Anticholinesterase basic pharmacology and uses

Anticholinesterase basic pharmacology and uses

1. Anticholinesterase: Basic Pharmacology and Various Uses Presenter: Dr. Suresh Pradhan Moderator: Dr. Yogesh Dhakal

2. Synthesis and Hydrolysis of ACh

3. Acetylcholinesterase type B carboxylesterase enzyme ‘True Cholinesterase’ / ‘Specific Cholinesterase’ one of the most efficient enzymes known a single molecule able to hydrolyze estimated 300,000 molecules of Ach every minute responsible for the control of neurotransmission at the neuromuscular junction by hydrolyzing acetylcholine rapid hydrolysis of acetylcholine removes excess neurotransmitter from the synapse preventing overstimulation and tetanic excitation of the postsynaptic muscle are present along the length of the muscle fiber

4. each molecule of acetylcholinesterase has an active surface with two important binding sites an anionic site and an esteratic site negatively charged anionic site on acetylcholinesterase molecule is responsible for electrostatically binding the positively charged quaternary nitrogen group on the acetylcholine molecule esteratic site forms covalent bonds with the carbamate group at the opposite end of the acetylcholine molecule and is responsible for the hydrolytic process a secondary or peripheral anionic site has been proposed binding of ligands to the peripheral anionic site results in inactivation of the enzyme

5. Classification REVERSIBLE IRREVERSIBLE CARBAMATES ACRIDINE Physostigmine Neostigmine Pyridostigmine Rivastigmine ORGANOPHOSPHORUS Compounds Tacrine PIPERIDINES Donepezil NON - CARBAMATE QUATERNARY AMMONIUM Edrophonium Echothiophate is the only organophosphorus used clinically (Glaucoma)

6. Chemical Structure Quaternary Ammonium group Carbamate moiety renders lipid insoluble so cannot cross BBB covalent bonding with AChE lacks Carbamate group so binds non-covalently to AChE lipid insoluble due to Quaternary ammonium group structure similar to Neostigmine but quaternary ammonium group incorporated into the phenol ring has Carbamate group but no quaternary Ammonium; thus lipid soluble : Crosses BBB

7. Reversal of neuromuscular blockade theoretically possible by three principal mechanisms: a decrease in enzymatic metabolism of acetylcholine by cholinesterase, thereby increasing receptor binding competition an increase in presynaptic release of acetylcholine a decrease in the concentration of the NMBD, hence, freeing the postsynaptic receptors

8. Mechanism of Action enzyme inhibition inhibit the enzyme acetylcholinesterase reversibly-results in greater availability of ACh at its sites of action, presynaptic effects in the absence of nondepolarizing neuromuscular-blocking drugs, administration of an anticholinesterase drug may produce spontaneous contractions ( fasciculations ) of skeletal muscles these presynaptic effects are abolished by a small dose of a nondepolarizing neuromuscular-blocking drug, suggesting that acetylcholine receptors are involved direct effects on the neuromuscular junction

9. Neostigmine and to some extent pyridostigmine display some limited pseudocholinesterase - inhibiting activity, but their effect on acetylcholinesterase is much greater. Edrophonium has little or no effect on pseudocholinesterase

10. Metabolism and Clearance Hepatic metabolism accounts for 50% elimination of Neostigmine 30% of Edrophonium 25% of Pyridostigmine metabolites of anticholinesterases do not contribute significantly to the effects of parent drug Physostigmine is almost completely metabolized by plasma esterases .

11. Metabolism and Clearance… renal clearance : 50% elimination of Neostigmine 75% elimination of Edrophonium and Pyridostigmine actively secreted into the lumens of renal tubules elimination half times greatly prolonged in Renal dysfunction

12. Antagonism of Nondepolarizing neuromuscular blockade by acetylcholinesterase inhibitors depends primarily on following factors: the depth of the blockade when reversal is attempted the anticholinesterase chosen the dose administered the rate of spontaneous clearance of the neuromuscular blocker from plasma the choice and depth of anesthetic agents administered

13. reversal of ND-NMB requires only the nicotinic cholinergic effects of the anticholinesterase drugs muscarinic cholinergic effects of Anticholinesterase drugs are attenuated or prevented by concurrent administration of anticholinergic drugs when reversing neuromuscular blockade, the primary goal is to maximize nicotinic transmission with a minimum of muscarinic side effects

14. Muscarinic Side Effects

15. NEOSTIGMINE c arbamate with Quaternary Ammonium Group lipid Insoluble ; doesn’t cross BBB recommended dosage- 0.04 – 0.08 mg/kg (maximum of 5 mg in adults) repeating the dose has no benefit as AChE are already maximally inhibited onset : 5 to 10 minutes ( peak at 10 min) duration : lasts for more than 1 hour paediatric and geriatric patients: onset is more rapid requires smaller dosing duration of action is prolonged in elderly

16. Glycopyrrolate is the preferred anticholinergic to be used along with Neostigmine 0.2 mg Glycopyrrolate per mg of Neostigmine If Atropine is used, 0.4 mg per mg of Neostigmine Neostigmine crosses placenta and can result in Fetal Bradycardia Atropine preferred in Pregnant patients receiving Neostigmine With higher doses of Neostigmine Paradoxical potentiation of NM Blockade may cause ACh channel blockade can cause a weak Depolarizing neuromuscular Blockade

17. PYRIDOSTIGMINE carbamate with Quaternary Ammonium Group only as 20% as potent as Neostigmine dose : 0.1 to 0.4 mg/kg (Max of 20 mg in adults) onset : Slower – 10 to 15 minutes duration : Longer - > 2 hours preferred Anticholinergic : Glycopyrrolate 0.05 mg per mg of Pyridostigmine If Atropine used; 0.1 mg per mg of Pyridostigmine

18. EDROPHONIUM Quaternary Ammonium Group lacks carbamate group unlike other agents, it forms reversible electrostatic attachment to the enzyme Edrophonium appears to have presynaptic effects : Enhancement in the release of Ach less than 10% as potent as Neostigmine dose : 0.5 – 1 mg/kg most Rapid Onset : 1-2 min shortest duration / but higher doses prolong the duration to >1 hour

19. Preferred Anticholinergic : Atropine Rapid onset is well matched to that of Atropine 0.014 mg Atropine per mg Edrophonium If Glycopyrrolate used; it must be given several minutes prior to avoid Bradycardia (0.007mg/mg) muscarinic effects of Edrophonium are less pronounced pediatric and geriatric patients are not more sensitive to it not as effective as Neostigmine in reversing intense NM blockade more effective in reversing Mivacurium blockade

20. PHYSOSTIGMINE natural alkaloid derived from Calabar bean ( Physostigma venenosum ) tertiary amine lacks quaternary ammonium : lipid soluble penetrates CNS: limits use as reversal agent effective in reversing: central anticholinergic actions due to Atropine or Scopolamine overdosages benzodiazepine and volatile anaesthetic induced CNS depression and delirium

21. effective in preventing post-operative shivering (0.04 mg/kg) may partially antagonize the respiratory depression caused by Morphine. glycopyrrolate will not reverse the CNS effects of Physostigmine . almost completely metabolized by plasma esterases -- renal excretion not important

22. Uses of Anticholinersterases primary use : to reverse the Nondepolarizing neuro-muscular blockade reversal agents are routinely given to patients who have received non-depolarizing muscle relaxants

23. OTHER USES OF ANTICHOLINESTERASES Edrophonium - Tensilon test - diagnosis of Myasthenia gravis TENSILON TEST 2 mg IV Edrophonium Myasthenia gravis : Improvement of the symptoms LEMS : No improvement Cholinergic crises : Worsening of symptoms

24. Neostigmine, Pyridostigmine and Ambenonium – Standard Anticholinesterases used in Myasthenia gravis. Oral dose is much higher as- Neostigmine and Pyridostigmine are lipid insoluble. Muscarinic side effects need to be controlled with anticholinergic agents Bromide toxicity – with Pyridostigmine Bromide

25. Decrease intraocular pressure in Narrow angle and wide angle Glaucoma Physostigmine eye drops Ecothiophate (Organophosphate with quaternary structure) Demecarium GLAUCOMA

26. Neurodegenerative : Cholinergic neurons also affected Mild to moderate Alzheimer disease. Cerebroselective AChEi : donepezil rivastigmine tacrine (significant liver toxicity) galantamine ALZHEIMER’S DISEASE

27. Overdosage of Atropine or Scopolamine Restlessness and Confusion Physostigmine used – Lipid soluble Central Anticholinergic Syndrome

28. Physostigmine abolishes the somnolent effects of Opioids and Volatile anaesthetics Physostigmine may also be used to reverse the ventilatory depression caused by Morphine without decreasing its analgesic effects Physostigmine (40ugm/kg IV) following anaesthesia decreases the incidence of postoperative shivering

29. Diagnosis and management of Cardiac Dysrhythmias Edrophonium – Paroxysmal SVTs 5-10mg slows heart rate with no effect on ventricular contractility, conduction or peripheral vascular tone Post-operative Ileus / Urinary Retention Neostigmine 0.5 to 1 mg SC Organic Obstruction has to be ruled out first Belladonna Poisoning Anticholinergic excess Physostigmine preferred

30. Neostigmine as neuraxial anaesthesia adjunct Intrathecal (50 – 100 mcg) Epidural (1 – 4 mcg/kg) Analgesia produced is probably by inhibiting the breakdown of spinal released Ach which is increased in presence of pain Disadvantages – High incidence of nausea and vomiting, pruritis , prolongation of sensory and motor block

31. Sugammadex Sugammadex is in the family of cyclic dextrose units used as solubilizing agents since 1953 Modfied gamma- cyclodextrine -comprised of 8 sugar molecules that form a rigid ring with a central lipophilic cavity Initially discovered when a compound was needed to increase the solubility of rocuronium in a specific media Observed permanent binding of the rocuronium molecule to the center of the sugammadex molecule in a 1:1 ratio

32. Mechanism of action Hydrophobic interactions trap the drug in the cyclodextrine cavity forming a tight water-soluble complex in a 1:1 ratio (encapsulation) A concentration gradient is created with no free unbound NDMR in the plasma as compared to the extravascular compartment Favors movement of NDMR ( rocuronium or veuronium ) into the plasma where they are rapidly encapsulated Terminates the NDMR’s action and restrains the drug in extracellular fluid where it cannot interact with nicotinic acetylcholine receptors

33. Pharmacodyamics Sugammadex is biologically inactive and does not bind to plasma proteins Metabolism of sugammadex very limited, and the drug is predominantly eliminated unchanged by the kidneys- approximately 75% sugammadex should be avoided in patients with a creatinine clearance of <30 mL per minute

34. Pharmacokinetics Sugammadex , used in appropriate doses, is capable of reversing any depth of neuromuscular blockade (profound or shallow) induced by rocuronium or vecuronium During rocuronium or vecuronium -induced neuromuscular blockade, intravenous administration of sugammadex results in rapid removal of free rocuronium or vecuronium molecules from the plasma Sugammadex is ineffective against succinylcholine and benzylisoquinolinium neuromuscular blockers such as mivacurium , atracurium , and cisatracurium because it cannot form inclusion complexes with these drugs

35. Dosing Available: 2mL or 5mL vials (100mg/mL) Dose of Sugammadex Indication Mean Recovery time to TOF 0.9 16mg/kg Immediate Reversal after 1.2 mg/kg rocuronium 1.5 minutes 4mg/kg Routine reversal of deep neuromuscular block 3 minutes 2mg/kg Routine reversal of moderate block 2 minutes

36. Safety and Tolerability The U.S. Food and Drug Administration has expressed concerns about the safety of sugammadex , citing its possible association with allergic reactions, and bleeding sugammadex has not been approved for clinical use in the United States more than 5 million doses of sugammadex have been administered worldwide

37. THANK YOU!!!

38. SUCCINYLCHOLINE and Depolarizing Blockade Neostigmine and other AChEi prolong the depolarizing blockade produced by Succinylcholine increased Ach concentration will increase the motor end plate depolarization neostigmine and pyridostigmine has some Psuedocholinesterase inhibiting action

39. General Findings Extensive research and numerous clinical trials have evaluated the safety, efficacy, and usefulness of sugammadex A metaanalysis including 18 randomized controlled trials demonstrated that sugammadex can reverse rocuronium induced blockade faster than neostigmine at all levels of blockade in a dose dependent manner In trials of immediate reversal sugammadex (16mg/kg) was administered 3 minutes after profound blockade by rocuronium and showed faster recovery than patients who underwent spontaneous recovery from succinylcholine