The Autonomic Nervous System

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The Autonomic Nervous System

• ISRAA OMAR

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Autonomic drugs

• Autonomic drugs Drugs that produce their
  primary therapeutic effect by mimicking or
  altering the functions of the autonomic nervous
  system .
• The autonomic nervous system is composed of
  efferent neurons.
• These innervate smooth muscle, cardiac muscle
  and the exocrine glands, thereby controlling
  digestion, cardiac output, blood flow, and
  glandular secretions.

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Activity of the Sympathetic Nervous System

• Prepares body for physical action
• Fight or Flight
• Increased heart rate
• Increased blood pressure
• Redistribution of blood flow - ? flow to skeletal
  muscle, ? flow to skin and organs
• ? GI activity
• Dilation of pupils and bronchioles
• ? blood glucose

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Activity of the Parasympathetic Nervous System

• Opposite effects to SNS
• Prepares the body for feeding and digestion
• Slows heart rate
• Lowers blood pressure
• Promotes GI secretions
• Stimulates GI movement
• Constricts the pupil
• Empties bladder and rectum

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• In general, the parasympathetic division and the
  sympathetic division of the ANS are antagonistic
  in their effects on organ systems.

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The enteric division of the ANS

• It is a very large and highly organized
  collection of neurons located in the walls of the
  gastrointestinal (GI) system.
• It regulates and coordinates the motor activity
  and secretory functions of the GI system.

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Anatomy of the ANS

• Afferent nerve fibers (sensory nerves)
• Non-myelinated information is carried to the CNS
  by the vagus, pelvic, splanchnic and somatic
  nerves.
• Efferent nerve fibers (motor nerves)
• Sympathetic division
• Thoracolumbar division (T1 L2)
• Parasympathetic division
• Craniosacral division (cranial nerves III, VII,
  IX, and X) and sacral region of spinal cord (S2
  S4)

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• Consists of 2 neurons arranged in series
• Preganglionic nerve fiber
• Postganglionic nerve fiber
• Adrenal Medulla is the exception to the two
  neuron arrangement (a modified ganglion that
  mainly secretes adrenaline hormone)

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The Peripheral Nervous System
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PRE-GANGLIONIC
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GANGLIA
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POST-GANGLIONIC
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Cholinergic Agonists

• The cholinergic drugs act on receptors that
  are activated by acetylcholine.
• Location of cholinergic neurons (releases Ach)
• Preganglionic fibers terminating in the adrenal
  medulla
• Preganglionic fibers terminating in autonomic
  ganglia (both parasympathetic and sympathetic),
• The postganglionic fibers of the parasympathetic
  division .
• Cholinergic neurons innervate the muscles of the
  somatic nervous system
• also found in the central nervous system (CNS).

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Neurotransmission at cholinergic neurons

• Involves sequential six steps.
• Synthesis, Choline acetyltransferase catalyzes
  the reaction of choline with acetyl coenzyme A
  (CoA) to form acetylcholine.
• Choline acetyl coenzyme A (CoA)
• ? Choline
  acetyltransferas
• Acetylcholine
• Storage

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• Release, When an action potential arrives at a
  nerve ending, voltage-sensitive calcium channels
  on the presynaptic membrane open, causing an
  increase in the concentration of intracellular
  calcium.
• Elevated calcium levels promote the release of
  acetylcholine into the synaptic space.
• This release can be blocked by botulinum toxin.
• Binding of acetylcholine to a receptor
• Degradation of the neurotransmitter in the
  synaptic gap by acetylcholinesterase enzyme to
  choline and acetic acid.
• Reuptake of choline by the cholinergic neurons
  for synthesis of new ACh.

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Cholinergic Receptors (Cholinoceptors)

• The postsynaptic cholinergic receptors on the
  surface of the effector organs are divided into
  two classes muscarinic and nicotinic.

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A. Muscarinic receptors

• There are five subclasses of muscarinic
  receptors M1, M2, M3, M4, and M5
• Only M1, M2 and M3, receptors have been
  functionally characterized.

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Mechanisms of Acetylcholine Signal Transduction

• Activation of the M1 or M3 receptors the
  receptor undergoes a conformational change and
  interacts with Gq protein, which in turn
  activates phospholipase C. This leads to an
  increase in intracellular Ca2.
• Ca2 can then interact to produce the response
  (e.g. Secretion, contraction, etc.)
• Activation of M2 subtype on the cardiac muscle
  stimulates Gi protein,
• Gi protein inhibits adenylyl cyclase and
  increases K conductance, to which the heart
  responds with a decrease in rate and force of
  contraction.

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Selective Muscarinic antagonists

• Pirenzepine, a tricyclic anticholinergic drug,
  selective M1 muscarinic receptor antagonist
  (such as those of the gastric mucosa).
• Darifenacin is a competitive muscarinic receptor
  antagonist at M3 receptor. The drug is used in
  the treatment of overactive bladder.

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B. Nicotinic receptors

• The nicotinic receptor is composed of five
  subunits, and it functions as a ligand-gated ion
  channel.
• Binding of two acetylcholine molecules elicits a
  conformational change that allows the entry of
  sodium ions, resulting in the depolarization of
  the effector cell.

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• Nicotine (or high doses of acetylcholine)
  initially stimulates and then blocks the
  receptor.
• Nicotinic receptors are located in the CNS,
  adrenal medulla, autonomic ganglia, and the
  neuromuscular junction.
• The nicotinic receptors of autonomic ganglia
  (called nicotinic neuronal) differ from those of
  the neuromuscular junction (which are called
  nicotinic muscular) .

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I. Direct-Acting Cholinergic Agonists

• Cholinergic agonists (also known as
  parasympathomimetics) mimic the effects of
  acetylcholine by binding directly to
  cholinoceptors.
• Classified into two groups
• Choline esters, which include acetylcholine and
  synthetic esters of choline, such as carbachol
  and bethanechol.
• Naturally occurring alkaloids, such as
  pilocarpine constitute the second group .

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• All direct-acting drugs have longer durations of
  action than acetylcholine.
• Drugs (e.g. pilocarpine and bethanechol) which
  bind to muscarinic receptors are also referred to
  as muscarinic agents.

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1. Acetylcholine

• Acetylcholine is a quaternary ammonium compound
  that cannot penetrate membranes.
• It is not useful therapeutically because of its
  multiplicity of actions and its rapid
  inactivation by the cholinesterases (unstable).

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Major Actions of Acetylcholine

• Acetylcholine has both muscarinic and nicotinic
  activity. Its actions include
• CVS
• Decrease in heart rate (negative chronotropic
  effect) and cardiac output
• The actions of acetylcholine on the heart mimic
  the effects of vagus nerve stimulation.

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• Decrease in blood pressure
• Acetylcholine activates M3 receptors found on
  endothelial cells lining the smooth muscles of
  blood vessels. This results in the production of
  nitric oxide from arginine.
• Note nitric oxide is also known as
  endothelium-derived relaxing factor and is a
  vasodilator

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• Other actions
• In the gastrointestinal tract, acetylcholine
  increases salivary secretion and stimulates
  intestinal secretions and motility.
• In the lungs, Bronchiolar secretions are also
  enhanced.
• In the genitourinary tract, the tone of the
  detrusor urinae muscle is increased, causing
  expulsion of urine.

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• In the eye, acetylcholine is involved in
  stimulating ciliary muscle contraction for near
  vision and in the constriction of the pupillae
  sphincter muscle (circular muscle), causing
  miosis (marked constriction of the pupil).

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2. Bethanechol

• Bethanechol is not hydrolyzed by
  acetylcholinesterase
• It posses strong muscarinic activity, but lacks
  nicotinic activity.
• It is used to treat urinary retention. as well
  as megacolon.
• Adverse effects sweating, salivation, flushing,
  decreased blood pressure, nausea, abdominal pain,
  diarrhea, and bronchospasm.

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3. Carbachol

• Carbachol has both muscarinic as well as
  nicotinic actions .
• It is a poor substrate for acetylcholinesterase
• Therapeutic uses carbachol is rarely used
  therapeutically except in the eye as a miotic
  agent to treat glaucoma by causing pupillary
  constriction and a decrease in intraocular
  pressure.

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4. Pilocarpine

• The alkaloid pilocarpine is a tertiary amine and
  is stable to hydrolysis by acetylcholinesterase .
  
• Pilocarpine is the drug of choice in both
  narrow-angle (also called closed-angle) and
  wide-angle (also called open-angle) glaucoma.

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II. Indirect-Acting Cholinergic
Agonsists(Anticholinesterases)

• These drugs can provoke a response at all
  cholinoceptors in the body, including
• - both muscarinic and nicotinic receptors of
  the autonomic nervous system,
• - nicotinic receptors of skeletal muscle
• - and muscarinic and nicotinic receptors in
  the brain.

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A. Reversible anticholinesterases 1.
Physostigmine

• Used in treatment of atony of intestine and
  bladder as it increases motility of either
  organ.
• It is used to treat glaucoma
• Used in the treatment of overdoses of drugs with
  anticholinergic actions, such as atropine,
  phenothiazines, and tricyclic antidepressants.

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• Adverse effects (shown by high doses)
• Convulsions .
• Bradycardia and a fall in cardiac output
• Accumulation of acetylcholine and, ultimately,
  paralysis of skeletal muscle.

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2. Neostigmine

• Similar actions to that of physostigmine.
• Unlike physostigmine, neostigmine has a
  quaternary nitrogen hence, it is more polar and
  does not enter the CNS.
• Neostigmine is used to stimulate the bladder and
  GI tract, and it is also used as an antidote for
  tubocurarine

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• Also used in symptomatic treatment of myasthenia
  gravis ( an autoimmune disease caused by
  antibodies to the nicotinic receptor at
  neuromuscular junctions. This causes their
  degradation and, thus, makes fewer receptors
  available )
• Adverse effects include salivation, flushing,
  decreased blood pressure, nausea, abdominal pain,
  diarrhea, and bronchospasm.

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3. Pyridostigmine and ambenomium

• Cholinesterase inhibitors that are used in the
  chronic management of myasthenia gravis.
• Their durations of action are longer than that of
  neostigmine.
• Adverse effects of these agents are similar to
  those of neostigmine.

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4. Demecarium

• Cholinesterase inhibitor used to treat chronic
  open-angle glaucoma (primarily in patients
  refractory to other agents) and closed-angle
  glaucoma after irredectomy.
• Mechanism of actions and side effects are similar
  to those of neostigmine.

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5. Edrophonium

• Prototype short-acting agent (duration of action
  is 10 to 20 minutes).
• The actions are similar to those of neostigmine,
  except that it is more rapidly absorbed and has a
  short duration of action
• Edrophonium is used in the diagnosis of
  myasthenia gravis. Intravenous injection of
  edrophonium leads to a rapid increase in muscle
  strength.

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6. Other reversible anticholinesterases

• Tacrine, donepezil, rivastigmine, and
  galantamine
• Are useful in patients with Alzheimer's disease
  (they have a deficiency of cholinergic neurons in
  the CNS).
• Gastrointestinal distress is their primary
  adverse effect.

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B. Irreversible Anticholinesterases

• Some synthetic organophosphate compounds have
  the capacity to bind covalently to
  acetylcholinesterase. The result is a
  long-lasting increase in acetylcholine at all
  sites where it is released.
• Many of these drugs are extremely toxic and were
  developed by the military as nerve gases (sarin,
  soman, tabun).
• Related compounds, such as parathion, are
  employed as insecticides.

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1. Echothiophate

• Echothiophate is an organophosphate.
• It is an irreversible anticholinesterase
• The enzyme becomes permanently inactivated, and
  restoration of acetylcholinesterase activity
  requires the synthesis of new enzyme molecules.
• Echothiophate is used in treatment of open-angle
  glaucoma.
• Atropine in high dosage can reverse many of the
  muscarinic and some of the central effects of
  echothiophate.
• Pralidoxime can reactivate inhibited
  acetylcholinesterase enzyme.

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2. Other irreversible anticholinesterases

• Nerve gases sarin, soman, tabun
• These are organophosphorus compounds
• Used as chemical warfare
• Malathion and Parathion
• These are organophosphorus compounds
• Used as insecticides
• Toxic effects could be treated with immediate
  administration of pralidoxime and atropine

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Cholinergic Antagonists

• The cholinergic antagonists (also called
  cholinergic blockers, parasympatholytics or
  anticholinergic drugs) bind to cholinoceptors.
• Include
• Antimuscarinic Agents block muscarinic synapses
  of the parasympathetic nerves.
• The ganglionic blockers, which block the
  nicotinic receptors of the sympathetic and
  parasympathetic ganglia.
• The skeletal neuromuscular blocking agents

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A. Antimuscarinic Agents

• Antimuscarinic drugs have little or no action at
  skeletal neuromuscular junctions or autonomic
  ganglia.

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1. Atropine

• Atropine, a tertiary amine belladonna alkaloid,
  that binds competitively to muscarinic receptors,
  preventing acetylcholine from binding to those
  sites.
• Atropine acts both centrally and peripherally.

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• Pharmacological action
• Eye
• Persistent mydriasis and cycloplegia (inability
  to focus for near vision).
• In patients with narrow-angle glaucoma
  intraocular pressure may rise dangerously.
• Gastrointestinal (GI)
• Antispasmodic, gastric motility is reduced but
  hydrochloric acid production is not significantly
  affected.
• Urinary system
• Reduces hypermotility states of the urinary
  bladder.

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• Cardiovacular
• With higher doses of atropine, the M2 receptors
  on the sinoatrial node are blocked, and the
  cardiac rate increases (tachycardia).
• Secretions
• Atropine blocks the salivary glands, producing a
  drying effect on the oral mucous membranes
  (xerostomia).
• Sweat and lacrimal glands are also affected.
  Note Inhibition of secretions by sweat glands
  can cause elevated body temperature.

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• Therapeutic uses of atropine
• Ophthalmic for eye examination. Atropine may
  induce an acute attack of eye pain due to sudden
  increases in eye pressure in individuals with
  narrow-angle glaucoma.
• Antispasmodic to relax the GI tract and bladder.
• For the treatment of overdoses of cholinesterase
  inhibitor insecticides and some types of mushroom
  poisoning (muscarine poisoning).
• As preanesthetic medication to block secretions
  in the upper and lower respiratory tracts prior
  to surgery.

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• Pharmacokinetics
• Atropine is readily absorbed, partially
  metabolized by the liver, and eliminated
  primarily in the urine. It has a half-life of
  about 4 hours.
• Adverse effects
• Dry mouth, blurred vision, tachycardia, and
  constipation.
• Effects on the CNS include restlessness,
  confusion, hallucinations, and delirium
• Contraindications
• In older individuals, the use of atropine may
  exacerbate an attack of glaucoma and / or
  urinary retention.

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2. Scopolamine

• Tertiary amine belladonna alkaloid,
• Used prophylactically for treatment of motion
  sickness.
• Produces sedation (atropine causes excitation).
• Scopolamine may produce euphoria and is subject
  to abuse.

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3. Ipratropium

• Inhaled ipratropium, a quaternary derivative of
  atropine, is useful in treating asthma.
• Ipratropium is also useful in chronic
  obstructive pulmonary disease(COPD).

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4. Tropicamide and cyclopentolate

• Used as ophthalmic solutions as mydriatics.
• Their duration of action is shorter than that of
  atropine.

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B. Ganglionic Blockers

• Ganglionic blockers act on the nicotinic
  receptors of both parasympathetic and sympathetic
  autonomic ganglia.
• These drugs are not effective as neuromuscular
  blockers

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1. Nicotine

• A component of cigarette smoke and a poison with
  many undesirable actions.
• Nicotine is available as patches, lozenges,
  gums, and other forms.
• The drug is effective in reducing the craving
  for nicotine in people who wish to stop smoking.

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• Pharmacological action
• Nicotine initially stimulates, then blocks all
  sympathetic and parasympathetic ganglia.
• The stimulatory effects include increased blood
  pressure and cardiac rate (due to release of
  noradrenaline from adrenergic terminals and
  adrenaline hormone from the adrenal medulla)
• Nicotine causes increased peristalsis and
  secretions

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2. Mecamylamine and trimethaphan

• These are ganglion blockers.
• They are used to lower blood pressure in
  emergency situations.

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Drugs affecting the sympathetic nervous system

• Drugs that act directly on the adrenergic
  receptor (adrenoceptor) and activate them are
  said to be sympathomimetics.
• Blockers of adrenoceptors are called
  sympatholytics
• There are drugs which affect presynaptic
  adrenergic function.

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Adrenergic neurons

• Adrenergic neurons synthesize, store and release
  norepinephrine (noradrenalin).
• Adrenergic neurons are found in the sympathetic
  nervous system (postganglionic sympathetic
  neurons) and in the central nervous system (CNS).
  

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Neurotransmission At Adrenergic Neurons

• The process involves five steps
• Synthesis,
• Storage,
• Release,
• Receptor binding of norepinephrine
• Removal of the neurotransmitter from the synaptic
  cleft.

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Synthesis of norepinephrine

• Tyrosine is transported into the axoplasm of the
  adrenergic neuron, where it is hydroxylated to
  DOPA by tyrosine hydroxylase.
• This is the rate-limiting step in the formation
  of norepinephrine.
• DOPA is then decarboxylated by dopa
  decarboxylase to form dopamine.
• Dopamine is hydroxylated to form norepinephrine
  by the enzyme, dopamine ß-hydroxylase.
• In the adrenal medulla, norepinephrine is
  methylated to yield epinephrine (adrenaline).

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Binding with adrenoceptors

• Binding of norepinephrine to the membrane
  receptors triggers a cascade of events, resulting
  in the formation of intracellular second
  messengers.
• Adrenergic receptors use both the cyclic
  adenosine monophosphate (cAMP) second-messenger
  system, and the phosphatidylinositol cycle, to
  transduce the signal into an effect.

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Termination of norepinephrine actions

• Norepinephrine may
• Diffuse out of the synaptic space and enter the
  general circulation,
• Be metabolized by catechol o-methyltransferase
  (COMT) in the synaptic space,
• Be recaptured by an uptake system that pumps the
  norepinephrine back into the neuron. Uptake of
  norepinephrine into the presynaptic neuron is the
  primary mechanism for termination of
  norepinephrine's effects.

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Fate of reuptaken norepinephrine

• Norepinephrine may be released by another action
  potential, or it may stored,
• Alternatively, norepinephrine can be oxidized by
  monoamine oxidase (MAO) present in neuronal
  mitochondria.

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Adrenergic receptors (adrenoceptors)

• Adrenoceptors are designated a and ß.
• For a receptors, the rank order of potency is
  epinephrine gtnorepinephrine gtgt isoproterenol
  (isoprenaline).
• For ß receptors, the rank order of potency is
  isoproterenol gt epinephrine gt norepinephrine.

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A. a adrenoceptors

• The a adrenoceptors are subdivided into two
  subgroups, a1 and a2
• a1 Receptors
• Found on the postsynaptic membrane of the
  effector organs
• Activation of a1 receptors initiates a series of
  reactions through a G protein resulting in the
  generation of inositol-1,4,5-trisphosphate (IP3)
  and diacylglycerol (DAG) from phosphatidylinositol
  .
• IP3 initiates the release of Ca2 from the
  endoplasmic reticulum into the cytosol, and DAG
  turns on other proteins within the cell.
• The a 1 receptors are further divided into a 1A,
  a 1B, a 1C, and a 1D

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• a2 Receptors
• are located primarily on presynaptic nerve
  endings.
• The stimulation of a2 receptor causes
  inhibition of further release of norepinephrine.
• a2 Receptors are also found on presynpatic
  parasympathetic neurons. Norepinephrine can
  diffuse and interact with these receptors,
  inhibiting acetylcholine release.
• The effects of binding at a2 receptors are
  mediated by inhibition of adenylyl cyclase and a
  fall in the levels of intracellular c-AMP.
• a 2 receptors are further divided into a 2A, a
  2B, a 2C, and a 2D.

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• Tamsulosin
• is a selective a 1A antagonist
• is used to treat benign prostate hyperplasia. The
  drug is clinically useful because it targets a1A
  receptors found primarily in the urinary tract
  and prostate gland.

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B. ß-adrenoceptors

• The ß-adrenoceptors can be subdivided into three
  major subgroups, ß1, ß2, and ß3,.
• ß1 Receptors
• Have approximately equal affinities for
  epinephrine and norepinephrine (mainly found in
  the heart)
• ß2 receptors
• Have a higher affinity for epinephrine than for
  norepinephrine (mainly found in the bronchioles)
• ß3 receptors
• Are involved in lipolysis.

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• Binding of a neurotransmitter at any of the three
  ß receptors results in activation of adenylyl
  cyclase and, therefore, increased concentrations
  of cAMP within the cell.

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Distribution of receptors

• Tissues such as the vasculature skeletal muscle
  have both ß1 and ß2 receptors, but the ß2
  receptors predominate.
• The heart contains predominantly ß1 receptors.

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Effects mediated by the adrenoceptors

• Stimulation of ß1 receptors characteristically
  causes cardiac stimulation,
• Stimulation of ß2 receptors produces
  vasodilatation (in skeletal vascular beds) and
  bronchiolar relaxation.

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Desensitization of receptor

• Prolonged exposure to the catecholamines reduces
  the responsiveness of these receptors, a
  phenomenon known as desensitization.

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Catecholamines

• Sympathomimetic amines that contain the
  3,4-dihydroxybenzene group (such as epinephrine,
  norepinephrine, isoproterenol, and dopamine) are
  called catecholamines.
• These compounds share the following properties
• High potency
• Rapid inactivation by COMT and by MAO .
• Poor penetration into the CNS because they are
  polar

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Adrenergic agonists

• Classification of the adrenergic agonists
• Direct-acting agonists include
• epinephrine, norepinephrine, isoproterenol, and
  phenylephrine.
• Indirect-acting agonists include
• amphetamine, cocaine and tyramine.
• Mixed-action agonists include
• ephedrine, pseudoephedrine and metaraminol, may
  act directly and indirectly.

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A. Direct-Acting Adrenergic Agonists

• 1. Epinephrine
• Is a catecholamine.
• Interacts with both a and ß receptors.
• At low doses, ß effects (vasodilatation)
  predominate, whereas at high doses, a effects
  (vasoconstriction) are strongest.

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• Pharmacological effects
• Epinephrine strengthens the contractility of the
  myocardium (positive inotropic ß1 action) and
  increases the heart rate (positive chronotropic
  ß1 action).
• Epinephrine increases systolic blood pressure,
  coupled with a slight decrease in diastolic
  pressure.
• Epinephrine causes powerful bronchodilation (ß2
  action).

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• Epinephrine inhibits the release of allergy
  mediators such as histamines from mast cells.
• Epinephrine has a significant hyperglycemic
  effect because of increased glycogenolysis in the
  liver (ß2 effect), increased release of glucagon
  (ß2 effect), and a decreased release of insulin
  (a2 effect).
• Lipolysis Epinephrine initiates lipolysis
  through its agonist activity on the ß receptors
  of adipose tissue

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Metabolism of Epinephrine

• Epinephrine is metabolized by two enzymatic
  pathways MAO, and COMT.
• The final metabolites found in the urine are
  metanephrine and vanillylmandelic acid.

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Therapeutic uses

• Treatment of acute asthma and anaphylactic
  shock, epinephrine is the drug of choice.
• Glaucoma in open-angle glaucoma. It reduces the
  production of aqueous humor.
• Cardiac arrest Epinephrine may be used to
  restore cardiac rhythm.
• Anesthetics Local anesthetic solutions usually
  contain 1100,000 parts epinephrine. The effect
  of the drug is to greatly increase the duration
  of the local anesthesia. It does this by
  producing vasoconstriction at the site of
  injection.

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Adverse effects

• CNS disturbances include anxiety, fear,
  tension, headache, and tremor.
• Cerebral hemorrhage as a result of a marked
  elevation of blood pressure.
• Cardiac arrhythmias
• Pulmonary edema.

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Interactions

• Hyperthyroidism Epinephrine may have enhanced
  cardio-vascular actions in patients with
  hyperthyroidism.
• Cocaine In the presence of cocaine, epinephrine
  produces exaggerated cardiovascular actions.
• Diabetes Epinephrine increases the release of
  endogenous stores of glucose. In the diabetic,
  dosages of insulin may have to be increased.

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2. Norepinephrine

• Cardiovascular actions
• Vasoconstriction Both systolic and diastolic
  blood pressures increase
• Norepinephrine is used to treat shock, because
  it increases vascular resistance and, therefore,
  increases blood pressure. However, metaraminol is
  favored.

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3. Isoproterenol

• Isoproterenol is a direct-acting synthetic
  catecholamine that predominantly stimulates both
  ß1- and ß2-adrenergic receptors
• Therapeutic uses
• It can be employed to stimulate the heart in
  emergency situations.

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4. Dobutamine

• Dobutamine is a synthetic, selective ß1 agonist.
  
• Dobutamine is used to increase cardiac output in
  congestive heart failure.

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5. Oxymetazoline

• Oxymetazoline is a direct-acting synthetic
  adrenergic agonist that stimulates both a1- and
  a2-adrenergic receptors.

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6. Phenylephrine

• Phenylephrine is a direct-acting, synthetic a 1
  receptors agonist.
• It is not a catechol derivative and, therefore,
  not a substrate for COMT.
• Phenylephrine is a vasoconstrictor that raises
  both systolic and diastolic blood pressures.
• Phenylephrine acts as a nasal decongestant and
  produces prolonged vasoconstriction.

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7. Methoxamine and clonidine

• Methoxamine is a direct-acting, synthetic a1
  receptor agonist.
• Clonidine is an a2 agonist that prevents further
  release of noradrenaline.
• It is used in hypertension as it acts on a2
  receptors in the CNS..
• It can be used in withdrawal from opiates or
  benzodiazepines.

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• 8. Metaproterenol
• The drug is an agonist at ß2 receptors,
  producing little effect on ß1 receptors of the
  heart.
• The drug is useful as a bronchodilator in the
  treatment of asthma
• 9. Albuterol, pirbuterol, and terbutaline
• are short-acting ß2 agonists used primarily as
  bronchodilators .
• 10. Salmeterol and formoterol
• are selective ß2-agonists, long-acting
  bronchodilators.
• These agents are highly efficacious when combined
  with a corticorsteroid.

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B. Indirect-Acting Adrenergic Agonists

• They potentiate the effects of norepinephrine
  produced endogenously, but these agents do not
  directly affect postsynaptic receptors.

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1. Amphetamine

• Central stimulant, abused drug
• Its peripheral actions are mediated primarily
  through the release of stored norepinephrine and
  the blockade of norepinephrine uptake.

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2. Tyramine

• It is not a clinically useful drug, but it is
  important because it is found in fermented foods,
  such as cheese.
• Normally, it is oxidized by MAO in the
  gastrointestinal tract, but if the patient is
  taking MAO inhibitors, it can precipitate a
  hypertensive crisis in him.

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3. Cocaine

• Cocaine is a local anesthetic (sodium channel
  blocker) and is a CNS stimulant (blocks the
  reuptake of norepinephrine, thus potentiating NA
  effects).
• Drug of abuse.

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C. Mixed-Action Adrenergic Agonists

• Mixed-action drugs induce the release of
  norepinephrine, and they activate postsynaptic
  adrenergic receptors.
• Ephedrine, and pseudoephedrine are plant
  alkaloids, that are now made synthetically.
• Ephedrine produces bronchodilation
• Pseudoephedrine is used to treat nasal and sinus
  congestion.

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D. Adrenergic Antagonists (also called blockers
or sympatholytic agents)

• A. a-Adrenergic Blocking Agents
• The a-adrenergic blocking agents,
  phenoxybenzamine and phentolamine, have limited
  clinical applications, they are nonselective a
  blockers

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• 1. Phenoxybenzamine
• is used in the treatment of pheochromocytoma, a
  catecholamine-secreting tumor of the adrenal
  medulla.
• Adverse effects Phenoxybenzamine can cause
  postural hypotension, nasal stuffiness, nausea,
  and vomiting.
• 2. Phentolamine
• Phentolamine is also used for the short-term
  management of pheochromocytoma.

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• 3. Prazosin terazosin, doxazosin, and tamsulosin
  
• are selective competitive blockers of the a1
  receptor.
• The first three drugs are useful in the treatment
  of hypertension.
• Tamsulosin is indicated for the treatment of
  benign prostatic hyperplasia.
• Doxazosin is the longest acting of these drugs.

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• The first dose of these drugs produces an
  exaggerated orthostatic hypotensive response that
  can result in syncope (fainting). This action,
  termed first-dose effect.
• Tamsulosin is a more potent inhibitor of the a1A
  receptors found on the smooth muscle of the
  prostate. This selectivity accounts for
  tamsulosin's minimal effect on blood pressure.

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• 4. Yohimbine
• Is a selective a2 blocker.
• It is found as a component of the bark of the
  yohimbe tree and is sometimes used as a sexual
  stimulant (aphrodisiac) or cardiovascular
  stimulant.

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B. ß-Adrenergic Blocking Agents

• Nonselective ß-blockers act at both ß1 and ß2
  receptors, whereas cardioselective ß antagonists
  block ß1 receptors
• Note There are no clinically useful ß2
  blockers.
• Although all ß-blockers lower blood pressure in
  hypertension, they do not induce postural
  hypotension, because the a-adrenoceptors remain
  functional.

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• ß-Blockers are also effective in treating
• Angina,
• Cardiac arrhythmias,
• Myocardial infarction,
• Congestive heart failure,
• Hyperthyroidism,
• Glaucoma, as well as serving in the prophylaxis
  of migraine headaches.

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1. Propranolol

• A nonselective ß blocker
• Sustained-release preparations for once-a-day
  dosing are available.
• Actions
• Cardiovascular Propranolol diminishes cardiac
  output, having both negative inotropic and
  chronotropic effects.
• Cardiac output, work, and oxygen consumption are
  decreased by blockade of ß1 receptors these
  effects are useful in the treatment of angina.
• The reduction in cardiac output leads to
  decreased blood pressure.

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• Bronchoconstriction Blocking ß2 receptors in the
  lungs of susceptible patients causes contraction
  of the bronchiolar smooth muscle.
• Non-selective ß-blockers, are contraindicated in
  patients with COPD or asthma.
• ß-blockade leads to decreased glycogenolysis and
  decreased glucagon secretion, thus pronounced
  hypoglycemia may occur after insulin injection in
  a patient using propranolol.
• ß-Blockers also mask the normal physiologic
  response to hypoglycemia.

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Mechanisms of action

• Propranolol lowers blood pressure in hypertension
  by
• Decreased cardiac output is the primary
  mechanism,
• Inhibition of renin release from the kidney and
  decreased sympathetic outflow from the CNS also
  contribute to propranolol's antihypertensive
  effects

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• Adverse effects
• Bronchoconstriction
• Arrhythmias Treatment with ß-blockers must never
  be stopped quickly because of the risk of
  precipitating cardiac arrhythmias, which may be
  severe.
• Sexual impairment

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• Drug interactions
• Drugs that interfere with the metabolism of
  propranolol, such as cimetidine, fluoxetine,
  paroxetine, and ritonavir, may potentiate its
  antihypertensive effects.
• Conversely, those that stimulate its metabolism,
  such as barbiturates, phenytoin, and rifampin,
  can decrease its effects.

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• 2. Timolol and nadolol
• Nonselective ß blockers,
• are more potent than propranolol.
• 3. Acebutolol, atenolol, metoprolol, and esmolol
  
• Selective ß1 blockers
• Esmolol has a very short lifetime. It is only
  given intravenously if required during surgery or
  management of poisoning.
• 4. Pindolol and acebutolol
• blockers with partial agonist activity

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• 5. Labetalol and carvedilol
• blockers of both a- and ß- adrenoceptors
• Carvedilol also decreases lipid peroxidation and
  vascular wall thickening, effects that have
  benefit in heart failure.
• Labetalol may be employed as an alternative to
  methyldopa in the treatment of pregnancy-induced
  hypertension.
• Intravenous labetalol is also used to treat
  hypertensive emergencies, because it can rapidly
  lower blood pressure.

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Drugs Affecting Neurotransmitter Release or Uptake

• Some agents act on the adrenergic neuron, either
  to interfere with neurotransmitter release or to
  alter the uptake of the neurotransmitter.
• 1. Reserpine
• Reserpine, a plant alkaloid that causes the
  depletion of biogenic amines.
• Sympathetic function, in general, is impaired
  because of decreased release of norepinephrine.

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• 2. Guanethidine
• Guanethidine blocks the release of stored
  norepinephrine as well as displaces
  norepinephrine from storage vesicles (thus
  producing a transient increase in blood
  pressure).
• This leads to gradual depletion of norepinephrine
  in nerve endings except for those in the CNS.
• Guanethidine commonly causes orthostatic
  hypotension and interferes with male sexual
  function.

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• 3. Alpha methyl dopa
• Antihypertensive
• Mechanism Transformed to alpha methyl
  noradrenaline in adrenergic neuron,
• When released, alpha methyl noradrenaline acts as
  agonist on presynaptic alpha2 receptors. Thus
  further release of transmitter is inhibited.

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• GOOD LUCK