Cholinergic _ Anticholinergic drurgs

							 Cholinergic Agents
        and
Cholinergic Blocking
       Agents
         Speaker- Dr Anuj
         Moderator-Dr Sarkar
Somatic and Autonomic Nervous Systems

Somatic                    Autonomic
 Skeletal muscle           Smooth and cardiac

 Conscious and
                             muscle and glands
  unconscious regulation    Unconscious regulation
                            Target tissues stimulated
 Skeletal muscle
                             or inhibited
  contracts
                            Two synapses
 One synapse
                            Acetylcholine by
 Acetylcholine              preganglionic neurons
 Receptor molecules:        and ACh or norepinephrine
  nicotinic                  by postganglionic
                             neurons
                            Receptor molecules: varies
                             with synapse and NT
 • Sympathetic
 • Parasympathetic
      Work antagonistically
        Myelinated              Unmyelinated
CNS     motor        ganglion   motor neuron   effector
        neuron
ANS   : Homeostatic balancing




                 Figure 11-1: Homeostasis and the autonomic division
Physiology of ANS
   Neurotransmitters: primary substances produced by
    neurons of ANS
     – Acetylcholine released by cholinergic neurons
     – Norepinephrine released by adrenergic neurons
   Certain cells(eg muscle ) have receptors that
    combine with neurotransmitters (eg Ach) causing a
    response(contraction) in the cell
     – Cholinergic receptors: bind acetylcholine. Have
       two different forms: nicotinic and muscarinic
       receptors
         Nicotinic receptors: on postganglionic neurons,
          all skeletal muscles, adrenal glands
         Muscarinic receptors: on parasympathetic
          effectors, receptors of some sweat glands
     – Adrenergic receptors bind
       norepinephrine/epinephrine .Types-
         Alpha and beta receptors.
             CHOLINERGIC RECEPTORS



                 Cholinergic Receptors


     Nicotinic                           Muscarinic



Nm                   Nn
            CHOLINERGIC RECEPTORS


             Cholinergic Receptors


Nicotinic                            Muscarinic




             M1      M3         M5      M2        M4
    MUSCARINIC RECEPTORS
Muscarinic receptors are 7 transmembrane
domain, G-protein coupled receptors
           Nicotinic Receptors(Nm&Nn)

   Receptors are selectively activated by nicotine &
    blocked by tubocurarine or hexamethonium
   Nm—Present on NM junction(skeletal muscle end
    plate)--depolarization of muscle end plate --
    contraction of skeletal muscle
   Nn---Present on ganglionic
    cells(sympath&parasympath),adrenal medullary
    cells,spinal cord,certain areas of brain---primary
    pathway of transmision in ganglia
    Muscarinic Receptor Subtypes
M1 - mainly in CNS,gastric glands,autonomic ganglia
 Xn- stomach -  HCl secretion,histamine release,
     learning,memory &motor function

M2 – heart mainly
 Xn – SA Node - HR
      AV Node- velocity of conduction
      Atrium &ventricle-  contractility
      CNS- tremor,analgesia
      Visceral smooth muscle-contraction
Muscarinic Receptor Subtypes

M3 – visceral smooth muscle - contraction
     bronchospasm
    Iris-miosis (constriction of pupil)
     contraction of urinary bladder
      GIT motility
     exocrine gland secretion
     eg  saliva and digestive secretions
             ADRENERGIC RECEPTORS


                  ADRENERGIC RECEPTORS


      a1                  a2                  b


a1A   a1B   a1D     a2A   a2B   a2C      b1   b2   b3
Cholinergic Drugs

   Parasympathomimetics or cholinomimetics
   Stimulate parasympathetic nervous system in
    same manner as does acetylcholine
   May stimulate cholinergic receptors
    directly(DIRECT Xn) or may slow
    acetylcholine metabolism at synapses (effect
    the enzyme acetylcholinesterase)—
    INDIRECT Xn
NEUROMUSCULAR JUNCTION
    NEUROMUSCULAR JUNCTION

 Normal neuromuscular junction
  Acetylcholine binds to nicotinic receptors on
  cell membranes of muscle cells to cause
  contraction
 Myasthenia gravis autoantibodies
  presumably destroy nicotinic receptors; thus,
  acetylcholine less able to stimulate muscle
  contraction. Results in severe muscle
  weakness.
Acetylcholine(prototype-cholinergic
agonists)

   Main neurotransmitters of the ANS is
    acetylcholine
   Acetylcholine is released at:
     preganglionic fibers (both sympathetic and
    parasympathetic nervous system)
   Also released from
     Postganglionic sympathetic neurons that
    innervate the sweat glands Motor neurons
    that innervate the skeletal muscles
Drug Effects of Cholinergic Agents

 ―SLUDGE‖
    Salivation
    Lacrimation
    Urinary incontinence
    Diarrhea
    Gastrointestinal cramps
    Emesis
Drug Effects of Cholinergic Agents

   Stimulate intestine and bladder
    –   Increased gastric secretions
    –   Increased gastrointestinal motility
    –   Increased urinary frequency

   Stimulate pupil
    –   Constriction (miosis)
    –   Reduced intraocular pressure

   Increased salivation and sweating
Drug Effects of Cholinergic Agents

   Cardiovascular effects
    –   Decreased heart rate
    –   Vasodilation
   Respiratory effects
    –   Bronchial constriction, narrowed airways
Drug Effects of Cholinergic Agents

   At recommended doses, the cholinergics
    primarily affect the MUSCARINIC receptors.
   At high doses, cholinergics stimulate the
    NICOTINIC receptors.
Drug Effects of Cholinergic Agents

   DESIRED EFFECTS: from muscarinic
    receptor stimulation
   Many undesirable effects are due to
    stimulation of the nicotinic receptors
   Cholinergic drugs are classified into:
    DIRECT ACTING
    INDIRECT ACTING
Mechanisms of Action—Direct Acting
Cholinergics

   Direct acting cholinergics are lipid insoluble
   Do not readily enter the CNS so effects are
    peripheral
   Resistant to metabolism by
    acetylcholinesterase
   Effects are longer acting than with
    acetylcholine
Direct Acting Cholinergic Drugs cont.

Examples:
 Ach,
 Methacholine
 Carbachol
 Bethanechol
 Muscarine
 Pilocarpine
Indirect-Acting Cholinergic Drugs

 Action is by decreasing the inactivation
  of acetylcholine at the synapse
 Action against the enzyme
  acetylcholinesterase
 Accumulation of acetylcholine ----
  activation of the nicotinic and
  muscarinic receptors
Indirect-Acting or Anticholinesterase
Drugs cont.

 Indirect acting Anticholinesterase drugs are
  either
Reversible
Irreversible
 Reversible agents are egs-
  CARBAMATESEdrophodium,physostigmin
  ,neostigmine ,pyridostigmine,galantamine
  ACRIDINE----Tacrine
Indirect-acting agents cont.

   Irreversible anticholinesterases are:
     ORGANOPHOSPHATES-
    Dyflos,parathion,malathion{,tabun,sarin,
    soman—NERVE GASES for chemical
    warfare}TIK20(diazinon)
    CARBAMATES---
    Carbaryl,propoxur{Insecticides}
    CHOLINERGIC DRUGS-

   Physostigmine —only anticholinesterase
    capable of crossing the BBB.
   Is more lipid soluble.
    Used as an antidote for overdosage of
    anticholinergics such as: atropine,
    antihistamines, TCA, phenothiazines.
    May also be used in tx of glaucoma.
Indirect Acting Agents used to treat
Alzheimer’s disease

   Donepezil —said to delay progression of the
    disease by up to 55 weeks. Does not cause
    liver toxicity.
   Galantamine —newest kid on the block
   Rivastigmine -long acting. Twice a day
    dosing.
   Tacrine —hepatoxic. Elevated liver enzymes
  Cholinergic Blocking
       Agents

 Drugs that block or inhibit the
 actions of acetylcholine (ACh) in
 the parasympathetic nervous
 system (PSNS)
Cholinergic Blocking Agents:
Mechanism of Action

 Competitive antagonists
 Compete with ACh
 Block ACh at the muscarinic
  receptors
  in the PSNS
   .
Cholinergic Blocking Agents:
Chemical Class

Natural       Synthetic/Semisynthetic
atropine      anisotropine   clidinium
belladonna    dicyclomine    glycopyrrolate
hyoscyamine   hexocyclium    homatropine
scopolamine   ipratropium    isopropamide
              oxybutynin     propantheline
Cholinergic Blocking Agents:
Therapeutic Uses

Atropine (PROTOTYPE)
Used primarily for cardiovascular disorders
 Sinus node dysfunction
 Symptomatic second-degree heart
  block
 Sinus bradycardia with hemodynamic
  compromise (advanced life support)
Cholinergic Blocking Agents:
Therapeutic Uses
Respiratory
Blocking the cholinergic stimulation of the
  PSNS ---
  –   Decreased secretions from nose,
      mouth, pharynx, bronchi
  –   Relaxed smooth muscles in bronchi
      and bronchioles
  –   Decreased airway resistance
  –   Bronchodilation
Cholinergic Blocking Agents:
Therapeutic Uses

Respiratory agents are used to treat:
 Exercise-induced bronchospasms
 Chronic bronchitis
 Asthma
 Chronic obstructive pulmonary
  disease
Cholinergic Blocking Agents:
Therapeutic Uses

Gastrointestinal--
   Blockade of PSNS by anticholinergic drugs results
    in:
    – Decreased secretions
    – Relaxation of smooth muscle
    – Decreased GI motility and peristalsis
    As antisecretory (quart comp-eg glycopyrr)&
      antispamodic(tert amine-dicyclomine)
Cholinergic Blocking Agents:
Therapeutic Uses

Gastrointestinal agents are used to treat:
 Peptic  ulcer disease
 Irritable bowel disease
 GI hypersecretory states
 Antisecretory & antispasmodic
Cholinergic Blocking Agents:
Therapeutic Uses

Genitourinary
 Relaxed detrusor muscles of the
  bladder
 Increased constriction of the internal
  sphincter
 Reflex neurogenic bladder
 Incontinence
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