Autonomic Nervous System Pharmacology PDF

AUTONOMIC NERVEOUS SYSTEM PHARMACOLOGY BY DR ELIANI B. B.PHARM 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 1 COURSE OUTLINE Introduction Autonomic nervous system pharmacology; cholinergics and antagonists, adrenergics an...

AUTONOMIC NERVEOUS SYSTEM PHARMACOLOGY BY DR ELIANI B. B.PHARM 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 1 COURSE OUTLINE Introduction Autonomic nervous system pharmacology; cholinergics and antagonists, adrenergics and antagonists, prejunctional inhibitors, post junctional inhibitors; antiparkinsonian drugs, atropinics, dopaminergics, mono amine oxidase inhibitors, antivirals, amantadine 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 2  DRUGS ACTING ON THE AUTONOMIC SYSTEM (CHOLINERGICS AND ANTI CHOLINERGICS) DR. ELIANI B 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 3 THE NERVOUS SYSTEM 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 4 INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM The autonomic nervous system (ANS) functions below the level of consciousness and controls visceral functions. The ANS consists of afferents, centre and efferents. ANS consist of parasympathetic nervous system (rest and digest) mediated by Ach and sympathetic nervous system (fight and flight) mediated by epinephrine and NorEpi (Adrenaline or Nor Adrenaline) 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 5 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 6 Steps in neurohumoral transmission 1. impulse induction 2. Transmitter release 3. Transmitter action on postjunctional membrane 4. Postjunctional activity 5. Termination of transmitter action 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 7 CHOLINERGIC SYSTEM Acetylcholine (ACh) is a major neurohumoral transmitter at autonomic, somatic as well as central sites.(parasymphathetic nervous system). In the first diagram below, drug actions at each level include: 1 Hemicholinium 2 Botulinum toxin 3 Acetylcholinesterase (AChE) inhibitors 4 Receptor agonists and antagonists 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 8 Synthesis, storage and destruction of ACh 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 9  Acetylcholine (ACh) is synthesized from choline and acetate, stored in neuronal vesicles, and released into the synapse by nerve stimulation. Immediately after release, ACh is hydrolyzed by the enzyme cholinesterase and to choline and acetate, and choline is recycled. Hemicholinium blocks choline uptake by the neuron and inhibits Ach synthesis. Vesamicol blocks ACh storage, and botulinum toxin blocks ACh release. ACh breakdown is inhibited by cholinesterase inhibitors such as physostigmine. Postjunctional acetylcholine receptors are activated or blocked by acetylcholine receptor agonists or antagonists, respectively 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 10  Ach RECEPTORS 1. Muscarinic - Types: M1,M2,M3 ,M4, M5. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 11 2. Nicotinic NM: These are present at skeletal muscle endplate: are selectively stimulated by phenyl trimethyl ammonium (PTMA) and blocked by tubocurarine. They mediate skeletal muscle contraction. NN: These are present on ganglionic cells (sympathetic as well as parasympathetic), adrenal medullary cells and in spinal cord and certain areas of brain. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 12 CHOLINERGIC DRUGS 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 13 CHOLINERGIC DRUGS These are drugs which produce actions similar to that of ACh, either by directly interacting with cholinergic receptors (cholinergic agonists) or indirectly by increasing availability of ACh at these sites (anticholinesterases) They are also called cholinomimetics/Parasympathomimetics A. CHOLINERGIC AGONISTS (increase the action of Ach) 1. Choline esters- Acetylcholine, Methacholine ,Carbachol, Bethanechol. (Mnemonic: CMB) 2. Plant Alkaloid- Muscarine, Pilocarpine, Nicotine, Arecoline. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 14 B. Anti cholinesterase drugs Irreversible Reversible Organophosphates Physostigmine (Eserine) Echothiophate, malathion, Neostigmine diazinon, tabun, dyflos. Pyridostigmine Carbamates; Edrophonium Carbaryl , propoxur, Rivastigmine, Insectisides, nerve gases for Donepezil Galantamine chemical warfare Acridine: tacrine 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 15 CHOLINE ESTERS ACTIONS OF CHOLINE ESTERS. 1. MUSCARINIC ACTIONS; a) Heart- ACh hyperpolarizes the SA nodal cells and decreases their rate of diastolic depolarization. As a result, rate of impulse generation is reduced—Bradycardia or even cardiac arrest may occur. M2 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 16  2. Blood vessels All blood vessels are dilated, though only few (skin of face, neck, salivary glands) receive cholinergic innervation. Fall in BP and flushing, especially in the blush area occurs. Muscarinic (M3) receptors are present on vascular endothelial cells: vasodilatation is primarily mediated through the release of an endothelium dependent relaxing factor (EDRF) which is nitric oxide (NO). When the endothelium is damaged by disease, ACh can diffuse to the vascular smooth muscle and cause vasoconstriction via M3 receptors located on their plasma membrane. Stimulation of cholinergic nerves to the penis causes erection by releasing NO and dilating cavernosal vessels through M3 receptors 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 17  3. Smooth muscle Smooth muscle in most organs is contracted (mainly through M3 receptors). Tone and peristalsis in the gastrointestinal tract is increased and sphincters relax - abdominal cramps and evacuation of bowel. Peristalsis in ureter is increased. The detrusor muscle contracts while the bladder trigone and sphincter relaxes -voiding of bladder. Bronchial muscles constrict, asthmatics are highly sensitive - bronchospasm, dyspnoea, precipitation of an attack of bronchial asthma 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 18  4. Glands Secretions All parasympathetically innervated glands is increased via M3 and some M2 receptors: sweating, salivation, lacrimation, increased tracheobronchial and gastric secretion. The effect on pancreatic and intestinal glands is not marked. Secretion of milk and bile is not affected 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 19  5. Eye Contraction of circular muscle of iris -miosis. Contraction of ciliary muscle - spasm of accommodation, increased outflow facility, reduction in intraocular tension (especially in glaucomatous patients). Mediated by M1 or M2 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 20  B. Nicotinic actions 1. Autonomic ganglia Both sympathetic and parasympathetic ganglia are stimulated. This effect is manifested at higher doses. High dose of ACh given after atropine causes tachycardia and rise in BP due to stimulation of sympathetic ganglia and release of catecholamines. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 21  2. Skeletal muscles Iontophoretic application of ACh to muscle endplate causes contraction of the fibre. Intraarterial injection of high dose can cause twitching and fasciculations, but i.v. injection is generally without any effect (due to rapid hydrolysis of ACh). 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 22  C. CNS actions ACh injected i.v. does not penetrate blood-brain barrier and no central effects are seen. However, direct injection into the brain produces arousal response followed by depression. Cholinergic drugs which enter brain produce complex behavioral and neurological effects. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 23 Interactions Anticholinesterases potentiate ACh markedly, methacholine to less extent and have only additive action with carbachol or bethanechol, depending upon the role of ChE in the termination of action of the particular choline ester. Atropine and its congeners competitively antagonize muscarinic actions. Adrenaline is a physiological antagonist 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 24 Uses ACh is not used because of evanescent and nonselective action. Methacholine was occasionally as a diagnostic for atopic asthma. Bethanechol has been used in postoperative/ postpartum non- obstructive urinary retention, neurogenic bladder to promote urination. Dose: 10–40 mg oral, 2.5–5 mg s.c.; UROTONIN, BETHACOL 25 mg tab. Side effects are prominent belching, colic, involuntary urination/defecation, flushing, sweating, fall in BP, bronchospasm. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 25 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 26 CHOLINOMIMETIC ALKALOIDS Pilocarpine. It is obtained from the leaves of Pilocarpus microphyllus and other species. It has prominent muscarinic actions and also stimulates ganglia— mainly through ganglionic muscarinic receptors. Pilocarpine exhibits marked sweating, salivation and increase in other secretions. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 27  Applied to the eye, it penetrates cornea and promptly causes miosis, ciliary muscle contraction and fall in intraocular tension lasting 4–8 hours. Pilocarpine is used only in the eye as 0.5– 4% drops. It is a third-line drug in open angle glaucoma. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 28  side effects: An initial stinging sensation in the eye and painful spasm of accommodation are frequent. Other uses as a miotic are—to counteract mydriatics after they have been used for testing refraction and to prevent/break adhesions of iris with lens or cornea by alternating it with mydriatics. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 29  Muscarine It occurs in poisonous mushrooms Amanita muscaria and Inocybe species and has only muscarinic actions. It is not used therapeutically but is of toxicological implication. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 30 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 31 ANTI CHOLINESTERASES Anticholinesterases (anti-ChEs) are agents which inhibit AChE, protect ACh from hydrolysis—produce cholinergic effects in vivo and potentiate ACh both in vivo and in vitro. Some anti ChEs have additional direct action on nicotinic cholinoceptors. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 32 CLASSIFICATION Reversible Irreversible Indirect-acting, alcohol Indirect-acting, organophosphates Edrophonium Parathion-as insectiside Indirect-acting, carbamates Malathion-as insectiside Neostigmine Sarin, tabun, -as nerve gas Pyridostigmine Physostigmine Echothiophate Donepezil 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 33 MOA The anti-ChEs react with the enzyme essentially in the same way as ACh. The carbamates and phosphates respectively carbamylate and phosphorylate the esteratic site of the enzyme. The acetylated enzyme reacts with water extremely rapidly and the esteratic site is freed in a fraction of a millisecond, The carbamylated enzyme (reversible inhibitors) reacts slowly and the phosphorylated enzyme (irreversible inhibitors) reacts extremely slowly or not at all. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 34  Edrophonium and Tacrine attach only to the anionic site and do not form covalent bonds with the enzyme, while organophosphates attach only to the Esteratic site forming covalent bonds. Reactivation of Edrophonium-inhibited enzyme occurs in < 10 min, and does not involve hydrolysis of the inhibitor, but only its diffusion. The half-life of reactivation of carbamylated enzyme (about 30 min) is less than that of synthesis of fresh enzyme protein, while that of phosphorylated enzyme (in days) is more than the regeneration time. The phosphorylated enzyme may also undergo ‘aging’ by the loss of one of the alkyl groups and become totally resistant to hydrolysis. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 35 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 36 INDIVIDUAL COMPOUNDS PHYSIOSTIGMINE Natural alkaloid obtd from physostigma venenosum. It is rapidly absorbed from g.i.t. and parenteral sites. Applied to the eye, it penetrates cornea freely. It crosses blood-brain barrier and is disposed after hydrolysis. Dose: 0.1-1% eyedrops 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 37 Neostigmine and congeners Synthetically generated. These are poorly absorbed orally; oral dose is 20–30 times higher than parenteral dose. They do not effectively penetrate cornea or cross blood-brain barrier. They are partially hydrolysed and partially excreted unchanged in urine. Dose: 0.5-2.5mg i.m/s.c. Mostly used for treatment of myasthenia gravis. Myasthenia gravis (MG) is a relatively rare autoimmune disorder in which antibodies form against nicotinic acetylcholine (ACh) postsynaptic receptors at the neuromuscular junction (NMJ) of the skeletal muscles, causing muscle weakness and rapid muscle fatigue 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 38  Congeners include: Pyridostigmine, edrophonium, tacrine, rivastigmine Action is same as neostigmine. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 39  Organophosphates These are absorbed from all sites including intact skin and lungs. They are hydrolyzed as well as oxidized in the body and little is excreted unchanged. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 40  Precautions Anti-ChEs are contraindicated in sick sinus, A-V conduction defects and hypotensive states. They are to be used cautiously in peptic ulcer, asthma, COPD and seizure patients. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 41 uses 1. As miotic (a) In glaucoma: Miotics increase the tone of ciliary muscle (attached to scleral spur) and sphincter pupillae which pull on and somehow improve alignment of the trabeculae so that outflow facility is increased - falls in open angle glaucoma. Eg Echothiophate Pilocarpine is the preferred miotic. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 42  2. Myasthenia gravis Myasthenia gravis is an autoimmune disorder, due to development of antibodies directed to the nicotinic receptors (NR) at the muscle endplate. This leads to reduction in number of free NM cholinoceptors to 1/3 of normal or less and structural damage to the neuromuscular junction. This results in weakness and easy fatigability on repeated activity, with recovery after rest. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 43  Neuromuscular junction of myasthenic muscle In myasthenia gravis the population of nicotinic receptors (NR) available at muscle endplate for binding acetylcholine (ACh) is markedly reduced due to their obliteration by nicotinic receptor antibodies (NR-Ab). Acetylcholinesterase (AChE) molecules located strategically at the muscle endplate rapidly hydrolyse ACh. Anticholinesterases inhibit AChE, allowing the same ACh molecules to repeatedly interact with the available NRs; frequency of ACh-NR interaction is increased 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 44  Neostigmine and its congeners improve muscle contraction by allowing ACh released from prejunctional endings to accumulate and act on the receptors over a larger area, as well as by directly depolarizing the endplate. 3. Postoperative paralytic ileus/urinary retention This may be relieved by 0.5–1 mg s.c. neostigmine, provided no organic obstruction is present. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 45  4. Postoperative decurarization; Neostigmine 0.5–2.0 mg (30–50 microg/kg by atropine or glycopyrrolate 10 microg/kg to block muscarinic effects, rapidly reverses muscle paralysis induced by competitive neuromuscular block. 5. Cobra bite: Cobra venom has a curare like neurotoxin. Though specific antivenom serum is the primary treatment, neostigmine + atropine prevent respiratory paralysis. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 46 6. Belladonna poisoning; Physostigmine 0.5–2 mg i.v. repeated as required is the specific antidote for poisoning with belladonna or other anticholinergics. It penetrates bloodbrain barrier and antagonizes both central and peripheral actions. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 47 7. Other drug overdosages Tricyclic antidepressants, phenothiazines and many antihistaminics have additional anticholinergic property. Overdose symptoms and coma produced by these drugs are partly antagonized by physostigmine. 8. Alzheimer’s disease Characterized by progressive dementia, AD is a neurodegenerative disorder, primarily affecting cholinergic neurones in the brain. Use donezepil 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 48 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 49 Edrophonium and diagnosis of MG 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 50 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 51 Anticholinesterase/organophosphate poisoning Anticholinesterases are easily available and extensively used as agricultural and household insecticides; accidental as well as suicidal and homicidal poisoning is common. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 52  Manifestations: Local muscarinic manifestations at the site of exposure (skin, eye, g.i.t.) occur immediately and are followed by complex systemic effects due to muscarinic, nicotinic and central effects. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 53  Irritation of eye, lacrimation, salivation, sweating, copious tracheo- bronchial secretions, miosis, blurring of vision, bronchospasm, breathlessness, colic, involuntary defecation and urination 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 54  Fall in BP, bradycardia or tachycardia, cardiac arrhythmias, vascular collapse. Muscular fasciculations, weakness, respiratory paralysis (central as well as peripheral). Irritability, disorientation, unsteadiness, tremor, ataxia, convulsions, coma and death. Death is generally due to respiratory failure 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 55 Classic Clue AChE inhibitor poisoning: causes "Dumbbeelss" Diarrhea Urination Miosis Bradycardia Bronchoconstriction Emesis Excitation (CNS/muscle) Lacrimation Salivation Sweating 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 56  Treatment 1. Termination of further exposure to the poison— fresh air, wash the skin and mucous membranes with soap and water, gastric lavage according to need. 2. Maintain patent airway, positive pressure respiration if it is failing. 3. Supportive measures—maintain BP, hydration, control of convulsions with judicious use of diazepam 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 57 Specific antidotes. (a) Atropine For counteracting the muscarinic symptoms, higher doses are required to antagonize the central effects. All cases of anti-ChE (carbamate or organophosphate) poisoning must be promptly given atropine 2 mg i.v. repeated every 10 min till dryness of mouth or other signs of atropinization appear (upto 200 mg has been administered in a day). Continued treatment with maintenance doses may be required for 1–2 week 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 58 (b) Cholinesterase reactivators Oximes Are used to restore neuromuscular transmission only in case of organophosphate anti-ChE poisoning. Pralidoxime is injected i.v. slowly in a dose of 1–2 g (children 20–40 mg/kg) or 30 mg/kg i.v. loading dose adults, followed by 8–10 mg/kg/hour continuous infusion till recovery. It is rather contraindicated in carbamate poisoning, because not only it does not reactivate carbamylated enzyme, it has weak anti-ChE activity of its own 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 59  Pralidoxime is used to regenerate cholinesterase after organophosphate poisoning, which serves to decrease acetylcholine levels and is particularly helpful in reducing nicotinic receptor stimulation and relieving muscle weakness. The high affinity of pralidoxime for phosphorus enables it to break the phosphorus bond with cholinesterase and thereby regenerate the enzyme. It is important to administer pralidoxime as soon as possible after organophosphate exposure, because “aging” of the organophosphate reduces the ability of pralidoxime to regenerate cholinesterase. 11/4/2024 DR ELIANI-CHOLINERGIC PHARMACOLOGY 60