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Parasympathomimetic agents

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parasympathetic system

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Parasympathomimetic agents

  1. 1. A SEMINAR ON PARASYMPATHOMIMETIC AGENTS Presented By: Ms. Kirti Vadi 17MPHCT002 M.Pharm (pharmacolgy) Rpcp,changa Guided By: Dr. Jalpa Suthar Assistant Professor Dept. Of Pharmacology & Toxicology Rpcp,changa
  2. 2. CONTENT 2  Organization of nervous system  Acetycholine drug profile  Types of cholinergic receptors  Nicotinic receptors  Muscarinic receptors  Classification of drugs  Directly acting cholinergic drugs  Indirectly acting cholinergic drugs  Therapeutic uses of cholinergic drugs  AchE Poisoning (organophosphorous poisoning)  Side effects of cholinergic drugs  Reference
  3. 3. 3 ORGANIZATION OF NERVOUS SYSTEM The chief neurotransmitter in the parasymphathetic nervous system is acetylcholine. Hence it is also known as cholinergic system. The drugs that produce effect similar to that of acetylcholine are termed as cholinergic agents or parasympathomimetic agents.
  4. 4. ACETYCHOLINE (Prototype drug) DRUG PROFILE 4
  5. 5. TYPES OF CHOLINERGIC RECEPTORS 5 Cholinergic receptors Muscarinic receptor M1 M2 M3 M4 M5 Nicotinic receptor NM NN
  6. 6. NICOTINIC RECEPTORS 6 Features NM NN Location and function subserved Neuromuscular junction: depolarization of muscle end plate -contraction of skeletal muscle Autonomic ganglia: depolarization -postganglionic impulse, Adrenal medulla: catecholamine release CNS: site specific excitation or inhibition Nature Has intrinsic ion channel, pentamer of only α2 β Ɛ or  and  subunits, each subunit has 4TM Has intrinsic ion channel, pentamer of only αβ subunits, each subunit has 4TM Transducer mechanism Opening of cation (Na+, K+) channels Opening of cation (Na+, K+, Ca++) channel Agonist PTMA, Nicotine DMPP, Nicotine Antagonist Tubocurarine Hexamethonium, Trimethaphan
  7. 7. MUSCARINIC RECEPTORS 7 Features M1 M2 M3 Location and function sub served Autonomic ganglia: Depolarization (late EPSP) Gastric glands: Hist. release, acid secretion CNS: Learning, memory, motor functions Heart : reduces heart rate, slow AV node conduction, reduces force of contraction GIT & Gall bladder : Smooth muscle contraction Pupils : Regulate pupil constriction glands : Promote mouth, sinus, eye, lung & skin lubrication Blood vessels : Increase vasodilation Nature G-protein coupled, 7-TM G-protein coupled, 7- TM G-protein coupled, 7-TM Transducer mechanism IP3/DAG- ↑cytosolic Ca++ PLA2 ↑- PG synthesis K + channel opening, cAMP IP3/DAG- ↑cytosolic Ca++ PLA2 ↑- PG synthesis Agonists Oxotremorine Methacholine Bethanechol Antagonists Pirenzepine, Telenzepine Methoctramine, Tripitramine Hexahydrosiladifenidol, Darifenacin
  8. 8. CLASSIFICATION OF DRUGS 8 The parasympathomimetic agents are classified into the following: •Directly actingcholinergic drugs-These drugs mimic the actions of ACh at muscarinic and nicotinic receptors by binding directly to these receptors. •Indirectly acting cholinergic drugs-These drugs act by inhibiting the activity of acetylcholinesterase (AchE) enzyme which degrades ACh to inactive products: choline and acetic acid.
  10. 10. B. NATURAL ALKALOID 10 Pilocarpine  It is chief alkaloid obtain from the leaves of shrub Pilocarpus jaborandi. It crosses BBB.  It has muscarinic action and also mild nicotinic action. Therapeutic uses:- 1. Ophthalmic use:  For initial treatment of open angle glaucoma (0.5% to 4% solution), reduction in intraocular pressure occur within few min and lasts for 4-8 hrs.  To counteract mydriasis produce by atropine  To break the adhesion between the iris and lens 2. As sialagogue – used to stimulate salivary secretion in patients after laryngeal surgery. (5-10 mg orally)
  11. 11. C. MISCELLANEOUS AGENTS 11  TREMORINE and OXOTREMORINE are not used therapeutically, but used only as investigated research tool to stimulate Parkinsonism like symptoms in animal models.  Which results from activation of muscarinic receptors in basal ganglia and elsewhere in CNS.
  12. 12. INDIRECTLYACTING CHOLINERGIC DRUGS 12 Acetylcholinesterase (AchE) is an enzyme which degrades acetylcholine to inactive products: choline and acetic acid. These agents act by inhibiting the AchE, by reversible or irreversible binding which indirectly increase the concentration of acetylcholine in the synaptic cleft and ultimately at the respective cholinergic receptors.
  13. 13. A. REVERSIBLE (COMPETITIVE) INHIBITORS OF AChE 13 • The reversible anticholinesterase drugs have a similar structure to ACh. • They combine with the anionic and their esteric site of AChE. • This complex is less readily hydrolysed than AChE-ACh complex. • It results in a temporary inhibition of the enzyme. • This inhibition prolong the duration of action of ACh released in the synaptic cleft.
  14. 14. 14 PHYSOSTIGMINE  Its an alkaloid obtain from the dried ripe seeds of Physostigma venenosum.  It is highly lipid soluble and shows better absorption in the all the body compartments including CNS and can crosses BBB.  It has marked muscarinic effects and also stimulate ganglia but negligible nicotinic effects at neuromuscular junction.  It is highly toxic and so has only limited use.  It is having intermediate duration of action. (30min-2hr) Therapeutic uses:  Ophthalmic use  To counteract the effects of mydriatics  To prevent the adhesion between iris and the lens  for the treatment of glaucoma  Belladonna (atropine) poisoning
  15. 15. 15 Quaternary compounds  This drugs are least absorb and do not cross BBB.  This drugs have important therapeutic effects on skeletal muscle neuromuscular junction.  Low doses moderately prolong and intensify the action of released ACh at motor endplate, this results in strengthening of muscle weakness. EDROPHONIUM  A quaternary ammonium compound that binds to the anionic site of the enzyme only.  The ionic bond formed is readily reversible, and the action of the drug is very brief.  It is used mainly for diagnostic purposes, because improvement of muscle strength by an anticholinesterase is characteristic of myasthenia gravis but does not occur when muscle weakness is due to other causes.  Duration of action: 5-15 min
  16. 16. 16 Neostigmine  Hydrolysed by esterases in liver & plasma  Short duration of action (3-5 hours)  Direct action on nicotinic (NM) receptors present in neuromuscular junction (motor end plate) of skeletal muscle  Antagonizes (reverses) skeletal muscle relaxation (paralysis) caused by tubocurarine and other competitive neuromuscular blockers  Stimulates autonomic ganglia in small doses but Large doses block ganglionic transmission  No CNS side effects.
  17. 17. COMPARATIVE FEATURES OF PHYSOSTIGMINE AND NEOSTIGMINE 17 Physostigmine Neostigmine Source Natural Synthetic Chemistry Tertiary amine Quaternary ammonium compound Oral absorption Good Poor CNS action Present Absent Eye Penetrates cornea Poor penetration Effect Ganglia Muscle Uses Miotic Mysthenia gravis Dose 0.5-1 mg oral/parenteral 0.1-1% eye drop 0.5-2.5 mg IM/SC 15-30 mg orally Duration of action 4-6 Hrs 3-4 Hrs
  18. 18. B. IRREVERSIBLE INHIBITORS OF AChE 18  These agents are called irreversible blockers because they phosphorylated the esteratic site of AChE irreversibly by forming a covalent bond.  Pentavalent organo-phosphorous compounds containing fluoride or organic group.  During the process, this group is released leaving the remaining part of drug molecule attached covalently with the esteratic site of AChE through its phosphorous atom.  After phosphorylation, AChE becomes inactive and very stable due to covalent bonding. Recovery depends on new synthesis (few weeks)  Ecothiophate (exception) : is having a quaternary nitrogen which can bind also to the anionic site of the enzyme slow hydrolysis (few days)  not strictly irreversible  Sometimes phosphorylated enzyme losses one alkyl group and become resistant to hydrolysis – ageing
  19. 19. THERAPEUTIC USES OF CHOLINERGIC DRUGS 19  Myasthenia gravis: Edrophonium to diagnose Neostigmine, Pyridostigmine & Distigmine to treat  To stimulate bladder & bowel after surgery: Bethanechol, Carbachol, Distigmine  To lower IOP in chronic simple glaucoma: Pilocarpine, Physostigmine  To improve cognitive function in Alzheimer’s disease: Rivastigmine, Gallantamine, Donepezil  Physostigmine in Belladonna poisoning
  20. 20. MYASTHENIA GRAVIS 20  Autoimmune disorder affecting 1 in 10,000 population Causes: Development of antibodies directed to Nicotinic receptors in muscle end plate – reduction in number by 1/3rd of Nm receptors  Structural damage to NM junction Symptoms: Weakness of muscle and fatigue which worsens after the exrecise but goes off after the rest, slurring speech, diplopia, difficulty in swallowing Treatment:  Neostigmine – 15 to 30 mg, orally, every 6 hrly  Dose requirement may fluctuate time to time – adjustment required according to the response  Pyridostigmine – 60-120mg, 4-6hrly, orally
  21. 21. MYASTHENIC CRISIS 21  Acute weakness and respiratory paralysis  Tracheobronchial intubation and mechanical ventilation  Methylprednisolone IV with withdrawal of AChE  Gradual reintroduction of AChE  Thymectomy  Edrophonium is used for diagnosis of Myasthenic crisis (disease itself) and cholinergic crisis (overdose of Anti-ChE)  Improvement of symptoms – myasthenic crisis  Worsening – Cholinergic crisis
  22. 22. AChE POISONING (ORGANOPHOSPHOROUS POISONING) 22  Organophosphate poisoning is poisoning due to organophosphates(OPs).  The underlying mechanism involves the inhibition of acetylcholinesterase , leading to the buildup of acetylcholine in the body.  Diagnosis is typically based on the symptoms and can be confirmed by measuring butyryl-cholinesterase activity in the blood.  Poisoning may be – Occupational, accidental, Suicidal  Symptoms:  Fall in BP, bradycardia or tachycardia, cardiac arrhythmia and vascular collapse  Irritation of Eye, lacrimation, salivation, involuntary defection, breathlessness, blurring of vision  Muscular fasciculations and weakness  Death due to respiratory paralysis – peripheral and central
  23. 23. 23 The treatment consist of specific antidote or Cholinesterase Reactivators 1. Specific antidotes  Atropine-All cases of AChE poisoning, 2mg IV every `10 minutes – till muscarinic symptoms disappears 2. Cholinesterase Reactivators – Oximes  Oximes have generic formula R-CH=N-OH  Provides reactive group OH to the enzymes to reactivate the phosphorylated enzymes eg. Pralidoxime (2-PAM), Obidoxime Diacetyl monoxime (DAM)
  24. 24. SIDE EFFECTS OF CHOLINERGIC DRUGS 24  Diarrhoea  Urination  Miosis, muscle weakness  Bronchorrhea  Bradycardia  Emesis  Lacrimation  Salvation, sweating
  25. 25. REFERENCE 25 1. Sharma HL, Sharma KK. Principles of pharmacology. Paras medical publisher; 2007. 2. Tripathi KD. Essentials of medical pharmacology. JP Medical Ltd; 2013 Sep 30. 3. Goodman LS. Goodman and Gilman's the pharmacological basis of therapeutics. New York: McGraw-Hill; 1996. 4. H. P. Shah, J. M. Ritter. Rang & Dale’s pharmacology. Elsevier Ltd; 2016
  26. 26. 26 THANK YOU