Jim Middleton, Pharmacist, DEHY34, Kellogg Community College, Battle Creek, Michigan
Again, just that boring text, no purty pitchers

 At the completion of this section, the participant should be able to:
 1. Differentiate between the terms "autonomic" and "somatic"
 2. Identify the types of autonomic nerve fibers
 3. Present alternative terms for "Adrenergic" and "Cholinergic"
 4. Identify the primary location for alpha (?) and beta (?) receptors, and further divide the beta receptor sites into the beta-1 and beta-2 variety by location
 5. Identify the neurotransmitters for the "Adrenergic" and "Cholinergic" nervous systems
 6. Define the terms "chronotropic" and "inotropic"

I. Anatomy review and some more terms
  1. nerves serving glands, smooth muscle, cardiac muscle--  autonomic,  involuntary,  "vegetative" nervous system
    --this autonomic portion is an efferent system with only outgoing inpulses
    --also, this system utilizes intermediary structures called ganglia that have a secondary nerve lead to the effector organ or structure
    --therefore, the nerve going to the ganglia is called the preganglionic fiber; the one leading away is called the postganglionic fiber
    --in this ganglia the two nerve fibers link at a space called a synapse
    --it is at this synapse where we will discover the "neurohormonal transmitters"   --contrast this with the somatic portion that also has afferent (incoming) inpulses
    --the somatic portion also leads directly to its effector site, the skeletal muscle-- sensations of  pain, pressure, heat

 B. Concentrating on the AUTONOMIC nervous system
 WE ARE GOING TO FURTHER SUBDIVIDE the Autonomic Nervous System

 parasympathetic and sympathetic

  1. those leaving the brain stem and the sacral portion of the spinal cord are parasympathetic
  2. those leaving the spinal cord between those two areas are sympathetic

      cholinergic                                adrenergic
      the body at ease                       “fight or flight”
      mediator:                                  mediator:
        acetylcholine                                     adrenalin/epinephrine

                                     the "mediator" listed above refers to that  magic neurotransmitter at the synapse

II. Neurohormonal transmitters--chemical mediators
 A. Parasympathetic system: acetylcholine
      --the parasympathetic system is also known as the cholinergic system
      --drugs that imitate acetylcholine are known as parasympathomimetic or cholinergic drugs
      --drugs that block or inhibit acetylcholine are known as parasympatholytic or anticholinergic drugs

  1. two types of receptors in the parasympathetic system
       a. muscarinic
       b. nicotinic

 B. Sympathetic system:  epinephrine or "adrenalin"
      --the sympathetic system is also known as the adrenergic system
      --drugs that imitate epinephrine are known as sympathomimetic or adrenergic drugs
      --drugs that block or inhibit epinephrine are known as sympatholytic or antiadrenergic drugs

  1. sympathetic/adrenergic system receptors
           TWO TYPES: alpha and beta
           --located in effector tissues (sites of action) activated by the sympathetic system
           --one type (either alpha or beta) tends to predominate
               a. alpha
                      tend to be excitatory
               b. beta
                      tend to be inhibitory

(Note: be sure not confuse the beta receptors of the adrenergic system with the beta cells that are present in the Isle of Langerhans in the pancreas.)

 --beta receptors further divided into two subclasses:
               i. beta-1 :  primarily in the heart
               ii. beta-2 : in the lungs and in other tissue

  2. Tissue effects, drug effects of beta receptors
   a. in blood vessels
               --both alpha and beta are present
               --alpha predominates
            i. alpha: contraction of smooth muscle vasoconstriction
            ii. beta: inhibits contraction, causing vasodilation

Consideration time: which receptor would you wish to stimulate to lower blood pressure?  Which one would you stimulate to raise blood pressure?

          b. in the heart
             i. beta stimulation results in a    POSITIVE CHONOTROPIC ACTION and  POSITIVE INOTROPIC ACTION

Definition time: Chronotropic means– rate of contraction
Inotropic means – force of contraction
A positive effect on these two actions would mean: increase rate of contraction (positive chronotropic) and increase force of contraction (positive inotropic)

A negative effect on these two actions would mean: decrease in rate of contraction (negative chronotropic) and decrease in force of contraction (negative inotropic)

           c. in the lungs
              i. beta stimulation--BRONCHODILATION--consider the effects of beta blockade with asthmatics
                (beta blockade would allow the alpha receptors to take priority)
                Why is this important?

1. Definitions: You should know the difference between parasympathetic and sympathetic, you should know their other names as well.
2. You should know where you will primarily find beta-1 and beta-2 receptors.
3. You should know the meaning of chronotropic and inotropic.
4. You should know the effect of beta stimulation and inhibition on the lungs and heart.
5. You should know the effect of alpha stimulation on the blood system.

 The Autonomic Nervous System and Autonomic Drugs (Part II)

 By the completion of this section, the participant should be able to:
 1. Identify the components of the SLUD response
 2. Name and identify three anticholinergic agents
 3. Name an adrenergic agent and identify its cardiac effects
 4. Identify side effects of the primary anticholinergic agents discussed
 5. Identify a natural source for anticholinergic agents
 6. List contraindications for the use of anticholinergic agents
 7. Define the term "orthostatic hypotension"

III. Drugs Affecting the ANS
 A. Cholinergic Drugs
  1. those that act like acetylcholine
       2. general adverse effects: SLUD response
            a. salivation
            b. lacrimation
            c. urination
            d. defecation
  3. consider side effects of insecticides:
   a. Insecticides are not so much cholinergic agents as they are drugs that slow down the metabolism of acetylcholine; the net effect is to increase the levels of acetylcholine and bring on the SLUD response.
   --Insecticides inhibit cholinesterase, an enzyme that metabolizes acetacholine.
   b. Amanita muscaria mushrooms cause poisoning by overstimulating the muscarine receptors, which in turn stimulate the cholinergic response
 4. toxicity from cholinergic agents treated with
            a. pralidoxime (2-PAM, Protopam)
            b. atropine
 5. drugs used primarily for glaucoma
           (Miochol [acetacholine], IsoptoCarbachol [carbachol] and pilocarpine -- glaucoma agents)

 6. An oral cholinergic-type drug for the treatment of urinary retention: bethanechol (Urecholine)

 7. An oral pilocarpine-based product for the treatment of xerostomia: Saligen

B. Anticholinergic Drugs
  1. blocks receptor site for acetylcholine
  2. decrease salivary flow and respiratory secretions during surgery

C. Specific Anticholinergic agents
  1. Atropine
            a. decreases secretions and salivation
             b. adverse reactions
               --increase heart rate without increased cardiac output
               --red, mad, hot
             c. dose range in 0.2 to l.0mg
               --usually ranges from 0.4 to 0.6mg
             d. contraindicated in glaucoma and, over long term, among patients with prostatic hypertrophy
   –benign prostatic hypertrophy is an ailment that affects over half the male population over the age of 60; symptomatically, it is an enlargement of the prostate gland around the urethra, narrowing the passage for urine flow and resulting in residual urine in the bladder with the accompanying increase in likelihood of UTIs (urinary tract infections)

   e. atropine is in another combination product known as Lomotil (atropine with diphenoxylate), used to treat diarrhea

  2. Scopolamine
            a. like atropine, but with central sedative effect
             b. used to treat travel sickness
               --also to prevent secretions
               --manufactured in "patch" form (Transderm SCOP)
             c. main side effects include
                i. sedation
                ii. xerostomia (defined as: dry mouth )
                iii. xeropthalmia (defined as: dry eyes )

A drug that causes xerostomia is
   a. a cholinergic agent
   b. an anticolinergic agent
   c. an antiadrenergic agent
   d. a cholinesterase inhibitor
   e. an alpha-adrenergic blocking drug
Xerostomia means "dry mouth," so you'd look for an agent that is used to dry up secretions.  Cholinergic agents actually increase secretions, that SLUD response, you remember.... a cholinesterase inhibitor would also increase secretions because it would reduce the metabolism of acetylcholine (remember that the -ase suffix denotes an enzyme!).  So you'd go for an ANTICHOLINERGIC drug, a drug such as atropine or scopolamine, with emphasis on atropine.

 3. Belladonna
            a. historically, a tincture; not often used today
             b. in combination product Donnatal-- belladonna alkaloids with atropine
             c. from plant Atropa belladonna "Deadly Nightshade"
                    note how the plant’s name contains “atropa”-- it was an original source for atropine

  4. Propantheline Bromide (Pro-Banthine)
            a. occasionally, to stop secretions (dentistry)
            b. usually, for GI problems

   --before cimetidine (Tagamet) and ranitidine (Zantac) (and the other H2 antagonists), ProBantine and Donnatal were the main drug therapies for ulcers

     D. Specific Adrenergic/Sympathomimetic Agents
         1. Epinephrine (Adrenalin)
            a. comes from the adrenals
             b. can stimulate both alpha and beta receptors
                i. skin has primarily an alpha response

                ii. heart primarily beta response
                   –an increased beta response increases
                   (a) rate   POSITIVE CHRONOTROPIC
                   (b) force of contraction
                                POSITIVE INOTROPIC
                   (c) cardiac output
                     (d) oxygen utilization
    --oxygen utilization is increased tremendously, and is very inefficiently used

Tachycardia is characterized by
   a. rise in body temperature
   b. decrease in pulse rate
   c. an increase in pulse rate
   d. an increase in blood pressure
The term also used is "positive chronotropic" agent
    --consider the effects of stress on a heart with lousy arteries

             c. if cardiac problems present, can cause irregularities
             d. general anesthesia [including halothane (Fluothane), enflurane (Ethrane), isoflurane (Forane));
                --cause an increase in cardiac sensitivity to the effects of epinephrine
                --used very, very rarely and then with caution in patients with pre-existing cardiac problems
             e. concentration when used with local anesthetics
                1:50,000 to 1:250,000  most common:  1:100,000

            f. other effects
                   i. pancreas--alpha receptors inhibit insulin secretion

                  ii. oxygen consumption increases 20-30%
                  iii. lungs--primarily beta (which type of beta?)
                   --stimulation of beta receptors in the lung results in bronchodilation of the bronchi

           g. uses
               i. agent of choice in allergic reactions and asthmatic reactions
                  --counteracts effect of histamine
               ii. in such reactions, dose is 0.2-1.0ml of a l:l,000 solution, either SQ or IV

  A quick digression here on dilutions:
 When you see dilutions expressed as a ratio, such as the one above– 1:1000 –the ratio means 1 gram in 1000 milliliters of solution, or more simply, 1gm/1000ml.  This is equivalent to 1000mg/1000ml, or 1mg/1ml.  Therefore, a vial containing 1ml of a 1:1000 dilution of epinephrine contains 1mg.  Nobody said pharmacy math had to be easy, or that it had to make sense, for that matter.

            iii. light sensitive, ineffective orally
               --an example of how administration route affects performance of a drug
               --turns pink, then brown, with prolonged exposure to light; consider the implications of that long-held vial in the drug cabinet at the dentist’s office: Does the office have a policy on multiple dose vials?  Does the office store epinephrine containing vials in a light-protective cabinet?

        h. contraindicated in
           i. narrow angle glaucoma
           ii. with cyclopropane or halogenated general anesthetics, again for the reasons mentioned above

        c. use with caution in patients with
               i. cardiovascular disease –increases workload on the heart in a very inefficient manner; oxygen is rapidly consumed and patients with cardiovascular disease already have compromised access to adequate oxygen in the heart
               ii. hypertension–vasoconstriction can be throughout the body, including the muscles of the blood vessels

Which of the following actions is not caused by epinephrine?
   a. tremor
   b. miosis
   c. anxiety
   d. headache
   e. palpitations
Miosis is a closing of the pupil; epinephrine causes mydriasis, or pupil dilation.

 Which of the following is a sympathomimetic drug that can increase blood pressure?
 a. atropine
 b. epinephrine
 c. scopolamine
 d. phenylephrine
Sympathomimetic drugs are those which mimic the sympathetic (fight or flight) system, also known as the “adrenergic” system.  The mediator for this system is epinephrine.  That would be the MAJOR choice.  Phenylephrine is in the nasal product "NeoSynephrine" and MAY cause a slight increase in blood pressure with protracted use.... but that is rare and is not the main thrust of the question posed.

               iii. hyperthyroidism– when too much thyroid hormone is being produced, an increase in catecholamines such as epinephrine can further stimulate the release of thyroid hormone AND cause an increase in side effects of the hyperthyroid condition!

        2. Norepinephrine ("levarterenol" "Levophed")
              a. more alpha effects than beta
              b. not used with local anesthetics due to tissue destruction --necrosis possible
              c. still occasionally used in cardiac shock to elevate blood pressure–but not that often due to its very generalized activity throughout the body–  "levophed/leave 'em dead"

         3. Isoproterinol (Isuprel)
                a. mainly beta stimulation
                b. relaxes bronchial smooth muscle
                c. inhalation therapy for asthma

         4. Ephedrine
                 a. stimulates alpha and beta
                 b. lesser effects than epinephrine but with a longer duration of action
                 c. "used as inhalation for asthmatics"
                      --note: this is somewhat old fashioned therapy
                 d. occasionally used to "stimulate" a sluggish blood pressure after surgery
                 e. from “natural sources”

 Ephedrine, from the Ephedra plant, is making a reappearance as a “natural treatment” for weight loss programs.  It may also be sold under the TCM (Traditional Chinese Medicine) name of “Ma Huang.”  It is a stimulant and vasoconstrictor, closely related to pseudoephedrine (Sudafed) in chemical structure.  It has been used to synthesize amphetamine-like drugs.  It has also been implicated in at least one well-publicized death in a woman who was using it in conjunction with other stimulants as a diet aid.  Presently, the FDA is trying to put restrictions on the use of ephedrine and Ephedra and some states have limited the amounts that may be placed in any single dose.

       5. Phenylephrine (NeoSynephrine)
            a. stimulates alpha
            b. similar to epinephrine without cardiac effects
            c. has been used with local anesthetics
            d. in eye, for dilation of pupil for examination (pupil dilation--MYDRIASIS)
            e. main claim to fame: nasal decongestant, drops or spray, 0.25-1% solution, or as a jelly for small children

       6. Amphetamines
  –dextroamphetamine (Adderal, Dexedrine)
            a. alpha and beta stimulation
            b. only recognized use in the State of Michigan is for the treatment of hyperkinetic children
            c. side effects: hypertension/elevated pulse, increase in respiration
  Note: amphetamines can cause some gingival hyperplasia.

 A. Consequences of use to control bleeding:
       1. rebound vasodilation
        2. systemic absorption/systemic effects

 B. For patients with cardiac problems, use with caution if at all

    A. Drugs that affect the ANS have many uses in medicine
       1. hypertension therapy
       2. peripheral vascular disease
       3. certain cardiac consideration
  --these applications tend to concentrate on the sympathetic/ adrenergic portion of the system

 B. Patients on sympathetic/adrenergic blockers
       1. will be sensitive to changes in position
 C. Cholinergic agents can increase salivation

 D. Anticholinergic drugs
  1. atropine, scopolamine, glycopyrrolate (Robinul) reduce secretions
        --atropine: generally no cardiac effect in dental doses (0.2mg)
        --scopolamine: CNS depression could pose a problem, and it does affect vision
       2. "antisialagogues"
       3. preop use and in general anesthesia
       4. side effects
        a. visual disturbances (due to xeropthalmia)
        b. restlessness
        c. tachycardia
5. contraindications
   a. nursing mothers
   b. cardiac patients
   c. patients with glaucoma
   d. presence of an intestinal obstruction

  6. Patients already taking an anticholinergic drug will probably have xerostomia, increase in dental caries, plaque, and gingivitis

 E. Pilocarpine (as Salagen) has been used to increase salivary flow in dental practice.
       1. pilocarpine is a parasympathetic/cholinergic drug
       2. pilocarpine is used primarily to treat glaucoma
       3. side effects: sweating, vasodilation, visual disturbances

Review Questions for this section:
KCC Dental Hygiene Students: to send your homework, highlight the questions below, go to "edit," click on "copy," then click onto my email address below...when the email appears, go to "edit" in the email menu, click on "paste," and the questions will appear as the body of the email.  Answer the questions and then press "send." Your homework will be reviewed and returned via email within 72 hours.  Or just do it all on paper and bring your work to the next class session.

1. What are alternate names for the Autonomic Nervous System?
2. What are alternative names for the (a) sympathetic system and the (b) parasympathetic system?
3. What are the chemical mediators for the sympathetic and parasympathetic systems?
4. The alpha and beta receptors are part of which system?  Which type of beta receptors are found in (a) the heart and (b) the lungs?
5. Beta receptor stimulation in the lungs results in what action?  Beta blockade in the lungs results in what action?
6. What are the results of beta receptor stimulation in the heart?
7. What anticholinergic activity is useful in dentistry?
8. What drug(s) exhibit anticholinergic activity?
9. What anticholinergic drug is available as a topical patch to prevent motion sickness?
10. What is the agent of choice for severe allergic reactions and asthmatic crises?
11. What combination product containing atropine is used to treat diarrhea?
12. What cholinergic product is used to fight xerostomia?
13. What is xerostomia?  What is xerophthalmia?
14. What are some contra-indications for the use of atropine?
15. What are contra-indications for the use of epinephrine?
16. What is the SLUD response?  Which system of the ANS is involved?
17. What does positive chronotropic mean?
18. What does positive inotropic mean?
19. What is meant by the term orthostatic hypotension?
20. What is the herbal product that has epinephrine-like activity?  What are some of its uses and dangers?

End of Module Two
DEHY 34 Pharmacology for Dental Hygiene
Comments: Jim Middleton, Pharmacist
Kellogg Community College, Battle Creek Michigan