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Drugs affecting the parasympathetic
and somatic nervous system
BrainSpinal Cord
CNS
SomaticNS
PNS
Nervous System
Autonomic NS
Sympathetic
Parasympathetic
Drugs and Cholinergic Synapses
PRESYNAPTICPRESYNAPTIC POSTSYNAPTICPOSTSYNAPTIC
ACh
Choline uptake and Ach synthesis
Choline uptake and Ach synthesis
Metabolic RemovalMetabolic Removal
ActionActionS & S
M / N
ReceptorBinding
ReceptorBinding
AChE
Choline
ACh
PRESYNAPTICPRESYNAPTIC POSTSYNAPTICPOSTSYNAPTIC
ACh
Choline uptake Choline uptake and Ach synthesisand Ach synthesis
Choline uptake Choline uptake and Ach synthesisand Ach synthesis
Metabolic RemovalMetabolic Removal
ActionActionS & S
M / N
ReceptorBinding
ReceptorBinding
AChE
Choline
ACh
PRESYNAPTICPRESYNAPTIC POSTSYNAPTICPOSTSYNAPTIC
ACh
Choline uptake and Ach synthesis
Choline uptake and Ach synthesis
Metabolic RemovalMetabolic Removal
ActionActionS & S
M / N
ReceptorReceptorBindingBinding
ReceptorReceptorBindingBinding
AChE
Choline
ACh
PRESYNAPTICPRESYNAPTIC POSTSYNAPTICPOSTSYNAPTIC
ACh
Choline uptake and Ach synthesis
Choline uptake and Ach synthesis
Metabolic RemovalMetabolic RemovalMetabolic RemovalMetabolic Removal
ActionActionS & S
M / N
ReceptorBinding
ReceptorBinding
AChE
Choline
ACh
PRESYNAPTICPRESYNAPTIC POSTSYNAPTICPOSTSYNAPTIC
ACh
Choline uptake and Ach synthesis
Choline uptake and Ach synthesis
Metabolic RemovalMetabolic Removal
ActionActionS & S
M / N
ReceptorBinding
ReceptorBinding
AChE
Choline
ACh
Cholinomimetic Drugs
Direct Acting Indirect Acting
Receptor AgonistsReceptor Agonists Cholinesterase InhibitorsCholinesterase Inhibitors
● choline esters
● alkaloids
● carbamates
● organophosphates
ACh
muscarinicnicotinic(M)(N)
Cholinergic Receptors
M1: NEURONAL CNS AND ANS M1: NEURONAL CNS AND ANS PRESYNAPTICPRESYNAPTIC
M2: CARDIACM2: CARDIAC
M3: SMOOTH MUSCLE AND GLANDULARM3: SMOOTH MUSCLE AND GLANDULAR
M3: VASCULAR ENDOTHELIUM M3: VASCULAR ENDOTHELIUM (NON-INNERVATED)(NON-INNERVATED)
MUSCARINIC RECEPTOR SUBTYPESMUSCARINIC RECEPTOR SUBTYPES
CNS
AChNEN
1
2
1
N
ACh
MACh
C
T
L
SACh
NESG
AChN
ACh
SMN
Muscarinic Agonists/Antagonists
M
AChNEN
1
2
1
N
ACh
MACh
CNS
C
T
L
SACh
NESG
AChN
ACh
SMN
Nicotinic Agonists/Antagonists
M
SITE EFFECT
EFFECTS OF STIMULATING MUSCARINIC RECEPTORS (SLUDE)
BRONCHOSPASM
BRADYCARDIA
VASODILATION
MIOSIS
INCREASED URINATION
INCREASED GI MOTILITY
INCREASED SALIVATION
INCREASED TEARSLACRIMAL GLANDS
SALIVARY GLANDS
GI TRACT
BLADDER
IRIS
AIRWAYS
VASCULATURE
HEART
SWEAT GLANDS INCREASED SWEATNG
MUSCARINIC AGONISTS MUSCARINIC AGONISTS MUSCARINIC AGONISTS MUSCARINIC AGONISTS
AChACh - - no clinical useno clinical use AChACh - - no clinical useno clinical use
Choline EstersCholine Esters
carbacholcarbachol – muscarinic and nicotinic agonist – muscarinic and nicotinic agonist
bethanecholbethanechol – muscarinic agonist– muscarinic agonist
• • used to prevent urinary retentionused to prevent urinary retention
• • effects mostly on GI and urinary system effects mostly on GI and urinary system when administered p.o. or s.c.when administered p.o. or s.c.
• • used to produce miosis during ocular surgeryused to produce miosis during ocular surgery
•• adverse effects – overstimulation of adverse effects – overstimulation of muscarinic receptorsmuscarinic receptors
MUSCARINIC AGONISTS: MUSCARINIC AGONISTS: MUSCARINIC AGONISTS: MUSCARINIC AGONISTS:
AlkaloidsAlkaloids AlkaloidsAlkaloids
•• No nicotinic effectsNo nicotinic effects
•• Somewhat selective for salivary glandsSomewhat selective for salivary glands
• • Orally for the treatment of xerostomiaOrally for the treatment of xerostomia
•• Used topically to treat glaucomaUsed topically to treat glaucoma
Adverse Effects:Adverse Effects: ‘‘over stimulation’ of muscarinic receptorsover stimulation’ of muscarinic receptors
pilocarpinepilocarpine – muscarinic agonist – muscarinic agonist
• • Used for Sjorgren’s SyndromeUsed for Sjorgren’s Syndrome
GlaucomaGlaucoma
Chronic open-angle glaucoma (most common): The drainage angle of the eye becomes less efficient with time causing inefficient drainage of aqueous humour and increased pressure within the eye. Gradually produces optic nerve damage.
Closed (or narrow)-angle glaucoma: The drainage angle of the eye becomes physically blocked by a narrow angle, preventing drainage of aqueous humour slowly or suddenly.
Treatment – Increase outflow of aqueous humour
• • mitotic agents (parasympathomimetics; e.g. pilocarpine)mitotic agents (parasympathomimetics; e.g. pilocarpine)
Management of Glaucoma:Lower intraocular pressureManagement of Glaucoma:Lower intraocular pressure
• • Cholinesterase Inhibitors (physostigmine)Cholinesterase Inhibitors (physostigmine)
Treatment – Decrease ciliary body production of aqueous humour
• • Carbonic anydrase inhibitors; e.g. acetazolamide)Carbonic anydrase inhibitors; e.g. acetazolamide)
• • Other: prostaglandin analogs (latanoprost), alpha-2 Other: prostaglandin analogs (latanoprost), alpha-2 agonists (brimonidine)agonists (brimonidine)
• • Topical beta-blockers (timolol, levobunolol)Topical beta-blockers (timolol, levobunolol)
Antimuscarinic Drugs
● atropine
● ipratropium (quaternary)
● scopolamine
● glycopyrrolate
● oxybutynin
Natural Alkaloids
Semi-synthetic Derivatives
● tiotropium (quaternary; 24h duration)
AChNEN
1
2
1
N
ACh
MACh
CNS
C
T
L
SACh
NESG
AChM
N
ACh
SMN
Muscarinic Antagonists
XX
XX
ANTIMUSCARINIC AGENTSANTIMUSCARINIC AGENTS
BELLADONNA BELLADONNA ALKALOIDSALKALOIDS
• • ATROPINEATROPINE
• • SCOPOLAMINESCOPOLAMINE
TX: USED WHEN A REDUCTION OF PARASYMATHETIC TONE IS DESIRABLETX: USED WHEN A REDUCTION OF PARASYMATHETIC TONE IS DESIRABLE
• • Preop to reduce salivations / bronchial secretionsPreop to reduce salivations / bronchial secretions
• • Reduce intestinal motilityReduce intestinal motility
• • Treat overactive bladderTreat overactive bladder
• • Ophthalmological examinationsOphthalmological examinations
• • Prevent motion sicknessPrevent motion sickness
• • Treat asthmaTreat asthma
• • Treat AChE inhibitor poisoningTreat AChE inhibitor poisoning
• • Prevent vagal stimulation during anesthesia and surgeryPrevent vagal stimulation during anesthesia and surgery
ATROPINE: OVERVIEW OF TOXIC ACTIONSATROPINE: OVERVIEW OF TOXIC ACTIONS
DRY AS A BONEDRY AS A BONE DRY AS A BONEDRY AS A BONE
HOT AS A PISTOLHOT AS A PISTOL HOT AS A PISTOLHOT AS A PISTOL
REDRED AS A BEETAS A BEET REDRED AS A BEETAS A BEET
BLIND AS A BATBLIND AS A BAT BLIND AS A BATBLIND AS A BAT
MAD AS A HATTERMAD AS A HATTER MAD AS A HATTERMAD AS A HATTER
ATROPINE: OVERVIEW OF ACTIONS
0.5 mg: Paradoxical bradycardia; Some dryness of mouth; Inhibition of sweating
1.0 mg: Increased xerostomia; Thirst; Mild tachycardia; Mild mydriasis
2.0 mg: Marked tachycardia; Xerostomia; Pupilary dilation; Some blurring of vision and decrease in gastric acid secretion
ATROPINE: OVERVIEW OF ACTIONS
5.0 mg: Difficulty in speaking, swallowing and urination; Decreased intestinal motility; Restlessness; Headache; Dry hot skin
10 mg & UP: Rapid and weak pulse; Fixed, maximally dilated pupils; Blurred vision; Ataxia; Excitement; Hallucinations and delirium; Coma.
ATROPINE OVERDOSE: ANTIDOTE - Physostigmine
ATROPINE OVERDOSE: ANTIDOTE - Physostigmine
ACh ActionActionS & S
M Atro
pine
Atropin
e
AChE
Choline
ACh
ATROPINE OVERDOSE: ANTIDOTE - Physostigmine
ATROPINE OVERDOSE: ANTIDOTE - Physostigmine
ACh ActionActionS & S
M
Atropin
e
Atropin
e
AChE
Choline
ACh
Physostigmine
X
CHOLINESTERASE (AChE) CHOLINESTERASE (AChE) INHIBITORSINHIBITORS
AGENTS USED TO ENHANCE TRANSMISSIONAGENTS USED TO ENHANCE TRANSMISSION AT CHOLINERGIC JUNCTIONSAT CHOLINERGIC JUNCTIONS
•• Short-acting (noncovalent inhibitors)
•• Medium-duration (‘reversible’ carbamate inhibitors)
•• Irreversible (organophosphates)
AChNEN
1
2
1
N
ACh
MACh
CNS
C
T
L
SACh
NESG
AChM
N
ACh
SMN
CholinesteraseInhibitors
Cholinesterase Inhibitors - ActionCholinesterase Inhibitors - Action
ACh
Ach - normally removed from synapse via AChEAch - normally removed from synapse via AChE
ActionActionS & S
M / NM / N
ReceptorBinding
ReceptorBinding
AChEAChEXAChE Inhibitor
ACh
- DRUG OF CHOICE TO TREAT POISONING - DRUG OF CHOICE TO TREAT POISONING WITH ATROPINIC AGENTSWITH ATROPINIC AGENTS
• • PHYSOSTIGMINEPHYSOSTIGMINE
Cholinesterase Inhibitors (reversible)
- READILY PENETRATES CNS- READILY PENETRATES CNS
• • NEOSTIGMINE and PYRIDOSTIGMINENEOSTIGMINE and PYRIDOSTIGMINE
- DO - DO NOTNOT PENETRATE CNS PENETRATE CNS
- USED TO TREAT MYASTHENIA GRAVIS- USED TO TREAT MYASTHENIA GRAVIS
Carbamates; BIND TOCarbamates; BIND TO THE ESTERATIC SITE OF AChE THE ESTERATIC SITE OF AChE
- NEOSTIGMINE USED AS ANTIDOTE FOR - NEOSTIGMINE USED AS ANTIDOTE FOR OVERDOSE OF “CURARE-LIKE” DRUGSOVERDOSE OF “CURARE-LIKE” DRUGS
- USED TO TREAT ALZHEIMER’S AND DEMENTIA- USED TO TREAT ALZHEIMER’S AND DEMENTIA
- USED TO TREAT GLAUCOMA- USED TO TREAT GLAUCOMA
- Diagnostic agent used to test for - Diagnostic agent used to test for myasthenia gravismyasthenia gravis
• • EDROPHONIUMEDROPHONIUM
Cholinesterase Inhibitors
- Very short acting- Very short acting
CHOLINESTERASE INHIBITORS: ACUTE TOXICITYCHOLINESTERASE INHIBITORS: ACUTE TOXICITY
SYMPTOMS DUE TO EXCESS OF SYMPTOMS DUE TO EXCESS OF ACh AT SYNAPSEACh AT SYNAPSE
• • MUSCARINIC RECEPTORSMUSCARINIC RECEPTORS
- SLUDE- SLUDE
• • NICOTINIC RECEPTORSNICOTINIC RECEPTORS
- FASCICULATION, MUSCLE CRAMPS, - FASCICULATION, MUSCLE CRAMPS, WEAKNESS, RESPIRATORY PARALYSISWEAKNESS, RESPIRATORY PARALYSIS
Cholinesterase Inhibitors - Action and ReversalCholinesterase Inhibitors - Action and Reversal
ACh
Ach - normally removed from synapse via AChEAch - normally removed from synapse via AChE
ActionActionM / NM / N
ReceptorBinding
ReceptorBinding
AChEAChEXAChE Inhibitor
ACh
Antidote for Overdose of Carbamate Cholinesterase Inhibitors: AtropineAntidote for Overdose of Carbamate Cholinesterase Inhibitors: Atropine
ACh ActionActionM / NM / N
AChEAChEXAChE Inhibitor
Atropi
ne
ACh
• ORGANOPHOSPHATES: ORGANOPHOSPHATES: IRREVERSIBLY PHOSPHORYLATE IRREVERSIBLY PHOSPHORYLATE
SERINE HYDROXYL AT ACTIVE SITE OF AChESERINE HYDROXYL AT ACTIVE SITE OF AChE
•
Cholinesterase Inhibitors
• • Malathion, Parathion, DiazinonMalathion, Parathion, Diazinon
INSECTICIDESINSECTICIDES
NERVE GASESNERVE GASES
• • Sarin, Soman, TabunSarin, Soman, Tabun
Antidote for Overdose of Organophosphate Cholinesterase Inhibitors: 2-Pralidoxime (2-PAM)
GANGLIONIC BLOCKING AGENTSGANGLIONIC BLOCKING AGENTS
• • TRIMETHAPHANTRIMETHAPHAN
• • HEXAMETHONIUMHEXAMETHONIUM
- Used to produce controlled hypotension- Used to produce controlled hypotension
GANGLIONIC STIMULATING AGENTSGANGLIONIC STIMULATING AGENTS
• • NICOTINENICOTINE
NEUROMUSCULAR (NMJ)NEUROMUSCULAR (NMJ)BLOCKING AGENTSBLOCKING AGENTS
AChNEN
1
2
1
N
ACh
MACh
CNS
C
T
L
SACh
NESG
AChM
N
ACh
SMN
NMJ Blocking Agents
NMJ BLOCKING AGENTS USED IN SURGERY TO NMJ BLOCKING AGENTS USED IN SURGERY TO PROMOTE SKELETAL MUSCLE RELAXATIONPROMOTE SKELETAL MUSCLE RELAXATION
NMJ Blocking Agents
- Intubation- Intubation
- Maintain controlled ventilation- Maintain controlled ventilation
- Paralysis of skeletal muscle in area - Paralysis of skeletal muscle in area
of surgeryof surgery
NMJ BLOCKING DRUGSNMJ BLOCKING DRUGS
DEPOLARIZINGDEPOLARIZING
(non-competative)(non-competative)
•• SUCCINYLCHOLINESUCCINYLCHOLINE
NONDEPOLARIZINGNONDEPOLARIZING(competative)(competative)
• • TUBOCURARINETUBOCURARINE
Long DurationLong Duration
Short DurationShort Duration
• • MIVACURIUMMIVACURIUM
• • PANCURONIUMPANCURONIUM
Intermediate DurationIntermediate Duration
Nondepolarizing NMJ Blocking Agents:Mechanism of Action
Nondepolarizing NMJ Blocking Agents:Mechanism of Action
SMparalysis
SMparalysis
NN
AChEAChE
Tubo
cura
rine
ACh SM
ACh
Antidote for Overdose of nondepolarizing NMJ Blocking Agents: NeostigmineAntidote for Overdose of nondepolarizing NMJ Blocking Agents: Neostigmine
recovery from
SM paralysis
recovery from
SM paralysis
NN
AChEAChE
Tubocurarine
ACh SM
Neostigmine
ACh
X
NN
AChEAChE
Succi
nylc
holin
e
ACh SM
ACh SMparalysis
SMparalysis
Caution: Succinylcholine may produce hyperkalemia
Depolarizing NMJ Blocking Agents:Mechanism of Action
Depolarizing NMJ Blocking Agents:Mechanism of Action
Antidote for overdose of Succinylcholine: ‘no pharmacological approach’; ventilationAntidote for overdose of Succinylcholine: ‘no pharmacological approach’; ventilation
NN
AChEAChE
Succi
nylc
holin
e
ACh SM
ACh
butyrlcholinesterase
recovery from
SM paralysis
recovery from
SM paralysis