AUTONOMIC NERVOUS SYSTEM PHARMACOTHERAPEUTICS

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AUTONOMIC NERVOUS SYSTEM PHARMACOTHERAPEUTICS
Kirk W. Barron, PhD, PA-C Heart Failure Treatment
Program WP 3120, Cardiology OU Medical
Center office 271-2916 kirk-barron_at_ouhsc.edu
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OBJECTIVES

• Know the effects of activation of the
  sympathetic and parasympathetic nervous systems
  on different organ systems.
• Know the sites of cholinergic and adrenergic
  neurotransmission and the receptors involved
• List the steps in cholinergic and noradrenergic
  neurotransmission including the termination of
  action.
• Understand major classifications and
  subclassificaitons of cholinergic receptors.

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OBJECTIVES

• Describe the actions of agonists and antagonists
  of muscarinic receptors
• Understand major classifications and
  subclassifications of adrenergic receptors
• List and describe the actions of agonists and
  antagonists of alpha and beta-adrenergic
  receptors
• Know the major mechanisms, uses and adverse
  reactions of agents listed at the end of the
  lecture

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• I. Introduction
• The function of the autonomic nervous system is
  to
• maintain the internal environment of the body at
• near constant levels. This function is also
  referred to
• as homeostasis.
• Examples temperature, blood pressure, blood
  glucose
• Note that homeostasis not only applies to
• conditions of rest but also occurs during
  stressful
• situations.

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• II. Components of the Autonomic Nervous System
• The physiological function of the autonomic
• nervous system requires three components
• motor nerves,
• sensory nerves
• central nervous system which integrates the
  sensory information and sends out motor commands

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• The autonomic efferent pathways are always
• arranged as two nerves which are connected in
• series (Figure 1).
• The first nerve in the series is the
  preganglionic
• nerve. Preganglionic nerves have their cell
  bodies
• located within the CNS, their axons are
  myelinated,
• and they release acetylcholine to activate
  nicotinic
• receptors on postganglionic nerves (Figures 1
  2).

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• The second nerve in the series. Postganglionic
  nerves
• have their cell bodies located in autonomic
  ganglia,
• they are unmyelinated, and they release either
• acetylcholine or norepinephrine as a
  neurotransmitter
• at target organs.

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• Sensory or afferent nerves (labeled Sensor in
  Fig. 1) have a wide variety of sensory modalities
  such as stretch (mechanoreceptors),
  osmoreceptors, and chemoreceptors.
• Sensory nerve cell bodies can be located in
  sensory ganglia such as the spinal dorsal root
  ganglia or the nodose ganglia.
• Central Nervous System integrates input from
  sensory and dictates motor response

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• III. Divisions of Autonomic Nervous System
• Figure 2 shows the organization of the two major
  divisions. The efferent innervation consists of
  two efferent neurons connected in series.

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A. Parasympathetic Nervous System
(craniosacral division)

• 1. Preganglionic nerves are relatively long
• and extend to (or very close to) the target
• organ. The parasympathetic ganglia are
• located close to or on the target organ.
• 2. Postganglionic nerves are short,
  unmyelinated and release acetylcholine
  (ACh).

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FIG. 3
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• B. Sympathetic Division (thoracolumbar)
• The sympathetic division has relatively short
  preganglionic neurons and long postganglionic
  neurons.
• Preganglionic sympathetic nerves can synapse in
  either paravertebral ganglia (chain ganglia) or
  the prevertebral ganglia. A key feature of
  sympathetic preganglionic neurons is that they
  can diverge and innervate multiple postganglionic
  sympathetic neurons. This allows the possibility
  of a widespread or diffuse response.
  Preganglionic neurons are nonmyelinated

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• B. Sympathetic Division (thoracolumbar)
• The postganglionic neurons release norepinephrine
  to activate adrenergic receptors which are
  divided into two major subclassifications alpha
  (a )or beta (ß) receptors. Postganglionic
  neurons are unmyelinated
• (There is one exception to the rule that
  postganglionic neurons release norepinephrine -
  what is it?)

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FIG. 3
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C. Somatic motor neurons Somatic motor neurons
are myelinated and release acetylcholine as the
neurotransmitter. Synapse is monosynaptic
from spinal cord.
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• IV. Function of the Autonomic Nervous System.
• The information presented to this point
  describes the general anatomical components,
  the two divisions and receptors involved in
  autonomic nervous system function. The
  following section examines in more detail the
  responses to parasympathetic and sympathetic
  activation and inhibition/blockade

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• A. General Concepts
• 1. Dual innervation is found when both limbs
  of the autonomic nervous system innervate a
  given tissue or influence the same
  physiological function.

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• 2. Functional synergism refers to the fact that
  in organs receiving dual inneration the
  sympathetic and parasympathetic divisions of
  the autonomic nervous system work in concert.

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• B. Parasympathetic nervous system
• The parasympathetic nervous system is primarily
  active during resting conditions and generally
  acts to conserve or restore energy stores in
  the body.
• (rest, digest, divest)
• 1. Activation of the Parasympathetic nervous
  system. What types of physiological responses
  would you anticipate with a medication that
  either
• activates the parasympathetic nervous system
  
• or activates muscarinic receptors?

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pupil diameter decreased (miosis) heart
rate decreased (bradycardia
or negative chronotropic effect) myocardial
contractility no change - ventricles (inotr
opic effect) bronchial smooth muscle
tone constriction (bronchoconstriction)
salivation increased (sialogogic
effect) perspiration no effect with
parasympathetic stimulation increa
sed by muscarinic receptor activation
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GI motility increased GI secretions increas
ed Defecation increased Skeletal muscle
strength/tone no effect Micturition increased
Urinary frequency increased Bladder
tone increased
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GI motility increased GI secretions increas
ed Defecation increased Skeletal muscle
strength/tone no effect Micturition increased
Urinary frequency increased Bladder
tone increased
What are the effects of excessive stimulation of
the parasympathetic nervous system?
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B. Parasympathetic nervous system (cont) 2.
What are the effects of blockade of the
parasympathetic nervous system?
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pupil diameter decreased (miosis) heart
rate increased (tachycardia
or positive chronotropic effect) myocardial
contractility no change - ventricles (inotr
opic effect) bronchial smooth muscle
tone dilation (bronchdilation) salivat
ion decreased (dry mouth!) perspiration
impaired ability to sweat
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GI motility decreased GI secretions decreas
ed Defecation decreased Skeletal muscle
strength/tone no effect Micturition decreased
Urinary frequency decreased Bladder
tone decreased
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• C. Sympathetic nervous system
• The sympathetic nervous system is most active
  during stress or exercise. Classically the
  concept of fright, flight and fight have been
  associated with the sympathetic nervous system.

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• C. Sympathetic nervous system
• 1. Activation of the sympathetic nervous system
• If you are not sure of whether a response is
  sympathetically mediated consider if the response
  would help you overcome a stressful situation.
  If so then probably you are dealing with a
  sympathetic response or a drug that mimics
  activation of some element of the sympathetic
  nervous system.
• Activation of the sympathetic nervous system
  usually involves increased mobilization or use of
  energy stores in the body

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pupil diameter increased (mydriasis) hear
t rate increased (tachycardia
or positive chronotropic effect) myocardial
contractility increased (positive
inotropic effect) bronchial smooth muscle
tone dilation salivation increased
(thickened more viscous secretion) per
spiration increased (what receptor
mediates this response?)
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GI motility decreased GI secretions decreas
ed Defecation ? Skeletal muscle
strength/tone no effect Micturition decreased
Urinary frequency decreased Bladder
tone decreased
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2. Inhibition of inhibition of the sympathetic
nervous system?
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pupil diameter decreased (miosis) heart
rate decreased depending upon
sympathetic tone tone to the heart
(bradycardia or negative chronotropic
effect) myocardial contractility decreased
depending upon sympathetic tone tone to the
heart (inotropic effect) bronchial smooth
muscle tone possible bronchoconstriction sa
livation no much effect perspiration no
effect
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GI motility small increase? GI
secretions small increase? Defecation no
much effect? Skeletal muscle strength/tone no
effect Micturition small increase? Urinary
frequency small increase? Bladder tone small
increase?
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• V. Autonomic Neurotransmission
• A. Cholinergic synapse
• 1. Cholinergic neurotransmission
• Cholinergic synapses are similar regardless of
  the receptor on the target organ which is
  innnervated. Acetylcholine is synthesized by
  choline acetyltransferase (Chat) from acetate
  and acetyl CoA. ACh is then stored in vesicles
  and released by exocytosis when the action
  potential reaches the nerve terminal and Ca2
  enters the neuron.

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• V. Autonomic Neurotransmission (cont)
• ACh diffuses across the synaptic junction to
  interaction with the target organ. Once
  acetylcholine is released, it is hydrolyzed into
  the inactive components (choline and acetate)
  by acetylcholinesterase (AChase).
• AChase hydrolysis is the primary mechanism for
  termination of the action of Ach.

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Typical cholinergic synapse ACH acetylcholine
AChase acetylcholinesterase Chat
cholineacetyltransferase
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• 2. Substances that presynaptically affect
  cholinergic synapse
• botulinum toxin (botox)-prevents release of
  acetylcholine at all cholinergic synapses has
  a very long duration of action
• black widow spider venom - displaces
  acetycholine from presynpatic terminals.

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• 3. Cholinesterase inhibitors
  Anticholinesterase Agents
• a. Reversible carbamates
• physostigmine (calabar bean)
• neostigmine
• pyridostigmine
• carbaril
• edrophonium
• b. Irreversible inhibitors
• DFP (disisopropylflurophosphate)
• tuban, sarin, soman (potent toxins at
  submilligram doses)
• parathion, malathion (insecticides)

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• c. Applications of cholinesterase inhibitors
• Eye - miosis through constriction of sphinchter
  pupillae muscle block accomodation intraocular
  pressure falls due to facilitation of outflow of
  the aqeuous humor.
• Primary glaucoma narrow angle is a medical
  emergency and is treated initially with
  cholinesterase inhibitors. Primary open angle
  glaucoma can be treated with long-acting
  irreversible agents such as physostigmine
• GI - GU tracts - neostigmine used in treatment
  of paralytic ileus and atony of the urinary
  bladder.

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• c. Applications of cholinesterase inhibitors
  (cont).
• Treatment of anticholinergic intoxication (due to
  atropine but also agents such as phenothiazines
  and tricyclic antidepressants)
• Myasthenia gravis - edrophonium test. The only
  condition where cholinesterase inhibitors
  dramatically improve a disease process is in
  myasthenia gravis. Edrophonium is given in a 2
  mg dose iv followed by 45 seconds later by 8 mg
  if the initial dose is ineffective - a positive
  response is a rapid improvement of strength.
  Treatment - neostigmine, pyridostigmine,

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• V. B. Adrenergic synapse
• 1. Synthesis of catecholamines
• The regulatory step in catecholamine synthesis is
  the conversion of tyrosine by tyrosine
  hydroxylase into the catecholamine,
  deoxyphenylalanine (i.e. DOPA). A
  catecholamine is a substance with two hydroxyl
  moieties (-OH) connected to an aromatic ring.
• DOPA decarboxylase removes the carboxylic acid
  from the side chain carbon with the amino group
  to form dopamine.
• Dopamine is taken up into the vesicle and
  converted into norepinephrine by dopamine
  ß-hydroxylase. This conversion occurs within the
  neurotranmitter vesicle.
• In the adrenal medulla there is a fourth enzyme,
  phenylethanolamine N-methyltransferase (or PNMT).
  PNMT converts norepinephrine to epinephrine by
  adding a methyl (-CH3) group to the terminal
  carbon.

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Adrenergic varicosity and synapse
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• 2. Adrenergic synapse - Postganglionic
  sympathetic
• synapses involve release of norepinephrine
• (noradrenaline) but often referred to as
  adrenergic
• synapses.

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• 3. Termination of action of norepinephrine is
  primarily through neuronal uptake or presynaptic
  reuptake into the sympathetic nerve terminals.
• Agents that inhibit neuronal reuptake of
  norepinephrine
• cocaine
• tricyclic antidepressants (desipramine)
• Second, norepinephrine can diffuse away and is
• taken up by nonneural tissues.

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4. The adrenal medulla is innervated by
sympathetic preganglionic neurons which
originate in the intermediolateral cell column
of the spinal cord. Control of epinephrine
release from adrenal chromaffin cells is
similar to control of sympathetic postganglionic
nerve.
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VI. Autonomic Receptors can be divided into two
main groups cholinergic and adrenergic. The
following diagram shows the major classes and
subclassifications of autonomic receptors.
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A. Cholinergic Receptors 1. Nicotinic receptors
by definition are excited by low-doses of
nicotine and inhibited by high doses of
nicotine. a. Nicotininic receptors at the
neuromuscular junction (NM ) agonist -
nicotine (low doses) examples of nicotinic
receptor NM antagonists Muscle relaxants
such as as curare, gallamine and
succinylcholine, snake alpha-neurotoxins
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b. Nicotinic neuronal (NN) receptors at
autonomic ganglia prototype - hexamethonium
(not used clinically) trimethaphan (very rapid
and short lived inhibition of ganglionic
neurotransmission)
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2. Muscarinic receptors mediate the effects of
the parasympathetic nervous system on target
organs. Atropine is the prototypical
muscarinic receptor antagonist. At least 6
forms of muscarinic receptors have been
identified pharmacologically and several more
through molecular approaches
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• a. Muscarinic receptor agonists
  parasympathomimetic agents
• muscarine (Amanita mus
• pilocarpine - sialogogue, treatment of open
  angle glaucoma by causing ciliary muscle
  contraction which opens canal of Schlemm.
• acetyl-beta- methacholine (Amechol,
  Mecholyl). inhibit cardiac rate in conditions
  of SVTs. (no nicotinic agonist activity)
• Carbachol (carbamylcholine) - increases
  motility of gut and contractin of the bladder

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b. Muscarinic receptor antagonists
parasympatholytic agents (sometimes the term
cholinergic antagonist is used) cardiovascu
lar - tachycardia ( chronotropic acton)
inibition of gastrointestinal motility and
secretions that are driven by parasympathetic
outflow eye - mydriasis bronchial smooth
muscle - relaxation bladder - inhibition of
detrusor smooth muscle tone
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b. Muscarinic receptor antagonists 1. atropine
- prototype (from nightshade plant)
2. scopolamine 3. ipratropium (Atrovent)
(quarternary nitrogen so poor diffusion)
primarily used in COPD to open airways 4. D
itropan 5. Hyosciamin (Levsin)
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B. Adrenergic receptors are divided into two
major groups alpha (a) and beta (ß). As a first
approach in remembering the function of alpha and
beta receptors the following two statements may
be helpful. Alpha receptors are primarily
excitatory except in the G.I. tract, where they
exert inhibitory actions. Beta receptors
are primarily inhibitory except in the
myocardium, where they exert excitatory
actions.
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• 1. alpha receptors
• a. Therapeutic uses of alpha -1 receptor
  agonists
• low arterial pressure such as shock alpha-1
  agonists may be used in severe hypotension to
  maintain adequate CNS perfusion if cardiac
  function is adequate agents - norepinephrine or
  phenylephrine
• local vasoconstrictor epinephrine often added
  to local anesthetic injections
• nasal decongestants - act by decreasing
  resistance to airflow by vasoconstricting nasal
  mucosa. This may occur through activation of
  alpha-receptors on blood vessels in nasal tissue.

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• b. Alpha1 - adrenergic receptor (a1) agonists
• epinephrine - most potent endogeneous agonist
  but is not selective for alpha-1 receptors
  relieves allergic hypersensitivity responses( in
  part due to alpha-agonist activity) prolongs
  actions of local anesthetics also activates
  beta-receptors
• norepinephrine - as constrictor support for
  hypotension
• dopamine - low doses activate D1 receptors and
  cause vasodilation in renal, mesenteric and
  coronary beds. At high concentrations dopamine
  activates alpha1 adrenergic receptors.
  (activates beta receptors in the heart
• phenylephrine (Neosynphrine) nasal decongestant
• pseudoephedrine (pseudophed) nasal decongestant

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• c. Alpha1 - adrenergic receptor (a1) antagonists
• phentolamine - prototype of reversible
  antagonist
• phenoxybenzamine prototype of irreversible
  antagonist. blocks alpha1 and alpha2 receptors
• prazosin (Minipress) selective for alpha1
  receptors. Used as antihypertensive.
• terazosin (Hytrin) similar to prazosin in
  structure. The half-life is longer (12 hours).
  Used treatment of prostate BPH where is
  constricts smooth muscle in the prostate and
  reduces prostate size.

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d. Alpha2 - adrenergic receptor (a2) are
presynaptic but are also found postsynaptically.
Activation of alpha2- adrenergic receptors
inhibits release of norepinephrine from the
presynaptic terminal. The alpha2 receptor is
an example of an autoreceptor. Autoreceptors
are located presynaptically and influence
release of neurotransmitters from the nerve
terminal or varicosity.
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e. Therapeutic applications of alpha-2
agonists primarily in treatment of systemic
hypertension. clonidine - prototypical
alpha2-agonist. Acts by activating
alpha2-adrenoreceptors in the CNS (brainstem)
which results in decreased sympathetic outflow
and increased vagal outflow to the
heart. others (DNTK) guanabenz, guanfacine,
methyldopa
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2. beta receptors - Therapeutic applications of
beta - adrenergic receptors (ß1) rests primarily
on their cardiac actions. a. Nonselective
beta-adrenergic agonists i. Isoproterenol
(Isuprel) is an nonselective
beta-adrenergic agonist (beta1 and beta2).
Produces peripheral vasodilation and
cardiac activation. ii. dobutamine
(Dobutrex) - has beta1-adrenergic
agonist activity and also has minor stimulatory
effect on alpha1-receptors as well as
beta2- adrenergic receptors. The primary
use is for inotropic support to assist
when cardiac function is
depressed.
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• b. Non-selective beta antagonists
• propranolol - prototype
• labetolol - beta1 beta2 alpha1
• membrane stabilizer
• carvedolol - beta1 beta2 alpha1

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c. beta-1 selective antagonists metoprolol
(Lopressor, Toprol-XL) - antihypertensive
without direct membrane effects or intrinsic
activity on beta-adrenergic receptors. atenolo
l (Tenoramin) - antihypertensive without direct
membrane effects or intrinsic activity on
beta-adrenergic receptors. esmolol
(Brevibloc) - similar to first two but had rapid
onset and short duration
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• 3. Indirectly acting sympathomimetics
• Tyramine - releases catecholamines from nerve
  terminals. Tyramine has no therapeutic
  application but often found in cheddar cheese and
  chianti wines.
• Amphetamine - acts directly on adrenergic
  receptors but also has a very important effect to
  promote release of catecholamines from nerve
  terminals
• Ephedrine - both and alpha and beta agonist plus
  it releases catecholamines from presynaptic
  terminals. Pressor actions, bronchodilator, CNS
  stimulant, may cause urinary retention.
  Tachyphylaxis often occurs.

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Overview of the Autonomic Nervous System
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Major uses of autonomic agents

• 1. Antihypertensive
• 2. Antianginal
• 3. Congestive heart fialure
• 4. COPD
• 5. GI motility
• 6. Urninary tract incontenence
• 7. Urinary tract
• 8. Eyes pupillary size, glaucoma

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ALBUTEROL

• Trade Proventil, Ventolin
• Site beta-2 agonist, increased cAMP
• Indications relief of bronchospasm in patients
  with reversible obstructive airway disease
• Adverse Reactions nervousness, tremor,
  tachycardia, palpitations,
• Contraindications hypertension, hyperthyroidism

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AMPHETAMINE

• Trade ?
• Site adrenergic nerve terminal - indirectly
  acting sympathomimetic
• Indications narcolepsy, attention deficit
  disorder, exogenous obesity
• Contraindications symptomatic cardiovascular
  disease, hypertension, hyperthyroidism

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AMPHETAMINE

• Adverse Reactions palpitations, tachycardia,
  elevation of blood pressure, psychotic episodes
  at recommended doses (rare), overstimulation,
  restlessness, dizziness, insomnia, euphoria,
  dyskinesia, dysphoria, tremor, headaches

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ATENOLOL

• Trade Tenormin, Tenorectic
• Site beta-1 antagonist but selectivity not
  absolute
• Indications hypertension, angina pectoris
  associated with coronary atherosclerosis, acute
  myocardial infarction

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ATENOLOL

• Contraindications sinus bradycardia, heart block
  greater than first degree, cardiogenic shock, and
  overt cardiac failure, asthma, COPD
• Adverse Reactions bradycardia, dizziness, fatigue

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ATROPINE

• Trade
• Site muscarinic cholinergic antagonist
• Indications pre-anesthetic agent, bradycardia,
  heart block, antidote for cholinergics, urinary
  incontinence

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ATROPINE

• Contraindications glaucoma, pyloric stenosis or
  prostatic hypertrophy, except in doses ordinarily
  used for preanesthetic medication
• Adverse Reactions dry mouth skin, fever,
  irritability, delirium, tachycardia, flushing,
  convulsions

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BOTULINUM TOXIN

• Trade Botox, Oculinum
• Site motor nerve terminals, block
  acetylcholine release
• Notes use of botulinum toxin is very
  specialized, strabismus and blepharospasm
  associated with dystonia, including benign
  essential blepharospasm or VII nerve disorders
  in patients 12 years of age and above

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CARVEDOLOL

• Trade Coreg
• Site beta-1, beta-2, alpha-1 antagonist
• Notes higher ratio of beta to alpha blockade than
  labetolol, not advisable to discontinue abruptly,
  
• Indications angina, cardiomyopathy, heart
  failure, hypertension

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CARVEDOLOL

• Contraindications acute bronchospasm, bronchitis,
  emphysema, COPD, asthma, bradycardia, AV block,
  diabetes mellitus, hypoglycemia, liver disease,
  hyperthyroidism, pheochromocytoma, acute heart
  failure, do not uptitrate during acute volume
  exacerbation of CHF

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CARVEDOLOL

• Adverse Reactions bronchospasm, diarrhea,
  dyspnea, fatigue, headache, hyperglycemia,
  hypoglycemia, insomnia, jaundice, orthostatic
  hypotension, peripheral edema, sinus bradycardia,
  syncope, thromocytopenia, urine discoloration

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CLONIDINE

• Contraindications
• Adverse Reactions dry mouth, skin irritation
  (transdermal)

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COCAINE

• Trade
• Site amine uptake pump on sympathetic nerve
  terminals, Na channels of nerve membranes as
  local anesthetic
• Notes Cocaine causes sloughing of the cornea and
  is not meant for ophthalmic use.

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COCAINE

• Indications local (topical) anesthesia of
  accessible mucous membranes of the oral,
  laryngeal and nasal cavities
• Contraindications
• Adverse Reactions vasoconstriction, mydriasis,
  nervousness, restlessness, excitement, tremors,
  depression, respiratory failure, cardiac arrest
  /or fibrillation

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DOBUTAMINE

• Trade Dobutrex
• Site beta-1 agonist
• Notes patients with atrial fibrillation and rapid
  ventricular response should be digitalized before
  dobutamine.
• Indications short term inotropic support due to
  depressed contractility resulting from organic
  heart disease or cardiac surgery

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DOBUTAMINE

• Contraindications/Adverse Reactions tachycardia,
  hypertension, hypotension, ventricular
  arrhythmias Pharmacokinetics half life 2 min

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DOPAMINE

• Trade Intropin
• Site dopamine receptor agonist, beta-1 agonist,
  adrenergic nerve terminals as indirectly acting
  sympathomimetic
• Indications shock due to myocardial infarction,
  trauma, endotoxic septicemia, open-heart surgery,
  renal failure and c hronic cardiac decompensation
  as in congestive failure

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DOPAMINE

• Contraindications pheochromocytoma
• Adverse Reactions ectopic beats, nausea,
  vomiting, tachycardia, anginal pain,
  palpitations, dyspnea, headache, hypotension,
  vasoconstriction.

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EPHEDRINE

• Trade
• Site acts on presynaptic sympathetic nerve
  terminals as indirectly acting sympathomimetic
  releases catecholamines from nerve terminals,
  some direct receptor activation
• Notes available commercially in combination
  products
• Indications asthma

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EPHEDRINE

• Contraindications cardiovascular disease,
  hyperthyroidism, and hypertension
• Adverse Reactions excitation, tremulousness,
  insomnia, nervousness, palpitation, tachycardia,
  precordial pain, cardiac arrhythmias, vertigo,
  dry nose and throat, headache, sweating

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EPINEPHRINE

• Trade Adrenalin
• Site alpha agonist, beta-1 and beta-2 agonist
• Indications bronchospasm, cardiac arrest,
  anaphylaxis, prolong local anesthetic action,
  chronic simple glaucoma

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EPINEPHRINE

• Contraindications narrow angle (congestive)
  glaucoma, shock, local anesthesia of certain
  areas, e.g., fingers, toes
• Adverse Reactions palpitations, tachycardia,
  cardiac arrhythmias, sweating, N/V, dizziness,
  weakness, tremor, headache, apprehension,
  nervousness and anxiety.

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IMIPRAMINE

• Trade Tofranil
• Site inhibitor of amine uptake pump of nerve
  terminals (CNS action - tricyclic antidepressant)
• Notes prominent anticholinergic activity
  Indications depression, childhood enuresis
• Contraindications monoamine oxidase inhibitors,
  acute recovery after MI

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IMIPRAMINE

• Adverse Reactions orthostatic hypotension,
  hypertension, tachycardia, myocardial infarction,
  arrhythmias, congestive heart failure, stroke,
  hallucinations, nightmares, dry mouth, blurred
  vision, mydriasis, constipation, urinary
  retention, gynecomastia, impotence

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IPRATROPIUM

• Trade Atrovent
• Site muscarinic cholinergic antagonist
• Notes inhaled, most action local, not absorbed
  orally and does not cross BBB
• Indications maintenance treatment of bronchospasm
  associated with chronic obstructive pulmonary
  disease, including chronic bronchitis and
  emphysema

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IPRATROPIUM

• Contraindications/Adverse Reactions tachycardia,
  palpitations, headache, dry mouth, nausea,
  coughing, dyspnea, bronchitis, upper respiratory
  tract infection

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METOPROLOL

• Trade Lopressor, Toprol XL
• Site beta-1 antagonist
• Indications hypertension, angina pectoris,
  congestive heart failure
• Contraindications sinus bradycardia, heart block,
  cardiogenic shock, overt cardiac failure,
  myocardial infarction, asthma or asthma history

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METOPROLOL

• Adverse Reactions dizziness, depression,
  nightmares, bradycardia, Raynaud type arterial
  insufficiency, palpitations, congestive heart
  failure peripheral edema, wheezing
  (bronchospasm), diarrhea, nausea, dry mouth,
  gastric pain, constipation, flatulence, pruritus

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NEOSTIGMINE

• Trade Prostigmin
• Site acetylcholinesterase inhibitor
• Indications myasthenia gravis, acute myasthenic
  crisis
• Contraindications patients with peritonitis or
  mechanical obstruction of the intestinal or
  urinary tract

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NEOSTIGMINE

• Adverse Reactions salivation, fasciculation,
  diarrhea, anaphylaxis, dizziness, convulsions,
  bradycardia, tachycardia, A-V block and nodal
  rhythm, cardiac arrest, respiratory arrest,
  bronchospasm , emesis, flatulence, increased
  peristalsis, incontinence, sweating

103
NICOTINE

• Trade Habitrol, Nicoderm, Nicotrol, Prostep
• Site nicotinic cholinergic agonist (low dose)
  antagonist (high doses)
• Indications as an aid to smoking cessation,
  relief of nicotine withdrawal symptoms

104
NICOTINE

• Contraindications/Adverse Reactions local
  erythema, pruritus, and/or burning at the
  application site, diarrhea, dry mouth, insomnia,
  nervousness

105
NOREPINEPHRINE (LEVARTERENOL)

• Trade Levophed (leavem dead)
• Site alpha-1, alpha-2, beta-1agonist
• Indications blood pressure control in acute
  hypotensive states (e.g., spinal anesthesia,
  myocardial infarction, septicemia, blood
  transfusion, and drug reactions), adjunct in
  treatment of cardiac arrest

106
NOREPINEPHRINE (LEVARTERENOL)

• Contraindications hypotension from volume
  deficits, except in an emergency measure to
  maintain coronary and cerebral artery perfusion,
  mesenteric or peripheral vascular thrombosis
• Adverse Reactions ischemic injury, bradycardia,
  arrhythmias, anxiety, headache, substernal pain

107
PHENYLEPHRINE

• Trade Neo-Synephrine
• Site alpha agonist
• Indications vasoconstrictor (maintain BP during
  anesthesia or shock, prolong regional
  anesthesia), decongestant, mydriatic (refraction
  without cycloplegia), paroxysmal supraventricular
  tachycardia

108
PHENYLEPHRINE

• Contraindications narrow angle glaucoma, severe
  atherosclerotic cardiovascular or cerebrovascular
  disease, severe hypertension, ventricular
  tachycardia, infants, patients with aneurysms

109
PHENYLEPHRINE

• Adverse Reactions bradycardia, decreased cardiac
  output, pallor, arrhythmias, anginal pain,
  respiratory distress, tremor, dizziness, central
  excitation

110
PSEUDOEPHEDRINE

• Trade pseudophed
• Site indirectly acts on sympathetic nerve
  terminal to release norepinephrine and directly
  stimulates alpha-receptors
• Indications decongestant
• Contraindications MAO inhibitors, narrow angle
  glaucoma, severe CAD, hypertension, caution if
  hyperthyroidism, arrhythmias
• Adverse reactions insomnia, nausea, headache,
  nervousness, anxiety, palpitations, tachycardia

111
PRALIDOXIME (2-PAM)

• Trade Protopam
• Site acetylcholinesterase reactivates enzyme
  inhibited by some organophosphates, must be used
  with atropine to protect patient
• Notes ineffective after 'aging' of inhibited
  enzyme
• Indications antidote for treatment of poisoning
  due to organophosphates which inhibit
  acetylcholinesterase, control of overdosage by
  anticholinesterase drugs (muscle weakness and
  respiratory depression) in myasthenia gravis

112
PRALIDOXIME (2-PAM)

• Contraindications/Adverse Reactions difficult to
  separate toxicity of atropine or organophosphates
  from pralidoxime, in volunteers pain at the site
  of injection, blurred vision, diplopia and
  impaired accommodation, dizziness, headache,
  drowsiness, nausea, tachycardia

113
PROPRANOLOL

• Trade Inderal
• Site beta-antagonist
• Indications hypertension, angina pectoris,
  supraventricular arrhythmias, ventricular
  arrhythmias, tachyarrhythmias of digitalis
  intoxication, arrhythmias during anesthesia,
  myocardial infarction, essential tremor,
  hypertrophic subaortic stenosis, pheochromocytoma

114
PROPRANOLOL

• Contraindications cardiogenic shock, sinus
  bradycardia and greater than first degree block,
  bronchial asthma, congestive heart failure unless
  the failure is secondary to a tachyarrhythmia
  treatable with propranolol
• Adverse Reactions bradycardia CHF, heart block
  hypotension thrombocytopenic purpura Raynaud
  type arterial insufficiency, insomnia, weakness,
  fatigue reversible mental depression progressing
  to catatonia hallucinations, vivid dreams,
  bronchospasm, male impotence

115
SALMETEROL

• Trade Serevent
• Site beta-2 agonist
• Notes 50 times more selective for beta-2 than
  albuterol beta-2 are 10 to 50 of the total
  beta-receptors in heart function ?? but raises
  possibility that even highly selective beta-2
  agonists have cardiac effects

116
SALMETEROL

• Indications chronic BID treatment of asthma,
  prevention of bronchospasm in patients (12 years
  ), including patients with symptoms of nocturnal
  asthma who require regular treatment with inhaled
  short-acting beta2-agonists, prevention of
  exercise- induced bronchospasm
• Contraindications/Adverse Reactions tachycardia
  palpitations immediate hypersensitivity
  reactions urticaria, angioedema, rash,
  bronchospasm headache, tremor, nervousness,
  paradoxical bronchospasm

117
SALMETEROL

• Pharmacokinetics salmeterol acts locally plasma
  levels do not predict effect, following
  inhalation salmeterol in plasma in 5 to 10
  minutes in healthy subjects plasma half-life was
  about 5.5 hours following oral dosing (one
  volunteer only)

118
SCOPOLAMINE

• Trade Transderm Scop
• Site muscarinic cholinergic antagonist
• Notes dosage form no longer available?
  Indications prevention of nausea and vomiting
  associated with motion sickness in adults
• Contraindications glaucoma

119
SCOPOLAMINE

• Adverse Reactions dry mouth, drowsiness, blurred
  vision, pupillary dilation, disorientation,
  memory disturbances, dizziness, restlessness,
  hallucinations, confusion, difficulty urinating
  rashes and erythema, acute narrow-angle glaucoma,
  and dry itchy, or red eyes

120
TUBOCURARINE CHLORIDE

• Trade -
• Site Nm antagonist
• Notes also releases histamine
• Indications muscle relaxant adjunct to
  anesthesia, adjunct to convulsive therapy,
  facilitate management of patients on mechanical
  ventilation, diagnostic agent for myasthenia
  gravis when the results of tests with neostigmine
  or edrophonium are inconclusive

121
YOHIMBINE

• Trade Actibine, Aphrodyne, Erex, Yocon
• Site alpha-2 antagonist
• Notes blocks central alpha-2, ANS effect is
  increased parasympathetic decrease sympathetic,
  erection is linked to cholinergic and to alpha-2
  adrenergic blockade, hence (coupled with CNS
  actions) possible aphrodisiac effect

122
YOHIMBINE

• Indications blocks central alpha-2, ANS effect is
  increased parasympathetic decrease sympathetic,
  erection is linked to cholinergic and to alpha-2
  adrenergic blockade, hence (coupled with CNS
  actions) possible aphrodisiac effect