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Cholinergic (Cholinoceptor
Activating) Drugs-1

     Dept. of Pharmacology
   Faculty of Medicine & Health
             Sciences
              AIMST
Cholinergic Drugs-1-Lecture
Outline
                 Cholinoceptors(Review)
                     Types
                          Muscarinic
                       
                           Nicotinic
                     Characteristics
                     Typical Locations
                 Cholinergic Drugs
                     Classification
                     Direct Acting
                          Choline Esters
                          Cholinomimetic
                           Alkaloids
Cholinergic Drugs-1-Lecture
Outline(contd.)
                 Cholinergic Drugs (contd.)
                      Indirect Acting
                       (Anticholinesterase Agents)
                           Reversible
                           Irreversible
                      ACh-Pharmacological
                       Actions
                      Choline Esters
                           Properties
                           Therapeutic Uses
                      Cholinomimetic Alkaloids
                 Cholinomimetic Drugs
                      Contraindications
Cholinergic Receptors(Cholinoceptors)-
Types & Characteristics
   Acetylcholine Receptors (Cholinoceptors)
       Main subdivision is into muscarinic
        (mAChR) and nicotinic (nAChR) subtypes
       In smooth muscle, cardiac muscle and
        glands the cholinergic receptors are of the
        muscarinic (mAChR) type (i.e. stimulated
        by muscarine, an alkaloid from Amanita
        muscaria mushrooms)
Cholinergic Receptors(Cholinoceptors)-
Types & Characteristics
   Acetylcholine Receptors (Cholinoceptors)
       In striated (skeletal) muscle and autonomic
        ganglia (sympathetic and parasympathetic)
        the cholinergic receptors are nicotinic (nAChR)
        (i.e. stimulated by nicotine)
       mAChR’s are G-protein coupled receptors,
        causing:
            Activation of phospholipase C
            Inhibition of adenylate cyclase
         
             Activation of potassium channels
         
             Inhibition of calcium channels
Cholinergic Receptors(Cholinoceptors)-
Types & Characteristics
   Muscarinic Acetylcholine
    Receptors(mAChR’s)
       Five types occur, viz.:
            M1-receptors (neural)- Selectively blocked by
             pirenzepine
            M2-receptors (cardiac)- Decrease cardiac
             contractility and heart rate; selectively blocked by
             gallamine
            M3-receptors (glandular)- causing secretion, visceral
             smooth muscle contraction, vascular relaxation
            M4-receptors & M5-receptors- largely confined to
             CNS; functional role not well understood
Autonomic Nervous System(ANS)-
Cholinergic Receptors
   M1-receptors -
       M1, M3 and M5
        receptor subtypes
        have stimulatory
        effect on the target
        tissue
       M2 and M4 subtypes
        are inhibitory
Cholinergic Muscarinic Receptors
Cholinergic Receptors(Cholinoceptors)-
Types & Characteristics
   Nicotinic Acetylcholine Receptors(nAChR’s)
       Two types occur, viz.:
            NM receptors (muscle type)- located at
             skeletal muscle neuromuscular junction,
             Na+, K+ depolarizing ion channel, blocked by
             d-tubocurarine
            NG receptors (neuronal type)- located at
             postganglionic cell body, Na+, K+
             depolarizing ion channel, blocked by
             hexamethonium
Cholinergic (Cholinoceptor Activating)
Drugs
   Cholinergic Drugs(Cholinomimetics/
    Parasympathomimetics)
       Drugs producing actions similar to that of
        Acetylcholine (ACh)
   Two modes of action:
       May directly interact with cholinergic
        receptors
       Increase availability of ACh at receptor
        sites
Cholinergic (Cholinoceptor Activating)
Drugs-Classification
   Cholinergic Drugs
       Direct-acting drugs (bind to & activate muscarinic or nicotinic
        receptors)
            Choline esters
                  Acetylcholine
                  Bethanechol
                  Carbachol
                  Methacholine
         
             Cholinomimetic Alkaloids
                  Pilocarpine
                  Muscarine
                  Nicotine
                  Lobeline
                  Arecoline
                  Oxotremorine
Cholinergic (Cholinoceptor Activating)
Drugs-Classification
   Cholinergic Drugs (contd.)
       Indirect-acting drugs (↑ ACh/Cholinesterase
        inhibitors/Anticholinesterases)
            Reversible (water soluble)
                  Edrophonium
                  Physostigmine
                  Neostigmine
                  Pyridostigmine
                  Ambenonium
                  Demecarium
                  Eptastigmine
                  Rivastigmine
                  Donepezil
Cholinergic (Cholinoceptor Activating)
Drugs-Classification
   Cholinergic Drugs (contd.)
       Indirect-acting drugs (↑ ACh/
        Cholinesterase inhibitors)
            Irreversible (lipid soluble)
                 Organophosphates (e.g., Echothiophate,
                  Diisopropylfluorophosphate, Malathion, Parathion,
                  Diazinon, Soman, Sarin, Tabun, etc.)
                 Carbamates (e.g., Carbaryl, Propoxur)
Acetylcholine (ACh)- Actions
   Muscarinic
       Heart
         
             SA Node
                  Hyperpolarization of SA nodal cells
                  Decreased rate of impulse generation (Bradycardia,
                   negative chronotropy)
         
             Atria
                  Decrease in contractile strength(negative inotropy)
            Atrioventricular Node
                  Decrease in conduction velocity (negative dromotropy)
            Ventricles
                  Small decrease in contractile strength
Acetylcholine (ACh)- Actions
   Muscarinic
        Blood vessels
          
              Very few blood
              vessels receive
              cholinergic
              innervation
          
              Muscarinic receptors
              present on vascular
              endothelial cells
          
              Arteries
                  Dilation (via
                   EDRF(NO))
          
              Veins
                  Dilation (via
                   EDRF(NO))
Acetylcholine (ACh)- Actions
   Muscarinic
       Lung
         
             Bronchial muscle
                  Contraction (Bronchoconstriction)
            Bronchial glands
                  Stimulation of secretion
       Gastrointestinal tract (evacuation of bowel)
         
             Motility
                  Increase
         
             Sphincters
                  Relaxation
         
             Secretion
                  Stimulation
Acetylcholine (ACh)- Actions
   Muscarinic
       Urinary bladder (voiding of bladder)
         
             Detrusor
                  Contraction
         
             Trigone & sphincter
                  Relaxation
       Ureter
            Increased peristalsis
       Glands
         
             Sweat/salivary/lacrimal/nasopharyngeal
                  Increased secretions
Acetylcholine (ACh)- Actions
   Muscarinic
       Eye
           Sphincter (circular) muscle of iris
                 Contraction (miosis)
        
            Ciliary muscle
                 Contraction for near vision
                 Spasm of accomodation
                 Increased aqueous outflow
                 Reduction in intraocular tension
Acetylcholine (ACh)- Actions
   Nicotinic
       Autonomic ganglia
            Both parasympathetic & sympathetic ganglia stimulated
            High dose ACh after atropine administration leads to
                  Tachycardia
                  Rise in BP
       Skeletal muscles
         
             Iontophoretic application of ACh to motor endplate leads
             to skeletal muscle contraction
Choline Esters-Properties
Choline Ester   Susceptibility   Muscarinic   Nicotinic
                to               Action       Action
                Cholinesteras
                e
Acetylcholine   ++++             +++          +++
chloride
Methacholine    +                ++++         None
chloride
Carbachol       Negligible       ++           +++
chloride
Bethanechol     Negligible       ++           None
chloride
Choline Esters-Properties
   Bethanechol
       Not destroyed by cholinesterase (both true & pseudo)
       Has mainly muscarinic actions (well antagonized by
        atropine)
       Negligible CVS effects
       Acts chiefly on the bladder & bowels
       Preferable to carbachol because of this partial selectivity
   Carbachol
       Not destroyed by cholinesterase (both true & pseudo)
       More potent than bethanechol & methacholine
       Muscarinic effects not adequately antagonized by atropine
Choline Esters-Properties
   Carbachol(contd.)
       Stimulates autonomic ganglia & skeletal muscles
       Actions are most pronounced on the bladder & bowels
       Used to stimulate bladder & intestines after surgery
   Methacholine
       Effective orally (though its absorption upon oral
        administration is variable)
       3 times more resistant to hydrolysis by true cholinesterase
        w.r.t. ACh
       Totally resistant to hydrolysis by pseudocholinesterase
       Longer duration of action than ACh
Choline Esters- Uses
   Acetylcholine not used because of its transient & non-
    selective action
   Others rarely used nowadays
   Bethanechol has been used in
       Postoperative paralytic ileus & gastric atony
       Postoperative/postpartum nonobstructive urinary retention
       Neurogenic bladder atony
       Congenital megacolon, and
       Gastroesophageal reflux
   Methacholine was occasionally used to terminate
    paroxysmal supraventricular tachycardia (PSVT)
Cholinomimetic Alkaloids
   Pilocarpine(Tertiary amine)
       Obtained from leaves of Pilocarpus microphyllus
       Prominent muscarinic actions
       Causes marked sweating, salivation & increases
        other secretions
       Applied to the eye, it penetrates cornea and
        promptly causes miosis, ciliary muscle contraction
        and fall in intraocular tension
       Initial therapy (pilocarpine + physostigmine) in
        acute angle-closure glaucoma
       Used as 0.5-4% drops to treat chronic simple
        glaucoma
Cholinomimetic Alkaloids
   Muscarine
       Occurs in poisonous mushrooms (Amanita muscaria &
        Inocybe spp.)
       Quaternary amine
       Has only muscarinic actions
       Not used therapeutically
   Nicotine
       Derived from the plant Nicotiana tabacum
       Tertiary amine
       Has only nicotinic actions
   Lobeline
       Plant derivative similar to nicotine
Cholinomimetic Drugs-Contraindications
   Bronchial Asthma
       Cholinergic drugs can precipitate an
        asthmatic attack in susceptible individuals
        as they can cause bronchoconstriction
   Peptic Ulcer
       Enhance gastric acid production and hence
        can aggravate symptoms of acid peptic
        disease
Cholinergic Drugs-1(Summary)
   Two types of cholinergic receptors
    (muscarinic & nicotinic)
   Muscarinic receptors-smooth muscles/cardiac
    muscle/glands/CNS
   Nicotinic receptors-skeletal muscles/ganglia/
    CNS
   Cholinergic Drugs(Direct & Indirect-acting)
   ACh actions on various organ systems
   Choline esters & cholinomimetic alkaloids
THANK YOU !

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cholinergic drugs

  • 1. Cholinergic (Cholinoceptor Activating) Drugs-1 Dept. of Pharmacology Faculty of Medicine & Health Sciences AIMST
  • 2. Cholinergic Drugs-1-Lecture Outline  Cholinoceptors(Review)  Types  Muscarinic  Nicotinic  Characteristics  Typical Locations  Cholinergic Drugs  Classification  Direct Acting  Choline Esters  Cholinomimetic Alkaloids
  • 3. Cholinergic Drugs-1-Lecture Outline(contd.)  Cholinergic Drugs (contd.)  Indirect Acting (Anticholinesterase Agents)  Reversible  Irreversible  ACh-Pharmacological Actions  Choline Esters  Properties  Therapeutic Uses  Cholinomimetic Alkaloids  Cholinomimetic Drugs  Contraindications
  • 4. Cholinergic Receptors(Cholinoceptors)- Types & Characteristics  Acetylcholine Receptors (Cholinoceptors)  Main subdivision is into muscarinic (mAChR) and nicotinic (nAChR) subtypes  In smooth muscle, cardiac muscle and glands the cholinergic receptors are of the muscarinic (mAChR) type (i.e. stimulated by muscarine, an alkaloid from Amanita muscaria mushrooms)
  • 5. Cholinergic Receptors(Cholinoceptors)- Types & Characteristics  Acetylcholine Receptors (Cholinoceptors)  In striated (skeletal) muscle and autonomic ganglia (sympathetic and parasympathetic) the cholinergic receptors are nicotinic (nAChR) (i.e. stimulated by nicotine)  mAChR’s are G-protein coupled receptors, causing:  Activation of phospholipase C  Inhibition of adenylate cyclase  Activation of potassium channels  Inhibition of calcium channels
  • 6. Cholinergic Receptors(Cholinoceptors)- Types & Characteristics  Muscarinic Acetylcholine Receptors(mAChR’s)  Five types occur, viz.:  M1-receptors (neural)- Selectively blocked by pirenzepine  M2-receptors (cardiac)- Decrease cardiac contractility and heart rate; selectively blocked by gallamine  M3-receptors (glandular)- causing secretion, visceral smooth muscle contraction, vascular relaxation  M4-receptors & M5-receptors- largely confined to CNS; functional role not well understood
  • 7. Autonomic Nervous System(ANS)- Cholinergic Receptors  M1-receptors -  M1, M3 and M5 receptor subtypes have stimulatory effect on the target tissue  M2 and M4 subtypes are inhibitory
  • 9. Cholinergic Receptors(Cholinoceptors)- Types & Characteristics  Nicotinic Acetylcholine Receptors(nAChR’s)  Two types occur, viz.:  NM receptors (muscle type)- located at skeletal muscle neuromuscular junction, Na+, K+ depolarizing ion channel, blocked by d-tubocurarine  NG receptors (neuronal type)- located at postganglionic cell body, Na+, K+ depolarizing ion channel, blocked by hexamethonium
  • 10. Cholinergic (Cholinoceptor Activating) Drugs  Cholinergic Drugs(Cholinomimetics/ Parasympathomimetics)  Drugs producing actions similar to that of Acetylcholine (ACh)  Two modes of action:  May directly interact with cholinergic receptors  Increase availability of ACh at receptor sites
  • 11. Cholinergic (Cholinoceptor Activating) Drugs-Classification  Cholinergic Drugs  Direct-acting drugs (bind to & activate muscarinic or nicotinic receptors)  Choline esters  Acetylcholine  Bethanechol  Carbachol  Methacholine  Cholinomimetic Alkaloids  Pilocarpine  Muscarine  Nicotine  Lobeline  Arecoline  Oxotremorine
  • 12. Cholinergic (Cholinoceptor Activating) Drugs-Classification  Cholinergic Drugs (contd.)  Indirect-acting drugs (↑ ACh/Cholinesterase inhibitors/Anticholinesterases)  Reversible (water soluble)  Edrophonium  Physostigmine  Neostigmine  Pyridostigmine  Ambenonium  Demecarium  Eptastigmine  Rivastigmine  Donepezil
  • 13. Cholinergic (Cholinoceptor Activating) Drugs-Classification  Cholinergic Drugs (contd.)  Indirect-acting drugs (↑ ACh/ Cholinesterase inhibitors)  Irreversible (lipid soluble)  Organophosphates (e.g., Echothiophate, Diisopropylfluorophosphate, Malathion, Parathion, Diazinon, Soman, Sarin, Tabun, etc.)  Carbamates (e.g., Carbaryl, Propoxur)
  • 14. Acetylcholine (ACh)- Actions  Muscarinic  Heart  SA Node  Hyperpolarization of SA nodal cells  Decreased rate of impulse generation (Bradycardia, negative chronotropy)  Atria  Decrease in contractile strength(negative inotropy)  Atrioventricular Node  Decrease in conduction velocity (negative dromotropy)  Ventricles  Small decrease in contractile strength
  • 15. Acetylcholine (ACh)- Actions  Muscarinic  Blood vessels  Very few blood vessels receive cholinergic innervation  Muscarinic receptors present on vascular endothelial cells  Arteries  Dilation (via EDRF(NO))  Veins  Dilation (via EDRF(NO))
  • 16. Acetylcholine (ACh)- Actions  Muscarinic  Lung  Bronchial muscle  Contraction (Bronchoconstriction)  Bronchial glands  Stimulation of secretion  Gastrointestinal tract (evacuation of bowel)  Motility  Increase  Sphincters  Relaxation  Secretion  Stimulation
  • 17. Acetylcholine (ACh)- Actions  Muscarinic  Urinary bladder (voiding of bladder)  Detrusor  Contraction  Trigone & sphincter  Relaxation  Ureter  Increased peristalsis  Glands  Sweat/salivary/lacrimal/nasopharyngeal  Increased secretions
  • 18. Acetylcholine (ACh)- Actions  Muscarinic  Eye  Sphincter (circular) muscle of iris  Contraction (miosis)  Ciliary muscle  Contraction for near vision  Spasm of accomodation  Increased aqueous outflow  Reduction in intraocular tension
  • 19. Acetylcholine (ACh)- Actions  Nicotinic  Autonomic ganglia  Both parasympathetic & sympathetic ganglia stimulated  High dose ACh after atropine administration leads to  Tachycardia  Rise in BP  Skeletal muscles  Iontophoretic application of ACh to motor endplate leads to skeletal muscle contraction
  • 20. Choline Esters-Properties Choline Ester Susceptibility Muscarinic Nicotinic to Action Action Cholinesteras e Acetylcholine ++++ +++ +++ chloride Methacholine + ++++ None chloride Carbachol Negligible ++ +++ chloride Bethanechol Negligible ++ None chloride
  • 21. Choline Esters-Properties  Bethanechol  Not destroyed by cholinesterase (both true & pseudo)  Has mainly muscarinic actions (well antagonized by atropine)  Negligible CVS effects  Acts chiefly on the bladder & bowels  Preferable to carbachol because of this partial selectivity  Carbachol  Not destroyed by cholinesterase (both true & pseudo)  More potent than bethanechol & methacholine  Muscarinic effects not adequately antagonized by atropine
  • 22. Choline Esters-Properties  Carbachol(contd.)  Stimulates autonomic ganglia & skeletal muscles  Actions are most pronounced on the bladder & bowels  Used to stimulate bladder & intestines after surgery  Methacholine  Effective orally (though its absorption upon oral administration is variable)  3 times more resistant to hydrolysis by true cholinesterase w.r.t. ACh  Totally resistant to hydrolysis by pseudocholinesterase  Longer duration of action than ACh
  • 23. Choline Esters- Uses  Acetylcholine not used because of its transient & non- selective action  Others rarely used nowadays  Bethanechol has been used in  Postoperative paralytic ileus & gastric atony  Postoperative/postpartum nonobstructive urinary retention  Neurogenic bladder atony  Congenital megacolon, and  Gastroesophageal reflux  Methacholine was occasionally used to terminate paroxysmal supraventricular tachycardia (PSVT)
  • 24. Cholinomimetic Alkaloids  Pilocarpine(Tertiary amine)  Obtained from leaves of Pilocarpus microphyllus  Prominent muscarinic actions  Causes marked sweating, salivation & increases other secretions  Applied to the eye, it penetrates cornea and promptly causes miosis, ciliary muscle contraction and fall in intraocular tension  Initial therapy (pilocarpine + physostigmine) in acute angle-closure glaucoma  Used as 0.5-4% drops to treat chronic simple glaucoma
  • 25. Cholinomimetic Alkaloids  Muscarine  Occurs in poisonous mushrooms (Amanita muscaria & Inocybe spp.)  Quaternary amine  Has only muscarinic actions  Not used therapeutically  Nicotine  Derived from the plant Nicotiana tabacum  Tertiary amine  Has only nicotinic actions  Lobeline  Plant derivative similar to nicotine
  • 26. Cholinomimetic Drugs-Contraindications  Bronchial Asthma  Cholinergic drugs can precipitate an asthmatic attack in susceptible individuals as they can cause bronchoconstriction  Peptic Ulcer  Enhance gastric acid production and hence can aggravate symptoms of acid peptic disease
  • 27. Cholinergic Drugs-1(Summary)  Two types of cholinergic receptors (muscarinic & nicotinic)  Muscarinic receptors-smooth muscles/cardiac muscle/glands/CNS  Nicotinic receptors-skeletal muscles/ganglia/ CNS  Cholinergic Drugs(Direct & Indirect-acting)  ACh actions on various organ systems  Choline esters & cholinomimetic alkaloids