      DRUGS ACTING AT SYNAPTIC AND NEUROEFFECTOR JUNCTIONAL
      SITES - AUTONOMIC AND NEUROMUSCULAR PHARMACOLOGY (11)


      Subcommittee:
      W.W. Fleming (West Virginia)(Chairman)
      William J. Cooke (Eastern Virginia Med. School)
      James W. Gibb (Utah)
      Joseph J. Krzanowski (Univ. So. Florida)
      Robert J. Theobold (Kirksville Coll. Osteo. Med.)

      1.  In general, medical students come to us with a sound
background in the anatomy of the ANS but a somewhat inadequate
grasp of its physiology.  Therefore, we need to spend
considerable time on the latter and little time on the former in
ANS pharmacology.

      2.  The importance of autonomic pharmacology is greater than
that of its collective therapeutic agents.  It is the foundation
for understanding other areas such as cardiovascular pharmacology
and pharmacology of the central nervous system.  Autonomic nerves
and/or their effector cells are the site of action responsible
for the side effects of many drugs whose primary sites of action
are elsewhere.

1.    Introduction to autonomic N.S. (1)

      History - know the anatomical relationships of the two-
      neuron systems for both of the portions of the autonomic
      nervous system.  Know the relevance to the development of
      the concept of neurotransmitters and end-organ receptor
      specificity.

      1)    Define words containing the suffixes, -ergic,-mimetic,
            -lytic and -ceptive.
      2)    Understand homeostasis, fight-or-fight (as proposed by
            Cannon) and rest-and-repair with regard to sympathetic
            and parasympathetic activity.
      3)    Central control reflexes.
      4)    Dual innervation-recognize that sympathetic and
            parasympathetic innervations are not balanced in all
            organs.
      5)    Predominant tone.

2.    Cholinergic systems and related drugs (1)

      1)    Know the kinetics of the formation, storage, release
            and inactivation of ACETYLCHOLINE.  Be aware of
            receptor subtypes (e.g., M1, M2).
      2)    Acetylcholine-muscarinic and nicotinic receptor sites
            a)    know the locations and differences between
                  muscarinic and nicotinic receptor sites.
            b)    muscarinic agonists (mimic muscarine) may be used
                  to treat the following conditions:  paralytic
                  ileus, nonobstructive atony of the bladder and
                  glaucoma.  Less important are paroxysmal
                  supraventricular tachycardia, intoxication with
                  antimuscarinic agents (including tricyclic
                  antidepressants which may cause glaucoma).
                  i)     undesirable effects include salivation,
                         sweating, colic, defecation, headache and
                         loss of accommodation.
                  ii)    some esters may be potentiated by the
                         presence of anticholinesterase agents.
                  iii)   contraindications include peptic        
                         ulcer, asthma, coronary insufficiency and
                         hyperthyroidism.
                  iv)    drugs to be considered:  ACETYLCHOLINE
                         (prototype-not used clinically),        
                         BETHANECHOL, pilocarpine and MUSCARINE for
                         historical interest.

3.    Anticholinesterases (1)

      a)    Principles and knowledge objectives to be considered.

            The student should be able to:

            i)    Compare the two major cholinesterases-
                  acetylcholinesterase (ACHE) and
                  butyrylcholinesterase (BUCHE) as to anatomical
                  locations, sites of synthesis and function.
            ii)   Explain the chemical makeup of the active site of
                  ACHE (anionic and esteratic) as to attraction,
                  attachment and rates of breakdown of various
                  substrates and inhibitors.
            iii)  Relate the site and onset of action of
                  anticholinesterases and routes of administration;
                  also the duration of action of                 
                  anticholinesterases with sites and type of     
                  attachment to the enzyme.
            iv)   State and explain why anticholinesterases are
                  reversible or irreversible.
            v)    Relate the direct effects as being due to
                  quaternary ammonium nitrogen and the indirect
                  effects as being due to anticholinesterase
                  activity.
            vi)   Describe the effects of accumulated acetylcholine
                  at muscarinic sites (cardiac muscle, vascular
                  system, respiratory systems, glands, g.i. and  
                  g.u. and eye structures), nicotinic sites      
                  (ganglia and NMJ) as well as effects on central
                  nervous system.
            vii)  Indicate therapeutic uses for
                  anticholinesterases such as glaucoma,
                  gastrointestinal or urinary tract atony,
                  myasthenia gravis and treatment of atropine     
                  poisoning.
            viii) Describe adverse or toxic effects of
                  anticholinesterases as being due to
                  accumulation or excess acetylcholine and
                  overstimulation of muscarinic and nicotinic
                  receptors.
            ix)   Distinguish and characterize antidoting agents
                  that reactivate phosphorylated ACHE (pralidoxime)
                  and agents that block effects of excess
                  acetylcholine at muscarinic receptors (atropine).
                  Recognize the role of enzyme aging in the enzyme-
                  inhibitor interaction.

      b.    Drugs to be considered:

            i)    Recall all prototypical drugs such as: 
                  PHYSOSTIGMINE, NEOSTIGMINE, EDROPHONIUM and
                  ISOFLUROPHATE.
            ii)   Be familiar with anticholinesterase insecticides:
                  malathion, sarin, parathion and the nerve gases,
                  SOMAN and VX series.  Know that malathion and
                  parathion must be biotransformed.  Know that
                  poisoning with soman is not treatable with
                  PRALIDOXIME.
            iii)  Consider effect of age on muscarinic sites [heart
                  and cholinergic sites in the brain (Alzheimer's
                  disease) - use of choline derivatives.]
 
4.    Antagonists at muscarinic receptor sites (1)

      a)    Act as competitive antagonists.
      b)    Uses:  gastric or intestinal hypersensitivity or
            secretion, excessive salivation, motion sickness, to
            product mydriasis and cycloplegia, or an an adjunct
            prior to general anesthesia.
      c)    Undesirable effects include xerostomia, blurred vision,
            photophobia, tachycardia, anhidrosis, difficulty in
            micturition, hyperthermia, glaucoma and mental
            confusion in the elderly.
      d)    Contraindications:  glaucoma, obstructive disease of
            the gastrointestinal tract or urinary tract, intestinal
            atony.
      e)    Drugs to be considered:  ATROPINE, scopolamine and
            ipratropium.

5.    Drugs acting at autonomic ganglia  (1)

      a)    NICOTINE
            i)    Agonist and antagonist properties.
            ii)   Not used clinically, except as a smoking
                  deterrent.
            iii)  Historical, social and toxicological           

                  significance.
      b)    Antagonists acting at ganglionic nicotinic receptor
            sites.
            i)    Pharmacological effects and the role of
                  predominant tone.
            ii)   Use:  hypertension, autonomic hyperreflexia.
            iii)  Use severely limited by side effects:  loss of
                  accommodation, xerostomia, urinary hesitancy and
                  retention, impotence, constipation, anorexia,
                  eructation and orthostatic hypotension.
            iv)   Example:  trimethaphan, HEXAMETHONIUM

6.    Antagonists at nicotinic receptor sites in the skeletal
      neuromuscular junction (NMJ)  (1)

      a)    Know that selectivity of drugs between ganglionic and
            neuromuscular nicotinic receptors is only relative and
            the resulting clinical implications.
 
      b)    Physiology and Pathophysiology of transmission at NMJ.

      c)    Classes of neuromuscular antagonists:
            i)    Depolarizing agents - e.g. SUCCINYLCHOLINE.
                  (a)    know characteristics of phases I and II of
                         blockade and interactions with
                         anticholinesterases
                  (b)    metabolism (atypical cholinesterases) and
                         titration of effect
                  (c)    toxicity
            ii)   Competitive antagonists at NMJ.
                  (a)    prototypical drugs:  atracurium,
                         TUBOCURARINE, PANCURONIUM, vecuronium,
                         gallamine
                  (b)    interaction with anticholinesterase
                  (c)    metabolism
                  (d)    histamine release and toxicity
            iii)  Drugs with secondary actions as NMJ antagonists: 
                  peptide and aminoglycoside antibiotics,        
                  magnesium, and some general anesthetics (ether).
      d)    Know order of paralysis of muscles.

7.    Sympathetic systems, the adrenal medulla and related drugs 
      (5)

      1)    Know the steps and processes involved in sympathetic
            transmission and release from adrenal medulla.
            a)    biosynthetic pathway and enzymes, including short
                  (feedback inhibition) and long term (enzyme
                  induction) control.
            b)    storage of norepinephrine and epinephrine
            c)    release of norepinephrine and epinephrine
            d)    concept of biophase and location of receptors
            e)    removal of NE from biophase
                  i)     metabolism, including locations,
                         characteristics and roles of COMT and MAO
                  ii)    neuronal uptake [distinguish from       

                         vesicular uptake (changes with age;     

                         increases in heart, decreases in blood  

                         vessels, increase in brain)]
                  iii)   extraneuronal uptake
                  iv)    escape into and fate in blood
      2)    Know examples of drugs which interfere with specific
            steps in noradrenergic transmission (METHYLDOPA,
            RESERPINE, COCAINE, GUANETHIDINE, bretylium) and
            important drug interactions with these drugs.

      3)    Know the classification of adrenoceptors (alpha 1,
            alpha 2, beta 1, beta 2) and important locations of
            each receptor type.

      4)    Alpha 1 agonists are used to treat the following
            conditions:  nasal congestion, hypotension, paroxysmal
            atrial tachycardia and to cause mydriasis or to cause
            vasoconstriction with local anesthetics.
            a)    undesirable effects include hypertension,
                  headache, restlessness and excitability.
            b)    drug interactions may occur with halogenated
                  hydrocarbon anesthetics such as halothane,
                  oxytocic drugs and monamine oxidase inhibitors.
            c)    contraindications include severe hypertension or
                  cardiac disease.
            d)    drugs:  EPINEPHRINE, norepinephrine,
                  PHENYLEPHRINE, phenylpropanolamine and         
                  methoxamine (note norepinephrine has no        
                  selectivity among alpha 1 ,alpha 2, beta 1     
                  receptors; epinephrine has no selectivity.

      5)    alpha 2 agonists are used to treat hypertension
            a)    central site of action
            b)    undesirable side effects include xerostomia,
                  drowsiness, sedation, constipation, dizziness,
                  headache and profound hypotension.
            c)    cannot be given intravenously due to effects on
                  peripheral postjunctional alpha 1 & alpha 2
                  receptors which will cause hypertension.
            d)    CLONIDINE and alpha methylnorepinephrine
                  (metabolite of alpha methyldopa)

      6)    Nonselective alpha 1 - alpha 2 antagonists.
            a)    prototype:  phentolamine (reversible)
            b)    formerly used for hypertension
            c)    understand limitations of excessive tachycardia

      7)    alpha 1 selective antagonists are used to treat
            hypertension
            a)    understand value of relative selectivity
            b)    undesirable side effects include dizziness,
                  headache, drowsiness, weakness, postural
                  hypotension, tachycardia.
            c)    drug interactions may include synergism with
                  diuretics or other antihypertensive drugs
            d)    drugs:  PRAZOSIN (reversible), phenoxybenzamine
                  (irreversible).

      8)    alpha 2 selective antagonists - no therapeutic use
            (example is yohimbine).

      9)    Indirectly acting sympathomimetics.
            a)    understand mechanism of action and clarify that
                  some agents have mixed (direct/indirect) action.
            b)    interaction with monoamine oxidase inhibitors
                  (e.g., pargyline)
            c)    prototypical drugs
                  i)     TYRAMINE - not used therapeutically but
                         present in some cheeses, wines and beers
                  ii)    EPHEDRINE and pseudoephedrine - greater
                         central action than many other
                         sympathomimetics
                  iii)   AMPHETAMINE - predominant central actions,
                         use and limitations in appetite         

                         suppression, importance as a drug of abuse

      10)   Nonselective beta 1 and beta 2 agonists.
            a)    EPINEPHRINE
                  i)     no selectivity among alpha 1, alpha 2 and
                         beta 1 and beta 2 receptors
                  ii)    effective for bronchodilation but use   

                         limited by cardiovascular effects.
                  iii)   use in improving cardiac conduction, in
                         treatment of anaphylactic shock, as an
                         adjunct to local anesthetics
            b)    ISOPROTERENOL
                  i)     selective for beta 1 and beta 2 receptors
                  ii)    effective for bronchodilation (alpha 2) 

                         but usefulness limited by cardiac       

                         stimulation (beta 1) peripheral         

                         vasodilation (beta 2)

      11)   Beta 1 selective agonists are used for the short
            treatment of cardiac decompensation.
            a)    undesirable side effects include tachycardia,
                  hypertension (residual alpha 1 effect) and
                  arrhythmias
            b)    contraindicated in idiopathic hypertrophic
                  subaortic stenosis
            c)    drugs:  dobutamine

      12)   Beta 2 agonists are used to treat asthma, bronchospasm
            and emphysema.
            a)    undesirable side effects include nervousness,
                  headache, tachycardia, palpitations, sweating,
                  muscle cramps, (note selectivity for beta 1 over
                  beta 2 receptors is only relative)
            b)    drugs:  terbutaline, ALBUTEROL
            c)    effective orally and by inhalation
            d)    longer acting than ISOPROTERENOL
            e)    have made the use of isoproterenol (by         

                  inhalation) and ephedrine (oral) for relief of 

                  bronchospasm obsolete
            f)    Reduction in both beta 1 and beta 2 agonists
                  response in older organisms (e.g., trachea,    

                  heart, blood vessels)

      13)   Nonselective beta 1 and beta 2 antagonists.
            a)    prototypical drugs - 1-PROPRANOLOL, nadolol,
                  timolol and pindolol
            b)    uses:  hypertension, angina, arrhythmias
            c)    limitation:  bronchoconstriction due to        

                  antagonism of beta 2 receptors

      14)   Beta 1 antagonists are used to treat hypertension.
            a)    Undesirable side effects include tiredness,
                  dizziness, shortness of breath, bradycardia,
                  congestive heart failure, diarrhea, flatulence 

                  and heartburn.
            b)    Generally contrainindicated in sinus bradycardia,
                  heart block, cardiogenic shock and overt cardiac
                  failure, careful in asthmatics-relative
                  selectivity.
            c)    drugs:  e.g. METOPROLOL, ATENOLOL

      15)   DOPAMINE
            a)    Dopamine receptors
            b)    Established role of dopamine as a transmitter in
                  CNS; effect of age on dopaminergic receptors: 
                  decline in nigrostriatal areas.
            c)    Use as a renal vascular dilator

      16)   Labetolol
            a)    Discuss as an example of a drug which block both
                  alpha 1 and beta 1, beta 2 adrenoceptors
            b)    Consider its use in hypertension.

--------------------------------------------------
Minimum list of drugs in autonomic and neuromuscular pharmacology

ACETYLCHOLINE
+ALBUTEROL
AMPHETAMINE
+ATENOLOL
atracurium
+ATROPINE
BETHANECHOL
bretylium
CLONIDINE
COCAINE
dobutamine
DOPAMINE
EDROPHONIUM
EPHEDRINE
EPINEPHRINE
gallamine
GUANETHIDINE
HEXAMETHONIUM
+ipratropium
ISOFLUROPHRATE
ISOPROTERENOL
+labetalol
malathion
methoxamine
+METHYLDOPA
+METOPROLOL
MUSCARINE
+nadolol
NEOSTIGMINE
+NICOTINE
NOREPINEPHRINE
PANCURONIUM
PARATHION
PARGYLINE
PHENOXYBENZAMINE
+PHENYLPROPANOL-
AMINE
PHENTOLAMINE
+phenylephrine
physostigmine
pilocarpine
pindolol
+pseudoephedrine
PRALIDOXIME
+PRAZOSIN
+PROPRANOLOL
RESERPINE
scopolamine
SOMAN
SUCCINYLCHOLINE
terbutaline
+timolol
trimethaphan
TUBOCURARINE
TYRAMINE
vecuronium

PRIMARY DRUGS - All capital letters
SECONDARY DRUGS - small letters

+Indicates that drug is listed in the 200 most commonly
prescribed drugs in 1989 (National Prescription Audit).  All of
the first 100 and most of the second 100 of the top 200 drugs
prescribed are included in this document.


 

