Autonomics Parasympathetic

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  • Both the cholinergic and adrenergic drugs act either by stimulating or blocking neurons of the autonomic nervous system.
  • Cholinergic neurons = this are fibers that secretes acetylcholine The fibers that secrete Ach are said to be cholinergic
  • The fibers that secrete Ach are said to be cholinergic and those that secrete NE are said to be adrenergic All preganglionic neurons are cholinergic in both the SNS and PNS Almost all post ganglionic neurons of the PNS are also cholinergic
  • Neurotransmission at cholionergic neurons Neurotransmission in cholinergic neurons involves six steps.   Synthesis of Acetylcholine : Choline is transported from the extracellular fluid into the cytoplasm of the cholinergic neuron by a carrier system that cotransprot Na and can be inhibited by the drug Hemicholinium. Choline acetyltransferase catalyzes the reaction of choline with acetyl CoA to form acetylcholine in the cytosol.   Storage of Acetylcholine in Vesicles : The acetylcholine is packaged into vesicles by an active transport process coupled to the efflux of protons. Transporter can be blocked by Vesanicol.   Release of Acetylcholine : The release of the neurotransmitter is dependent of extracellular Ca and occurs when an action potential reaches the terminal and triggers sufficient influx of Ca ions. Ca ions destabilized the storage vesicle and release acetylcholine. This release is blocked by Botulinum toxin . Binding to Receptor: Acetylcholine released from the synaptic vesicles across the synaptic space and binds to the post synaptic receptors on the target cell or effector organ and the presynaptic receptor in the membrane of the neuron that released actylcholine. Binding to the receptor leads to a biological response within the cell.   Degradation of Acetylcholine: The signal at the postjunctional effector site is rapidly terminated. This occurs in the synaptic cleft where acetylcholinesterase cleaves acetylcholine to choline and acetate.     Recycling of Choline: Choline may be recaptured by a sodium coupled high affinity uptake system transport the molecule back into the neuron.  
  • Acetylcholine activates 2 type of receptors Nicotinic & Muscarinic receptors.
  • Neuronal nicotinic receptors are found in the synapses between preganglionic fiber & postganglionic fiber of both SNS & PNS. They are also found in the adrenal medulla. Muscular nicotinic receptor are found in the striated muscle supplied by the somatic nervous sysytem. Muscarinic receptors are found on all effector cells stimulated by the postganglionic neuron of the PNS
  • Comparing Ach with other choline esters with regard to :
  • Indirect Acting: Anticholinesterase Agents Produce their primary effect by inhibiting the action of Acetylcholinesterase which hydrolyzes acetylcholine to choline and acetic acid. It increases the concentration of endogenous acetylcholine in the synaptic clefts and neuroeffector junctions and in turns stimulates the cholinoreceptors. They are in effect amplifiers of endogenous acetylcholine and act primarily where acetylcholine is physiologically released.  
  • Produce their primary effect by inhibiting the action of Acetylcholinesterase which hydrolyzes acetylcholine to choline and acetic acid. It increases the concentration of endogenous acetylcholine in the synaptic clefts and neuroeffector junctions and in turns stimulates the cholinoreceptors. They are in effect amplifiers of endogenous acetylcholine and act primarily where acetylcholine is physiologically released.  
  • GIT – increase motility and GIT secretion, relax sphincters Urinary Bladder - contraction of detrusor muscle and relaxation of trigone and sphincter Eye - contraction of sphincter muscle of the iris (miosis). Contraction of ciliary muscles (near vision accommodation) Glands – stimulate secretion – sweat, salivary, lacrimal, nasopharyngeal
  • The antimuscarinic drugs. The prototype drug is atropine. Atropine acts by competing with acetylcholine for the muscarinic receptor by competitive surmountable inhibition. Hence, it is indirect acting . When it binds with the muscarinic receptor produces no action potential. Hence, it is paralyzing or blocking the parasympathetic. Since there is dual innervation for most organs, the sympathetic dominates. Therefore by indirect action, it becomes a sympathomimetic.  
  • When it binds the muscarinic receptor produces no action potential. Hence, it is paralyzing or blocking the parasympathetic. Since there is dual innervation for most organs, the sympathetic dominates. Therefore by indirect action, it becomes a sympathomimetic.
  • Smaller dose depress the secretion of the salivary, bronchial and sweat gland With larger dose the pupils are dilated, accomodation of the lens to near vision is inhibited, vagal effect of the heart is blocked so that heart rate is increased
  • Larger doses inhibit the parasympathetic control of the urinary bladder & GIT, thereby inhibiting micturition & decreasing the tone & motility of the gut Thus doses of atropine that reduce the tone of the GIT & depress gastric secretion also almost invariably affect salivary secretion, ocular accomodation & micturition Since the antagonism of atropine is competitive it can be overcome if the concentration of Ach at receptor sites of effector organ is increased sufficiently
  • Action Eye = mydriasis, unresponsiveness to light and cycloplegia (inability to focus to near vision) Secretions = inhibit secretion of the salivary , sweat and lacrimal glands GIT = decrease peristalsis and tone of musculature Increase tone of sphincter UT = decrease motility of urinary bladder

Transcript

  • 1. Autonomics Claro M. Isidro M.D.
  • 2. Parasympathetic Drugs
    • Drugs Affecting the ANS:
    • Cholinergic drugs – act on the receptor that is activated by acetylcholine
    • Adrenergic drugs – acts on the receptor that are stimulated by norepinephrine or epinephrine
  • 3. Cholinergic Neurons
    • Preganglionic fibers terminating in the adrenal medulla
    • Preganglionic fibers of both parasympathetic & sympathetic nervous system
    • Postganglionic fibers of the parasympathetic nervous system
    • Voluntary muscles of the somatic nervous system
  • 4.  
  • 5.  
  • 6.
    • Neurotransmission at Cholinergic neurons
    • Synthesis of acetylcholine
    • Storage of acetylcholine in vesicles
    • Release of acetylcholine
    • Binding to receptor
    • Degradation of acetylcholine
    • Recycling of choline
  • 7.
    • Cholinergic Receptors
    • Muscarinic :
    • M1 – nerves
    • M2 – heart, nerves, smooth
    • muscles
    • M3 – glands, smooth muscles
    • Endothelium
    • M4 - ? CNS
    • M5 - ? CNS
    • Nicotinic:
    • Nm – skeletal muscles
    • Neuromuscular junction
    • Nn – Preganglionic parasympathetic & sympathetic
  • 8.  
  • 9. Effector Organs Receptors Action Eye sphincter m. ciliary m. M3 M3 Contraction (meiosis) Contraction (accomodation) Heart SA node AV node Contractility M 2 M 2 M 2 ↓ Heart rate ↓ conduction velocity & ↑ refractory period ↓ contraction Lung bronchial m. M 3 contraction
  • 10. Effector Organs Receptor Action Blood Vessels most BV skeletal m. - - Small doses – vasodilatation Large doses – vasoconstriction GIT sphincter motility & tone M 3 M 3 Relaxation Increase GUT trigone & sphincter m. bladder wall & detrusor m. Penis, seminal v. M 3 M 3 M Relaxation Contraction Erection
  • 11. Effector Organs Receptor Action Secretory glands sweat intestinal bronchial lacrimal M M 3 M M Generalized secretion ↑ secretion ↑ secretion Profuse secretion
  • 12.
    • Cholinomimetics / Parasympathetic Agonist/Cholinergic Agonist
    • Drugs that have effects producing parasympathetic dominance
    • Direct-Acting Cholinoceptor Stimulants
      • A. Esters of Choline: Synthetic
      • 1. Acetylcholine 3. Carbachol
      • 2. Metacholine 4. Betanechol
      • B. Alkaloids: Naturally occurring
      • 1. Muscarinic
      • Muscarine, Pilocarpine, Oxotremorine
      • 2. Nicotinic
      • Nicotine, Lobeline,
      • Dimethylphenylpiperazinium (DMPP)
  • 13.
    • Direct-Acting (Choline Esters) :
    • Acetylcholine
      • quarternary ammonium compound
      • muscarinic & nicotinic receptors equally
      • Actions:
        • ↓ HR and CO, ↓ BP
        • ↑ salivary & intestinal secretion and GI motility
        • Enhances bronchiolar secretions
        • ↑ detrussor muscle tone
        • stim. Ciliary m. -> near vision
        • miosis
  • 14. Susceptibility to Cholinesterase Muscarinic Effects Nicotinic Effects Therapeutic Use Ach + +++ +++ Miotic Metacholine + ++++ + Dx of bronchial hyperactivity Carbachol - +++ ++ Miotic Betanechol - ++ - Non-obstructive urinary retention
  • 15.
    • Direct-Acting (Choline Esters):
    • Naturally-occurring:
    • Pilocarpine
      • tertiary amine
      • dominant muscarinic action
      • resistant to acetylcholinesterase
      • Use as topical eye drop. Produce rapid meiosis & contraction of ciliary muscle
      • Increase gastric acid secretion & bronchoconstiction
      • Potent stimulator of secretions (sweat, tears, saliva)
      • Therapeutic Use:
        • DOC in emergency lowering of IOP in glaucoma
      • Adverse Effects: CNS disturbances, profuse sweating and salivation
  • 16.
    • ARECOLINE
    • chief alkaloid of areca or betel nuts
    • muscarinic & nicotinic receptors
    • enhances salivary secretion
    • no therapeutic indication
    • MUSCARINE
    • quarternary amine
    • muscarinic receptors
    • found in mushrooms (Amanita muscaria)
    • small amounts  edible
    • large amounts  poisonous
    • effects: fall in BP, temporary cessation of heart beat, diaphoresis
    • antidote: ATROPINE
  • 17. Indirect-Acting : Anticholinesterase
    • REVERSIBLE (Anticholinesterases)
    • IRREVERSIBLE (Organophosphate)
  • 18. Anticholinesterase
    • AcetylCholine Choline + Acetic acid
    • Cholinesterase
    -
  • 19.
    • Indirect-Acting :
    • REVERSIBLE (Anticholinesterases):
        • Physostigmine
        • Neostigmine
        • Pyridostigmine
        • Ambenonium
        • Edrophonium
        • Tacrine, Donezepil, Rivastigmine, Galantamine
    • IRREVERSIBLE
      • 1. Organophosphates
        • Isoflurophate
        • Echothiophate
        • Malathion, Parathion
      • 2. Chemical Warfares
        • Sarin, Soman
  • 20.
    • PHYSOSTIGMINE
      • Alkaloid, tertiary ammmonium grp.
      • Enters the CNS
      • DOA: O.5 to 2 hrs.
      • Therapeutic Uses:
          • 1 . Atony of intestines and bladder
          • 2. Glaucoma  lowers IOP
          • 3. Antidote  atropine, phenothiazines, TCA
          • 4. NDMR (tubocurarine) reversal
      • Adverse effects: convulsions, bradycardia, CO
  • 21.
    • NEOSTIGMINE
      • Quarternary ammonium grp.
      • Does not enter the CNS  peripheral
      • DOA: 0.5 to 2 hrs
      • Therapeutic Uses:
          • Atony of intestines and bladder
          • Myasthenia gravis
          • NDMR (tubocurarine) antidote
      • Adverse effects: salivation, flushing, ↓ BP, nausea, abdominal pain, diarrhea, bronchospasm
  • 22.
    • PYRIDOSTIGMINE and AMBENONIUM
      • DOA: PYRIDOSTIGMINE - 3 to 6 hrs
      • AMBENONIUM – 4 to 8 hrs
      • Therapeutic Uses:
          • Myasthenia gravis
          • NDMR (tubocurarine) antidote
      • Adverse effects: salivation, flushing, ↓ BP, nausea, abdominal pain, diarrhea, bronchospasm
  • 23.
    • EDROPHONIUM
      • Quarternary amine
      • DOA: 5 to 15 mins
      • Therapeutic Uses:
          • Diagnosis of Myasthenia gravis
          • NDMR (tubocurarine) antidote
          • Arrhythmias (SVT)
      • Antidote: Atropine
      • Adverse effects: salivation, flushing, ↓ BP, nausea, abdominal pain, diarrhea, bronchospasm
  • 24.
    • Tacrine, Donezepil, Rivastigmine,
    • Galantamine
      • Alzheimer disease  deficiency of cholinergic neurons in the CNS
      • Tacrine – hepatotoxic
      • Adverse effect: GI distress
  • 25.
    • Indirect-Acting  IRREVERSIBLE :
      • ORGANOPHOSPHATES
        • ISOFLUROPHATE
          • tx of open angle glaucoma
        • ECHOTHIOPHATE
          • Produce intense miosis  tx of open angle glaucoma
        • PARATHION, MALATHION
          • Insecticides
  • 26.
    • ORGANOPHOSPHATE POISONING:
      • Signs & Symptoms
      • miosis
      • salivation, frothy secretions
      • sweating
      • bronchial constriction
      • vomiting and diarrhea
      • muscle fasciculation
  • 27.
    • ORGANOPHOSPHATE POISONING:
      • Therapy:
        • maintenance of VS  respiration
        • Decontamination
        • Drugs: Atropine + Pralidoxime
          • ATROPINE sulfate
          •  1 to 2 mg IV every 5-15 min until muscarinic effect disappears (maximum of 1 gm per day)
          • PRALIDOXIME
          •  A cholinesterase enzyme regenerator compound
          • - 1 to 2 gm given over 30 min by IV infusion
  • 28.  
  • 29.
    • Parasympathetic Antagonists/Cholinergic Antagonist (Parasympatholytics)
    • ANTIMUSCARINIC
      • Tertiary Amines:
        • Natural – atropine, scopolamine
        • Semisynthetic – tropine, homatropine
        • Synthetic – dicyclomine, oxybutyrine, oxyphencyclimine
      • Quarternary Amines:
        • Anisotropine
        • Propantheline
        • Methanteline
  • 30.  
  • 31.
    • ATROPINE
      • prototype
      • Belladona alkaloid
      • high affinity for muscarinic receptors
      • central and peripheral muscarinic blocker
      • causes reversible (surmountable) blockade of the actions of cholinomimetics at muscarinic receptors
      • Unopposed sympathetic action
  • 32.
    • ATROPINE
    • Actions:
    • 1. CNS
      • minimal stimulant effect
    • 2. Eye
      • mydriasis, unresponsiveness to light
      • cycloplegia  inability to focus for near-vision
    • 3. GIT
      • antispasmodic  reduce GIT activity
    • 4. GUT
      • reduce urinary bladder hypermotility
    • 5. SECRETIONS
      • blocks salivary glands  antisialogogue
      • decrease also lacrimal & sweat glands secretion
  • 33.
    • ATROPINE
    • 6. CVS
    • divergent effects depending on dose
    • Low dose – (-) M 1  ↑ Ach release
    • Higher dose – (-) M 2 on SA node  ↑ CR
  • 34.
    • Effects in relation to dose:
    Dose Effects 0.5 mg Slight cardiac slowing some dryness of mouth inhibition of sweating 1.0 mg Definite dryness of mouth; thirst acceleration of heart, sometimes preceded by slowing mild pupillodilatation
  • 35. Dose Effects 2.0 mg Rapid HR; palpitations marked dryness of mouth Dilated pupils; some blurring of vision 5.0 mg All of the above symptoms marked; difficulty in speaking and swallowing; Restlessness and fatigue; Headache; dry, hot skin Difficulty in micturition Reduced intestinal peristalsis
  • 36. Dose Effects 10.0 mg and more Above symptoms more marked Pulse rapid and weak Iris practically obliterated Vision very blurred Skin flushed, hot, dry, and scarlet Ataxia, restlessness and excitement Hallucinations and delirium Coma
  • 37.
    • ATROPINE
    • Therapeutic Uses:
    • 1. Ophthalmic
      • Permits measurement of EOR
    • 2. Antispasmodic
    • 3. Antidote for cholinergic agonists
      • Organophosphate poisoning
      • Mushroom poisoning
      • acetylcholinesterase inhibitors
    • 4. Antisecretory agent
  • 38.
    • SCOPOLAMINE
    • Belladona alkaloid
    • Peripheral effects similar to atropine
    • Greater and longer CNS action
    • Action:
      • Anti-motion sickness
      • Blocks short-term memory
      • Produces sedation,
      • excitement
  • 39.
    • Therapeutic Uses:
      • anti-motion sickness
      • adjunct in anesthesia procedures
      • > in obstetrics, + morphine  sedation
      • & amnesia
    • IPRATROPIUM
    • Quarternary derivative of atropine
    • Does not enter CNS
    • Therapeutic Uses:
      • Treat asthma in patients who are unable to take adrenergic agonists
      • Management of COPD
  • 40.
    • GANGLIONIC BLOCKERS
    • Specifically act on NICOTINIC receptors
    • No selectivity towards PNS or SNS
    • Blocks entire ANS output
  • 41.
    • GANGLIONIC BLOCKERS
    • NICOTINE
    • TRIMETHAPHAN
    • MECAMYLAMINE
    • HEXAMETHONIUM
  • 42.  
  • 43.
    • The End
  • 44.
    • Write A if cholinergic agonist
    • B if cholinergic antagonist
    • Bethanicol
    • Scopolamine
    • Isoflurophate
    • Trimethaphan
    • Arecoline
    • 6. Main neurotransmitter of PNS
    • Amino acid precursor of Ach
    • Drug of choice in emergency lowering of IOP
    • Antidote for organophosphate poisoning
    • Aids in the diagnosis of myasthenia gravis
  • 45. Short Quiz
    • 1. Describe the pharmacodynamic difference between direct and indirect acting cholinomimetics
    • 2. Describe the effects of acetylcholine on the major organs
    • 3. Describe the effects of atropine on the major organ system
    • 4. Clinical uses of atropine & scopolamine
  • 46.
    • A. NICOTINE
    • Low dose :
    •  ganglionic stimulation by depolarization
    •  CNS: euphoria, arousal, relaxation
    • improves attention, learning, problem solving & reaction time
    •  Peripheral: ↑ BP & HR, vasoconstriction
    • High dose  ganglionic blockade
    •  BP falls, blocks GIT & bladder activity