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Ganglionic Blocking Drugs

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					                                                                                                               P. Palade
                                                                                                            Topic No. 23
                                                                                                      September 29, 2008


                       NICOTINIC RECEPTORS AND GANGLIONIC BLOCKING DRUGS

I.       Nicotinic Receptors
     A. Molecular Structure     ION CHANNELS
         1.   Nicotinic AChR is the prototype of the ligand gated ion channels. It belongs to a huge family of related
              ligand-gated ion channels called the ―cys-loop‖ receptors. They share the following common features:
              a) There is one or more disulfide bond formed by two cysteine residues in the extracellular domain (hence
                   the name ―cys-loop‖ receptors).
              b) All are pentameric, i.e. each ion channel is formed by five subunits of the same type (homomer) or of
                   different types (heteromer).
              c) There are four transmembrane (TM) domains that are presumably -helices in each subunit. The
                   second one (TM2) of each subunit lines the ion conducting pore of the channel.
         2.   Nicotinic receptors at the neuromuscular junction
              a) They are comprised of four distinct subunits (or). The subunits are arranged in the
                   circular order of  in fetal muscle, or  in adult muscle. Adult muscle =  replaced by
                    subunit
              b) There are two binding sites for ligands, one at the interface between  and , the other at the interface
                   between  and .
                    subunit responsible for ACh
                   binding and opening the pore
              c) The channel opens when both
              sites are occupied by agonists.
         3.   Neuronal nicotinic receptors
              a) To date, nine nAChR  subunits
                 (2-10) and three  subunits
                 (2-4) have been cloned from
                 brain tissues.
              b) Neuronal nAChRs are either
                 homoligomers composed of 7,
                 8, 9 subunits as well as
                 heteroligomers made up from a
                 combination of different 
                 subunits (such as 78,910)
                 or  and  subunits.
              c) The composition of ganglionic
                 nAChRs are mainly 32,
                 352, 34, 354 or 7.
                 Changing the subunits changes the Ca2+ permeability  Important for muscle cells!
     B. Pharmacology
         1.   Pharmacological properties of nAChRs depend on the subunit composition. However, the functional or
              pathophysiological relevance of these variations are not clear. Especially in toxicity by  bungarotoxin
         2.   In general, the homomeric nAChRs are sensitive to -Bungarotoxin just like the muscle nAChR.
              Heteromeric neuronal nAChRs are generally insensitive to -Bungarotoxin.
         3.   The muscle nAChR has very low calcium permeability. Heteromeric neuronal nAChRs have moderate
              calcium permeability. The homomeric neuronal nAChRs are highly permeable to calcium. Difference based
              on subunit conformation
         4.   In general, the homomeric nAChRs (such as homomeric 7) are fast desensitizing when the agonist binding
              sites are occupied by nicotine or ACh. Heteromeric nAChRs desensitize less.



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        5.   There is no clear cut pharmacological distinction between nAChRs in the CNS and the ganglionic nAChRs.
    C. Autonomic Function
        1.   Both sympathetic and parasympathetic systems will be altered by drugs acting at ganglionic nAChRs.
             Because ACh used at SNS and PSNS ganglia
        2.   The net effect depends on the predominance of sympathetic or parasympathetic tone at various effector site.
             Ganglionic stimulant will increase the predominant tone. Ganglionic blockers will produce the opposite
             effects. STIMULANTS =  tone BLOCKERS =  tone
    D. Others
                                        Idea is to decrease muscle contraction
        1.   Neuromuscular junction: Neuromuscular blocking agents (will be covered in Topic 51) target the
             nAChRs at the neuromuscular junction and are used clinically with anesthetics as muscle relaxant.
             However, most of them also block ganglionic nAChRs to various degree, therefore producing side effects in
             the ANS. They rarely cause side effect in the CNS since they cannot pass the blood-brain-barrier in general
             (there are exceptions).
        2.   The CNS: ACh is not the principal excitatory neurotransmitter in the brain. (Glutamate is) Nicotine is
             addictive. The nAChRs in the CNS and their role in nicotine addiction will be covered later.

II. Ganglionic stimulants
    A. Introduction
        1.   Nicotine and tetramethylammonium (TMA). Primary stimulants of ganglia, NOT PRESCRIBED but
             pharmacologically relevant
        2.   Nicotine is used as an insecticide and rodenticide, and is present in tobacco products. Important as a
             poison.
        3.   Nicotine is available in transdermal patches and gum for use as an aid to smoking cessation; prevents some
             of the signs and symptoms observed in smokers during "withdrawal" (nervousness, irritability, drowsiness,
             sleep disturbances, increased appetite, headache and constipation). An orally administered partial agonist,
             varenicline, has recently been introduced for smoking cessation as well.
    B. Mechanism of action.
        1.   Binds to and activates nicotinic receptors on postganglionic membranes  membrane depolarization  fast
             EPSP  effects of autonomic ganglionic stimulation (sympathetic and parasympathetic effects).
             *There are also M receptors at ganglia – M2 (slow IPSP), M1 (slow EPSP, stimulate SNS)
        2.   High concentration of nicotine blocks ganglionic neurotransmission due to depolarizing block (Keeps cells
             depolarized for prolonged time period causing desensitization) and desensitization. TMA activate
             ganglionic nAChRs without depolarizing blockage.
        3.   Nicotine also acts at other sites: Chemoreceptors in aortic arch and carotid bodies - respiratory and CV
             effects; Brainstem; NMJ-toxic effects at high doses.
    C. Absorption, metabolism and excretion of nicotine.
       1. Nicotine is a volatile liquid base.
       2. Well absorbed from oral, buccal, GI and respiratory membranes.
       3. Widely distributed; crosses blood-brain and placental barriers.
       4. Metabolized by liver (primary site), kidneys and lungs.
       5. Nicotine and metabolites are rapidly eliminated by the kidneys.
    D. Pharmacological actions and toxic effects (nicotine poisoning) - complex and unpredictable due to many
       different and often opposing actions. In general, nicotine causes a transient stimulation and subsequently
       persistent depression. Often biphasic effects
        1.   Cardiovascular system - usually mimics effects of the sympathoadrenal system;  HR,  contractility, 
             systolic and diastolic blood pressure; blood pressure drops with severe toxicity. Must  PSNS to cause this


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         2.   Neuromuscular junction-mostly neuromuscular blockade due to depolarizing blockade.


         3.   Respiratory system. Spectrum of effects depending on dosage
              a) Low doses stimulate respiration via activation of chemoreceptors in the aortic arch and carotid bodies.
              b) Moderate doses directly stimulate medullary respiratory centers.
              c) Toxic doses cause respiratory depression and paralysis due to inhibition of brain stem respiratory
                  centers and action at the neuromuscular junction of respiratory muscles (effect like succinylcholine).
         4.   CNS
              a) Stimulant effect, increased alertness, confusion.
              b) Tremors, convulsions, ADH release.
              c) Nausea and vomiting; often seen with first exposure to tobacco smoke; results from stimulation of the
                 emetic chemoreceptor trigger zone in the medulla oblongata; tolerance to this develops rapidly.
         5.   GI tract -  gastric acid secretion,  GI tone and  GI motility.
         6.   Diaphoresis.
         7.   Exocrine Glands – salivation, cold sweats
    E. Symptoms for acute nicotine poisoning—with increased severity:
       1. Nausea and vomiting, abdominal pain, diarrhea; salivation, cold sweat; headache, dizziness, mental
          confusion.
       2. BP falls, faintness, difficulty in breathing, weak, rapid and irregular pulse.
       3. Convulsion, failure of respiration, leading to death.
    F.   Treatment of nicotine poisoning.
         1. Gastric lavage and/or induction of vomiting. Get rid of anything left in stomach, only helpful if nicotine was
             swallowed
         2. Activated charcoal introduced via gastric tube.
         3. Respiratory support.
             Ex. Green Tobacco Sickness  excess skin absorption, seen in tobacco pickers

III. Ganglionic blocking drugs
    A. The clinically useful ganglionic blocker is mecamylamine. Hexamethonium ("C6"), the prototype, is not
       available for clinical use. Trimethaphan has been replaced by newer drugs.
    B. Mechanism of action - competitive antagonists of ACh.
       1. Compete with ACh for nicotinic receptors in the ganglia but do not stimulate the receptor.
       2. No initial ganglionic stimulation.
    C. Absorption, distribution and excretion.
         1.   Trimethaphan
              a) Positively charged—poorly absorbed in the GI tract.
              b) Parenteral use only.
              c) Confined to the extracellular space.
              d) Excreted unchanged by the kidney.
              e) Very short acting.
         2.   Mecamylamine
              a) Secondary amine; oral use.
              b) Crosses BBB and placental barrier.
              c) Concentrated in the liver and kidney.
              d) Excreted slowly by the kidney--may accumulate in the body. Hangs around longer = easier to
                 administer dose-wise




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    SITE                 PREDOMINANT TONE              EFFECT OF GANGLIONIC BLOCKADE
    arterioles           Sympathetic (adrenergic)   Vasodilation, hypotension,       ↑ peripheral blood flow
    veins                Sympathetic (adrenergic)   Dilation, pooling of blood; ↓ venous return & cardiac output
    heart                parasympathetic            tachycardia
    Iris                 parasympathetic            Mydriasis
    Ciliary muscle       parasympathetic            Cycloplegia (Loss of accommodation due to ciliary m.
                                                   paralysis)
    GI tract             parasympathetic            Constipation; ↓tone, motility, gastric & pancreatic secretions
    Urinary bladder      parasympathetic            Urinary retention
    Salivary glands      parasympathetic            Xerostomia No saliva production
    Sweat glands         Sympathetic (cholinergic) Anhidrosis No sweating
    Genital tract        Sympathetic & parasymp. ↓ stimulation
                        parasympathetic
    D. Pharmacological activity.
         1.   Effects are produced in all tissues innervated by the autonomic nervous system (ANS). The effect in a
              given system is best understood by knowing which division of the ANS is dominant in that system at the
              time of administration.
              Affects ALL ANS innervated organs … Must know which system is dominant to know what the effects of
              ganglion blockade will be
         2.   Common actions. Ganglion blockers are NOT the preferred way of achieving these results … Use an end-
              organ blocker instead!
              a) Cardiovascular system.
                  (1) Heart -  heart rate, little effect on contractility.
                  (2) Arterioles - vasodilation, hypotension.
                  (3) Veins - vasodilation, venous pooling,
                        venous return,  cardiac output.
              b) Eye - mydriasis and cycloplegia.
              c) GI tract -  tone and motility;  volume and acidity of gastric secretions.
              d) Urinary hesitancy or retention.
              e) Dry mouth -  salivary secretion.
              f) Reduced secretion of sweat glands.
    E. Clinical uses - usually not a desirable therapeutic strategy because both divisions of the ANS are affected.
         1.   To treat a hypertensive crisis - trimethaphan was used in treatment of hypertension in the past; better agents
              (vasodilators) are available.
         2.   To generate controlled hypotension - trimethaphan was used during plastic, neurological, ophthalmic or
              orthopedic surgery; supplanted by nitroprusside.
              **1 and 2 not used anymore in favor of better methods
         3.   To treat autonomic hyperreflexia (autonomic neurovegetative syndrome), which may occur following spinal
              cord injury, is treated with mecamylamine. Will block all ANS pathways
    F.   Adverse reactions - any pharmacological action may become an adverse effect.
         1.   Mild side effects - mydriasis, difficult visual accommodation, dry mouth, urinary hesitancy, constipation,
              abdominal discomfort, anorexia, syncope, anhidrosis.
         2.   More serious, less frequent side effects - postural hypotension, anginal pain, paralytic ileus, urinary
              retention.
         3.   Mecamylamine may cause CNS effects; mania, depression, seizures, confusion. B/c it can cross BBB
         4.   Trimethaphan can stimulate histamine release. Not used anymore



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    G. Dosage considerations.
         1.    Trimethaphan - positively charged at body pH. Not used because of short half life
               a) Parenteral use only.
               b) Very short acting.
         2.    Mecamylamine.
               a) A secondary amine; available for oral use.
               b) Crosses blood-brain and placental barriers - therefore rarely used. Risk of side effects
               c) May accumulate in the body.

At this point, you should be able to:
    1.   Compare the general pharmacological properties of nicotinic AChRs at the neuromuscular junction,
         ganglionic neurons in the autonomic nervous system, and neurons in the central nervous system.
    2.   Describe the physiological effects of nicotinic AChR activation in the autonomic nervous system.
    3.   Describe the symptoms and treatment options for acute nicotine poisoning.
    4.   List the therapeutic uses and adverse side effects of ganglionic blockers.

Drug List:

    Nicotine                Trimethaphan                Mecamylamine




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                  P. Palade
               Topic No. 23
         September 29, 2008




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