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DRUGS AND AUTONOMICC NERVOUS SYSTEM

AND AND EFFECTS OF MAO INHIBITORS –PART


II

Dr A J Karki
Tutor,Anesthesiology
NAMS,Bir Hospital
PARASYMPATHETIC DIVISION OUTFLOW

Cranial nerves Ganglion Effector


organs
Cranial outflow III Ciliary eye
VII submaxillary Submaxillary
and sublingual
glands
IX otic Parotid glands
X Within walls of Heart, lungs,
target organs stomach,esophag
us,liver,small
intestine
GB,pancreas,
uterus(upper
pole)

Sacral outflow S2-S4 Within walls of large


target organs intestines,UB,des
colon,rectum,uter
us(lower pole)
SYNTHESIS OF ACETYLCHOLINE
 Choline(from the extra-cellular fluid into the cytoplasm of
the cholinergic neuron by an energy-dependent carrier
system )
 Choline acetyltransferase catalyzes the reaction of choline
with acetyl coenzyme A (CoA) to form acetylcholine in the
cytosol.
 Acetyl CoA is derived from the mitochondria and is
produced by the Krebs cycle and fatty acid oxidation
STORAGE OF ACETYLCHOLINE IN
VESICLES
 Ach packaged into presynaptic vesicles by an active
transport process coupled to the efflux of protons.
 The mature vesicle contains Ach
 The neurotransmitters in vesicles will appear as bead-like
structures(varicosities) along the nerve terminal of the
presynaptic neuron
RELEASE OF ACETYLCHOLINE
Action potential propagated by the action of voltage sensitive sodium
channels arrives at a nerve ending

Voltage-sensitive Ca channels on the presynaptic membrane open

Increase in the concentration of intracellular calcium

Elevated Ca levels promote the fusion of synaptic vesicles with the


cell membrane
Release of their contents into the synaptic space.

 Release can be blocked by botulinum toxin and toxin in black


widow spider venom causes all the ach stored in synaptic vesicles
to empty into the synaptic gap.
BINDING TO THE RECEPTOR
 Ach released from the synaptic vesicles diffuses across the
synaptic space, and it binds to either of two postsynaptic
receptors on the target cell or to presynaptic receptors in
the membrane of the neuron that released the
acetylcholine.
 The postsynaptic cholinergic receptors (muscarinic and
nicotinic)
 Binding to a receptor leads to a biologic response within the
cell.
DEGRADATION OF ACETYLCHOLINE
 The signal at the postjunctional effector site is rapidly
terminated by acetylcholinesterase to cholin and acetate.
RECYCLING OF CHOLINE
 Choline recaptured by a sodium-coupled uptake system and
transported back into the neuron
 where it is acetylated into acetylcholine that is stored until
released by a subsequent action potential
MUSCARINIC RECEPTORS
 Found in effectors stimulated by cholinergic fibers
 In addition to binding Ach, also recognize muscarine, an
alkaloid.
 Super family of G protein coupled receptors
 Muscarinic receptors show weak affinity for nicotine
 Sub-types:M1-M5
 M1, M2 and M3, receptors have been functionally
characterized.
 M1
 CNS, autonomic ganglia, gastric parietal cells
 Stimulation increases IP3+DAG = decrease K+ conduction

 M2
 Atria, conducting tissues of heart and smooth muscle
 Decrease cAMP and increase K+ conductance

 M3
 Excitatory effect=exocrine gland and visceral smooth muscle contraction by
stimulation of IP3
Drugs with muscarinic actions preferentially stimulate muscarinic receptors on
these tissues, but at high concentration they may show some activity at
nicotinic receptors
NICOTINIC RECEPTOR
 Sub-types:
 N1: Present in autonomic ganglia, adrenal medulla, CNS
 N2: Present in neuromuscular junction
NICOTINIC RECEPTORS
 Belong to the superfamily of ligand gated ion channels
 5 subunits ;2-alpha, beta, epsilon, delta sub-units.
 Channel opens when Ach occupies both the alpha
 Channel closes when Ach occupies only 1 alpha subunit
 In addition to binding acetylcholine, has weak affinity for
muscarine
CHOLINERGIC AGONISTS
DIRECT-ACTING CHOLINERGIC AGONISTS/
PARASYMPATHOMIMETICS
 mimic the effects of acetylcholine by binding directly to
cholinoceptors
 All of the direct-acting cholinergic drugs have longer
durations of action than acetylcholine
ACETYLCHOLINE
 Although it is the neurotransmitter of parasympathetic
and somatic nerves as well as autonomic ganglia
 it is therapeutically of no importance because of its rapid
inactivation by the cholinesterases.
 Acetylcholine has both muscarinic and nicotinic activity.
EFFECTS OF ACH OTHER
EFFECTS

 CVS;
 on the heart mimic the
effects of vagal
stimulation; Decrease in
heart rate and cardiac
output
 Decrease BP(vasodilation )
OTHER CHOLINERGIC DRUGS

 Non-selective actions

 Rapid hydrolysis

 Limited therapeutic use


Examples:
Methacholine : provocative test in asthma

Bethanechol : post-op non obstructive urinary retention, atonic


bladder, gastroesophageal reflux,
 Congenital megacolon

Carbachol: wide angle glaucoma


PILOCARPINE

 Only Muscarinic action


Uses:
 Glucoma

 As miotic

 Non obstructive urinary retention

 Atropine fever
CHOLINERGIC ANTAGONISTS
CHOLINERGIC BLOCKERS, PARASYMPATHOLYTICS OR
ANTICHOLINERGIC DRUGS

 Compete with neurally released Ach for access to


muscarinic receptors and blocks its effects.
 Antagonize actions of muscarinic agonists
 agents selectively block muscarinic synapses of the
parasympathetic nerves.
 The effects of parasympathetic innervation are thus
interrupted, and the actions of sympathetic stimulation
are left unopposed.
 second group of drugs, the ganglionic blockersnicotinic
receptors of the sympathetic and parasympathetic ganglia.
CHOLINERGIC ANTAGONISTS
CLASSIFICATION
natural semisynthetic synthetic

Atropine homatropine glycopyrrolate

scopolamine Atropine methonitrate Trihexyphenidyl

Hyoscine butyl bromide propanthaline

Ipratropium bromide Oxybutynin


Tiotropium bromide isopromide
SITES OF ACTIONS OF CHOLINERGIC
ANTAGONISTS
COMPARISON BET
ANTICHOLINERGICS
Atropine scopolamine glycopyrrolate
sedation + +++ o
antisialagogue + +++ + ++
Inc HR +++ + ++
Mydriasis,cyclope + +++ o
gia
Motion sickness + +++ o
prevention
Dec gastric acid + + +
sec
FHR + ? O
Onset With in min 7-8 min
T½ ~45min ~3hrs
Bronchodilation ++ + ++
ATROPINE
 Tertiary amine
 Atropa Belladona plant

 Metabolism=50% liver,rest unchanged in urine

 Onset within min

 T1/2=45min

 Dose:as premed-i/v or i/m=0.01-0.02mg/kg

 Upto 0.4-0.6 in adults

 Full vagal blokade=3mg


DOSE-DEPENDENT EFFECTS OF
ATROPINE
SCOPOLAMINE
 Tertiary amine

 Shorter duration of action

 Metabolism=50% liver,rest unchanged in urine


 0.3-0.5mg oral
 Transdermal patch
IPRATROPIUM BROMIDE

 Derivative of atropine
 Quarternary amine
 0.5mg/2.5ml-Rx of COPD asthma along with B-
agonist
GLYCOPYRROLATE
 Quaternary compd
 Dose=0.005-0.01mg/kg upto=0.2-0.3mg in adults

 Sol=0.2mg/ml

 Duration of action=2-4hrs
INDICATION OF ANTICHOLINERGICS
 Bradycardia
 Rx of op poisoning

 Premed

 antiemetic

 As an antispasmodic

 anti-parkinsonism

 Anti motion sickness

 Dental and oral surgery

 COPD/asthma
C/I
 Acute cong glucoma
 CCF

 Enlarged prostrate

 GOO
S/E OF ANTI CHOLINERGICS
 Blurred vision
 Confusion,restlessness,anxiety

 Mild postop memory deficit

 Mydriasis

 Constipation

 Urinary retention

 Dry mouth

 Hot dry skin,hyperthermia(atropine fever)


CAS
Seen with Atropine and Scopolamine
S/S:
 agitation

 restlessness

 delirium in old age

 hallucinations

 dry mouth

 somnolence

 unconsciousness

 atropine fever

 Blockade of muscarinic cholinergic receptors


Competitive inhibition of ACh in the CNS
Rx: ABC
 Drug: Physostigmine:0.01-0.03mg/kg
 Repeated after 15-30 mins
Thank you