Adrenergic Agonists

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Adrenergic Agonists

• Dr. Asmah Nasser, M.D.

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Steps of Catecholamie Synthesis

• Tyrosine tyrosine hydroxylase DOPA
• DOPA DOPA decarboxylase dopamine
• DA DA ß-decarboxylase NE
• NE is taken up and stored in granules
• NE not stored in storage granules are called as
  mobile pool (MAO can metabolize these)
• NE releases via exocytosis as Ca enters.
• NE attaches to receptors in the post-synaptic
  neuron

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Routes of NE after metabolism/after release

• NE can be transported back into the pre-synpatic
  neuron (reuptake)
• NE can activate the presynaptic receptors (a-2
  for negative feedback)
• NE can be metabolized by COMT enzyme
• End product of EPI metabolism ? VMA
• End product of DOPA metabolism ? VHA

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• Know the rate limiting enzyme
• Know routes of NE after release
• Know about metabolism within pre-synapse

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Theoretical drug targets

• MAO inhibitors increase the prejunctional levels
  of NE
• Mobile pool displace NE from mobile pool
• Uptake inhibit the uptake into nerve cell
  ?increases levels of NE)
• Activation of pre-synapse alpha receptors
• Postsynaptic receptors

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About the adrenergic system.

• Sympathetic nervous system exerts its effects by
  acting on
• ? , ß, and D receptors
• ? receptors are subdivided into ?1 and ?2
• ß receptors are subdivided into ß1 and ß2 and ß3
• D Dopamine receptors

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Role of SSNS

• Important regulator of the activities of heart
  and peripheral vasculature, especially in
  responses to exercise and stress
• Drugs that mimic the actions of epinephrine are
  called sympathomimetic drugs or adrenergic drugs
• Has a wide range of effects and uses

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Indirectly acting drugs

• Two types of drugs, which involve
• Displacement of stored catecholamines from the
  pre-synaptic nerve (amphetamine and tyramine)
• Inhibition of reuptake of catecholamines already
  released (cocaine)
• Some drugs have both direct and indirect actions.
  
• Both types of sympathomimetics, direct and
  indirect, ultimately cause activation of
  adrenoceptors, leading to the characteristic
  effects of catecholamines

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Review of the receptors of the SNS
A1 Blood vessels Pupil (Iris) Smooth muscle (GI/GU) Vasoconstriction Mydriasis sphincter contraction ?Constipation and Urinary retention
A2 Presynaptic neurons Reduces release of norepinephrine (as a negative feedback mechanism) ? bradycardia,hypotension
B1 Heart Contraction ? Increased heart rate
B2 Smooth muscles Relaxation ?Bronchodilation, urinary retention, constipation, uterus relaxation
D Arteries Arteriodilation of Arteries (Renal, Mesenteric, Coronary)
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• Net activity of a drug depends on its affinity
  for the receptor.

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Cardiovascular System

• Blood Vessels
• Vascular smooth muscle tone is regulated by
  adrenoceptors
• ?1 increase arterial resistance.
• ß1 increases heart rate.
• ß2 causes smooth muscle relaxation with slight
  decrease in arterial resistance ? decrease BP

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Blood Pressure

• A relatively pure ?1 agonist such as
  phenylephrine increases peripheral arterial
  resistance
• This leads to a dose-dependent rise in blood
  pressure
• A relatively pure ß agonist such as isoproterenol
  decreases peripheral resistance by activating ß2
  receptors (smooth muscle relaxation )

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Organ system effects CNS

• Catecholamines do not cross the BBB effectively
• Some drugs i.e. amphetamine/cocaine does cross
  the BBB and produces stimulant effects
• Starts with reducing fatigue and progresses as
  anorexia, euphoria and insomnia
• Very high doses-aggressiveness, marked anxiety
  and convulsions

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Amphetamine

• Used and misused as a CNS stimulant
• Amphetamine easily enters the CNS
• It has marked stimulant effects on mood and
  alertness and a depressant effect on appetite.
• Its peripheral actions are mediated primarily
  through the release of catecholamines
• Methamphenidate (N-methylamphetamine) is very
  similar to amphetamine with a higher ratio of
  central to peripheral actions .
• ??? Lipolysis from Beta3

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Eye

• The radial pupillary dilator muscle of the iris
  contains ?1 receptors
• Activation causes mydriasis
• ? and ß stimulants also have important effects on
  intraocular pressure.
• ? agonists decreases the outflow of aqueous humor
  from the eye and ß antagonists (timolol) decrease
  the production of aqueous humor.

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Respiratory Tract

• Bronchial smooth muscle contains ß2 receptors
  that cause bronchodilation
• The blood vessels of the upper respiratory tract
  mucosa contain a1 receptors. Decongestants are
  a1 agonists, causes vasoconstriction.

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Genitourinary Tract

• The bladder base, urethral sphincter, and
  prostate contain ?1 receptors that mediate
  contraction and therefore promote urinary
  rentention.
• ß are found in the Uterus causing smooth muscle
  relaxation.

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Epinephrine

• A very potent vasoconstrictor and cardiac
  stimulant.
• The rise in systolic blood pressure that occurs
  after epinephrine is due to its positive
  inotropic and chronotropic actions on the heart
  (predominantly ß1 receptors) and the
  vasoconstriction induced in many vascular beds
  (?1 receptors).
• Epinephrine also activates ß2 receptors in
  skeletal muscle blood vessels, leading to their
  dilation. Consequently, TPR may fall,
• Contributes to increased blood flow during
  exercise.
• Not absorbed if given orally. Must be given IV

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Epinephrine

• Uses
• Anaphylactic Shock
• Increases local anesthestic action (by
  vasoconstriction)
• Cardiac arrest
• Contraindications
• Hyperthyroidism
• HTN
• Arrthymias

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Anaphylaxis

• Anaphylaxis
• Immediate (type I) IgE-mediated reactions
• Characterized by bronchospasm, mucous membrane
  congestion, angioedema, and severe hypotension
• Treatment Epinephrine and Steroids

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?1 Selective Agonists

• Phenylephrine
• MOA Alpha 1 receptor agonist
• Metabolism Degraded rapidly by MAO
• Very low Bioavailability
• Causes vasoconstriction of vessels.
• Nasal and ophthalmic preparations.
• Uses
• Nasal Decongestant
• Mydriasis (doesnt cause cycloplegia)
• Side effects/Contraindications Closed angle
  Glaucoma. Rebound congestion.

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?2 Selective Agonists

• Clonidine
• Alpha 2 receptor agonist ? negative feedback ?
  Decreased release of NE
• Used in Hypertension, diabetic diarrhea, narcotic
  addicts and to treat benzodiazepam withdrawal
  effects
• Crosse BBB
• Side effects Orthostatic hypotension, dry mouth,
  sedation, rebound hypertension, Sexual Dysfunction

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?2 Selective Agonists

• ?-methyldopa
• Doesnt cross placenta
• Uses HTN, Gestational HTN, Chronic HTN during
  Pregnancy

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Non-selective ? agonists

• Oxymetazoline and Xylometazoline
• Higher affinity for ?1 than ?2 (partial ? 2
  agonist)
• Also causes vasoconctriction.
• Used as a nasal decongestant

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Dopamine

• At low concentrations Stimulates D receptors,
  causes Vasodilation of arteries (renal, coronary,
  GI)
• At intermediate doses Stiumates Beta 1 receptors
  ? tachycardia
• At high doses stimuates alpha 1 receptors ?
  Vasoconstriction
• Uses Cardiogenic shock (beta 1 stimulation),
  CHF, Hypotension (alpha 1 stimulation)
• Adverse effects HTN, Tachycardia, arrythmias

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Special Sympathomimetics

• Cocaine
• is a local anesthetic with a peripheral
  sympathomimetic action
• The action results from inhibition of transmitter
  reuptake at pre-synapse.
• Readily enters the CNS and produces an
  amphetamine-like effect that is shorter lasting
  and more intense.
• The major action of cocaine in the central
  nervous system is to inhibit dopamine reuptake
  into neurons in the "pleasure centers" of the
  brain.
• Increased epinephrine leads to systemic symptoms
  of sympathetic effects.

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Tri-cyclic Anti-depressants

• Drugs used in Depression
• Like Cocaine, TCA inhibits the reuptake of NE to
  the pre-synaptic neuron, as well as serotonin.
• If TCA Is given in adjunct with another
  adrenergic agonist ? Hypertensive Crisis

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Tyramine

• It is a normal by-product of tyrosine metabolism
  in the body
• Also found in high concentrations in fermented
  foods such as cheese and fish.
• If administered parenterally, it has an indirect
  sympathomimetic action caused by the release of
  stored catecholamines.
• Just like amphetamines, it increases the number
  of catecholeamines at the synapse.

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Clinical implications

• In patients treated with MAO inhibitors (drug
  used in Depression and Parkinsons disease)
  causes an increase in NE levels.
• Effect of tyramine is greatly intensified,
  leading to marked increases in BP and HR
  hypertensive crsis, AKA Cheese syndrome
• ? Arrythemia or Stroke
• Patients taking MAO inhibitors must be very
  careful to avoid tyramine-containing foods.

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Amphetamines

• Legitimate indications of amphetamine include
• Causes released of stored NE from the pre-synapse
  into the synapse.
• Narcolepsy ADHD
• Obesity???
• Side effects Insomnia, Decreased apetite,
  decreases respiratory center

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Isoproterenol

• Very potent ß-receptor agonist and has little
  effect on ? receptors.
• Leads to an increase and Heart rate (ß1) with a
  decrease in blood pressure (ß2)
• This lead to a marked increase in cardiac output
  associated with a fall in diastolic and mean
  arterial pressure

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Beta 1 agonists

• Dobutamine Increases heart rate. Used in
  cardiogenic shock, acute heart failure.

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Beta 2 agonists

• Terbutaline used in pre-term labor. Causes
  smooth muscle relaxation in the uterus.
• Ritodrine Also used in preterm labor

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Beta 2 agonists for Asthma

• Short acting (rescue drugs) Albuterol,
  Terbutaline
• Long acting (maintenance drugs) Salmetrol
• Inhaled Beta agonists is used in Asthma. Causes
  smooth muscle relaxation at the bronchus
  (bronchodilaton)
• Adverse drug effects Tachycardia, tremors,
  palpitations

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Summary

• Know about production and metabolism of NE
• Know the different receptors of the SNS, the
  organs they are in, and their net effects
• Know about SNS effect of Eyes, BP, HR,
  Respiratory system, and GU tract
• Know about Cocaine, Amphetamine, and Tyramine,
  TCA
• Know about alpha 1 agonists, alpha 2 agonists,
  and Beta agonists. Mechanism, Indictions, Side
  effects
• ?

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Pretest Question

• Of the many types of adrenergic receptors found
  throughout the body, which is most likely
  responsible for the cardiac stimulation that is
  observed following an intravenous injection of
  epinephrine?
• a. a1-adrenergic receptors
• b. a2-adrenergic receptors
• c. ß1-adrenergic receptors
• d. ß2-adrenergic receptors
• e. ß3-adrenergic receptors

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Pretest Question

• Ritodrine hydrochloride is used in the treatment
  of
• a. Parkinsons disease
• b. Bronchial asthma
• c. Depression
• d. Hypertension
• e. Premature labor

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Pretest Question

• Epinephrine may be mixed with certain
  anesthetics, such as procaine, in order to
• a. Stimulate local wound repair
• b. Promote hemostasis
• c. Enhance their interaction with neural
  membranes and their ability to depress nerve
  conduction
• d. Retard their systemic absorption
• e. Facilitate their distribution along nerves and
  fascial planes

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Pretest Question

• The drug of choice for the treatment of
  anaphylactic shock is
• a. Epinephrine
• b. NE
• c. Isoproterenol
• d. Diphenhydramine
• e. Atropine

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Pretest Question

• A 60-year-old male with congestive heart failure
  (CHF) is treated with dobutamine. Select the
  mechanism of action of dobutamine.
• a. a-adrenergic agonist
• b. a-adrenergic antagonist
• c. ß-adrenergic agonist
• d. ß-adrenergic antagonist
• e. Mixed a and ß agonist
• f. Mixed a and ß antagonist

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Pretest Question

• Of the following structures, which does not
  respond to ß-adrenergic receptor stimulation?
• a. Ciliary muscle of the iris
• b. Radial muscle of the iris
• c. Bronchial muscle
• d. Atrioventricular (AV) node
• e. Sinoatrial (SA) node

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Pretest Question

• A 16-year-old male treated for bronchial asthma
  develops skeletal muscle tremors. Which of the
  following agents may be responsible for this
  finding?
• a. Ipratropium
• b. Zileuton
• c. Beclomethasone
• d. Cromolyn
• e. Salmeterol

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Pretest Question

• Which of the following agents should a patient
  take for a stuffy, runny nose?
• a. Oxymetazoline
• b. Albuterol
• c. Clonidine
• d. Terbutaline
• e. Metoprolol

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Pretest Question

• A 10-year-old male displays hyperactivity and is
  unable to focus on his schoolwork because of an
  inability to focus on the activity. Which of the
  following might prove effective in this patient?
• a. Methylphenidate
• b. Terbutaline
• c. Dobutamine
• d. Pancuronium
• e. Prazosin
• f. Scopalamine