Cholinoceptor blocking drugs (PowerPoint) by mikeholy


									Clinical importance of anticholinesterases
  Ophthalmologic   applications
  Diagnosis and treatment of myasthenia
  Treatment of atropine and curare type
  Some chemicals (from agricultural or
   military sources) are themselves
   significant sources of poisoning.
Physostigmine (Eserine, Antilirium)

    Non-quaternary, well absorbed   and
     distributed to CNS and other tissues.
    Pharmacological effects result from the
     increase in concentration of acetylcholine
     at muscarinic and nicotinic sites following
     inhibition of cholinesterases.
  CNS:           restlessness, convulsions
  eye:           miosis, accommodation
  bronchioles:   constriction, increased secretions
  glands:        increased lacrimation, salivation,
  GIT:           increased tone and motility
  bladder:       increased tone,
  CV:            effect variable, low doses decrease
                   HR; higher could increase HR and BP.
    NMJ:         fasciculations and tremor; paralysis

   Clinical uses reserved for reversal of serious
    atropine or scopolamine type poisoning where
    CNS is involved.
   Not routinely used for overdose of drugs with
    anticholinergic side effects (e.g., may
    exacerbate arrhythmia in tricyclic
    antidepressant overdose)
   Toxicity is predictable based upon ANS effects.
    CNS stimulation and coma often result.
Edrophonium (Tensilon, Reversol)
   Brief duration of action, rapid onset
   Uses
     –   Diagnostic aid for myasthenia gravis (not primary
         diagnostic, but useful for distinguishing MG from other
         neurological disorders)
     –   Differentiation of myasthenia crisis from cholinergic crisis
         during therapy for MG
     –   Antidote for non-depolarizing neuromuscular blockers
     –   Treatment for paroxysmal atrial tachycardia (PAT)

   Toxicities limited because of brief action
Irreversible Cholinesterase Inhibitors
     Highly lipid soluble (except echothiopate)
   Bind covalently to and inhibit cholinesterases
   Have muscarinic and nicotinic actions
   Readily penetrate the CNS

     Absorbed by all routes
     Hydrolyzed slowly in the body by
Organophosphates: Clinical relevance
     Treatment of open angle glaucoma
       –   Echothiopate and isoflurophate (DFP) are used but not preferred
           because of potential for development of cataracts and other
     Insecticides (malathion; parathion)
       –   In insects, parathion is converted to paraoxon; malathion to
       –   Mammals can preferentially oxidize these chemicals to less
           toxic compounds. Parathion and malathion are only
           preferentially toxic to insects.
     Nerve gas (soman, tabun, sarin)
       –   Developed for volatility, rapid absorption and “aging”
Organophosphates: Toxicity

    Muscarinic, nicotinic and CNS manifestations:
     Muscarinic             Nicotinic                CNS
     Bronchoconstriction    Muscular fasciculation   Restlessness
     Bronchial secretion    Tachycardia              Insomnia
     Sweating               Hypertension             Tremors
     Salivation                                      Confusion
     Lacrimation                                     Ataxia
     Bradycardia                                     Convulsions
     Hypotension                                     respiratory
     Miosis                                          circulatory
     Blurring of vision
     Urinary incontinence
Organophosphates: Toxicity
    Limited reversibility if treated rapidly
    Enzyme/drug bond becomes increasingly
     irreversible with time. “Aging” is related to loss of
     alkoxy groups which result in more stable bonds.
    Aging rate varies with compounds
    Treatment [Atropine; pralidoxime (2-PAM)]:
      –   support respiration
      –   large doses of atropine
      –   cholinesterase reactivator pralidoxime
Cholinergic Receptor Antagonists
Cholinoceptor blocking drugs: Overview
  Definition   and classification
   – Alkaloids
   – Quaternary and non-quaternary synthetics

  Sitesof action
  Prototypes: atropine; scopolamine
  Therapeutic uses
  Toxicity
  Contraindications
Cholinergic Receptor Antagonists
Cholinoceptor blocking drugs

   Drugs which occupy muscarinic receptors
   and prevent the muscarinic actions of
   endogenous acetylcholine or other
   muscarinic agonists.

   Often referred to as anticholinergics or
                     Anticholinergic drugs

          Antimuscarinic               Antinicotinic

M 1- selective   Nonselective   Ganglion      Neuromuscular
                                blockers      blockers
Naturally occurring compounds
  (Belladonna alkaloids)

  plant                    drug
  Atropa belladonna        atropine
  Dautura stramonium       atropine
  Hyosacyamus niger        scopolamine
Synthetic/semisynthetic compounds

 Quaternary   compounds:
  Ipratropium (Atrovent)
  Propantheline (Pro-Banthine)
Synthetic/semisynthetic compounds
  Non-quaternary compounds

  Dicyclomine (generic, Bentyl)

  Homatropine (Isopto Homatropine)

  Tropicamide (Nydriacyl)
Prototypes: Atropine & scopolamine
  The  actions of these drugs upon
   peripheral tissue/organ activity are
   similar to that which would occur
   following reduction of activity in
   postganglionic, parasympathetic and
   postganglionic cholinergic
   sympathetic nerves.
  Both drugs also block CNS
   muscarinic receptors
Pharmacokinetics of atropine and other tertiary amines

Atropine is relatively lipid soluble and readily crosses membrane
barriers. The drug is well distributed into the CNS and other organs
and is eliminated partially by metabolism in the liver and partially
by renal excretion. The elimination half-life is approximately
2 hours, and the duration of action of normal doses is 4-8 hours
except in the eye, where effects last for 72 hours or longer.

Other tertiary amines are able to enter the eye after conjunctival
administration. Similar ability to cross lipid bariers is important
for the agents used in parkinsonism.
Cardiovascular system effects
   Heart:   low dose    bradycardia
             high dose   tachycardia

   Vascular
    – no (direct) effect
    – except, dilate cutaneous vessels (red as a
    – block hypotensive effect of muscarinic
Extravascular smooth muscle
   Eye:
    –   mydriasis         (dilation of iris sphincter)
    –   cycloplegia       (relaxation of ciliary muscle)
   Bronchial:        dilation
   GIT:              decreased tone, motility
                      (antispasmodic effect)
   Urinary:          relaxation of detrusor, ureter;
                      constriction of sphincter
   Glands            decrease in all secretions
Eye Fluid Production and Pressure
                        Anterior chamber angle
                                 Trabecular meshwork
                                     Schlemm’s canal
Pupil                                        Posterior chamber

                                                       Ciliary body
    Lens                                                      (in)


                                         Cassel, Billig, Randall Fig 8-2
Types of Glaucoma

Open-Angle Glaucoma                           Closed-Angle Glaucoma
  Blocked drainage of aqueous                      Blocked drainage of aqueous
            Anterior chamber open                             Anterior Chamber
                 Blockage at trabecular                       angle closure

          Cassel, Billig, Randall   Fig 8-4         Cassel, Billig, Randall   Fig 8-3
Central nervous system
 Slowing of  heart after therapeutic doses (??)
 Action at respiratory center
  – therapeutic dose:        faster deeper breathing
  – larger doses:            depression of respiration
 Cerebral centers:
  – low doses:          sedation
  – high doses:         restlessness, amnesia, delirium
  – higher doses:       stupor; coma
      with therapeutic doses, atropine
 Note:
 generally has less CNS sedative effects
Tissue organ specificity of antimuscarinics
    Order of appearance of physiological
     effects with increasing dosage:

      Salivary, bronchial, sweat secretions
      Micturition
        Tachycardia, mydriasis, cycloplegia
      Intestinal motility
      Gastric secretion
Quaternary vs Non-quaternary antimuscarinics

    Absorption. Quaternary compounds are
    less well absorbed and lack CNS actions

             actions. Quaternary compounds
    Nicotinic
    can block nicotinic receptors and may
    have ganglion or neuromuscular blocking
Therapeutic uses of antimuscarinics
  Anesthesiology     (partly historical)
   – Prevention   of bronchial and salivary
   – Prevent bronchospasm
   – Reversal of reflex bradycardia or
     hypotension during surgery
   – Drugs:     Belladonna alkaloids, some
Therapeutic uses of antimuscarinics

 Respiratory   disorders:
  – Ipratropium (Atrovent). Inhalational drug
    to reverse bronchial constriction and
  – Asthma, emphysema, chronic bronchitis (
Therapeutic uses of antimuscarinics
 Ophthalmology
  – production  of mydriasis and cycloplegia
    of long or short duration
  – choice of agent depends upon
  – routine examination: short duration;
    minimal cycloplegia.
  – many appear in combinations with alpha
    adrenergic drugs
Mydriatic antimuscarinics
Therapeutic uses of antimuscarinics
 Gastroenterology: Peptic ulcer treatment.
  – Can reduce basal and nocturnal acid secretion
    (other drugs are better, e.g., H2 antagonists)
  – Inhibit gastrointestinal motility
  – Reduce pain and prolong actions of antacids
  – Drugs:
    atropine, dicyclomine, propantheline
Therapeutic uses of antimuscarinics
 Gastroenterology: Irritable bowel syndrome
  – Reduce  motility for reduction of pain,
    constipation, or diarrhea
  – Drugs:
    atropine, dicyclomine, propantheline
Therapeutic uses of antimuscarinics
 Urologic   disorders
  – Detrusor hyperreflexia, enuresis
  – Increase bladdercapacity
  – Decrease bladder pressure
  – Drugs: dicyclomine, oxybutynin
Therapeutic uses of antimuscarinics
 Motion     sickness
  –   Scopolamine is useful in prophylactic
      treatment via CNS action in vestibular
      nuclei and reticular formation
 Muscarine poisoning
  – poisoning with muscarinic mushrooms
    (Inocybe) or cholinesterase inhibitors
  – Drugs: Belladonna alkaloids or synthetics
Sources of Belladonna Poisoning:

  Nonprescription   drugs
   Plantsof the Solanaceae family
   Antiparkinsonian drugs
Classic symptoms of belladonna poisoning:
             Hot   as a hare
             Dry   as a bone
             Red   as a beet
             Blind   as a bat
             Mad as   a hatter
             Bloated   as a toad
Contraindications for Antimuscarinics

    Glaucoma

    Prostatic hypertrophy
    Toxicity more severe in children
    Urinary retention    hyperthermia
    Mydriasis            headache
    Blurred vision       Dizziness
    Flushing, dry skin   Excitement
    Heart palpitation    Mental confusion,
                         memory loss,
Drugs with anticholinergic side-effects
   Antihistamines

   Monoamine oxidase   inhibitors
   Antipsychotics

   Lithium

   Tricyclic Antidepressants

   Antiparkinsonian drugs

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