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pharm.11
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1996-05-06
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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.