CHOLINOCEPTOR-­‐ACTIVATING

   
(Cholinergic  Agonist)  
and  
CHOLINESTERASE-­‐INHIBITING  
DRUGS  
Perfecto  B.  Soriano,  MD,  FPPS,  FPSECP,  MSc.  
LNU-­‐FQD  MEDICAL  FOUNDATION  COLLEGE  OF  MEDICINE  
Department  of  Pharmacology  &  TherapeuNcs  
q SymphatheNc  Division  
Ø Preganglionic  cell  
bodies  in  lateral  
horns  of  spinal  cord  
T1-­‐L2  
q  ParasympatheNc  Division  
Ø  Preganglionic  cell  bodies  in  
nuclei  of  brainstem  or  lateral  
parts  of  spinal  cord  gray  
ma;er  from  S2-­‐S4  
–  Preganglionic  axons  from  
brain  pass  to  ganglia  
through  cranial  nerves  
–  Preganglionic  axons  from  
sacral  region  pass  through  
pelvic  nerves  to  ganglia  
Ø  Preganglionic  axons  pass  to  
terminal  ganglia  within  wall  of  
or  near  organ  innervated  
q Sites  of  Cholinergic  AcNvity  
Ø Preganglionic  synapses  of  both  sympatheNc  and  
parasympatheNc  ganglia  
Ø   ParasympatheNc  postganglionic  neuroeffector  
juncNons  
Ø   All  somaNc  motor  end  plates  on  skeletal  muscles  
•  NeurotransmiUers  and  Neuroreceptors  
Ø Acetylcholine  and  Norepinephrine  
Ø All  preganglionic  neurons  are  cholinergic  
Ø ParasympatheCc  post  ganglionic  neurons  are  
cholinergic    
Ø SympatheCc  post  ganglionic  neurons  are  
adrenergic  except  sympathe1cs  innerva1ng  
sweat  glands,  blood  vessels  in  skeletal  muscle,  
and  piloerec1on  muscles  are  cholinergic  
•  ParasympatheNc  Nervous  System  Receptors:  Cholinergic  
Receptors    
1.  Muscarinic  receptors  -­‐  are  associated  with  
parasympatheCc  funcCons  and  are  located  at  the  
ends  of  postganglionic  neurons  in  peripheral  Cssues  
(effectors,  e.g.,  internal  organs,  glands,  smooth  
muscle)  innervated  by  the  parasympatheCc  system.  
SCmulaCon  of  the  muscarinic  receptors  may  result  in  
either  excitaCon  or  inhibiCon,  depending  on  the  
organ  involved.  
•  a  membrane  protein:    upon  sCmulaCon  by  
neurotransmi;er,  it  causes  the  opening  of  ion  
channels  indirectly,  through  a  second  messenger.  For  
this  reason,  the  acCon  of  a  muscarinic  synapse  is  
relaCvely  slow.  
 Sites  of  Cholinergic  AcNvity  
 

RECEPTOR   M2   M4   M1   M3   M5  

Gi                      Go   Gq  
INTRACELLULAR  
TRANSDUCER   Adenylyl  cyclase   Phospholipase  C  
cAMP   Diacyl-­‐glycerol          IP3  

ELECTRICAL   HyperpolarizaNon  (heart)  

MECHANICAL   Cardiac  inhibiNon   DepolarizaNon  
PHYSIOLOGICAL   Smooth  muscle  contracNon  
Antagonism  of  smooth    
RESPONSES   muscle  relaxaNon   Glandular  secreNon  
 
Muscarinic  receptors  and  its  locaNon  
§  M₁  receptor-­‐  nerve  endings  
§  M₂  receptor-­‐  heart  and  some  nerve  endings  
§  M₃  receptor-­‐  effector  cells,  smooth  muscle,  glands  and  
endothelium  
§  M₄  &  M₅-­‐  CNS  
•  Muscarinic  AcNon  
§  eye  (miosis  &  set  lens  for  near  vision)  
§  smooth  muscle,  exocrine  glands  
§  bronchoconstricCon,  ↑secreCon,  ↑  GI  moClity  
§  ↑  urinaCon  
§  heart  &  vascular  beds  (vagal  sCmulaCon)  
§  ↓  SA  &  AV  conducCon  velocity  
§  ↓  force  of  atrial  contracCon  
§  ↓  vascular  resistance  -­‐  due  to  acCvaCon  of  
§  receptors  on  endothelium→    EDRF  (Endothelium  Derived  
RelaxaCon  Factor)  
§  Effects  modified  by  reflexes  
2.  NicoNnic  receptors  –  are  located  in  the  autonomic  
ganglia  of  both  the  sympatheCc  and  parasympatheCc  
systems  (and  the  nerve  endings  of  the  somaCc  motor  
system(  e.g.  motor  nerves  and  skeletal  muscle).  
SCmulaCon  results  in  muscle  contracCon  
 
•  a  channel  protein  that,  upon  binding  by  acetylcholine,  
opens  to  allow  diffusion  of  caCons  
 
•  NN  -­‐  autonomic  ganglia  (NN)  
•  NMJ  (NM)-­‐    muscle  contracNon  →  paralysis  
 
 Classes  of  Cholinergic  Drugs/SNmulants  

Direct-­‐acNng   Indirect-­‐acNng  

Receptor  agonists   Cholinesterase  inhibitors  

Carbamates  
PHYSOSTIGMINE   Phosphates  
Choline  esters   NEOSTIGMINE   DIISOPROPYL    
ACETYLCHOLINE   Alkaloids   PYRIDOSTIGMINE   FLUROPHOSPHATE  
METHACHOLINE   PILOCARPINE   (DFP)  
EDROPHONIUM  
CARBACHOL   MUSCARINE   PARATHION  
BETHANECOL   ARECOLINE   AnNdote  
NICOTINE   PRALIDOXIMINE  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Choline  Esters  

AbsorpNon:  polarity  dependent  (poor  for  ACh,  

quaternary  ammonium),  intravenous,  
subcutaneous  and  intramuscular  for  local  
effects  (Ach)    
 Metabolism:  Highly  dependent  on  the  
suscepCbility  to  acetylcholinesterase  (AChE)  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Choline  Esters  
ProperCes  of  Choline  Esters  
Choline  Esters   SuscepNbility  to   Muscarinic   NicoNnic  
Cholinesterase   AcNon   AcNon  
Acetylcholine  Chloride   ++++   +++   +++  
Methacholine  chloride   +   ++++   +  
Carbachol  chloride   Negligible   ++   +++  
Bethanechol  chloride   Negligible   ++   None  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Choline  Esters  
Pharmacologic  Effects  
Eyes:  contracCon  of  ciliary  muscle  and  smooth  muscle  of  the  iris  
sphincter  (miosis)  –  aqueous  humor  ouclow,  drainage  of  the  
anterior  chamber,  

Cardiovascular:  Bradycardia  (possibly  preceded  by  tachycardia),  

vasodilaCon  (all  vascular  beds  including  pulmonary  and  
coronary  –  M3)  and  hypotension,  reducCon  of  the  contracCon  
strength  (atrial  and  ventricular  cells,  IK+        ,  ICa2+    diastolic  
depolarizaCon  ,  NO-­‐inhibitable  ATP?),  negaCve  inotropic  &  
chronotropic  effect  (inhibiCon  of  adrenergic  acCvaCon),  
variable  BP  effects  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Choline  Esters  
GI  -­‐  increases  in  tone,  amplitude  of  contracCons,  and  peristalCc  
acCvity  of  the  stomach  and  intesCnes,  enhances  secretory  
acCvity  of  the  salivary  glands  and  gastrointesCnal  tract.  
Urinary  bladder  -­‐  increase  ureteral  peristalsis,  contract  the  
detrusor  muscle  of  the  urinary  bladder,  increase  the  maximal  
voluntary  voiding  pressure,  and  decrease  the  capacity  of  the  
bladder,  relaxaCon  of  the  sphincter  
Other  effects  –increased  secreCon  from  all  glands  that  receive  
parasympatheCc  innervaCon  (salivary,  lacrimal,  
tracheobronchial-­‐  increased  respiratory  secreCon,  digesCve  
and  exocrine  sweat  glands),increased  tone  and  contracClity  of  
bronchial  smooth  muscle  
•  IMPORTANT  -­‐  BROCHOCONSTRICTION  
 DIRECT  ACTING  CHOLINERGIC  AGONIST  
Choline  Esters  
•  Modes  of  acCon:    
Ø Direct  ac0ng  cholinergics  are  lipid  insoluble  
Ø Do  not  readily  enter  the  CNS  so  effects  are  peripheral  
Ø Resistant  to  metabolism  by  acetylcholinesterase  (except  
for  Acetylcholine  chloride)  
Ø Effects  are  longer  acCng  than  with  acetylcholine  
(endogenous  neurotransmi;er)  
Ø Widespread  systemic  effects  when  they  combine  with  
muscarinic  receptors  in  cardiac  muscle,  smooth  muscle,  
exocrine  glands  and  the  eye  
  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Choline  Esters  
1.  Acetylcholine  
 
•  Quarternary  ammonium  ester  that  is  rapidly  
hydrolyzed  by  acetylcholinesterase  and  plasma  
cholinesterase  
•  TherapeuCc  uses:  
Ø Used  as  a  mioCc  in  cataract  surgery  

 
 
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Choline  Esters  
Quaternary  ammonium    

TerNary  amine  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Choline  Esters  
2.    Methacholine  
Ø  Chemistry:  differs  chemically  from  acetylcholine  by  the  
addiCon  of  a  methyl  group  to  the  β  posiCon  of  a  choline.  As  a  
result:  
§  Hydrolyzed  only  by  acetylcholinesterase→has  a  longer  
duraCon  of  acCon  than  acetyl  choline  
§  It  becomes  vitually  a  pure  muscarinic-­‐acCng  agent  
Ø  Pharmacologic  effects  is  similar  to  acetylcholine.  
 
Ø  Methacholine  chloride  (acetyl-­‐b-­‐methylcholine  chloride;  
 PROVOCHOLINE)  may  be  administered  for  diagnosis  
 of  bronchial  hyperreacCvity  and  asthmaCc  condiCons  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Choline  Esters  
•  Carbachol  
Ø Has  a  carbamic  acid-­‐ester  link,  which  is  not  readily  
suscepCble  to  hydrolysis  by  cholinesterases  
Ø Has  all  the  pharmacologic  properCes  of  acetylcholine.  It  
exerts  both  nicoCnic  and  muscarinic  effects.  
Ø Used  ophthalmically  as  a  mioCc  agent  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Choline  Esters  
4.  Bethanechol  
Ø  Structural  features  of  both  methacholine  and  carbachol.  
Ø  Resistant  to  hydrolysis  by  cholinesterases  
Ø  Mainly  muscarinic  in  acCon  
Ø  Used  therapeuCcally  for  abdominal  distenCon,  esophageal  
reflux,  and  urinary  bladder  distenCon  
Ø  alternaCve  to  pilocarpine  to  promote  salivaCon-­‐  Xerostomia  
(dryness  of  the  mouth).  
Ø  Sjogren  syndrome  (immunologic  disorder  with  destrucCon  of  
the  exocrine  glands)  leading  to  mucosal  dryness  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Choline  Esters  
•  Bethanechol   should   be   administered   only   by   the   oral   or  
subcutaneous  route  for  systemic  effects;  they  also  are  used  
locally  in  the  eye.  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Choline  Esters  
Adverse  Effects:  
Ø  Among  the  major  contra-­‐indicaCons  to  the  use  of  the  choline  
esters  are  asthma,  hyperthyroidism,  coronary  insufficiency,  
and  acid-­‐pepCc  disease.  
Ø  Bronchoconstrictor  acCon  could  precipitate  an  asthmaCc  
a;ack  
Ø  Hyperthyroid  paCents  may  develop  atrial  fibrillaCon.  
Ø  Hypotension  induced  by  these  agents  can  severely  reduce  
coronary  blood  flow,  especially  if  it  is  already  compromised.  
Ø  The  gastric  acid  secreCon  produced  by  the  choline  esters  can  
aggravate  the  symptoms  of  acid-­‐pepCc  disease.  
 
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Choline  Esters  
Ø POSSIBLE  SIDE  EFFECTS  :  sweaCng  (very  
common),  abdominal  cramps,  a  sensaCon  of  
Cghtness  in  the  urinary  bladder,  difficulty  in  visual  
accommodaCon  for  far  vision,  headache,  and  
salivaCon.  
 
Ø AnNdote  -­‐  atropine.  

Ø Epinephrine  may  be  used  to  overcome  severe  

cardiovascular  or  bronchoconstrictor  responses.  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Alkaloids  
•  1.  Pilocarpine  
Ø Isolated  from  Pilocarpus  jaborandi,  P.  
microphyllus  
Ø Plant  family:  Rutaceae  (citrus  family)  
Ø Common  name:  Jaborandi  (means  slobber  mouth  
plant  in  Tupi  language)  
Ø Origin:  lowland  wet  forests  of  Tropical  America,  
West  Indies  
Ø Ethnomedical  uses:  members  of  the  Tupi  culture  
in  Brazil  chew  leaves  to  induce  salivaCon  and  
sweaCng  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Alkaloids  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Alkaloids  
•  Chemical  class:  terCary  amine  alkaloid  
•  Mechanism  of  acNon:  cholinergic  receptor  
agonist  with  strong  postganglionic  (muscarinic  
receptor)  sCmulaCon  and  mild  ganglionic  
(nicoCnic  receptor)  sCmulaCon  
•  Muscarinic  receptor  sNmulaNon  effects:  
–  salivaCon  
–  intesCnal  moClity  
–  pupil  constricCon  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Alkaloids  
TherapeuNc  uses:    
•  Topical  applicaCon  on  eyes-­‐  constricts  pupils  
Ø treats  open-­‐angle  glaucoma  by  reducing  intraocular  
pressure  
•  Oral  administraCon  treats  dry  mouth  (xerostomia)    
•  Also  used  to  reduce  side  effects  of  morphine  treatment,  
including:  
Ø dry  mouth  
Ø consCpaCon  
Ø urinary  retenCon  
•  Overdose  may  cause  cardiovascular  collapse  
•  Antedote  is  atropine  (conversely,  pilocarpine  is  someCmes  
used  as  an  antedote  in  cases  of  atropine  poisoning)  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Alkaloids  
•  Other  terNary  amines:  NicoNne    
•  NicoNne:    
Ø  A  liquid,  sufficiently  lipid-­‐soluble  to  be  absorbed  across  the  skin  
Ø  Used  as  gum  or  transdermal  patch  
Ø  DuraCon  of  acCon-­‐  4-­‐  6  hours  
Ø  Toxic  effect  associated  with  smoking  
Ø  Acute  Toxicity:    
§  Central  sCmulant  acCons-­‐  convulsions→coma,  respiratory  
arrest  
§  Skeletal  muscle  endplate  depolarizaCon  
blockade→depolarizaCon  blockade  and  respiratory  paralysis  
§  Hypertension  and  cardiac  arrhythmias  
§  Fatal  dose-­‐  40  mg  or  1  drop  of  pure  liquid  
Ø  Treatment:  
§  Symptom  directed  
•  Succinylcholine  
§  N-­‐receptor,  moderately  selecCve  for  neuromuscular  (NM)  
end  plate  
§  NM  relaxaCon  
§  Highly  polar,  IV  administraCon  
§  DuraCon  of  acCon:  5-­‐10  minutes  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Alkaloids  
Ø  Treatment:  
§  Symptom  directed    
§  Muscarinic  excess  resulCng  from  parasympatheCc  
ganglion  sCmulaCon  can  be  controlled  by  atropine.  
§  Central  sCmulaCon  is  usually  treated  with  
anCconvulsants.  
Ø  Chronic  Toxicity:    
§  Cardiovascular  diseases  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Alkaloids  
•  2.  Muscarine  
•  compound  isolated  from  various  species  of  fungi:  
•  Amanita  muscaria,  Amanita  phalloides  –  deadly  
nightcap,  Amanita  spp.,  Inocybe  spp.  and  Clitocybe  
spp.  
•  Common  Name:  amanita,  fly  agaric  
•  Origin:  Siberia,  North  America  
•  Habit:  mushroom  with  red,  orange,  yellow  or  
cream  colored  cap  with  white  spots.  Grows  on  
forest  floor  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Alkaloids  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Alkaloids  

A.  phalloides   A.  muscaria  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Alkaloids  
•  Ethnomedical/cultural  uses:  
–  mushroom  eaten  by  Siberian  indigenous  people  as  
hallucinogen  
–  dried  mushrooms  repel  flies  
•  compounds  with  hallucinogenic  (CNS)  acCvity:  
–  ibotenic  acid,  muscimole,  muscazone  
•  AcCve  compound:  muscarine  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Alkaloids  
•  Chemical  class:  quaternary  ammonium  alkaloid  
Ø Less  completely  absorbed  from  the  GIT  than  terCary  
amines  
•  Chemical  derivaNves:  muscarine  à  oxotremorine  
•  Muscarine  effects:  
Ø diaphoreCc,  salivaCon,  lacrimaCon,  visual  problems,  
nausea,  vomiCng,  diarrhea,  hypotension,  bradycardia,  
bronchiospasm  
Ø Amanita  phalloides-­‐  :  inhibits  mRNA  synthesis  –  24  h  
symptom  free  period  followed  by  liver  and  kidney  
malfuncCon,  death  within  4-­‐7  days  
•  Oxotremorine  effects:  sCmulates  receptors  in  basal  ganglia  
and  produces  parkinsons-­‐like  effects  (spasCcity  or  tremor)  
 
•  Modern  medical  uses:  neurobiological  research  
(understanding  muscarinic  receptors)  
 
•  Antedote:  1  –  2  mg  of  atropine  IM  every  30  min  
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Alkaloids  
3.  Arecoline  
•  From  Areca  catechu    
•  Plant  family:  Arecaceae  (palm  family)  
•  Common  name:  betelnut,  betel,  areca  nut  
•  Origin:  tree  inwet  forests  of  S  Asia,  Indomalaysia,  
Oceania,  probably  originally  from  Sulawesi  (Indonesia)  
•  Ethnobotanical  use:  Used  as  a  masCcatory  (chew):  the  
areca  seed  is  rolled  in  leaves  of  Piper  betel  and  mixed  
with  gambir  (a  spice  made  from  the  boiled  leaves  of  
Unicaria  gambir)  and  shell  lime  (which  changes  pH  to  
release  acCve  compounds)  
 
DIRECT  ACTING  CHOLINERGIC  AGONIST  
Alkaloids  
•  Ethnomedical  uses:  
Ø euphoreCc  
Ø cardiac  tonic  
Ø energizer  
Ø anChelminthic  
•  Chemical  structure:  arecoline  is  an  alkaloid  
•  Chemical  derivaNve:  arecoline  à  aceclidine  
(glaucoma  treatment  in  Europe)  
•  Arecoline  sCmulates  both  muscarinic  and  
nicoCnic  receptors  (in  ANS  and  CNS)  
 INDIRECTLY-­‐ACTING  CHOLINERGIC  AGONIST  
ANTICHOLINESTERASE  (AchE)  
•  2  Major  Chemical  Classes:  
1.  Carbamic    acid  esters  (Carbamates)-­‐  reversible  
ü  Physos1gmine  
ü  Neos1gmine  
ü  Pyridos1gmine  
 
2.  Phosphoric  acid  esters  (Organophosphates)-­‐
irreversible  
ü Insec1cide    (Parathion,  Malathion,  DFP;  Diisopropyl  
phosphorofluoridate,  Echothiophate)  
ü  Isoflurophate  
3.  *Edrophonium-­‐  is  an  alcohol  (not  an  ester)  
 
 INDIRECTLY-­‐ACTING  CHOLINERGIC  AGONIST  
ANTICHOLINESTERASE  (AchE)  
•  Mode  of  acCon:  
•  Both  carbamates  and  organophosphate  inhibitors  bind  
to  cholinesterase  and  undergo  prompt  hydrolysis→the  
alcohol  porCon  of  the  molecule  is  then  released.  The  
acidic  porCon  (carbamate  ion  and  phosphate  ion)  is  
released  more  slowly,  and  this  retained  porCon  
prevents  the  binding  and  hydrolysis  of  endogenous  
acetylcholine,  thus  amplifying  acetylcholine  effects  
whenever  the  transmi;er  is  released.  
 INDIRECTLY-­‐ACTING  CHOLINERGIC  AGONIST  
ANTICHOLINESTERASE  (AchE)  
•  A.    Carbamates  
1.  PhysosCgmine  
§  Mechanism  of  AcCon:  
§  Forms  a  reversible  complex  at  the  site  of  
acetylcholinesterase  where  acetylcholine  is  
broken  down  
§  Both  muscarinic  and  nicoCnic  receptors  
§  PharmacokineCcs:  
§  Well-­‐absorbed  from  the  GIT,  subcutaneous  
Cssues  and  mucous  membrane  
§       duraCon  of  acCon-­‐  0.5-­‐  2    hours  
   
INDIRECTLY-­‐ACTING  CHOLINERGIC  AGONIST  
ANTICHOLINESTERASE  (AchE)  
§  Pharmacologic  Effects:      
§  mimics  the  pharmacologic  effects  of  acetylcholine  
§   enter  &  sCmulate  the  CNS  
§  Produces  miosis-­‐  can  antagonize  the  mydriasis  
induced  by  atropine-­‐  topical  use  
§  DuraCon  of  acCon-­‐  2-­‐4  hours  
§  In  large  doses-­‐  causes  fasciculaCon,  then  paralysis  
of  skeletal  muscle  because  of  the  accumulaCon  of  
acetylcholine  at  the  neuromuscular  juncCon  that  
results  when  acetylcholine  is  not  broken  down.  
INDIRECTLY-­‐ACTING  CHOLINERGIC  AGONIST  
ANTICHOLINESTERASE  (AchE)  
§  TherapeuCc  effects:  
§  Treatment  of  atropine,  phenothiazine,  and  tricyclic  
anCdepressant  intoxicaCon  
§  Treatment  of  glaucoma,  especially  simple  and  
secondary  glaucoma  
§  Treatment  of  early  stages  of  Alzheimer’s  disease  
because  of  degeneraCon  of  corCcal  cholinergic  
axons.  
§  Adverse  Effects  
§  convulsion  (high  dose),  bradycardia,  
§  paralysis  of  skeletal  muscle  (ACh  accumulaCon  at  
NMJ)  
 INDIRECTLY-­‐ACTING  CHOLINERGIC  AGONIST  
ANTICHOLINESTERASE  (AchE)  
•  2.    NeosCgmine  
§  SyntheCc  reversible  anCcholinesterase  that  contains  a  
quarternary  nitrogen  
§  Mechanism  of  AcCon:  
§  Moderately  polar  but  acCve  orally  
§  Does  not  penetrate  the  blood-­‐brain-­‐barrier-­‐  
minimizes  the  toxicity  due  to  inhibiCon  of  
acetylcholinesterase  
§  It    is  destroyed  by  plasma  esterases  and  is  
excreted  in  the  urine  
§  DuraCon  of  acCon    2-­‐  4    hours  
INDIRECTLY-­‐ACTING  CHOLINERGIC  AGONIST  
ANTICHOLINESTERASE  (AchE)  
§  Pharmacologic  Effects:      
§  mimics  the  pharmacologic  effects  of  acetylcholine  
§  It  has  a  direct  acCon  on  nicoCnic  receptors  in  
addiCon  to  blocking  acetylcholinesterase  
§  It  reverses  the  neuromuscular  blockade  produced  
by  curare  and  its  derivaCves;  the  mechanism  of  
acCon  involves  the  release  of  increased  amounts  of  
acetylcholine  from  nerve  endings,  cholinesterase  
inhibiCon,  and  a  direct  acCon  on  skeletal  muscle  
cholinergic  receptors.  
INDIRECTLY-­‐ACTING  CHOLINERGIC  AGONIST  
ANTICHOLINESTERASE  (AchE)  
§  TherapeuCc  Uses:  
§  Used  to  reverse    the  effects  of  compeCCve  blocking  
agents  
§  management  of  paralyCc  ileus  and  atony  of  the  urinary  
bladder  
§  SymptomaCc  treatment  of  myastenia  gravis  
 INDIRECTLY-­‐ACTING  CHOLINERGIC  AGONIST  
ANTICHOLINESTERASE  (AchE)  
•  3.    PyridosCgmine  
§  Used  in  the  chronic  management  of  myasthenia  gravis  
§  DuraCon  of  acCon  3-­‐6  hours  (longer  than  NeosCgmine)  
§  Adverse  effects  :  generalized  cholinergic  sCmulaCon  

§  Other  physosNgmine-­‐like  anNcholinesterase  

§  Ambenonium-­‐  used  in  the  symptomaCc  treatment  of  
myastenia  gravis  
§  Demecarium  is  used    as  an  ophthalmic  soluCon  for  the  
treatment  of  chronic  glaucoma  
INDIRECTLY-­‐ACTING  CHOLINERGIC  AGONIST  
ANTICHOLINESTERASE  (AchE)  
•  Edrophonium  (simple  alcohol)  
§  Reversible  anCcholinesterase  
§  PharmacokineCcs:  
§  More  rapidly  absorbed  and  has  a  shorter  duraCon  of  acCon  
than  neosCgmine  
§  Administered  parenterally  
§  DuraCon  of  acCon-­‐  5-­‐15  minutes  
§  Pharmacologic  Effects:  
§  Similar  to  neosCgmine  except  that  with  doses  it  can  
sCmulate  the  neuromuscular  juncCon  without  affecCng  
muscarinic  effector  organ  
§  TherapeuCc  Uses  
§  Diagnosis  of  myastenia  gravis  
§  Antagonism  of  curare-­‐like  agents  
INDIRECTLY-­‐ACTING  CHOLINERGIC  AGONIST  
ANTICHOLINESTERASE  (AchE)  
•  B.    Organophosphate  Cholinesterase  
Inhibitors  (Irreversible  AnNcholinesterase)  
§  1.  Diisopropyl  fluorophosphate  (DFP)  
§  Forms  a  covalent  bond  between  its  phosphorus  atom  
and  esteraCc  site  of  cholinesterase  
§  Limited  to  treatment  of  certain  types  of  glaucoma  
§  2.  Parathion  
§  Used  as  insecCcide  
§  AcCve  form  is  the  metabolite-­‐  Maraoxon  
§  Pharmacologic  effects  similar  to  DFP  
 INDIRECTLY-­‐ACTING  CHOLINERGIC  AGONIST  
ANTICHOLINESTERASE  (AchE)  
•  3.  Echothiophate  
§  Long-­‐acCng  organophosphate  cholinesterase  
inhibitor  with  pharmacologic  properCes  similar  to  
DFP  
§  Spontaneous  regeneraCon  of  phosphorylated  
enzyme  can  occur  
§  Major  use  is  in  the  treatment  of  glaucoma    
 INDIRECTLY-­‐ACTING  CHOLINERGIC  AGONIST  
ANTICHOLINESTERASE  (AchE)  
•  Adverse  effects  of  Organophosphate  
Cholinesterase  Inhibitors:  
ü Miosis  
ü Increased  bronchial    secreCon,  profuse  sweaCng  and  
increased  lacrimaCon  
ü Anorexia,  vomiCng,  and  involuntary  diarrhea  
ü Bradycardia  
ü Weakness  of  all  skeletal  muscle,  esp.  muscles  of  
respiraCon,  azer  twitching  and  fasciculaCons  
ü Anxiety,  confusion,  and  convulsions,  followed  by  
vasomotor  depression  
•  Reversal  of  cholinesterase  inhibiNon-­‐  Pyridine-­‐2-­‐
aldoxime  methyl  chloride  (PAM,  Pralidoxime)  
§  It  combines  with  and  splits  off  the  phosphorus  from  
the  esteraCc  site  on  cholinesterase  in  such  a  way  that  
the  enzyme  is  restored  
§  With  reacCvaCon  of  the  enzyme,    the  effects  of  
acetylcholine  begin  to  disappear  
§  Treatment  must  be  within  hours,  because  the  
phosphorated  enzyme  slowly  changes  to  a  form  that  
cannot  be  reversed.