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					Cholinergic Drugs


 Chapter 5: Autonomic Pharmacology: Cholinergic Drugs
http://www.pharmacology2000.com/Autonomics/Cholinergics/Cholin1.htm



                                      Table of Contents
         Cholinergic Spectrum of               Indirect-acting Cholinomimetic Drugs
          Action                                    o Acetylcholinesterase Inhibitors
         Cholinergic Receptors                              Overview
             o Muscarinic Coupling                                 "Reversible", short-
             o Nicotinic Muscle                                       acting
                 Receptor                                          "Reversible",
             o Nicotinic Neuronal                                     intermediate-acting
                 Receptor                                          "Irreversible", long-
             o Muscarinic Receptors                                   acting
                      Type M1                               Indirect Acting Agents-Table
                      Type M2                               Pharmacokinetics
         Differences between                                Clinical use in anesthesia
          muscarinic and nicotinic                           Parathion & Malathion
          receptors: signal transduction                     Inhibition Mechanisms
          mechanisms                                         ACHE Locations
         Differences between "direct"              o Organ Systems
          and "indirect" cholinoceptor                       Eye: Ophthalmological Uses
          agonists                                           Gastrointestinal and Urinary
         Choline esters: Comparisons                          Bladder
          and Contrasts                                      Myasthenia Gravis
             o Potentiation by                               Alzheimer's Disease
                 Acetylcholinesterases                       Conditions Resembling
         Pharmacological Effects of                           Myasthenia Gravis
          Cholinergic Agonists                  Cholinergic Antagonists
             o Cardiovascular Effects               o Antimuscarinics
                      Vasodilation                 o Clinical Applications
                      Negative                              CNS Overview
                        Chronotropic                         Preoperative medications
                      Decreased SA                          Management of reflex
                        and AV nodal                           bradycardia
                        conduction                           Combinations with
                        velocity                               anticholinesterase agents
                      Negative                                during pharmacological
                        inotropism                             antagonism of
                        (decreased                             nondepolarizing
                        contractility)                         neuromuscular-blocking
                      Effect on ionic                         agents
                        currents                             Bronchodilation
             o Gastrointestinal and                          Sedation

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                 Urinary Tracts                                 Management of gastric or
         Cellular Events following                              intestinal hypersensitivity or
          Cholinergic Receptor                                   secretion
          Activation                                           Respiratory Tract Effects
         Second Messenger Systems                             Ophthalmological Effects
         Nitric Oxide and Muscarinic                 o Adverse Effects
          Receptor Activation                      Ganglionic Blocking Agents
         Some Cholinergic Agents                  Antimuscarinic drug effects on various
                                                    organ systems

         Clinical Uses-Agonists
             o Gastrointestinal &
                 Genitourinary
             o Opthalmological
             o Contraindications
                     Adverse Effects:
                        Muscarinic
                        Agonists



.

                      Spectrum of Action of Choline Esters
         Location of cholinergic synapses mainly determine the spectrum of action of
          acetycholine and choline esters.
         Cholinergic Synaptic Sites
             o autonomic effector sites: innervated by post-ganglionic parasympathetic fibers
             o some CNS synapses
             o autonomic ganglia and the adrenal medulla
             o skeletal muscle motor endplates (motor nerves)
         Systemic administration of acetylcholine (ACh) may theoretically act at these sites, but
          poor CNS penetration (ACh is a charged, quaternary nitrogen compound) and plasma
          butyrylcholinesterase which hydrolysizes ACh limit systemic effects.
         Acetylcholine (and other choline esters) effects are initiated by interaction with
          cholinergic receptors, designated either as muscarinic or nicotinic.
             o Muscarinic receptors (so defined based of their response to muscarine) are found
                 not only at post-ganglionic parasympathetic effector sites but also at autonomic
                 ganglion cells and adrenal medulla where they modulate nicotinic receptor-
                 mediated effects.
             o Nicotinic receptors are the primary cholinergic receptors at autonomic ganglia and
                 skeletal muscle neuromuscular junctions. These receptors were named because of
                 their responsiveness to the alkaloid nicotine.
         Cholinergic influences are prominent in many organ systems:

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  Choline        Sensitivit Cardiovascul Gastrointestin      Urinar     Eye     Atropin Activity
   Ester           y to          ar            al              y      (Topica      e        at
                  ACHE                                       Bladd       l)     Sensitiv Nicotini
                                                               er                  e     c Sites
Acetylcholi
    ne
Methacholi
    ne
Carbachol           No
Bethanecho          No           ? ?                                                         No
     l
                     1. Modified from Table 7-1: Brown, J.H. and Taylor, P. Muscarinic Receptor
                        Agonists and Antagonists, In, Goodman and Gillman's The
                        Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E,
                        Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill
                        Companies, Inc.,1996, p 143
                     2. Brown, J.H. and Taylor, P. Muscarinic Receptor Agonists and
                        Antagonists, In, Goodman and Gillman's The Pharmacologial Basis of
                        Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W,
                        and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, p 142-
                        143.

Return to Table of Contents.



  Cholinergic Receptors: Subtypes, Tissues, Responses and Molecular Mechanisms

                          Muscarinic Receptor Coupling Mechanisms

         Five types of cholinergic receptors have been identified by molecular cloning methods.
         The possibility of multiple forms was suggested by the pharmacology of piprenzipine
          which is an effective antimuscarinic in blocking gastric acid secretion, but was not
          effective in blocking other responses to muscarinic agonists.
         The five muscarinic receptor subtypes, M1 - M5, are associated with specific anatomical
          sites. For example:
              o M1 -ganglia; secretory glands
              o M2 - myocardium, smooth muscle
              o M3 , M4 :smooth muscle, secretory glands

                               Nicotinic Muscle Receptor
   Antagonists                Tissue               Responses          Molecular Aspects
  Tubocurarine            Neuromuscular           Membrane            Nicotinic (muscle)
                             Junction            Depolarization       receptor's cation
     alpha-                                    leading to muscle         ion channel
  bungarotoxin                                    contraction              opening

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                           Nicotinic Neuronal Receptor
   Antagonists              Tissue                Responses         Molecular Aspects
  Mecamylamine         Autonomic Ganglia        Depolarization:      Nicotinic (muscle)
   (Inversine)                                  postsynaptic cell   receptor's cation ion
                                                   activation         channel opening
                        Adrenal Medulla          Catecholamine
                                                    secretion
                               CNS                 unknown



                                 Muscarinic Type M1
    Antagonist              Tissue               Responses          Molecular Aspects
     Atropine          Autonomic Ganglia      Depolarization (late Stimulation of
                                                    EPSP)          Phospholipase C
Pirenzepine (more              CNS                Unknown          (PLC): activation of
    selective)                                                     inositol-1,4,5
                                                                   triphosphate (IP3 )
                                                                   and diacylglycerol
                                                                   (DAG) leading to
                                                                   increased cytosolic
                                                                   Ca2+



                                 Muscarinic Type M2
      Tissue (Heart)                    Responses                Molecular Aspects
         SA node               decreased phase 4             K+ channel activation
                               depolarization;               through ß-gamma Gi
                               hyperpolarization             subunits;
           Atrium              decreased contractility;
                               decreased AP duration         Gi -mediated inhibition of
          AV node              decreased conduction          adenylyl cyclase which
                               velocity                      decreases intracellular Ca2+
          Ventricle            decreased contractility       levels.

                                                             (Gi can inhibit directly
                                                             Ca2+ channel opening)

Return to Table of Contents.

Adapted from Table 6-2: Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The
Autonomic and Somatic Motor Nervous Systems, In, Goodman and Gillman's The


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Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon,
R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, p119.



         Signal Transduction: Comparison of Muscarinic and Nicotinc Receptors
             o   Nicotinic Receptors
                        Ligand-gated ion channels
                        Agonist effects blocked by tubocurarine
                        Receptor activation results in:
                                                      +       2+
                             rapid increases of Na and Ca conductance
                             deplorization
                             excitation
                        Subtypes based on differing subunit composition: Muscle and Neuronal
                        Classification
             o   Muscarinic Receptors
                        G-protein coupled receptor system
                        Slower responses
                        Agonist effects blocked by atropine
                        At least five receptor subtypes have been described by molecular cloning.
                        Variants have distinct anatomical locations and differing molecular
                        specificities

Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic
Motor Nervous Systems, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,
(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The
McGraw-Hill Companies, Inc.,1996, pp.112-137.

         Direct vs. Indirect-Acting Cholinomimetics
             o   A direct-acting cholinomimetic drug produces its pharmacological effect by
                 receptor activation.
             o   An indirect-acting drug inhibits acetylcholinesterase, thereby increasing
                 endogenous acetylcholine levels, resulting in increased cholinergic response.

Return to Table of Contents.



                            Choline esters: Comparisons and Contrasts
Choline Ester       Sensitivity Cardiovascular Gastrointestinal Urinary Atropine         Activity
                    to ACHE                                     Bladder Sensitive           at
                                                                                         Nicotinic
                                                                                           Sites
Acetylcholine
Methacholine
 Carbachol             No

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 Bethanechol         No         ? ?                                                         No
 (Urecholine)
        Potentiation by Acetylcholinesterases
   Choline Ester Agent        Sensitivity to ACHE
Acetylcholine (potentiated
   by AchE inhibitors)
Methacholine (potentiated
   by AchE inhibitors)
Carbachol (AchE inhibitors             No
      have no effect)
 Bethanechol (Urecholine)              No
 (AchE inhibitiors have no
          effect)




              Pharmacological Effects of Cholinomimetics
                               Cardiovascular: Four major effects

                                          Vasodilation:

   This effect is mediated by muscarinic receptor activation and is especially prominent in the
                                 salivary gland and intestines.

   1. The vascular response is due to endothelial cell nitric oxide (NO) release
      following agonist interactions with endothelial muscarinic receptors.
   2. Increased NO activates guanylate cyclase which increases cyclic GMP
      concentrations.
   3. Subsequent activation of a Ca2+ ion pump reduces intracellular Ca2+.
   4. Reduction in intracellular Ca2+ causes vascular smooth muscle relaxation.
   5. Ca2+ complexes with calmodulin activating light-chain myosin kinase
          o   Increased cGMP promotes dephosphorylation of myosin light-chains.
          o   Smooth-muscle myosin must be phosphorylated in order to interact
             with actin and cause muscle contraction.


         Vasodilation may also occur due to ACh inhibition of N.E. release from post-ganglionic
          sympathetic fibers.
         Damaged endothelium can result in ACh causing vasoconstriction by direct action on
          vascular smooth muscle.
         Negative chronotropic effect (Decrease in heart rate)
             o    Decreases phase 4 (diastolic depolarization)
                      As a result, it takes longer for the membrane potential to reach threshold.
             o     Mediated by M2 muscarinic receptors

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         Decreased SA nodal and AV nodal conduction velocity
             o Excessive vagal tone may induce bradyarrhythmias including partial or total heart
                 block (impulses cannot pass through the AV node to drive the ventricular rate; in
                 this case, the idioventricular or intrinsic ventricular rate must maintain adequate
                 cardiac output)
                                                                                       +
             o Transmission through the AV node is especially dependent on Ca2 currents.
                         ACh decreases calcium currents in the atrioventricular node.
         Negative inotropism (decreased myocardial contractility)
             o more prominent in atrial than ventricular tissue.
             o due to a decrease in ICa2+ inward current
             o in the ventricle, adrenergic tone dominates;
                      at higher levels of sympathetic tone, a reduction in contractility due to
                         muscarinic stimulation is noted.
                      Muscarinic stimulation reduces the response to norepinephrine by
                         opposing increases in cAMP in addition to reducing norepinephrine
                         release from adrenergic terminals
         Effect of muscarinic receptor activation on cardiac currents
             o increase in I K (Ach) in atrial muscle and in SA and AV nodal tissue
             o decrease in slow, inward calcium (ICa2+) current (decreased atrial contractility;
                 decreased AV nodal conduction)
             o decrease in diastolic depolarizing current (If)--decreases heart rate, because it
                 takes longer for the membrane potential to reach threshold (less depolarizing If
                 current)
         Gastrointestinal and Urinary Tracts
             o   Muscarinic agonists increase intestinal peristalsis, tone, and contraction
                 amplitude.
             o   Carbachol and bethanecol (not ACh or methacholine) stimulate the urinary tract
                 by increasing ureteral peristalsis and by contraction of the urinary bladder
                 detrusor muscle.
             o

Return to Table of Contents.



                  Cellular Events following Cholinergic Receptor Activation

         Nicotinic Muscle Receptor
             o Response:
                      Membrane Depolarization leading to muscle contraction
             o Molecular Aspects:
                      Nicotinic (muscle) receptor's cation ion channel opening
         Nicotinic Neuronal Receptor
             o Responses:
                      Depolarization: postsynaptic cell activation
                      Catecholamine secretion


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             o   Molecular Aspects
                    Nicotinic (muscle) receptor's cation ion channel opening
         Muscarinic Type M1
             o   Response:
                     Depolarization (late EPSP)
             o   Molecular Aspects
                     Stimulation of Phospholipase C (PLC) with formation of inositol-1,4,5
                       triphosphate (IP3 ) and diacylglycerol (DAG)resulting in increased
                       cytosolic Ca2+
         Muscarinic Type M2
             o   SA node
                      Responses: decreased phase 4 depolarization; hyperpolarization
                                               +
                      Molecular Aspects: K channel activation through ß-gamma Gi subunits.
             o   Atrium
                      Responses: decreased contractility; decreased AP duration
                      Molecular Aspects: Gi -mediated inhibition of adenylyl cyclase which
                        decreases intracellular Ca2+ levels (reduces contractility);(Gi can inhibit
                        directly Ca2+ channel opening)
             o   AV node
                      Responses: decreased conduction velocity
             o   Ventricle:
                      Responses: decreased contractility
                      Molecular Aspects: Gi -mediated inhibition of adenylyl cyclase which
                        decreases intracellular Ca2+ levels (reduces contractility);(Gi can inhibit
                        directly Ca2+ channel opening)

Adapted from Table 6-2: Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The
Autonomic and Somatic Motor Nervous Systems, In, Goodman and Gillman's The
Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon,
R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, p119



                      Muscarinic Receptors: Second Messenger Systems

         Activation of IP3, DAG cascade
                                                          2+
              o DAG may activate smooth muscle Ca channels
                                  2+
              o IP3 releases Ca from endoplasmic and sarcoplasmic reticulum
         Increase in cGMP
         Increase in intracellular K+ by cGMP-K+ channel binding
         inhibition of adenylyl cyclase activity (heart)

Pappano, A.J. Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs, In Basic and
Clinical Pharmacology, 7th Edition, (Katzung, B.G.,ed) Appleton & Lange, 1998, p. 93-94



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         Nitric Oxide and Muscarinic Receptor Activation
             o   Activation of salivary gland and intestinal parasympathetic systems produce
                 significant vasodilation.
             o   This effect depends on nitric oxide (EDRF) release and subsequent guanylate
                 cyclase activation. (NO binding to the heme group of guanylate cyclase).
             o   Increased levels of cGMP results in stimulation of ion pumps which lower
                 intracellular Ca2+ promoting relaxation.
             o   Increased nitric oxide production may be mediated by:
                      acetylcholine
                      substance P
                      bradykinin
                      direct mechanical (shear forces) on endothelial membranes.
         Nitric oxide synthase2
             o   Nitric oxide synthase catalyzes the conversion of L-arginine and molecular
                 oxygen to nitric oxide.
             o   Three forms of nitric oxide synthase
                      form 1 (constitutive): release nitric oxide over short time periods in
                         response to increase in intracellular Ca2+ .
                                                     2+
                      form 2: responsible for Ca - dependent nitric oxide neuronal release.


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                       form 3: induced following cytokine or endotoxin cellular activation. This
                        form catalyzes nitric oxide synthesis for an extended time. This form is
                        Ca2+ - independent and is responsible for some pathophysiological
                        responses to endotoxin (hypotension, e.g.).
1
  Granger,D.N., Regulation of Regional Blood Flow, In Essential Physiology,(Johnson, L.,ed)
Lippincott-Ravin,1998, p. 231.
2
  Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic
Motor Nervous Systems, In, Goodman and Gillman's The Pharmacologial Basis of
Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds)
The McGraw-Hill Companies, Inc.,1996, pp.136-137




         Cholinergic Agents
             o   Choline Esters
                     Acetylcholine
                     Bethanechol (Urecholine)
                     Carbachol
                     Methacholine (Provocholine)
             o   Alkaloids
                     Muscarine
                     Pilocarpine (Pilocar)


                                        Clinical Uses
         Gastrointestinal & Genitourinary
             o   Bethanechol (Urecholine)
                       GI smooth muscle stimulant
                            postoperative abdominal distention
                            paralytic ileus
                            esophageal reflux; promotes increased esophageal motility (other
                               drugs are more effective, e.g. dopamine antagonist
                               (metoclopramide) or serotonin agonists (cisapride)
                       Urinary bladder stimulant
                            post-operative; post-partum urinary retention
                     alternative to pilocarpine to treat diminished salivation secondary e.g. to
                       radiation
                     Carbachol not used due to more prominent nicotinic receptor activation
             o   Methacholine used for diagnostic purposes.
                     testing for bronchial hyperreactivity and asthma
         Opthalmological Uses

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             o   Acetylcholine and Carbachol may be used for intraocular use as a miotic in
                 surgery
             o   Carbachol may be used also in treatment of glaucoma.
             o   Pilocarpine is used in management of glaucoma and has become the standard
                 initial drug for treating the open-angle form.
             o   Sequential adminstration of atropine (mydriatic) and pilocarpine (miotic) is used
                 to break iris-lens adhesions.
         Major contraindication to the use of muscarinic agonists
             o   Asthma: Choline esters (muscarinic agonists) can produce bronchoconstriction. In
                 the predisposed patient, an asthmatic attack may be induced.
             o   Hyperthyroidism: Choline esters (muscarinic agonists) can induce atrial
                 fibrillation in hyperthyroid patients.
             o   Peptic ulcer: Choline esters (muscarinic agonists), by increasing gastric acid
                 secretion, may exacerbate ulcer symptoms.
             o   Coronary vascular disease: Choline esters (muscarinic agonists), as a result of
                 their hypotensive effects, can further compromise coronary blood flow.
          Adverse Effects: Muscarinic Agonists
             o   salivation
             o    diaphoresis
             o    colic
             o    GI hyperactivity
             o    headache
             o    loss of accommodation

Return to Table of Contents.

                    Indirect-acting Cholinomimetic Drugs
         Acetylcholinesterase Inhibitors
            o Overview
                       Three domains describe the acetylcholinesterase active site: an acyl
                        binding region, the choline binding region, and a peripheral anionic site.
                       There are three classes of anticholinesterase agents
             o   Reversible, Short-Acting Anticholinesterases
                       Reversible inhibitors, edrophonium (Tensilon) and tacrine (Cognex),
                        associate with the choline binding domain.
                              The short duration of edrophonium (Tensilon) action is due to
                                its binding reversibility and rapid renal clearance.
                              Tacrine (Cognex), being more lipophillic, has a longer
                                duration.
                       Some reversible inhibitors, propidium and fasiculin, a toxic peptide, bind
                        at the peripheral anionic site.
             o   Carbamylating Agents: Intermediate-Duration Acetylcholinesterase
                 Inhibitors


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                       Physostigmine and Neostigmine are acetylcholinesterase inhibitors that
                        form a moderately stable carbamyl-enzyme derivative.
                       The carbamyl-ester linkage is hydrolyzed by the esterase, but much more
                        slowly compared to acetylcholine.
                       As a result, enzyme inhibition by these drugs last about 3 - 4 h (t ½ = 15 -
                        30 min).
                       Neostigmine possesses a quaternary nitrogen and thus has a
                        permanent positive charge.
                       By contrast, physostigmine is a tertiary amine
             o   Phosphorylating Agents: Long-Duration Acetylcholinesterase Inhibitors
                       Organophosphate acetylcholinesterase inhibitors, such as diisopropyl
                        fluorophosphate (DFP) form stable phosphorylated serine derivatives.
                       For DFP the enzyme effectively does not regenerate following inhibition.
                             Furthermore, in the case of DFP, the loss, termed "aging", of an
                                isopropyl group, further stabilizes the phosphylated enzyme.
                             The application of the terms "reversible" and "irreversible"
                                depends on the duration of enzyme inhibition rather than strictly
                                based on mechanism. (see above)
                       Examples of "reversible" acetylcholinesterase inhibitors that may be used
                        clinically include both carbamylating agents and those that associate only
                        with the choline binding domain.
             o   "Reversible" Anticholinesterases Used Clinically
                       edrophonium
                       pyridostigmine-Used in treatment of myasthenia gravis
                       neostigmine
                       physostigmine
                       demecarium
                       ambenonium-Used in treatment of myasthenia gravis
         Pharmacokinetics of Acetylcholinesterase Inhibitors
             o   Duration of Action: Principles
                     Anticholinesterase duration of action: based on rate of disappearance from
                       plasma.
                     Clinical Anesthesia Context:
                            Anticholinesterase drugs are administered when effects of
                              nondepolarizing neuromuscular-blocking agents are diminishing
                            Note: duration of action of edrophonium is approximately the same
                              compared to that of neostigmine in anesthetized patients.
                              (edrophonium had been usually considered a short-acting agent)
             o   Renal Clearance:anticholinesterase drugs
                     Actively secreted into renal tubule lumen
                     Renal clearance:
                              50% for neostigmine elimination
                              75% for edrophonium and pyridostigmine elimination
                              Elimination halftimes -- significantly prolonged in renal failure
                                   In renal failure, plasma clearance of anticholinesterase
                                      drugs is prolonged more substantially than plasma

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                                        clearance of neuromuscular-blocking agents-- making
                                        recurarization
                       In the absence of renal clearance (renal insufficiency), hepatic metabolism
                        is involved to the following extents::
                              Neostigmine -- 50%
                              Edrophonium -- 30%
                              Pyridostigmine -- 25%
             o   Carbamates
                        Physostigmine, a tertiary amine, is readily absorbed following systemic
                        administration and may be absorbed systemically after conjunctival use.
                        Neostigmine, also a carbamylating inhibitor, is a quaternary nitrogen
                        compound and, as a result, is poorly absorbed.
                        Neostigmine is hydrolyzed by plasma esterases with metabolites excreted
                        in the urine.
             o   Organophosphates
                       Most organophosphorous acetylcholinesterase inhibitors are well-
                        absorbed lipophillic agents.
                       Organophosphates are generally hydrolyzed by serum and tissue esterases
                        and hydrolytic products are renally excreted.
                       Some organophosphorus chemicals are substrates for mixed-function
                        oxidases that convert phosphorothioates (P=S) to phorphorates (P=O).
                       Organophosphate anticholinesterases are themselves hydrolyzed by liver
                        esterases also called A-esterases or paraoxonases. The extent of paraoxon
                        toxicity in humans is dependent on an A-esterase genetic polymorphism.
                       Lipophillicity and intrinsic reactivity (phosophorylation rate constant) are
                        two important factors in determining the lethality of human exposure to
                        organophosphate inhibitors.

Stoelting, R.K., "Anticholinesterase Drugs and Cholinergic Agonists", in Pharmacology and
Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 224-237; Taylor, P.
Anticholinesterase Agents, In, Goodman and Gillman's The Pharmacologial Basis of
Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds)
TheMcGraw-Hill Companies, Inc.,1996, pp.161-174.

         Differences between Parathion & Malathion
             o   Parathion
                     Parathion, a low volatility and aqueous-stable, organophosphate is used as
                       an agriculural insecticide.
                     Parathion is converted to paraoxon by mixed function oxidases. Both the
                       parent compound and its metabolite are effective acetylcholinesterase
                       inhibitors (P=S to P=O).
                       Parathion probably is the most common cause of accidental
                       organophosphate poisoning and death.
                     The phosphothioate structure is present in other common insecticides:
                       dimpylate, fenthion, and chlorpyrifos.
             o   Malathion

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                       Malathion is converted to the oxygen form (P=S to P=O).
                       Inactivation rates (hydrolysis) vary between species.
                       Inactivation rates are much higher in mammals and birds than insects.
                       Accidental poisoning and death is not observed with malathion with acute
                        toxicity seen in suicide or deliberate poisoning. (lethal dose in man is
                        about 1g/kg)
                       Spraying over populated areas with malathion has been used in control of
                        Medierranean fruit flies and mosquitoes.
                       Malathion is used in treatment of lice infestations.

Taylor, P. Anticholinesterase Agents, In Goodman and Gillman's The Pharmacologial Basis of
Therapeutics, (Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman,
A.G.,eds) The McGraw-Hill Companies, Inc.,1996, p. 167.

         Inhibition Mechanisms
             o   Overview:
             o   Inactivation of acetylcholinesterase by organophosphates or carbamates requires
                 either carbamylation or phosphorylation of an active-site reactive serine.
             o   Phosphorylation of this serine leads to a very stable acyl-enzyme complex.
             o   Deacylation (dephosphorylations) reactions may occur very slowly, thus effective
                 inhibiting enzyme activity for long periods.
             o   Reactivation of phosphorylated enzyme may be possible using a nucleophile
                 such as pyridine-2-aldoxime (2-PAM).
             o    2-PAM reactivation may be not be possible, depending on the stability of the
                 phosphoryl enzyme derivative.
         Acetylcholinesterase Locations
             o   Acetylcholinesterase: post-synaptic cholinergic membranes.
             o   Inhibition of acetylcholinesterase with subsequent acetylcholine accumulation
                 causes:
                     1. enhanced muscarinic responses at parasympathetic effector sites.
                     2. nicotinic receptor stimulation and then paralysis (depolarization block) at
                         autonomic ganglia and skeletal muscle.
                     3. CNS cholinergic neuronal stimulation
             o   Effects of increased acetylcholine levels can be blocked or reduced by atropine
                 (muscarinic antagonist) at:
                      parasympathetic effector sites
                      autonomic ganglia (muscarinic receptor population)
                      subcortical CNS sites.
         Organ Systems Affected by Anticholinesterase Agents
             o Opthalmological Uses of Anticholinesterase Drugs
                       When applied to the conjunctiva, acetylcholinesterase inhibitors produce:
                             constriction of the pupillary sphincter muscle (miosis)
                             contraction of the ciliary muscle (paralysis of accommodation or
                                 loss of far vision).
                       Loss of accommodation disappears first, while the miotic effect is longer
                        lasting.

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                       During miosis, elevated intraocular pressure (glaucoma) declines due to
                        enhanced flow of aqueous humor.
                        In glaucoma, elevation of intraocular pressure can cause damage to the
                        optic disc and blindness.
                       There are three types of glaucoma:
                             primary
                             secondary (aphakic (no lens) glaucoma, following cataract
                                removal)
                             congenital.
                             Of the three, primary glaucoma responds to anticholinesterase
                                treatment.
                       Primary glaucoma may either be narrow angle (acute, congestive) or wide-
                        angle (chronic, simple) depending on the angle configuration of the
                        anterior chamber.
                       Narrow angle glaucoma, a medical emergency, may rely on drug treatment
                        to control the attack, although surgery may be required for long-term
                        management (iridectomy, peripheral or complete).
                       Anticholinesterase used for management of glaucoma or accommodative
                        esotropia (esotropia (eso- (inward) + Gr. trepein to turn) [Deviation of
                        visual axis toward that of the other other when fusion is possible]
                       Anticholinesterases Used in Treating Glaucoma
                            1. Physostigmine (eserine)
                            2. Demecarium (Humorsol)
                            3. Echothiophate (Phospholine)
                            4. Isoflurophate (Floropryl)
           o   Gastrointestinal and Urinary Bladder
                       Neostigmine is the anticholinesterase agent of choice for treatment of
                        paralytic ileus or urinary bladder atony.
                       Direct acting cholinomimetic drugs are also useful.
           o   Myasthenia Gravis
                       Myasthenia Gravis appears to be caused by the binding of anti-nicotinic
                        receptor antibodies to the nicotinic cholinergic receptor.
                       Binding studies using snake alpha-neurotoxins determined a 70% to 90%
                        reduction of nicotinic receptors per motor endplate in myasthenic patients.
                        Receptor number is reduced by:
                             increased receptor turnover (rapid endocytosis)
                             blockade of the receptor binding domain
                             antibody damage of postsynaptic muscle membrane
                       A related disease, Lambert-Eaton syndrome, is a presynaptic disorder in
                        which acetylcholine release is impaired due to autoantibodies against P/Q
                        type calcium channels.
                             Most patients with this syndrome have a malignancy, usually small
                                cell lung carcinoma.
                             Treatment includes immunosuppression and plasmapheresis.
                       Anticholinesterase, edrophonium (Tensilon), is useful in differential
                        diagnosis for myasthenia gravis.

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                               In this use, edrophonium (Tensilon) with its rapid onset (30 s) and
                                short duration (5 min) may cause an increase in muscle strength.
                             This change is due to the transient increase in acetylcholine
                                concentration at the end plate.
                             Edrophonium (Tensilon) may also be used to differentiate between
                                muscle weakness due to excessive acetylcholine (cholinergic
                                crisis) and inadequate drug dosing.
                       Anticholinesterase drugs provide partial improvement in myasthenia
                        gravis by increasing the amount of acetylcholine available at
                        neuromuscular junctions.
                       Of the anticholinesterases listed below, pyridostigmine (oral) is the one
                        most widely used in the U.S.
                             Anticholinesterases Used in Treating Myasthenia Gravis
                                     Neostigmine (Prostigmin)
                                     Pyridostigmine (Mestinon)
                                     Ambenonium
                       Conditions that resemble myasthenia gravis include:
                              Lambert-Eaton myasthenic syndrome, a presynaptic disorder.
                               (NEJM 332: 1467, 1995 review)
                                    Patients with Lambert-Eaton disorder have depressed or
                                      absent reflexes, show autonomic changes such as
                                      xerostomia and impotence and incremetal responses to
                                      repetitive nerve stimulation. Treatment includes
                                      plamapheresis and immunosupression.
                              Neurasthenia
                                    muscle testing indicates a nonorganic disorder,
                                      characterized by feelings of fatigue rather than by a loss of
                                      muscle power.
                              Thyroid abnormalities (either hyper or hypo- thyroidism) can
                               increase myasthenic weakness.
                                    Thyroid testing is definitive.
                              Associated Disorders:
                                      Myasthenia gravis patients often have associated disorders
                                      including:
                                              thymic abnormalities: >70%
                                              hyperthyroidism 3% - 8%
                                              other autoimmune disorders--test for rheumatoid
                                              factor and antinuclear antibody
                                              ventilatory dysfunction
                                      Thymic abnormalities: about 35% of patients with
                                      epithelial thymoma have myasthenia gravis; furthermore,
                                      acetylcholine receptor autoantibody secretion by
                                      thymocytes have been reported {Yoshikawa, H and
                                      Lennon, V.A. Acetylcholine receptor autoantibody
                                      secretion by thymocytes: Relationship to myasthenia
                                      gravis, Neurology, 49:562-567,1997}

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                                     Of the patients who do not have thymomas, most of the
                                     rest have thymic hyperplasia (germinal follicles in the
                                     thymus)
                                          Most thymomas express acetylcholine receptor
                                             epitopes on the surfaces of the neoplastic cells
                                             (Lancet 339: 707, 1992; Am. J. Path. 148: 1359 &
                                             1839, 1996). This expression may trigger the
                                             disease.
                                          Seronegative myasthenia gravis patients do not have
                                             thymoma: Neurology 42: 586, 1992.
                                          Extended thymectomy is the procedure of choice
                                             (Ann. Thoracic Surg. 62: 853, 1996).

Sites of Drug Intervention in Management of Myasthenia Gravis




Drachman, D.B. Myasthenia Gravis and Other Diseases of the Neuromuscular Junction , In
Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E.,
Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health
Professions Division), 1998, p. 2469-2472.: Figure adapted from Figure 382-2, p. 2471

                                                                                    Page 17 of 27
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         Alzheimer's Disease
             o Tacrine (Cognex) or other cholinesterase inhibitiors are useful in treating mild to
                moderate Alzheimer's dementias.



                     1. Taylor, P. Anticholinesterase Agents, In, Goodman and Gillman's The
                        Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E,
                        Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill
                        Companies, Inc.,1996, pp. 172-173.;
                     2. Moroi, S.E. and Lichter, P.R. Ocular Pharmacology In, Goodman and
                        Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G,
                        Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The
                        McGraw-Hill Companies, Inc.,1996, p. 1634;
                     3. Drachman, D.B. Myasthenia Gravis and Other Diseases of the
                        Neuromuscular Junction , In Harrison's Principles of Internal Medicine
                        14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B.,
                        Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions
                        Division), 1998, p. 2469-2472



         Adverse Effects: Overstimulation of Muscarinic and Nicotinic Receptors
         miosis
         salivation
         sweating
         bronchial constriction
         vomiting and diarrhea
         myasthenia gravis
         neuromuscular blockade (nicotinic effect)
         CNS effects: high doses



                            Indirect Cholinomimetic Agents
  Acetylcholinesterase                Acetylcholinesterase Inhibitors ("Irreversible")
Inhibitors ("Reversible")
    Neostigmine                      Soman
       (Prostigmin)                   Parathion
    Physostigmine                    Malathion
       (Antilirium)                   Isoflurophate
    Edrophonium                      (Diisopropylflurorphosphate DFP)
       (Tensilon)                     Echothiophate




                                                                                         Page 18 of 27
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Return to Table of Contents




                          Cholinoceptor-Blocking Drugs
         Introduction: Muscarinic Receptor Antagonists
             o   Antimuscarinic agents were of plant origin.
             o   Belladonna (beautiful woman, a reference to the drug's mydriatic effects,) are
                 found in many plants.
             o   Atropa belladonna (Solanaceae) or the deadly nightshade contains atropine (dl-
                 hyoscyamine) as does Datura stramonium (Jamestown or jimsonweed, thorn-
                 apple, etc.)
             o   Scopolamine, also an alkaloid, is found in the shrub Hyosyamus niger and
                 Scopolia carniolica.
                     An alkaloid is one of a large group of organic, basic plant substances.
                         They are usually pharmacologically active and bitter in taste
                       Alkaloids
                               atropine
                               caffeine
                               morphine
                               nicotine
                               quinine
                               strychnine
             o   Tertiary and Quaternary Antimuscarinic Agents
                       Atropine, scopolamine, and the semisynthetic agent homatropine
                        (Isopto Homatropine) are tertiary amines, generally well-absorbed
                        and able to penetrate the CNS.
                       Each drug can be converted to a quaternary form by addition of a
                        methyl group to the nitrogen, resulting in methylatropine nitrate,
                        methscopolamine bromide and homatropine methybromide.
                       Quaternary muscarinic receptor antagonists tend to be more potent
                        as muscarinic blockers and have increased ganglionic blocking action.
                       Quaternary (permanently charged) antagonists do not penetrate the
                        CNS to a significant extent. Therefore, CNS activity is limited.

Brown, J.H. and Taylor, P. Muscarinic Receptor Agonists and Antagonists, In, Goodman and
Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff,
P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.149-150




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 Clinical Applications of Cholinergic Receptor Blockers
Return to Table of Contents

         Anticholinergic Drugs -- Anesthesia Applications/Issues
             o   Overview:
             o   Preoperative medication
             o   Management of reflex bradycardia
             o   Use in antagonism of nondepolarizing neuromuscular-blocking agents
         Common Applications-- anesthesia related (anticholinergic agents)
             o Preoperative medications
             o Management of reflex bradycardia
             o Combinations with anticholinesterase agents during pharmacological antagonism
                 of nondepolarizing neuromuscular-blocking agents
         Other Applications of anticholinergic drugs:
             1. bronchodilation (e.g.,asthma)
             2. biliary/ureteral smooth muscle relaxation
             3. to cause mydriasis/cycloplegia
             4. inhibition of parietal cells acid secretion
             5. prevention of motion sickness (nausea)
             6. component in cold remedies
         Central Nervous System Effects of Antimuscarinic Agents
             o   In normal doses, atropine produces little CNS effect.
                      In toxic doses, CNS excitation results in restlessness, hallucinations, and
                         disorientation.
             o   At very high doses, atropine can lead to CNS depression which causes circulatory
                 and respiratory collapse.
             o   By contrast, scopolamine at normal therapeutic doses causes CNS depression,
                 including drowsiness, fatigue and amnesia.
                      Scopolamine also may produce euphoria, a basis for some abuse potential.
             o   Scopolamine may exhibit more CNS activity than atropine because scopolamine
                 crosses the blood brain barrier more readily.
             o   Antimuscarinics are used clinically as preanesthetic medication to reduce vagal
                 effects secondary to visceral manipulation during surgery.
             o   Antimuscarinics with L-DOPA are used in Parkinson's disease.
             o   Extrapyramidal effects induced by some antipsychotic drugs may be treated with
                 antimuscarinic agents.
             o   Scopolamine (transdermal) is effective in preventing motion sickness.
             o    Atropine is also an effective antidote to excessive cholinergic stimulation
                 following organophosphate intoxication.
                      By blocking muscarinic receptors, the consequences of cholinesterase
                         inhibition is attentuated.
                      Atropine may be used in conjunction with 2-PAM which may reactivate
                         phosphorylated, inhibited acetylcholinesterase by nucleophilic
                         displacement.
         Preoperative Medication
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             o   Primary current therapeutic rationale:
                       Sedation
                       Antisialagogue
             o Historical: IM atropine was used prior to anesthesia induction to limit excessive
                 salivary secretion and reduce vagal reflex influence on the heart
                       current inhaled/injected anesthetic agents are not consistently associated
                         with these effects
                       Anticholinergic drugs are not mandatory as part of preoperative
                         medication
             o Gastrointestinal effects:
                       Usual anticholinergic drug doses for preoperative medication (and adults)
                         does not affect either gastric volume or pH
             o    Special considerations:
                       Patients with glaucoma:
                              mydriatic effects of scopolamine > atropine; caution with
                                  scopolamine use in patients with glaucoma
                              atropine + anticholinesterase causes little/no change in pupil size,
                                  therefore appearing apparently safe
                              Glycopyrrolate (Robinul): least effect on pupil size of all
                                  anticholinergic drugs used in preoperative medication
                       Parturients:
                              atropine & scopolamine: crosses the placenta; fetal heart rate-- not
                                  significantly changed following atropine or glycopyrrolate IV
                                  administration
         Sedation
             o Scopolamine is preferred when sedation is the objective for including
                 anticholinergic drug in preoperative medication
             o Atropine:
                         less sedation compared to scopolamine
                         associated with increased incidence of memory deficit associated with
                         anesthesia, compared to glycopyrrolate
                       delayed arousal in the first 30 minutes after anesthesia if atropine-
                         neostigmine mixtures were used to antagonize nondepolarizing
                         neuromuscular-blocking drug effects {compared to glycopyrrolate-
                         neostigmine mixtures}
             o Scopolamine enhances significantly sedative effects of other drugs administered
                 at the same time, i.e. benzodiazepines and opioids
             o Scopolamine plus morphine: reliable preanesthetic sedation
             o Glycopyrrolate (Robinul): does not readily cross the blood-brain barrier; no
                 sedative effects
             o CNS effects of anticholinergic drugs -- particularly scopolamine:
                         restlessness or somnolence
                         such symptoms more likely to occur in the elderly
                         inhaled anesthetics may potentiate anticholinergic CNS drug
                         effects®increased postoperative restlessness/somnolence incidence



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Return to Table of Contents

   
             o   Treatment of Reflex-Mediated Bradycardia
                     Anticholinergic drugs: drugs of choice for management of intraoperative
                       bradycardia --especially if due to increased vagal tone
                     First Degree Heart Block




      P Wave                PR Interval           QRS (sec.)          Characteristics
 Before each QRS              > 0.20               < 0.12               Regular
    (identical)

          Marquette Medical Systems, Inc (http://www.mei.com)

         Second Degree AV Block (Mobitz Type I)




P Wave                  PR Interval           QRS (sec.)            Characteristics
Conduction              Increasingly          < 0.12                QRS dropped in a
Intermittent            Prolonged                                   repeating pattern

Marquette Medical Systems, Inc (http://www.mei.com)

         Third Degree (Complete) Block
             o Atropine increases heart rate (by blocking acetylcholine effects on the SA node)
             o Young adults are most sensitive to atropine effects on heart rate {higher vagal
                 tone} compared to infants or elderly patients

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                        in the elderly: atropine may have no effect on heart rate
             o   During anesthesia with a volatile agent, atropine dosage required to raise the heart
                 rate may be less than that required in an awake patient -- suggesting vagal center
                 depression during anesthesia




      P Wave                 PR Interval            QRS (sec.)          Characteristics
  Normal but not               none                   N/A               No relationship
  related to QRS                                                       between P & QRS
                                                                           complex

Marquette Medical Systems, Inc (http://www.mei.com)

         Halothane (Fluothane) (like opioids) probably increases central vagal tone, explaining
          why atropine administration is more likely to result in an increase in heart rate compared
          to patients anesthetize with enflurane (Ethrane).
         Antagonist-assisted neuromuscular-blockade reversal
             o   Edrophonium (Tensilon), neostigmine (Prostigmin), or pyridostigmine
                 (Mestinon)-- effective by increasing acetylcholine availability of neuromuscular
                 junction {secondary to acetylcholinesterase inhibition}
             o    Physostigmine (Antilirium): not used because dosage requirement is excessive
             o   Anticholinesterase agents are usually administered during spontaneous
                 neuromuscular-blockade recovery
                         Recovery rate is the sum of:
                             (1) spontaneous recovery from the blocking drug and
                             (2) the activity of the pharmacologic antagonist (anticholinesterase
                                drugs)
                        Therefore: pharmacologic antagonism is more effective for short-or
                        intermediate-acting neuromuscular-blocking drugs (undergoing plasma
                        hydrolysis or Hoffmann elimination) compared to long-acting
                        nondepolarizing neuromuscular-blocking agents
             o   Special Considerations: use of muscarinic antagonists with anticholinesterases in
                 Reversal of Neuromuscular Blockade
                     Reversal of nondepolarizing neuromuscular-blockade: necessitates only
                        nicotinic cholinergic effects of anticholinesterases agents


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                       Minimizing muscarinic receptor-mediated effects of anticholinesterase
                        drugs is beneficial an accomplished by a concurrent administration of
                        atropine or glycopyrrolate (antimuscarinics)
                     The antimuscarinic agent should have a more rapid onset than the
                        anticholinesterase drugs -- reducing drug-induced bradycardia
                                if edrophonium (Tensilon)(0.5 mg/kg) is used; atropine 7 µg/kg is
                                appropriate
                                a higher dose atropine (10-15 µg/kg) has been recommended,
                                particularly if nonopioid-based maintenance anesthetic has been
                                used
                                if neostigmine is used (slower onset of action compared
                                edrophonium (Tensilon)), then atropine or glycopyrrolate
                                (Robinul) may be administered as the antimuscarinic agent;
                                      concurrent administration of these drugs results in an initial
                                        tachycardia because of atropine's more rapid onset
             o Factors influencing the speed and extent of neuromuscular blockade reversal by
                anticholinesterase agents
                     intensity neuromuscular-blockade when reversal is initiated (train-of-four
                        visible twitches)
                     which nondepolarizing neuromuscular-blocking drug is being reversed
                             Edrophonium (Tensilon): less effective than neostigmine in
                                reversing deep neuromuscular blockade (twitch height < 10% of
                                control) produced by continuous atracurium (Tracrium),
                                vecuronium (Norcuron), or pancuronium (Pavulon) infusions.
                                Edrophonium (Tensilon), probably better than neostigmine
                                (Prostigmin)for reversing atracurium (Tracrium)blockade
                                Neostigmine (Prostigmin), probably better than edrophonium
                                (Tensilon) for reversing vecuronium (Norcuron) blockade
                     Prevention/inhibition of anticholinesterase-mediated antagonism of
                        neuromuscular-blockade -- Possible factors
                                certain antibiotics
                                hypothermia
                                respiratory acidosis (PaCO2 >50 mm Hg
                                 hypokalemia/metabolic acidosis
                     Reversal of phase II block (following prolonged/repeated succinylcholine
                        (Anectine)): may be reversed with edrophonium (Tensilon) or neostigmine
                        (Prostigmin) in patients with normal plasma cholinesterase
                                in patients with atypical plasma cholinesterase, phase II block
                                reversal may not be reliable, requiring mechanical ventilation until
                                blockade subsides.
         Bronchodilation
             o Bronchodilation following anticholinergic drug administration is due to blockade
                of acetylcholine effects on airway smooth muscle muscarinic receptors.
             o Extent of the response depends on vagal tone (pre-existing bronchomotor tone)
                     e.g. a clinical dose of scopolamine may decrease airway resistance and
                        increase dead space by about 1/3


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             o   Preferred Route of Administration for bronchodilation: aerosol
             o   Ipratropium (Atrovent):anticholinergic drug most commonly used for aerosol
                 administration -- synthetic quaternary ammonium atropine congener
                         most effective in preventing/treating bronchospasm due to ß-adrenergic
                         antagonists
                         more effective than ß-adrenergic agonists in producing bronchodilation in
                         patients with chronic bronchitis or emphysema (high cholinergic tone)
                         Patients with bronchial asthma: usually respond better to beta-agonist
                         because of direct smooth muscle relaxation through beta-receptor
                         activation and by inhibition of histamine & leukotriene release (chemical
                         mediators of smooth muscle contraction)

Stoelting, R.K., "Anticholinesterase Drugs and Cholinergic Agonists", in Pharmacology and
Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 241-244

         Gastrointestinal Tract
             o Vagal effects on the gut are mediated not only by acetylcholine but also by
                actions on intramural serotonergic and dopaminergic neurons.
             o Atropine can block Ach effects while having no effect on non-cholinergic
                modulation of GI motility.
             o Vagal input affects gastrin release and may be blocked by atropine; however,
                gastric acid release is more effectively prevented by M1 specific antimuscarinic
                drugs (pirenzapine) and H2-selective histamine receptor blockers.

Brown, J.H and Taylor, P. Muscarinic Receptor Agonists and Antagonists In, Goodman and
Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff,
P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.149-
159.

         Respiratory Tract
             o Parasympathetic activity produces bronchoconstriction.
             o Activation of nicotinic and M1-muscarinic receptors is parasympathetic ganglia
                which lie in the airway wall then activate postganglionic fibers.
             o These postganglionic fibers release acetylcholine which activate M3 muscarinic
                receptors which produce bronchiolar smooth muscle contraction. M2 receptors
                may also be present.
             o Muscarinic antagonists attenuate pulmonary smooth muscle constriction, often
                resulting in bronchodilation.
                     The magnitude of the effect depends on the basal parasympathetic tone.
                     Ipratropium bromide has been prominent in treating respiratory disease.

                                 Muscarinic Type M3
   Agonists          Antagonists      Tissue        Responses              Molecular
                                                                            Aspects
acetylcholine,         atropine          Smooth          Contraction     Phospholipase
                                         muscle                          C (PLC)

                                                                                      Page 25 of 27
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                                        Secretory         Increased      stimulation
methacholine                             glands           Secretion      through Gq/11

                                                                         formation:
                                                                         (IP3 ) +
                                                                         diacylglycerol
                                                                         (DAG):
                                                                         increased
                                                                         cytosolic Ca2+

         Atropine and other antimuscarinic inhibit mouth, bronchial, and pharyngeal
          secretion which reduce reflex laryngospasm during general anesthesia.
              o Also, atropine or other antimuscarinics are given during general anesthesia to
                 blunt increases in vagal tone due to mechanical effects on viscera during
                 abdominal surgeries.
         Antimuscarinics, especially ipratropium, along with sympathomimetics, are useful in
          management of asthma. Ipratropium (Atrovent) has an advantage in asthma
          compared to atropine because:
              o ipratropium does not inhibit mucociliary clearance (atropine does)
              o ipratropium has no significant CNS effects.
              o Inhaled ipratropium (a quaternary, charge molecule) has limited or no systemic
                 effects.
              o ipratropium is more effective that beta-adrenergic agonists in COPD (cholinergic
                 tone may be the only component that may be attenuated)
         Ophthalmological
              o Muscarinic receptor antagonists block parasympathetic responses of the ciliary
                 muscle and iris sphincter muscle, resulting in paralysis of accommodation
                 (cycloplegia) and mydriasis (pupillary dilation).
              o Mydriasis results in photophobia, whereas cycloplegia fixes the lens for far vision
                 only (near objects appear blurred).
              o Systemic atropine at usual doses does not produce significant ophthalmic effect.
              o By contrast, systemic scopolamine results in both mydriasis and cycloplegia.
              o Note that sympathomimetic-induced mydriasis occurs without loss of
                 accommodation.
              o   Atropine-like drugs can increase intraocular pressure, sometimes dangerously, in
                 patients with narrow-angle glaucoma.
              o Increases in intraocular pressure is not typical in wide-angle glaucoma.
         Cholinergic Blockers:Adverse effects
              o   Dry mouth (xerostromia)
              o   Blurred vision (cycloplegia)
              o   Photophobia (mydriasis)
         Ganglion Blocking Drugs
              o Ganglionic blockers act mainly at the primary nicotinic-type cholinergic receptor
                 at sympathetic and parasympathetic autonomic ganglia.
                      Agents which are classified as ganglionic blockers are not included among
                          those drugs which block neuromuscular junctions.

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Cholinergic Drugs


           o   One class of blocker produces a depolarization block: Nicotine could produce this
               effect.
           o   The second class of agents include hexamethonium & trimethaphan These agents
               either competitively block the receptor or block the open channel configuration.
           o   For essential hypertension, ganglionic blockers have been replaced by better
               drugs.
                    Ganglionic blockers may be used for initial blood pressure control in
                       patients with dissecting aortic aneurysm because, in addition to reducing
                       blood pressure, blunting of sympathetic responses reduce sheer forces at
                       the tear.

               Taylor, P. Agents Acting at the Neuromuscular Junction and Autonomic Ganglia
               In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman,
               J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The
               McGraw-Hill Companies, Inc.,1996, pp.193-195

              Predominary Sympathetic or Parasympathetic Tone
   Antatomical Site      Predominant Autonomic        Effect of Ganglionic
                                  Tone                      Blockade
      Arterioles          Sympathetic-adrenergic   vasodilatation; increased
                                                     peripheral blood flow;
                                                          hypotension
         Veins            Sympathetic-adrenergic dilatation; blood pooling;
                                                   decreased venous return;
                                                   decreased cardiac output
         Heart              Parasympathetic-              tachycardia
                               cholinergic
    Ciliary Muscle          Parasympathetic-           cycloplegia (loss of
                               cholinergic              accommodation)
 Gastrointestinal Tract     Parasympathetic-      reduced tone and motility;
                               cholinergic          constipation; decreased
                                                           secretions
   Salivary Glands          Parasympathetic-       Xerostomia (dry mouth)
                               cholinergic
     Sweat Glands         Sympathetic-cholinergic     Anhidrosis (lack of
                                                            sweating)

Taylor, P. Agents Acting at the Neuromuscular Junction and Autonomic Ganglia In, Goodman
and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E,
Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996,
pp.193-195. Adapted from Table 9-3.




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