Introduction to the Autonomic Nervous System and Drugs by sammyc2007

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									Introduction to the Autonomic
  Nervous System and Drugs
affecting the Parasympathetic
       Nervous System

Brody’s Human Pharmacology
        Chapters 8 & 9
    Peripheral Nervous System

Somatic                   Autonomic

               Sympathetic     Parasympathetic

                adrenergic        cholinergic

               NE, EPI, Ach           Ach
 Anatomy of Autonomic Nervous
        System (ANS)
• Preganglionic neurons - cell bodies are within
  the CNS
• Postganglionic neurons - Originate at the
  ganglion and terminate in the innervated
• Sympathetic neurons - Originate from thoracic
  and lumbar spinal nerves
• Parasympathetic neurons - Originate from the
  cranial and sacral nerves
    Autonomic Nervous System
Two Opposing divisions
  – Sympathetic
     • Fight or flight

  – Parasympathetic
     • Rest and Digest

• Fig 8-1, p 90
 Sympathetic Nervous System
• Actions due to both direct stimulation
  and by stimulation of adrenal medulla
  – Increase heart rate and BP
  – Mobilize energy stores
  – Increase blood flow from skin and internal
    organs to skeletal muscles and heart
  – Dilation of pupils and bronchioles
• Adjusts body to stressful situations
  but does not play a major role in
  maintaining normal body function
  Parasympathetic System
• Rest and Digest - Maintains essential body

• Preganglionic neurons - cranial & sacral
  areas and are longer than the preganglionic
  fibers of the sympathetic system

• Necessary for life
  Chemical Signaling Between Cells
• Neurotransmitters -
   – Method used by neurons (nerve cells)
   – Each neuron is individual unit
   – Neurotransmitters are released at nerve terminals
   – Rapid system
• How does the nervous systems use of neurons
  compare to the endocrine systems use of
   – Hormones are released by endocrine cells into the
     blood stream
   – Broad effects on target cells
   – Slower system than neurotransmitters
Schematic Diagram of ANS
                    Acetylcholine (Ach)
                    Norepinephrine (NE)
                    Epinephrine (Epi)
                    Dopamine (D)

                    Nicotinic (N)
                    Adrenergic (a and B)
                    Muscarinic (M)

                   Note - Preganglionic
                   nerve length
                   Note - Neurotransmitter
  Cholinergic Neurotransmitter
• Acetylcholine

• Cholinergic receptors at preganglionic synapses of
  the parasympathetic and sympathetic systems,
  parasympathetic synapses, adrenal medulla and
  somatic junction

• Nicotinic receptors - preganglionic synapses - Not
  important pharmacologically

• Muscarinic receptors - postganglionic synapses of
  the parasympathetic system and in the sweat glands
  of the sympathetic system
   – Multiple subtypes however medications that bind
     to specific muscarinic receptors have not been
  Adrenergic Neurotransmitters
• Norepinephrine
  – Adrenergic receptors - Postganglionic sympathetic

• Epinephrine
  – Adrenergic receptors
• Dopamine
  – D1 Dopaminergic receptors - Activation will
    increase blood flow to the kidneys due to
    vasodilation of the renal vascular beds
Neurochemical Transmission
         Autonomic Receptors
• Multiple receptors types are involved with the autonomic
  nervous system. The major ones we will discuss in this
  class are:
   – Cholinoceptors (Cholinergic)
      • Muscarinic
      • Nicotinic
   – Adrenoceptors (Adrenergic)
      • Alpha
          – Alpha 1
          – Alpha 2 (Presynaptic receptor)
      • Beta
          – Beta 1
          – Beta 2
            Autonomic Reflexes
• Not all autonomic drugs will cause the exact effect
  expected because of autonomic reflexes (feedback loops)
• Homeostatic Response – compensatory response
  produced by the body to try and counteract a drug
  induced response
• Example – Norepinephrine when used as a drug is an
  adrenergic agonist with more alpha effects than beta
   – The direct beta effects should still cause an increase
     heart rate however, the heart rate goes down with a
     slow infusion. Why?
   – The alpha induced vasoconstriction raises the blood
     pressure. To compensate the body stimulates the
     parasympathetic system to reduce the heart rate.
     Organs Controlled by Multiple
            ANS pathways
• Eye - example of an organ system controlled by multiple
  pathways ANS
• Autonomic drugs are used in the eye in the treatment of
  glaucoma and for diagnostic purposes
 Muscles of the eye        Major receptor     Effect      Effect on
   – Iris
        • Radial muscle      alpha 1        Contraction   Mydriasis

       • Circular muscle    muscarinic      Contraction   Miosis
         Drug effects:
         Cholinergic                                      Miosis
         Anticholinergic                                  Mydriasis

   – Ciliary                muscarinic      Contraction
                            beta 2           Relaxation
     Drugs Affecting the ANS
• Sympathetic (NE)
  – Sympathomimetics
  – Adrenergic antagonists (beta/alpha

• Parasympathetic (Ach)
  – Cholinergic
  – Anticholinergic
     Autonomic Drugs used to treat
• Cholinergic agents – contract circular muscle which
  puts pressure on trabecular meshwork to increase
  aqueous humor outflow
   – Ocular Side effects:
   – Miosis
   – Accommodation
• Sympathomimetics – contract radial muscle which
  increase the outflow of aqueous humor
   – Ocular Side effects
      • Mydriasis
• Beta blockers – decreases the production of
  aqueous humor
   – Ocular Side effects - None
     Cholinergic Agonists (Ch 9)
• Act on receptors that are activated by acetylcholine

• Mechanism of Action
   – Direct Acting - resemble acetylcholine
   – Indirect Acting – Inhibit acetylcholinesterase
       • Reversible (competitive)
       • Irreversible (non-competitive)

• Receptor types
   – Muscarinic
   – Nicotinic

• Cholinergic receptors are located in multiple locations
  but these drugs are mainly used to stimulate the
  parasympathetic system
            Receptor Types

• Muscarinic receptors – found mainly on the
  effector cells of the parasympathetic

• Nicotinic receptors – stimulate nerve cells
  of the sympathetic, parasympathetic
  ganglia, and skeletal muscle
  neuromuscular junctions
  – No clinical value to artificial stimulation
  Other Cholinergic Receptors

• Central Nervous System
• Neuromuscular junction of the
  somatic nervous system
• Ach is a major neurotransmitter
  Effects of Cholinergic Drugs on Organ
• Eye - Pupil contracts (miosis), contraction of
  ciliary muscle for near vision

• Cardiovascular - decrease cardiac rate, force,
  usually reduces peripheral vascular resistance

• Respiratory - Contract bronchial smooth
  muscle and increase secretory activity

• GI - Increase peristalsis and relax sphincters,
  Increase secretory activity (salivary and
  gastric secretion glands)
Effects of Cholinergic Drugs (cont)
• Genitourinary- Contracts detrusor and relax

• Secretory glands – Stimulates sweat,
  lacrimal and nasopharyngeal glands

• SLUDE – salivation/sweating, lacrimation,
  urination, defecation, excretion
       Major Therapeutic Uses of
         Cholinergic Agonists
• Glaucoma
• GI and Urinary tract stimulation
• Neuromuscular Junction
   myasthenia gravis (Current Medical Diagnosis &
    Treatment 2007 – p. 1058)
   curare-induced neuromuscular paralysis (reverse)
• Anticholinergic Overdose
• Alzheimer’s Disease
         Direct Cholinergic Agonists
            Bethanechol (Urecholine®)

• Resistant to acetylcholinesterase
• MOA – stimulate cholinergic receptors causing
  contraction of bladder detrusor and sphincter
• Indication – Urinary retention after surgery or
• Adverse affects – sweating, salivation, flushing,
  decreased blood pressure, nausea, abdominal pain,
  diarrhea and bronchospasm
• Contraindications – Physical obstruction and asthma
• Oral tablets and injection for subcutaneous use
                  (Current page 161-163)

• A condition of increased intraocular pressure (IOP)

• 2% of individuals over 40 have glaucoma

• Open Angle Glaucoma – Aqueous humor outflow is
  constantly subnormal, Gradual and asymptomatic onset

• Angle-Closure Glaucoma – Results from closure of the
  anterior chamber angle causing severe pain and vision
  loss. No abnormal resistance to aqueous humor
  outflow , Medical emergency with acute onset
        Pilocarpine (Isopto Carpine®,
              Ocusert®) {BCF}
• MOA - Contraction of ciliary muscle attached to the
  trabecular meshwork to enhance aqueous humor outflow
• IOP decreases in 1 hour
• Adverse reactions – Miosis (reduced night vision),
  decreased far vision and brow aches
• Products
   – Ophthalmic: 0.25 – 10% drops, 4% ointment and
   – Oral pilocarpine (Salagen®) is used to treat xerostomia
     (dry mouth)
• Place in therapy – Historically an initial treatment of
  choice for glaucoma but has been replaced by newer
• Indicated for both angle-closure and open-angle
          Cholinesterase Inhibitors
• Indirect Cholinergic agents
• Acetylcholinesterase cleaves acetylcholine to
  acetate and choline both in the pre and post synaptic
• Inhibiting enzyme prolongs the duration of
  endogenous acetylcholine
• Agents divided into two categories
   – Reversible – Inhibitors that compete with cholinomimetic
     substrates for acetylcholinesterase binding sites
      • Most of the agents that have therapeutic applications
   – Irreversible – Inhibitors that permanently bind with
      • Most of these agents are used as Insecticides or nerve agents
  Physostigmine                    (Antilirium®)

• Mechanism of action - binds with
  acetylcholinesterase and prevents it from
  destroying acetylcholine – prolongs action of Ach

• Indications – Treatment for anticholinergic
  overdose (atropine, tricyclics and phenothiazines)

• Adverse reactions -
   – Can enter CNS and cause convulsions in high doses
   – Vomiting, salivation, and bradycardia from systemic use
   – Miosis and allergic irritation from ophthalmic use

• Injection
   Neostigmine (Prostigmin®)
• Mechanism of action – Anticholinesterase agent that
  does not enter CNS

• Clinical Indication – antidote for neuromuscular
  blockers, myasthenia gravis and GI and urinary tract

• Adverse reactions – salivation, flushing, decreased
  BP, diarrhea

• Available systemic injection
 Pyridostigmine (Mestinon®, NAPP)

• MOA: Reversible anticholinesterase

• Used for myasthenia gravis treatment more often
  than neostigmine due to its longer duration of action

• Fewer side effects than neostigmine in myasthenia

• Available as oral tablets & syrup; injection
       Nerve Agent Pre-treatment
        Pyridostigmine (NAPP)
• Mechanism of action - Protects
  acetylcholinesterase enzymes from irreversible
  anticholinesterases (nerve gas {soman}) by
  using a reversible anticholinesterase

• Approved by the FDA for this indication 2003

• Stocked by US forces starting in 1996 and used
  during the Gulf war
  Excerpt from DoD, Rand Study on Gulf
       War Health Issues, Oct 99
• After lengthy deliberation, permission to use the drug
  was granted by the FDA in 1990. … the Defense
  Department agreed to some special requirements,
  including special labeling, record keeping, and the
  provision of information "to medical and paramedical
  personnel, and to individual service members for ...
  products intended for self-administration." Actual
  implementation was inconsistent, record keeping
  inadequate, and information - prepared for distribution to
  the troops - not delivered.
• Learning point – Even though this drug is now approved
  (Feb 03) for nerve agent prophylaxis, if you are involved
  with investigational drugs – Document as required and
  inform your troops as required
     Edrophonium (Tensilon®)

• Clinical indication – diagnosis of
  myasthenia gravis

• More rapidly absorbed and shorter
  duration of action than neostigmine
   Irreversible Anticholinesterases
      (Cholinesterase Inhibitors)
• Toxins, Poisons, Nerve agents, Insecticides

• Permanently inactivates acetylcholinesterase
  enzymes requiring the synthesis of new enzyme

• Antidote = Pralidoxime / 2 PAM Chloride (Protopam)
  will reactivate cholinesterase if used before aging (the
  loss of an isopropyl group from the enzyme)
   – most reactivation occurs at neuromuscular
     junction (prolonged use results in paralysis)
   – Atropine (an anticholinergic agent) in conjunction
     with Pralidoxime for muscarinic effects
     (bronchoconstriction,vomiting, bradycardia,
     miosis, incontinence)
 Echothiophate (Phospholine®)
• Irreversible anticholinesterase used to
  treat glaucoma

• Echothiophate is only irreversible
  anticholinesterase agent used
  medically on a regular basis

• Side effects are similar to pilocarpine
              Other Agents
• Use in Alzheimer’s – not ANS drugs;
  cholinesterase inhibitors that work on the
  CNS to treat mild to moderate Alzheimer’s

• Mechanism of action – Increase cerebral
  concentrations of acetylcholine by inhibiting

•   Tacrine (Cognex®)- First agent approved
•   Donepezil (Aricept®)
•   Galantamine (Reminyl®)
•   Rivastigmine (Exelon®)
          General Toxic Effects
• Direct acting cholinergic agonists
   – Muscarinic symptoms - Vasodilation (flushing),
     sweating, bradycardia, bronchoconstriction, GI
     distress, belching, nausea and vomiting, diarrhea,
   – Nicotinic symptoms – All the above and
     convulsions, coma, respiratory arrest,
     hypertension and cardiac arrhythmias

• Anticholinesterase Agents (Organophosphates)
   – Signs of acute intoxication
      • Same as the symptoms above but miosis
        (reduction in pupil size) also occurs as well
   Cholinergic Antagonists (Ch 9)

• May be referred to as cholinergic blockers,
  cholinoceptor-blocking drugs, anticholinergic
  drugs, antimuscarinic

• Interrupts parasympathetic signals

• Antinicotinic
  – Ganglionic Blockers, little therapeutic use
  – Neuromuscular Blockers, used as muscle
     Antimuscarinic Agents

• Block muscarinic receptors on the effector
  organs parasympathetic nervous system and
  on sweat glands (exception from sympathetic

• Specificity for muscarinic receptors is key
  reason behind their usefulness because they
  have little effect at skeletal neuromuscular
  junction or autonomic ganglia
                Atropine Sulfate
• General Pharmacological Effects - A belladonna
  alkaloid competitively blocks muscarinic receptors
  from acetylcholine - ability to cross the CNS

• Indications
   – Eye - Diagnostic use only - Causes mydriasis (pupil dilation)
     and cycloplegia (inability to focus). Increases intraocular
     pressure in patients with glaucoma
   – GI - Antispasmodic agent for GI tract and bladder - Reduces
     motility and slightly reduces hydrochloric acid secretion.
   – Antidote for cholinergic agonists - organophosphate
   – Cardiovascular applications

• Adverse Reactions - (autonomic)- dry mouth, blurred
  vision, dry eyes, tachycardia, and constipation; (CNS)
  - restlessness, confusion, and hallucinations
      Belladonna Alkaloid
Belladonna alkaloid means the drug is
 derived form the deadly nightshade
 plant (Atropa belladonna)
Atropine Cardiovascular Effects
• Atropine is used in ACLS protocols
   – In Pulseless Electrical Activity and Asystole it is
     used after Epinephrine
   – Bradycardia – First drug used for symptomatic
     sinus bradycardia

• Improves sinus node and atrioventricular node
  conduction by inhibiting vagal activity

• Cardiovascular effects vary depending on dose
   – both tachycardia and bradycardia (low dose) are possible.
   – At normal doses it blocks vagal slowing resulting in
  Anticholinergic Contraindications
• Contraindications - Narrow angle glaucoma,
  Tachycardia, GI or GU Obstructive disease,
  Myasthenia gravis, Asthma (Atropine only)

• Myasthenia gravis - Anticholinergics contraindicated
  however (Atropine and propantheline) may be used
  in conjunction with Anticholinesterase medications
  to reduce GI side effects

• Atropine in asthma - Systemic absorption and CNS
  penetration results in side effects and toxicity
       Anticholinergic warnings
• Heat prostration - due to decreased
  thermoregulatory sweating

• Chronic diarrhea - Do not use chronic
  diarrhea - temporarily control diarrhea but
  may contribute to an intestinal obstruction

• Gastric ulcer - These will delay gastric
  emptying time
• Belladonna alkaloid with similar peripheral effects
  and greater CNS effects compared to atropine
• Indications
   – Motion Sickness - topical patch used to treat
     motion sickness (vertigo). One patch lasts for 3
   – Surgery; block short-term memory, reduce the
     flow of saliva (antisialagogue). Atropine also
     used for this purpose but does not cause the
     amnesia effect
• Adverse Reactions - Similar to atropine: drowsiness
  (17%), dry mouth (67%), blurred vision, pupil dilation.
  Wash hands after handling patch.
   Belladonna Alkaloids (Donnatal®)
• Indication – GI Antispasmodic
   – Only treats the symptoms not underlying problem
• Composed of atropine, scopolamine and hyoscyamine
  (another anticholinergic belladonna alkaloid)
   – In addition each preparation contains phenobarbital
      • 16.2mg per tablet and 5ml of elixir
• Causes drowsiness and anticholinergic side effects
  (dry mouth, urinary retention, constipation, and
  increased sensitivity to light)
• Preparations
   – Donnatal tablets and Donnatal Extentabs
   – Donnatal elixir – The elixir also contains 23%
    Dicyclomine (Bentyl®) {BCF}
• Another anticholinergic/ GI antispasmodic

• Indication - Treatment of dysfunctional
  bowel/irritable bowel syndrome.

• Dosage forms - Oral and injection. Oral dosing
  requires qid dosing and adverse effects may prevent
  effective dosing

• Contraindicated in infants less than six months old -
  deaths have occurred due to aspiration
   Oxybutynin (Ditropan®) {BCF}
• Anticholinergic that exerts direct antispasmodic effect
  on smooth muscle.
   – 1/5 the anticholinergic activity of atropine but 4-10 times the
     antispasmodic activity.

• Indication - Bladder instability and overactive bladder

• Agent most commonly used to produce
  anticholinergic effect in lower urinary tract, improves
  bladder capacity and voiding dysfunction

• Now available in a patch
      Tolterodine (Detrol®) {BCF}
• Anticholinergic indicated for overactive bladder

• Tolterodine and oxybutynin are equivalent in efficacy
  but tolterodine is reported to be better tolerated

• Currently, due to cost factors, reserve medication for
  patients who have failed or are intolerant to

• Trospium (Sanctura®) approved May 04
• Solifenacin (Vesicare®) approved Nov 04
• Darifenacin (Enablex®) approved Dec 04
     Ipratropium (Atrovent®) {BCF}
• Indication – Bronchospasm associated with COPD;

• Available as an inhaler, solution for nebulization, and
  nasal spray (for rhinorrhea)

• Bronchodilation - Effects localized predominantly in the
  lungs (minimal systemic absorption) - bronchodilation
  caused by inhibiting cyclic guanosine monophosphate
  in the lungs

• Has anti-secretory properties
   – Not an important clinical feature in COPD
   – Important in the nasal spray version used for perennial rhinitis
          Tiotropium (Spiriva®)
• Indication – Bronchospasm associated with COPD

• Available as a dry powdered inhaler

• Same MOA as ipratropium but dosed one puff daily

• Slowly (over 24 hours) dissociates from M1 and M3
  receptors (almost like non-competitive inhibition)
  Anticholinergics in Parkinson’s
• Several anticholinergics used to treat Parkinsonism
  – purpose is to lower the amount of acetylcholine in
  the CNS in an attempt to keep it in balance with
   – Benztropine, Trihexyphenidyl

• What pharmacokinetic trait would be important for
  an anticholinergic drug to be effective for this
             Ganglionic Blockers

• No selectivity - block receptors on both the
  parasympathetic and sympathetic ganglia

• Rarely used therapeutically

• Nicotine can act as a ganglionic blocker at high doses
   – Low doses – ganglionic stimulation causing
     euphoria and arousal. It also causes relaxation, and
     improves attention
   – High doses – ganglionic blockade (depolarization
     blockade) causing respiratory paralysis and
Neuromuscular Blocking Drugs

• Nicotinic receptors on the neuromuscular skeletal
  muscle junctions
   – Antagonists (nondepolarizing)
   – Agonists (depolarizing)

• Indication – Surgery to produce complete muscle
         Nondepolarizing blockers
• Tubocurarine - Developed from Curare - used to by
  Amazon hunters to paralyze game.
• Competitive blocker - action reversed by increasing
  concentration of acetylcholine with cholinesterase
  inhibitors (neostigmine, edrophonium and

  – Low dose - Combine with receptor and prevent
    ACh binding. Overcome by increasing
    concentration of acetylcholine (ie. Physostigmine)
  – High doses- the ability of acetylcholine reversal is
    reduced due to the blockage of the end plates

• Nondepolarizing agents - pancuronium and
           Depolarizing Agents
• Attaches to nicotinic receptor and depolarizes the
  junction but remains on the receptor for a “long”

• Succinylcholine – duration of action is short

• Indication - Rapid Intubation

• Adverse Effects – Malignant hyperthermia
Cholinergic agents
  – Direct (act like ACh)
    • Bethanechol (urinary retention)
    • Pilocarpine (glaucoma)
  – Indirect (take out AChe)
    • Reversible – Physostigmine, Neostigmine,
      Pyridostigmine, Edrophonium
       – Diagnosis/tx of MG; reversal of NMBs; anticholinergic
    • Irreversible – Nerve agents, Echothiophate

Anti-cholinergic agents
  – Competitive antagonists (with ACh) –
    •   Atropine (many uses)
    •   Scopolamine (Pre-op, motion sickness)
    •   Homatropine (diagnostic dilation)
    •   Donnatal, Dicyclomine (GI)
    •   Oxybutynin, Tolterodine, (GU)
    •   Ipratropium, Tiotropium (COPD)
• Somatic agents
  – Depolarizing agent (agonizes
    receptor) – Succinylcholine
  – Non-depolarizing agents (blocks
    • - oniums
    • Vecuronium, pancuronium

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