Anticholinergics and sedatives in anesthetic practice

Anticholinergics and sedatives in anesthetic practice

1. Anticholinergics and Sedatives in Anesthetic Practice, Roles and Uses Presenter- Dr. Suresh Pradhan Moderator- Prof. UC Sharma

2. Anticholinergics in Anesthetic Practice

3. Autonomic Nervous System (ANS) the portion of the nervous system that controls most visceral functions of the body activated mainly by centers located in the spinal cord , brain stem , and hypothalamus helps to control b lood pressure gastrointestinal motility gastrointestinal secretion urinary bladder emptying sweating body temperature s ome of these activities are controlled almost entirely and some only partially by the ANS ANS is divided into three main divisions Sympathetic ANS Parasympathetic ANS Enteric nervous system

4. Acetylcholine is the main neurotransmitter secreted at somatic nerves (at neuromuscular junction) at all preganglionic autonomic (sympathetic as well as parasympathetic) nerves postganglionic fibres in parasympathetic system acetylcholine is the principal neurotransmitter secreted by preganglionic as well as postganglionic fibers in Parasympathetic Nervous System. so , also known as cholinergic nervous system

5. Cholinergic Neuroeffector Junctions

6. Classification of Cholinergic Receptors

7. Nicotinic Receptor Activation

8. Muscarinic Receptor Activation

9. Antimuscarinic agents - blocks the actions of Ach especially mediated through muscarinic receptor Classification Natural alkaloids Atropine Scopolamine Semi synthetic derivatives Homatropine Ipratropium bromide Tiotropium bromide Hyoscine butyl bromide

10. 3. Synthetic compounds a ) Mydriatics Cyclopentolate Tropicamide b ) Antisecretory -antispasmodics I. Quaternary ammonium compounds Propantheline Oxyphenium Clidinium Glycopyrrolate II. Tertiary amines Dicyclomine Pirenzepine Telenzepine Oxybutynin c ) Antiparkinsonian drugs Benzhexol Biperiden Benztropine Ethopropazine

11. Mechanism of Action combine reversibly with muscarinic cholinergic receptors and prevent access of acetylcholine act as competitive antagonists

12. the most commonly used muscarinic antagonists in anesthesia are Atropine Scopolamine G lycopyrrolate

13. Pharmacokinetics Atropine Usually given IV and IM is relatively lipid soluble and readily crosses membrane barriers and well distributed into the CNS and other organs up to 50% of the dose is protein bound p eak effects on the heart occur within four minutes of IV and about one hour after IM administration p eak plasma concentration of atropine after IM administration is reached within 30 minutes elimination half-life varies between two and five hours plasma levels after IM and IV injection are comparable after one hour metabolised in the liver by oxidation and conjugation to give inactive metabolites a bout 50% of the dose is excreted within four hours in the urine

14. Scopolamine lipid soluble and penetrates BBB Glycopyrrolate poorly lipid soluble minimal ability to cross BBB and hence least CNS effects onset of action 2-3 mins; duration of action 30-60 mins 80% excreted unchanged in urine

15. Pharmacodynamics Central Nervous System Atropine-CNS stimulant at higher doses Scopolamine-CNS depression effect even at low doses Atropine stimulates many medullary centers – vagal, respiratory, vasomotor depresses vestibular excitation and has antimotion sickness property suppresses the tremor and rigidity of parkinsonism by blocking the cholinergic over activity in basal ganglia in high doses cause cortical excitation, restlessness, disorientation, hallucinations and delirium followed by respiratory depression and coma Eye topical instillation of atropine causes mydriasis, lack of light reflex and cycloplegia lasting 7-10days; resulting in photophobia and blurring of near vision Increase in IOP, specially in narrow angle glaucoma

16. Cardiovascular System Atropine causes bradycardia initially due to inhibition of presynaptic muscarinic receptors (M2) but further increase in dose causes tachycardia due to inhibition of post-synaptic M2 receptors useful in the treatment of AV block and digitalis induced bradycardia Blood Vessels has negligible effect on BP at high doses, has direct vasodilatory effect and also enhances the release of histamine; may lead to hypotension Respiratory System reverse the bronchoconstriction caused by stimulation of M3 receptors Ipratropium and tiotropium-treatment of COPD and bronchial asthma Glycopyrolate is used as a pre- anaesthetic medication to decrease the secretions and reflex bronchospasm during general anaesthesia

17. Smooth Muscles All visceral smooth muscles are relaxed by atropine (M 3 blockade) Gastro-intestinal Tract decrease the motility, tone and secretions constipation may occur, spasm may be relieved Genitourinary Tract decrease the motility of urinary tract may result in urinary retention in in older males with BPH Glands decrease sweat, salivary, tracheobronchial and lacrimal secretion (M3 blockade) skin and eye become dry, talking and swallowing may be difficult Body Temperature rise in body temperature occurs at higher doses due to both inhibition of sweating as well as stimulation of temperature regulating centre in the hypothalamus

18. Comparision between different drugs

19. Uses of Anticholinergic Drugs preoperative medication treatment of reflex-mediated bradycardia c ombination with anticholinesterase drugs during pharmacologic antagonism of non-depolarizing neuromuscular-blocking drugs Other uses of anticholinergic drugs bronchodilation anticholinesterase/organophosphate poisoning m ushroom poisoning ( m ycetism ) biliary and ureteral smooth muscle relaxation-as antispasmodics production of mydriasis and cycloplegia antagonism of gastric hydrogen ion secretion by parietal cells prevention of motion-induced nausea Parkinsonism a cute extrapyramidal symptoms caused by antipsychotics constituents in nonprescription cold remedies

20. Sedatives in Anesthetic Practice

21. chemically heterogeneous class of drugs produce dose dependent CNS depressant effect, relieve anxiety and induce sleep decrease activity, moderates excitement, and calms the recipient Includes Benzodiazepines Barbiturates Miscellaneous

22. GABA- main inhibitory neurotransmitter GABA receptor- supramolecular complex having pentameric structure enclosing a chloride channel s pan the post synaptic membrane d epending on types, number of subunits and brain region localization, activation of receptors results in different pharmacological effects o ther drugs also bind to receptor

23. two classes of GABA receptors: GABA A and  GABA B GABA A  receptors are ligand-gated ion channels activation causes increased Chloride influx GABA B  receptors are G protein-coupled receptors activation causes increased Potassium efflux Both mechanisms result in membrane hyperpolarization and makes the cell refractory to further electrical transmission via action potentials

24. Benzodiazepines Benzodiazepines are drugs that exert, in slightly varying degrees , five principal pharmacologic effects: anxiolysis sedation anti convulsant actions spinal cord-mediated skeletal muscle relaxation anterograde amnesia bind to specific high affinity sites that are separate but adjacent to GABA binding sites b inding enhances the affinity of receptor for GABA binding (GABA- facilitatory effect) without GABA they cannot produce effect potentiate inhibitory effect of GABA increased frequency of Cl channel opening

25. Mechanism of action

26. Classification- Duration of action

27. Classification- Therapeutic Use Sedative/ Hypnotics Temazepam Flurazepam Nitrazepam Anxiolytics Diazepam Oxazepam Lorazepam Anticonvulsants Diazepam Nitrazepam Clonazepam Central muscle relaxants Diazepam Flurazepam Clonazepam

28. Pharmacokinetics Absorption commonly administered orally, intramuscularly , and intravenously Diazepam and Lorazepam-well absorbed from the gastrointestinal tract, with peak plasma levels usually achieved in 1 and 2 hour, respectively intranasal ( 0.2–0.3 mg/kg), buccal (0.07 mg/kg), and sublingual ( 0.1mg/kg ) midazolam provide effective preoperative sedation i ntramuscular injections of diazepam are painful and unreliably absorbed. Midazolam and L orazepam are well absorbed after IM injection, with peak levels achieved in 30 and 90 min, respectively i nduction of general anesthesia with midazolam is convenient only with intravenous administration

29. Distribution Diazepam is relatively lipid soluble and readily penetrates the blood–brain barrier M idazolam is water soluble at reduced pH, its imidazole ring closes at physiological pH, increasing its lipid solubility moderate lipid solubility of lorazepam accounts for its slower brain uptake and onset of action r edistribution is fairly rapid for the benzodiazepines and is responsible for awakening a ll three benzodiazepines are highly protein bound (90–98 %)

30. Biotransformation liver for biotransformation into water-soluble glucuronidated end products the phase I metabolites of diazepam are pharmacologically active s low hepatic extraction and a large volume of distribution result in a long elimination half-life for diazepam (30 h ) although lorazepam also has a low hepatic extraction ratio, its lower lipid solubility limits its V d , resulting in a shorter elimination half-life (15 h ) the clinical duration of lorazepam is often quite prolonged due to increased receptor affinity Midazolam shares diazepam’s V d , but its elimination half-life (2 h) is the shortest of the group because of its increased hepatic extraction ratio

31. Excretion metabolites of benzodiazepine biotransformation are excreted chiefly in the urine Enterohepatic circulation produces a secondary peak in diazepam plasma concentration 6–12 h following administration Kidney failure may lead to prolonged sedation in patients receiving larger doses of midazolam due to the accumulation of a conjugated metabolite

32. Effects on Organ Systems Cardiovascular System minimal cardiovascular depressant effects even at general anesthetic doses decrease arterial blood pressure, cardiac output , and peripheral vascular resistance slightly, and sometimes increase heart rate intravenous midazolam tends to reduce blood pressure and peripheral vascular resistance more than diazepam

33. Respiratory System depress the ventilatory response to CO 2 depression is usually insignificant unless the drugs are administered intravenously or in association with other respiratory depressants v entilation must be monitored in all patients receiving intravenous benzodiazepines, and resuscitation equipment must be immediately available

34. Central Nervous System reduce cerebral oxygen consumption, cerebral blood flow, and intracranial pressure effective in preventing and controlling grand malseizures o ral sedative doses often produce antegrade amnesia , a useful premedication property mild muscle-relaxing property is mediated at the spinal cord level antianxiety, amnestic, and sedative effects seen at lower doses progress to stupor and unconsciousness a slower rate of loss of consciousness and a longer recovery have no direct analgesic properties

35. ADVERSE EFFECTS sedation hangover: confusional states in elderly, lethargy, lassitude ataxia in increased doses loss of memory GIT upset/ epigastric distress p aradoxical behavioral disturbance f loppy baby syndrome in neonates dependence tolerance- with short t1/2 cross tolerance between BDZ and other CNS depressants

36. Uses preoperative premedication Sedation intraoperatively during regional or local anesthesia postoperative ICU patients ambulatory anesthesia b alanced anesthesia remote anesthesia

37. Other uses : Muscle relaxants Anticonvulsant Anxiety Disorders Insomnia Alcohol withdrawl Delerium diagnostic aid for treatment in psychiatry Alprazolam- antidepressant

38. Benzodiazepine Receptor Antagonist- Flumazenil competitive antagonist at the benzodiazepine receptor antagonism is reversible and surmountable benzodiazepine receptor ligand with high affinity, great specificity low dose attenuates the deep CNS depression (loss of consciousness , respiratory depression) by reducing the fractional receptor occupancy short half life compared to BDZ so repeated doses required

39. Barbiturates are the derivatives of barbituric acid and act by increasing the Cl conductance across GABA A -BZD-Cl– channel complex were formerly the mainstay of treatment to sedate patients or to induce and maintain sleep have been largely replaced by the benzodiazepines , primarily because induce tolerance physical dependence are associated with very severe withdrawal symptoms Certain barbiturates , such as the ultra short-acting thiopental, used to induce anesthesia

40. Classification

41. Mechanism of action have GABA mimetic as well as GABA facilitatory action increase the duration of GABA mediated Cl – channel opening d epress neuronal activity in the reticular activating system in the brainstem, which controls multiple vital functions , including consciousness block excitatory neurotransmitter Glutamic acid

42. Pharmacokinetics Absorption thiopental , thiamylal , and methohexital administered intravenously for induction of general anesthesia in adults and children r ectal thiopental or, more often, methohexital has been used for induction in children intramuscular (or oral) pentobarbital was often used in the past for premedication of all age groups

43. Distribution duration of sleep doses of the highly lipid-soluble barbiturates (thiopental, thiamylal , and methohexital ) is determined by redistribution, not by metabolism or elimination. a lthough thiopental is highly protein bound (80%), its great lipid solubility and high non-ionized fraction (60 %) account for rapid brain uptake (within 30 s ) r edistribution to the peripheral compartment specifically , the muscle group lowers plasma and brain concentration to 10% of peak levels within 20–30 min

44. Biotransformation by hepatic oxidation to inactive water-soluble metabolites redistribution is responsible for the awakening from a single sleep dose full recovery of psychomotor function is more rapid due to its enhanced metabolism Excretion inactive metabolites are excreted in urine

45. CNS Low dose------------ sedation & anti-anxiety High dose------------- hypnosis Large dose----------- anesthesia, coma, death CVS a s the dose increases, depress the ganglion transmission then decrease heart rate and BP Respiration is a potent respiratory depressant decrease the sensitivity of respiratory centers to CO 2 Kidney Decrease urine out put at large doses due to hypotension & release of ADH . Blood can Induce porphyria Pharmacological actions

46. Clinical uses Induction of anesthesia Generalized anxiety Insomnia Convulsion Cerebral edema Hyperbilirubinemia in kernicterus in new born narcoanalysis and narcotherapy

47. Adverse effects

48. Other Drugs Zolpidem Zaleplon Eszopiclone Ramelteon Propofol 25–100 mcg/kg/min Ketamine 2.5–15 mcg/kg/min

49. Alpha 2 agonists Clonidine an imidazoline compound provides sedation without depression of ventilation improve perioperative hemodynamic and sympathoadrenal stability for premedication and supplementation to general anesthesia Oral clonidine: 3-5mcg/kg use has been limited due to its longer half life- 9-12hrs

50. Dexmedetomidine highly selective, specific and potent alpha 2 agonist used as a perioperative sedative and analgesic produces sedation by decreasing the SNSA and the level of arousal results in calm patient who can be easily aroused to full consciousness and has no respiratory depression 200-700mcg/kg/ hr IV useful for sedation of patients postoperatively or in ICU when the patient is mechanically ventilated

51. Thank You !!!