The document discusses the roles and uses of anticholinergics and sedatives in anesthetic practice, focusing on the autonomic nervous system and the effects of various medications. It covers the mechanisms, pharmacokinetics, and pharmacodynamics of anticholinergic drugs, such as atropine and scopolamine, as well as benzodiazepines, barbiturates, and alpha-2 agonists, emphasizing their uses, side effects, and interactions. The content targets medical professionals looking to understand the applications of these drugs in anesthesia and sedation management.

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
• blood pressure
• gastrointestinal motility
• gastrointestinal secretion
• urinary bladder emptying
• sweating
• body temperature
• some 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

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

11. 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

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

13. • the most commonly used muscarinic antagonists
in anesthesia are
• Atropine
• Scopolamine
• Glycopyrrolate

14. 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
 peak effects on the heart occur within four minutes of IV and
about one hour after IM administration
 peak 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
 about 50% of the dose is excreted within four hours in the urine

15. • 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

16. 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

17. • 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

18. • Smooth Muscles
• All visceral smooth muscles are relaxed by atropine (M3 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

19. Comparision between different drugs

20. Uses of Anticholinergic Drugs
• preoperative medication
• treatment of reflex-mediated bradycardia
• combination with anticholinesterase drugs during pharmacologic
antagonism of non-depolarizing neuromuscular-blocking drugs
Other uses of anticholinergic drugs
- bronchodilation
- anticholinesterase/organophosphate poisoning
- mushroom poisoning (mycetism)
- 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
- acute extrapyramidal symptoms caused by antipsychotics
- constituents in nonprescription cold remedies

21. Sedatives
in
Anesthetic Practice

22. • 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

23. • GABA- main inhibitory neurotransmitter
• GABA receptor- supramolecular complex having
pentameric structure enclosing a chloride channel
• span the post synaptic membrane
• depending on types, number of subunits and
brain region localization, activation of
receptors results in different pharmacological
effects
• other drugs also bind to receptor

26. • two classes of GABA receptors: GABAA and GABAB
 GABAA receptors are ligand-gated ion channels
 activation causes increased Chloride influx
 GABAB 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

27. 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
• binding 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

28. Mechanism of action

29. Classification- Duration of action

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

31. 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
 intramuscular injections of diazepam are painful and unreliably
absorbed.
 Midazolam and Lorazepam are well absorbed after IM injection,
with peak levels achieved in 30 and 90 min, respectively
 induction of general anesthesia with midazolam is convenient
only with intravenous administration

32. Distribution
• Diazepam is relatively lipid soluble and readily
penetrates the blood–brain barrier
• Midazolam 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
• redistribution is fairly rapid for the benzodiazepines and
is responsible for awakening
• all three benzodiazepines are highly protein bound (90–
98%)

33. Biotransformation
• liver for biotransformation into water-soluble glucuronidated
end products
• the phase I metabolites of diazepam are pharmacologically
active
• slow 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 Vd, 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 Vd, but its elimination half-life
(2 h) is the shortest of the group because of its increased
hepatic extraction ratio

34. 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

35. 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

36. • Respiratory System
 depress the ventilatory response to CO2
 depression is usually insignificant unless the
drugs are administered intravenously or in
association with other respiratory depressants
 ventilation must be monitored in all patients
receiving intravenous benzodiazepines, and
resuscitation equipment must be immediately
available

37. • Central Nervous System
 reduce cerebral oxygen consumption, cerebral blood flow,
and intracranial pressure
 effective in preventing and controlling grand malseizures
 oral 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

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

39. Uses
• preoperative premedication
• Sedation
 intraoperatively during regional or local anesthesia
 postoperative
 ICU patients
 ambulatory anesthesia
 balanced anesthesia
 remote anesthesia

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

43. 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

44. Barbiturates
• are the derivatives of barbituric acid and act by
increasing the Cl conductance across GABAA-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

45. Classification

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

47. Pharmacokinetics
• Absorption
 thiopental, thiamylal, and methohexital
administered intravenously for induction of
general anesthesia in adults and children
 rectal 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

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

49. • 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

50. • CNS
 Low dose------------ sedation & anti-anxiety
 High dose------------- hypnosis
 Large dose----------- anesthesia, coma, death
• CVS
 as 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 CO2
• Kidney
 Decrease urine out put at large doses due to hypotension &
release of ADH.
• Blood
 can Induce porphyria
Pharmacological actions

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

52. Adverse effects

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

55. 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

56. • 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

57. Thank You!!!