Esters Of Choline ACETYLCHOLINE: The prototypic cholinergic agent Neurotransmitter at all cholinergic sites Poorly absorbed from the gastric mucosa In the blood it is rapidly hydrolyzed by the enzyme cholinesterase into acetic acid and choline Synthetic derivatives of choline and include: Metacholine, carbachol and betanechol Advantages over acetylcholine: Have longer duration of action Effective orally as well as parenterally Relatively more selective in their actions 20

21. CHOLINE ESTERS Cholinesterase Susceptibility Muscarinic action Nicotinic action Acetylcholine ++++ +++ +++ Methacholine + ++++ None Carbachol Negligible ++ +++ Bethanechol Negligible ++ None 21

22. Direct-acting cholinergic drugs CARBACHOL Completely absorbed from the GIT Stable towards hydrolysis by cholinesterase enzyme Can be given both orally and parenteraly Indications Glaucoma Retention of urine (postoperative ) BETANECHOL S imilar to carbachol in all parameters Clinical indications: better advantage over carbachol  as a result of lack of nicotinic actions Contraindications of choline esters: Bronchial asthma Peptic ulcer disease 22

23. Direct-acting cholinergic drugs PILOCARPINE Readily absorbed from the gastrointestinal tract Not hydrolyzed by cholinesterase enzyme Stimulate muscarinic receptors to bring about all the muscarinic effects of acetylcholine Indication Glaucoma- facilitate outflow of aqueous humor into canal of Schlemn 23

24. Indirect-acting cholinergic 1. Reversible Physostigmine Neostigmine Pyridostigmine Amebonium Edrophonium Tacrine Donezepil Galantamine 2. Irreversible Echothiophate (useful clinically) Parathione Malathione Nerve gases “ tabun, sarin, and soman” 24

25. Indirect-acting Cholinomimetics Cholinesterase inhibitors fall into three groups: 1. Simple Alcohol Edrophonium 2. Carbamates Physostigmine, Neostigmine, Pyridostigmine… 3. Organophosphates React to form a stable phosphrylated enzyme which is essentially not hydrolyzed Echothiophate- less absorbable Parathion, malathion, tabun, sarin and soman 25

26. Cholinesterase inhibitors PHYSOSTIGMINE NEOSTIGMINE Can pass the blood brain barrier Prolong the effect of endogenous acetylcholine No direct effect on cholinergic receptors Indications Glaucoma Atropine over dosage (antidote) Cannot pass the blood brain barrier Unlike physostigmine, it has a direct nicotinic action on skeletal muscles Indications Myasthenia gravis Paralytic ileus Reversal of effect of muscle relaxants, e.g. tubocurarine Post operative urine retention 26

27. Toxication by cholinesterase inhibitors Sign and symptom Muscarnic manifestation Bronchonstriction and increased bronchial secretion Sweating, Salvation, lacrimation Bradycardia , hypotension Miosis , blurring of vision Urinary urgency Nicotinic manifestation Fasciculation's, weakness or paralysis of skeletal muscles Depolarizing blockade of neuromuscular junction Paralysis of muscles of respiration Hypertension, tachycardia 27

28. Toxication by cholinesterase inhibitors Sign and symptoms… CNS manifestation Restlessness, insomnia, confusion, tremor, convulsions, respiratory depression, and cardiovascular collapse. Treatment Supportive measures: Atropine: protects against peripheral muscarnic effects and some CNS effects Diazepam if seizures occurs Pralidoxime (2-PAM) is a potent antidote as reactivators of acetylcholiesterase if given early. But it is not used with reversible cholinesterase inhibitors like physostgimine. 28

29. PARASYMPATHOLYTIC DRUGS Anticholinergics block the effects of acetylcholine and other cholinergic drugs at cholinergic receptors They fall into two major families: Antinicotinics : include: Ganglion blockers : hexamethonium, trimethaphan Neuromuscular blockers : gallamine, tubocurarine, pancuronium 2. Antimuscarinics : Atropine, propantheline, Ipratropium, benztropine , Pirenzepine , hyocine 29

30. Antimuscarinics: Atropine Extracted from the plant: Atropa belladonna, Datura stramonium Pharmacokinetics Well absorbed from all sites of administration except from the skin wall About 60% of the drug excreted unchanged in urine . Mechanism of action Antagonizes the effect of acetylcholine by competing for the muscarinic receptors D oes not distinguish between M 1 , M 2 & M 3 subgroups of muscarinic receptors Organs differ in sensitivity for atropine Most sensitive: salivary glands, bronchial glands, sweat glands Intermediate sensitivity - heart tissues least sensitive - parietal cells 30

31. Pharmacological action of Atropine Atropine : CNS Sedation in therapeutic doses Hallucinations in toxic doses Bradycardia when given parenterally Antimotion sickness effects Antiparkinsonism effects Atropine – Eye Relaxes pupillary sphincter muscle Unopposed sympathetic effects Mydriasis or dilation Paralysis of the ciliary muscle - cycloplegia Reduction in lacrimal secretion - dry eye 31

32. Pharmacological action of Atropine Atropine: CVS Tachycardia due to blockade of vagal slowing Opposes Ach effects on SA depolarization Opposes Ach effects on AV conduction Ventricles are less affected Overall - little effect on BP Atropine: on other system Respiratory: - bronchodilatation and reduction of secretion GIT: - decreased motility and secretions: constipation GUS: - Relaxes smooth muscle of ureter and bladder wall Sweat Glands: - Suppresses sweating

33. Anticholinergics ... clinical indication: Atropine Pre anesthetic medication -to reduce secretion: atropine Anti-spasmodic: Dicyclomine: Organophosphate poisoning antidote Motion sickness: Hyoscine (scopolamine) Asthma: Ipratropium Anti-ulcer: pirenzepine Benztropine: anti-Parkinsonism Side effects • Dryness of mouth, tachycardia, blurred vision, retention of urine Contraindications Glaucoma Bladder outlet obstruction 33

34. Antcholinergics ... Atropine Poisoning Symptom term: Dry as a bone, Blind as a bat, Red as a beet Very dangerous in children – hyperpyrexia Peripheral symptom: dry mouth, blurred vision, difficulty swallowing, marked thirst, hot dry flushed skin, dilated skin, tachycardia, increased BP, micturition difficulty, respiratory/ cardiovascular collapse CNS symptom: nervousness, excitation, confusion, hallucination, weakness, giddiness, muscular incoordination, maniacal tendencies, medularly stimulation progressing to depression, coma, and finally death. Treatment: Gastric lavage, supportive measures for maintenance of circulation and respiration, physostigimine?

35. GANGLIONIC BLOCKING AND STIMULATING AGENTS C ompetitively block the action of acetylcholine at nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia Nicotine is a ganglion stimulant at low dose while at high dose it is a ganglion blocker. U sed in pharmacologic and physiologic research L imited clinical use Some ganglion-blocking drugs Nicotine Hexamethonium Tetraethylammonium Mecamylamine Trimethaphan 35

36. Ganglion stimulant Nicotine Depolarizes autonomic ganglias and component of cigarette Organ effects of nicotinic receptor stimulation : is determined by predominate branch of the autonomic nervous system in that organ CV effects and Eye mydiasis - largely sympathetic Increased Heat rate, cardiac output, increased BP Vasoconstriction of vascular beds GI & Urinary, salivary glands - largely parasympathetic Increase in motility and secretion Neuromuscular stimulation followed by blockade 36

37. Ganglionic blocking agent: Trimetaphan Mechanism: Competitively block nicotinic Nn receptors at both sympathetic & parasympathetic ganglia Adverse effects: Sympathetic block: Vasodilatation: PR,  BP (orthostatic hypotention) Sexual dysfunction: (  Ejaculation) Parasympathetic block: Dry mouth, constipation, urine retention, blurred vision Hot flushed skin &  body temp due to  sweating Use: During surgical anesthesia to reduce bleeding, which is due to hypotensive effect (orthopaedic & neuro-surgery) Adverse effects: orthostatic hypotension, dilation of pupils and blurred, dry mouth, urinary hesitancy, constipation, impotence in males, Orthostatic hypotension 37

38. NEUROMUSCULAR BLOCKERS P rimarily used as adjuncts during general anesthesia to facilitate tracheal intubation and optimize surgical conditions Competitive Antagonists of the Nicotinic Receptor D-tubocurarine (curare) Vecuronium Pancuronium Atracurium etc… Depolarizing Blockers Increase muscle strength until Acetylcholine depleted from the neural vesicles; then fasciculation and skeletal muscle paralysis Succinylcholine Decamethonium 38

39. Duration of action of neuromuscular blocking agents Ultra-Short: Succinylcholine Short: Mivacurium Intermediate: Rocuronium, Vecuronium, Atracurium Long: Pancuronium, curare, metocurine, Pipecuronium, Doxacurium

40. SYMPATHOMIMETIC DRUGS (ADRENERGICS) Sympathetic nerve stimulation results release of endogenous catecholamine's which effects the stimulation Endogenous catecholamine's includes: norepinephrine , epinephrine, and dopamine Effects of catecholamine can be intervened at metabolism or receptor level At metabolism: Storage, synthesis and release and termination of action At receptor level: β and α receptors 40

41. SYMPATHOMIMETIC DRUGS 41

42. Sympathomimetics Direct Acting : Directly stimulates receptors (NE, Epi, Isoproterenol) Indirect Acting : Displace stored NE from nerve endings Inhibit re-uptake of released NE (Amphetamine, tyramine, cocaine, imipramine) Mixed ( indirect & direct ) : Stimulates receptor sites & release of norep. from nerve endings (Dopamine, Ephedrine) 42

43. Sympathomimetics The α and β receptors are differentiated by agonist potency on them: epinephrine, norepinephrine and isopreternol For alpha receptors: Epinephrine ≥ Norepinephrine >> Isoproterenol For beta Receptors- β 1, 2, 3 : Isoproteronol > E > NE CATECHOLAMINES High potency in activating receptors Rapid inactivation Poor penetration into the CNS Nevertheless, most of these drugs have some clinical effects (anxiety, tremor, and headaches) that are attributable to action on the CNS. 43

44. Sympathomimetics: pharmacological action Sympathomimetics in general have the following action Mydriasis Increase heart rate and blood pressure Stimulation of glygenolysis Promote lipolysis Increase renin secretion by β 1 receptor, α 2?? Increase insulin secretion by β receptors but inhibited by α 2 receptor 44

45. Sympathomimetics: clinical indication Acute bronchial asthma : epinephrine , Sulbutamol Local haemostatic to stop bleeding : Epinephrine With local anesthesia to prolong the action : Epinephrine Cardiac arrest (Cardiogenic shock): Dopamine, dobutamine 45

46. EPINEPHRINE Ineffective when given orally and should be given intramuscularly or subcutaneous Epinephrine is synthesized in the adrenal medulla Stimulates all the adrenergic receptors α effects : vasoconstriction, mydriasis, increase in blood glucose ß1 effects : Increased contractility and rate of heart ß2 effects : Vasodilatation in muscles and coronary vessels, bronchial relaxation, uterine relaxation, hyperglycemia, lactic acidemia and increased circulating free fatty acids 46

47. NORADRENALINE Constitutes 20% of the adrenal medulla out put Like adrenaline ineffective orally Predominantly α receptor agonist with relatively less β agonist action when compared to adrenaline. ISOPRENALINE, DOPAMINE and DOBUTAMINE Isoprenaline and dobutamine- are synthetic These drugs are more selective in their action Dopamine and dobutamine are very useful drugs for the treatment of shock 47

48. sympathomimetics α 1 agonist selective β1 agonist selective Phenylephrine Methoxamine Oxymetazoline a 2 agonists selective Clonidine Methyldopa Guanabenz Guanfacine Tizanidine Dopamine Dobutamine Β 2 agonist selective Terbutaline Metaproterenol Albuterol /Sulbutamol Salmeterol Ritodrine Non selective β agonist Isoproterenol 48

49. β 1 -SELECTIVE AGONISTS Dopamine Increase renal blood flow (renal dopamine receptors) Moderate dose: Increase in contractility and heart rate, increase in C.O. High dose: Increase in T.P.R. (effect at α -ARs) Dobutamine Increase in contractility, heart rate and C.O. High dose: Increase in T.P.R. (effect at α -ARs) No effect on renal dopamine receptors 49

50. β 2- adrenoceptor selective agonists Albuterol [salbutamol] Relaxation of airway smooth muscle →used as aerosol in asthmatics Ritodrine Relaxation of uterine smooth muscle (delay or prevent premature parturition) 50

51. SYMPATHOLYTICS Non-selective α -AR antagonists Phentolamine- for pheochromocytoma α 1- Alpha-Adrenergic Receptor selective Prazosin T erazosin Alfuzosin Tamsulosin α-2 Adrenergic Receptor selective Yohimbine 51

52. Prazosin Effective drug for the management of hypertension Has high affinity for alpha1 receptor and relatively low affinity for alpha2 receptor Prazocin leads to relaxation of both arterial and venous smooth muscles Thus it: Lowers BP Reduces venous return and cardiac output Reduces the tone of internal sphincter of urinary bladder 52

53. Adverse effects of α 1 antagonists Postural hypotension Reflex Tachycardia Meiosis Nausea, vomiting, Dizziness lack of energy Nasal congestion 53

54. Beta-adrenergic receptor antagonists Non-selective β -AR antagonists Propranolol Nadolol P indolol T imolol β 1-AR selective antagonists Metoprolol Atenolol E smolol β 2-AR selective antagonists Butoxamine 54

55. Propranolol Actions: Bradycardia Reduces force of contraction of the heart Reduces BP Bronchoconstriction Hypoglycemia Anti-anxiety action Decrease the rate of Aqueous humor production Decrease renin secretion 55

56. Propranolol …. Indications: Cardiac arrhythmias Hypertension Prophylaxis against angina Myocardial infarction Thyrotoxicosis Anxiety states Prophylaxis against migraine attacks Glaucoma 56