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Lecture 1 Introduction to Pharmacology (PowerPoint)

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									INDIRECT-ACTING
CHOLINOMIMETICS
(ANTICHOLINESTERASE)

 Pharmacology I
 Lecture 3
 Dr. Hiwa K. Saaed HD, MSc. PhD
 Department of Pharmacology & Toxicology
    Basic Pharmacology of the Indirect-Acting
    Cholinomimetics
2



    Q. How do they work?
     By inhibiting ChE, protect Ach from hydrolysis.



       Their pharmacodynamic properties are almost
        identical.
       The chief differences between members of the group
        are chemical and pharmacokinetic.
    Chemistry

(1) Simple alcohols bearing a quaternary ammonium group,
  eg, edrophonium
(2) Carbamic acid esters of alcohols bearing
 Quaternary ammonium groups (eg, neostigmine)

 Tertiary ammonium groups (eg, physostigmine).

(3) Organic derivatives of phosphoric acid
  (organophosphates, eg, echothiophate).



                                     Physostigma 3venenosum
        Irreversible cholinesterase inhibitors
4




     Irreversible: Only the organophosphate inhibitors,
     because they bind covalently to ChE, and can
      permanently inactivate the enzyme.
     The effects of organophosphates can last as long
      as a week, which is approximately the time,
      needed to synthesize a new molecule of ChE.
Cholinesterase inhibitors

Reversible              Irreversible bind covalently to ChE.


Carbamates    Acridine organophosphates
Physostigmine tacrine   Dyflos  (DFP) , Echothiophate Drug
Neostigmine             Parathion, Malathion (insecticide)
Pyridostigmine          Diazinon, Tabun, sarin, soman (nerve
Edrophonium             gases for chemical warfare)
Rivastigmie
Donepezil

                                                     5
    Q. Is it at all possible to reverse the
      effects of organophosphates?
6



    In most cases, no.
     however, if Pralidoxime (a
      cholinesterase reactivator) is
      given before a process called
      aging;
     Aging: the organophosphate binds

      to ChE and loses one of its alkyl
      groups, then it may be possible to
      remove the organophosphate from
      ChE.
    Absorption, Distribution, and Metabolism of
7




Synthetic quaternary ammonium agents Edrophonium,
  Neostigmine, Pyridostigmine:
  Absorption from the conjunctiva, skin, and
  lungs is predictably poor.
 Distribution into the CNS is negligible.
    Absorption, Distribution, and Metabolism of
8


    Naturally occurring tertiary amine:
     Physostigmine (lipid soluble):

     is well absorbed from all sites and can be used

      topically in the eye.
     It is distributed into the CNS and is more toxic than
      the more polar quaternary carbamates.
Absorption, Distribution, and Metabolism of
9




     The organophosphate cholinesterase
      inhibitors
     All are well absorbed from the skin,

      lung, gut, and conjunctiva except for
      echothiophate;
     Therefore, dangerous to humans and

      highly effective as insecticides.
     Absorption, Distribution, and Metabolism of
10




     The thiohosphate insecticides (parathion, malathion, and
      related compounds)
     are quite lipid-soluble and are rapidly absorbed by all
      routes.
     They must be activated in the body by conversion to the
      oxygen analogs,
     a process that occurs rapidly in both insects and
      vertebrates.
      Malathion
11


    Malathion and a few other organophosphate insecticides
     are also rapidly metabolized by other pathways to inactive
     products in birds and mammals but not in insects;
    these agents are therefore considered safe enough for sale
     to the general public.
    Unfortunately, fish cannot detoxify malathion,
     Parathion
12



        Parathion is not detoxified effectively in vertebrates;
        thus, it is considerably more dangerous than
         malathion to humans and livestock and is not
         available for general public use.
     Actions of AChE Inhibitors
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1.   CNS:
•    Low doses: CNS activation
•    High: coma and respiratory arrest

2.   Eye, respiratory tract, GI & urinary tract: The
     same as muscarinic agonists
         Actions of AchEI
    14


3.       Cardiovascular:
•        Heart: Bradycardia, decrease contraction, COP
•        Blood vessels? No effect

4.       Neuromuscular junction:
•        low dose Increase force of contraction
•        high dose Muscle fasciculations and depolarizing
         blockade
 The major therapeutic uses of the cholinomimetics:
15


1.   Eye:
    glaucoma,
    accommodative esotropia
2.   Gastrointestinal & Urinary tracts:
    postoperative atony,
    neurogenic bladder
3.   Neuromuscular junction:
    myasthenia gravis,
    curare-induced neuromuscular paralysis
     Myasthenia gravis
16


        Cholinesterase inhibitors—but not direct-acting
         acetylcholine receptor agonists—are extremely
         valuable as therapy for myasthenia.
     Drugs Used in Myasthenia Gravis
17



 Drug                Duration of Action
 Diagnosis:
     Edrophonium     I.V (improvement)    5-15 min

 Treatment:
     Neostigmine (do not cross BBB)       0.5-2 hours
     Pyridostigmine                       3-6 hours
     Ambenonium                           4-8 hours
          Treatment of AChE Poisoning
18



     Adverse effects:
       Excessive cholinergic stimulation

     1.    Atropine: Reverses muscarinic but not nicotinic
     2.    Pralidoxime (2-PAM):

								
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