pharmacology Cholinergic drugs Ach is by gurjitsparhar


									Cholinergic drugs

Ach is a quaternary ammonium compound – doesn’t cross BBB

Neurotransmission at cholinergic neurons

       Acetyl CoA + choline  choline acetyltransferase  Ach
       Rate limiting step: transport of choline into nerve terminal
       Hemicholinium – inhibits transport of choline into terminal
       Ach actively transported into vesicles for storage by vesicle-associated transporter, VAT 
        inhibited by Vesamicol
       Ca influx triggers interaction between VAMPs – vesicle associated membrane proteins
        (synaptobrevin, synaptotagmin) and proteins associated with nerve ending membranes (SNAPs
        – synaptosome associated proteins– SNAP25, syntaxin)
            o Interaction causes fusion of vesicle membrane with nerve ending membrane
            o Botulinum toxin – alters synaptobrevin or other docking or fusion proteins to prevent
                 release process
       True cholinesterase / acetylcholinesterase
            o Cholinergic neurons, ganglia, RBCs, NMJ
            o Rapidly hydrolyzes Ach and choline ester methacholine
       Pseudo cholinesterase / butyrylcholinesterase
            o Not important in physiological termination of Ach action
            o Acts on many esters including Ach, but NOT on methacholine

Muscarinic receptors

       Stimulated by muscarine; blocked by atropine
       M1 – neuronal – CNS, autonomic ganglia, gastric glands
       M2 – cardiac – SA node, AV node, atrium, ventricles, pre-synaptic cholinergic nerve endings
       M3 – visceral smooth muscle, exocrine glands, vascular endothelium
        Receptor type                                    Cellular response
        M1 M3 M5                                         Gq coupled - Increase IP3, increase DAG
        M2 M4                                            Gi coupled -Decrease cAMP – open K channels

Nicotinic receptors

       Activated by nicotine ; blocked by tubocurarine, hexamethonium
       NM- skeletal muscle endplate
       NN – autonomic ganglia, adrenal medulla, CNS
        Receptor type                                       Cellular response
        NM                                                  Ion channel (Na, K) –depolarizes
        NN                                                  Ion channel (Na, K) – depolarizes
Direct-acting – cholinergic agonists - actions similar to Ach by interacting with receptor

Indirect-acting – anticholinesterases – increasing Ach available in synapse

Cholinergic agonists

       Esters of choline – Ach, methacholine, carbachol, bethanecol
       Alkaloids – muscarine, pilocarpine, nicotine
       Muscarinic Actions – Ach as prototype
           o   Heart – depresses SA node  decrease HR, CO
                     Decrease contractility
                     Depress AV conduction  AV block
           o Blood vessels – vasodilation
                     Release of endothelium dependent relaxing factor(EDRF)  decrease BP
                     Skin – flushing
           o Smooth muscle – contracted
                     Tone and peristalsis of GIT
                     Sphincters relax – evacuation of bowel
                     Detrusor contracts, trigone and sphincter relax  voiding
                     Bronchial muscle constriction  dyspnea
                     Glands  increase secretions in all parasymp. Innervated glands – sweating,
                        salivation, lacrimation, tracheobronchial and gastric secretions
           o Eye
                     Contraction of circular muscle of iris (sphincter pupillae) – miosis -->
                              decreased IOT
                     Contraction of ciliary muscle – spasm of accommodation
      Nicotinic actions – Ach
           o Autonomic ganglia
                     Both sympathetic and parasympathetic ganglia stimulated
           o Skeletal muscles
                     Contraction of fibers – spasm and fasciculation
                     Prolonged activation  paralysis
           o Adrenal medulla
                     Adrenaline discharge
      Choline esters
       Choline esters            Ach                       Carbachol                Bethanecol
       Metabolized by            True &                    Resistant to both        Resistant to both
                                 pseudocholinesterase      enzymes                  enzymes
       Muscarinic actions        +                         +                        +
       Nicotinic actions       +                          +                       -
       Uses                    Very short duration of     Glaucoma                Post-operative
                               action- not useful in                              urinary retention and
                               therapy                                            paralytic ileus

      Cholinomimetic alkaloids – Pilocarpine
          o Tertiary amine
          o Eye – penetrates cornea – miosis, ciliary muscle contraction – decrease IOP
          o Uses- open angle glaucoma, xerostomia
          o Civemeline – derivative of Ach – direct acting muscarinic agonist
                  Used for dry mouth associated with Sjogrens syndrome and that caused by
                      radiation damage to salivary glands

Anti-cholinesterases (Anti-ChEs)

      Indirect acting – inhibit acetylcholinesterase
      Some quaternary inhibitors have direct action as well – neostigmine
      Reversible
           o Carbamates – Physostigmine , Neostigmine, Pyridostigmine, Rivastigmine,
                Edrophonium, Donepezil
        o Acridine – Tacrine
   Irreversible
        o Organophosphorus compounds – echotiophate, malathion, parathion, soman, sarin
        o Carbamates – Carbaryl
   Ach binds to both anionic and esteratic site on AChE – binding reversible in milliseconds
   Edrophonium – binds only to anionic site – reversible in minutes
   Other reversible AntiChEs – bind to both sites – reversible in hours
   Organophosphorus compounds – bind only to esteratic site – reversible in days or Not at all
   Actions
        o Lipid soluble agents – physostigmine, organophosphates
                  Marked muscarinic and CNS effects
                  Stimulate ganglia
                  Less prominent action on skeletal muscles
        o Lipid-insoluble – Neostigmine
                  Prominent action on skeletal muscles
                  Direct action on muscle end plate receptors
                  Stimulates ganglia
                  Muscarinic effects – less prominent
   Physostigmine – reversible
        o Alkaloid, tertiary amine, enters CNS
        o Use – glaucoma
                  Atropine poisoning – reverses both central and peripheral actions of atropine
                           Slow IV injection as it may cause bradycardia and seizures
   Neostigmine – reversible
        o Synthetic, quaternary compound
        o Increases power of skeletal muscles in myasthenia gravis patients by anti-ChE and
             directly stimulating NM receptor on muscle end plate
        o Use – myasthenia gravis, post-op neurogenic ileus and urinary retention
   Pyridostigmine - reversible
        o Like neostigmine, but longer acting (4-6hr)
        o Used in myasthenia
   Tacrine, Donepezil , Galantamine, Rivastigmine – reversible
        o Lipophilic – crosses BBB (cerebroselective)
        o Increase Ach concentration in brain
        o Symptomatic improvement in Alzheimer’s patients
   Side effects
        o Due to overstimulation of both muscarinic and nicotinic actions
        o Nausea, vomiting, diarrhea, urinary urgency, salivation, sweating, cutaneous
             vasodilation, bronchial constriction
        o Fasciculation, tremors
   Uses
        o Miotic – in glaucoma; counteract effect of mydriatic after refraction testing
        o Myasthenia gravis – autoimmine, Abs to NM receptor
                  Symptoms – ptosis, diplopia, difficulty speaking, swallowing , extremity
                  Severe disease – affects all muscles , even those needed for respiration
                  Diagnosed by: signs, edrophonium test, circulating Abs
                  Treatment – long term therapy – pyridostigmine; neostigmine or ambenonium
                      are alternatives
                          Immunosuppressants like steroids, cyclosporine, azathioprine
                          Thymectomy
   Edrophonium
        o Rapid onset; brief action (5-10min)
        o Diagnostic test for myasthenia
        o Also used to assess adequacy of treatment with longer-acting anti-ChE in patients
        o Myasthenic crisis – severe weakness due to exacerbation of the disease
        o Cholinergic crisis – long term use of anti- cholinesterases leads to severe muscle
            weakness and paralysis
        o Test - IV mg edrophonium
                 Improvement in muscle power – myasthenic crisis
                 Condition worsens – cholinergic crisis
   Post-op paralytic ileus and urinary retention – Neostigmine
   Post-op decurarization – Neostigmine, edrophonium
   Belladonna poisoning – physostigmine
   Alzheimer’s – Tacrine, Donepezil, Galantamine, Rivastigmine
   Organophosphorus poisoning
        o Signs – muscarinic excess – moisis, salivation, sweating, bronchial constriction,
            vomiting, diarrhea
                 CNS involvement (cognitive disturbance, convulsion, coma)
                 Peripheral nicotinic effects – muscle fasciculation, weakness, resp. paralysis
        o Treatment – maintain vital signs, decontamination to prevent further absorption –
            remove all clothing and wash skin
        o Antidotes
                 Atropine – 1-2 mg IV atropine sulphate every 5-15mins until signs of effect
                    appear – dry mouth, reversal of miosis
                 Cholinesterase reactivators – Pralidoxime, obidoxime, diacetylmono-oxime
                          Have a higher affinity for the phosphorus in OP compounds than
                             receptor affinity for the phosphorus – can bind to OP and prevent its
                             binding to the AchE enzyme – so enzyme is regenerated
                          Should be given within 24hrs after poisoning- before receptor aging –
                             and they become resistant to reactivation
                          Pralidoxime has weak anti-cholinesterase activity at high doses
                 Preventive therapy for cholinesterase inhibitors used in warfare – autoinjection
                    containing pyridostigmine and atropine

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