Adrenergic Agents

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Adrenergic Agents
2015-02-17 14:33:10

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  1. Autonomic nervous system: (2) and its neurotransmitters
    • Paraympathetic Division (Ach)
    • Sympathetic Division (NE)
  2. are agent/drugs that mimic and initiate
    a response
  3. _____ stimulate more than one of the
    adrenergic receptor sites (also known as ___)
    • Adrenergic Agents
    • Adrenoceptor
  4. Adrenoceptors:
    • α, β receptors
    • α is subdivided into α1 and α2
    • β is subdivided into β1 and β2
  5. Symphathomimetics(___)
    Sympatholytics (____)
    • adrenergic stimulants
    • antiadrenergics/adrenergic-blocking agents
  6. Biosynthesis of catecholamines
  7. Adrenergic Agents
    Affects the following Neurotransmitters:
    • Norepinephrine (NE, aka? __)
    • Epinephrine(E, aka? ___)
    • Dopamine (DA)
  8. Examples Adrenergic agents: (3)
    __ (a bronchodilator) __(an antihypertensive) __(BN) – Antiparkinsonism
  9. proposed and designated α and β adrenoceptors based on their apparent drug sensitivity.
  10. a1 -receptors : (3)
    • Phenylephrine(_____)
    • Methoxamine (___)
    • Oxymetazoline(____)
  11. a2- receptors : (5)

    • Clonidine(____)
    • Methyldopa(___)
    • Guanabenz(_____)
    • Guanfacine(______)
    • Tizanidine(______)
  12. B-receptors:
    • Non-selective
    • Isoproterenol(Isuprel)

    • b1-selective
    • Dobutamine(Dobutrex)
    • Dopamine(Intropin)

    • b2-selective
    • Terbutaline(Brethine, Bricanyl)
    • Metaproterenol(Metaprel, Alupent)
    • Albuterol(Proventil, Ventolin)
    • Salmeterol(Serevent)
    • Ritodrine(Yutopar)
  13. Non-selective
    Isoproterenol (___)
  14. b1-selective (2)
    • Dobutamine (___)
    • Dopamine (_____)
  15. b2-selective (5)
    • Terbutaline (2)
    • Metaproterenol (2)
    • Albuterol (2)
    • Salmeterol (1)
    • Ritodrine (1)
  16. postsynaptic α-receptor
  17. presynaptic α-receptor
  18. Were designated as those that were excitatory
  19. -Present in skin and blood vessels
    -As Nasal Decongestant and Vasoconstrictors
    which causes hypertension
    a1 agonist
  20. -Blocks α1A-receptor in prostate smooth
    muscle and relax the muscle with implication of treating benign prostatic hyperplasia (BPH)
    -Vasodilator and Hypotensive with clear implications of treating Hypertension
    a1 antagonist
  21. -Act at CNS sites to decrease sympathetic outflow to the periphery, resulting in decreased NE release at sympathetic nerve terminal and therefore relaxed vascular smooth muscle
    -Treatment for Hypertension (e.g.Clonidine)
    a2 agonist
  22. __ suggested that β-receptors could be subdivided into β1 and β2 types
    Lands et al.
  23. Postsynaptic receptors :
    β1, β2, β3 including the α1 receptor
  24. -Causes  an increase in rate and force of contraction when β1 receptors in heart is activated
    -should be expected to slow the heart rate and decrease the force of contraction
    -Tx for Hypertension, Angina, and certain Cardiac Arrythmias
    β1 blockers
  25. -Relaxes the smooth muscles in the bronchi,
    thus dilating and opening airways.
    -In uterus, it relaxes also the muscle and used to inhibit uterine contractions
    β2 – Agonist
  26. Indirectly acting and sympathomimetic
    • •       Tyramine
    • •       Amphetamines
    • •       Ephedrine
  27. Mechanism for removing the NE from the
    synapse and terminating its action at the receptors. these mechanism include: (3)
    • a)  Reuptake of NE into the presynapticneuron
    • b)  Conversion of NE to an inactivemetabolite
    • c)  Diffusion of the NE away from thesynapse
  28. •  Recycling the NE
    •  Involves Na+ / Cl- dependent transmembrane (TM)
    •  This reuptake system also transports
    certain amines other than NE into the nerve terminal, and can be blocked by
    such drugs
    Uptake 1
  29. • Extraneuronal uptake process
    • Play a role in disposition of circulating CA’s
    Uptake 2
  30. • Second mechanism of CA removal
  31. Second enzyme of importance in the metabolism of Cas
    COMT (cathecol-O-methlytransferase)
  32. -   first enzyme of importance in the metabolism
    of Cas in the adrenergic neurons of human brain
    - Oxidatively deaminate Cas to the corresponding acid by the enzyme aldehyde
    •  MAO (monoamine oxidase)
  33. Two types of MAOs
    • MAO-B (metabolizes DA)
    • MAO-B inhibitor (would tend to preserve DA)
  34. major end product of several pathways of NE
    Vanillymadelic acid (VMA)
  35. – major metabolite of brain DA
    - Methylhydroxyphenylglycoaldehyde (MOPEG) is indicative of NE levels
    Homovanillicacid (HVA)
  36. - Used for preoperative management of PHEOCHROMOCYTOMA
    Metyrosine (a-methyl-L-tyrosine) (BN)
  37. Metyrosine
    - Lowers CA production by __ - __ %
    - Given orally ranging ___ grams / day
    • 35%-80%
    • 1-4g / day
  38. chromaffin cell tumor that produce large amounts of NE and E
  39. Side effects of  Metyrosine

    • Crystalluria
    • Sedation

  40. - Depletes the vesicle storage of NE
    - Depletes the storage of serotonin and DA in their respective neurons in the brain
    - Blocks the VMAT that transports NE and other biogenic amines from the cytoplasm in to the storage vesicles

  41. Reserpine is an indole alkaloid obtained from the root of
  42. - Used orally as active antihypertensives
    - They both accumulate within the neuronal storage vesicles.
    - They bind to the storage vesicles and stabilize the neuronal storage vesicle membranes, making them less responsive to nerve impulses
    Guanethidine (BN) and Guanadrel (BN)
  43. Guanethidine contains 2 basic nitrogen atoms with pKa __ and __
    9.0 and 13.43
  44. Guanethidine forms into:
    • - Guanethidine monosulfate
    • (C10H22N4 . H2SO4)
    • - Guanethidine sulfate
    • (C10H22N4)2 . (H2SO4)
  45. Guanethidine is:
    Absorbed orally %
    Half-life of about
    • (3%-50%)
    • 5 days
  46. - Treat moderate-to-severe hypertension
    - Orally absorbed
    - Half-life
    Guanadrel (BN)

    • 85%
    • 12 hrs
  47. • produce effects resembling those produced by stimulating of the sympathetic NS
    • Produce effect through Direct, Indirect, Mixed mechanism of action
    Sympathomimetic agents
  48. - Elicit a sympathomimetic response by interacting directly with adrenergic receptor

    - Maximal activity is seen in B-phenylethylamine derivatives contantaining cathecol and a –OH group on the ethylamine portion of the molecule
    Direct-acting sympathomimetics
  49. - Critical factor in the interaction of adrenergic agonists with their receptors is stereoslectivity
    Optical Isomerism
  50. - the greatest adrenergic activity occurs when 2 carbon atoms separate the aromatic ring from the amino group
    Separation of aromatic ring and amino group
  51. - Stereoselectivity is based on the presumed interaction of these 3 critical pharmacophoric groups with 3 complementary binding areas on the receptor and is known as the __________
    Easson-Stedman hypothesis
  52. -this is important for direct agonist activity because replacing nitrogen with carbon
    results in a large decline in activity
    R1-substituion on the Amino Nitrogen Determines a-B-receptor selectivity
  53. - Substitution by small alkyl group (e.g. CH3 or C2H5)
    - It helps the increase of the resistance to metabolism and lipophilicity
    R2-substitution on the a-Carbon
  54. - generally decreases CNS activity largely because it lowers lipid solubility
    - greatly enhances agonist activity at both a and b receptor
    OH substitution on the B-carbon (carbon1)
  55. - it can bring about selectivity at a-receptors as it appears that the cathecol moiety is more important for a2 activity than for a1 activity
    Substitution on the aromatic ring
  56. - it can bring about selectivity at a-receptors as it appears that the cathecol moiety is more important for a2 activity than for a1 activity
    Substitution on the aromatic ring
  57. - If it lacks OH groups on the ring and the B-OH group in the side chain act almost exclusively by causing the release of NE from sympathetic nerve terminals and thus results
    to direct sympathomimetic activity.

    Cas without OH groups
  58. - it increases the blood flow to the kidney and enhances the glomerular filtration rate
    - Increase cardiac output
    - Immediate precursor of NE and is a central NT particularly
    - important in the regulation of movement
    Dopamine (3’,4’ dihydroxyphenylethylamine)
  59. - It is used to counteract various hypotensive crises because a-activity raises BP and as an adjunct treatment in cardiac arrest because its B-activity stimulates the heart.
  60. - It is used in aqueous solution for inhalation as the free amine
    - Stimulates the heart in cardiac arrest
    - Differs from NE only by the addition of
    an N-methyl group
  61. prodrug of Epinephrine
    Dipiverine (Propine, Dipivalyl Epinephrine)
  62. - Differs from E only in lacking a p-OH group
    - Orally active and its DOA is about twice that of E
    - Potent vasoconstrictor
    - Treatment of severe hypotension
    • Phenylephrine (BN)
  63. - It is bioactivated by O-demethylation to an active m-phenolic metabolite
    - Slows the ventricular rate because of activation of the carotid sinus reflex
    - It has cardiac stimulatory properties
    Methoxamine (BN)
  64. - It has vasoconstrictor properties
    - Treatment of symptomatic orthostatic hypotension
    Midodrine (BN)
  65. -  Exhibit vasoconstrictive  as a result of stimulation of peripheral a-receptors
    -  Much longer lasting hypotensive effect
    -  It providesbeneficial effects in several other situations including glaucoma, spasticity,
    migraine prophylaxis, opiate withdrawal syndrome and anaesthesia
    Clonidine (BN)
  66. - Does not cross Blood Brain Barrier
    - Produces hypotension and sedation
    - Selective a2 agonist
    - It is used specifically to control elevations in intraocular pressure that can occur during laser surgery on the eye
    - First line tx ofglaucoma
    Apraclonidine (BN)
  67. - It is much more selective a2 agonist
    - Lower intraocular  pressure by reducing aqueous humor production and increasing uveoscleral outflow
    •      Brimonidine (BN)
  68. - The bridge of this compound is a –CH=N- group
    - Same with Guanfacine, conjugation of the quanidino moiety with the bridging noiety helps to decrease the pKa of the basic group, so that at physiological pH a significant portion of each drug exists in its nonionized form.
    Guanabenz (BN)
  69. - The bridge is –CH2CO- moiety
    - CNS penetration and
    high bioavailability (>80%)
    - It is more selective for a2 receptor than clonidine
    Guanfacine (BN)
  70. -  Differs structurally from L-dopa only in the presence of a a-methyl group
    -  Ultimately decreases the concentration of DA, NE, E and serotonin in the CNS and periphery
    - Originally synthesized as an AADC inhibitor
    - Affected by food (about 40%) and converted to methyldopa-O-sulfate
    Methyldopa (L-a-methyldopa, BN)
  71. • Act by releasing endogenous Norepinephrine.

    • Enter nerve ending by way of the
    active-uptake process and displace norepinephrine from its storage granules.
    Indirect Acting Sypathomimetics
  72. • It differs from amphetamine in the presence
    of p-OH group and so it has little or no CNS-stimulating action.
    • Used for diagnostic eye examinations and for surgical procedures on the eye.
    • Sometimes used with cholinergic blocking
    drugs like atropine.
    Hydroxyamphetamine (BN)
  73. • Produces vasoconstriction and a decongestant
    effect on the nasal membranes and produces fewer side effects on CNS.
    • Major use is for a local vasoconstrictive
    effect on nasal mucosa in the symptomatic relief of nasal congestion caused by
    common cold, allergic rhinitis, or sinusitis.
    • Aromatic ring has been replaced with a cyclohexane
    Propylhexedrine (BN)
  74. •  Diasterior of ephedrine.
    •  Acts mostly by indirect mechanism and has
    virtually no direct activity.
    • Lack of direct activity affords fewer CNS
    effects than does ephedrine.

    • Although it is less prone to increase blood
    pressure than ephedrine, it should be used with caution in hypertensive individuals, and it should not be used in combination with MAO inhibitors
    L- (+)-Pseudoephedrine (3 BNs)
  75. L- (+)-Pseudoephedrine is a naturally occuring alkaloid from _____ species
  76.   Drug acts on both α- and ß-receptors.
    •  Lacking H-bonding phenolic OH groups,
    ephedrine is less polar.
    • Drug is metabolized by either Mao or COMT and therefore has more roal activity and longer DOA than E.
  77. Ephedrine has two asymmetric carbon atoms;
    thereby creating four optically active isomers.
    • Erythro
    • Threo
  78. Erythro racemate is called

    Threo racemate is called
    • ephedrine
    • pseudoephedrine
  79. - Used locally to constrict the nasal mucosa
    and cause decongestion and to dilate the pupil or the bronchi.
    - Effective for asthma, hay fever, and
  80. plant containing ephedrine, was known to the Chinese in 2000 BC but ephedrine was not
    isolated until 1885.
    Ma Huang
  81. Slightly higher vasopressive action and lower central stimulatory action than ephedrine.
    Phenylpropanolamine (BN)
  82. - Used parenterally as a vasopressor in the treatment and prevention of the acute
    hypotensive state occuring with spinal anesthesia.

    —- Used to treat severe hypotension brought on by other traumas that induce shock.
    Metaraminol (BN)
  83. Nonselective  α-blockers
    • Tolazoline (BN)
    • Phentolamine (BN)
  84. is used to treat Raynaud syndrome and other peripheral vasospasm
  85. - used to prevent/control hypertensive episodes. In combination with papaverine, it is used to treat impotence.
  86. - Agents in this class, when given in adequate doses, produce a slowly developing, prolonged adrenergic blockade that is not overcome by Epinephrine.
    irreversible a-blockers
  87. - Old but powerful α-blocker, is a haloalylamine that blocks α1- and α2- receptors irreversibly.

    - It is capable of blocking acetylcholine, histamine, and serotonin receptors, its
    primary pharmacological effects, especially that of vasodilation, may be attributed to its α-adrenergic blocking capability.

    —- Administration is frequently associated with tachycardia, increased cardiac output and
    postural hypotension.

    - Onset of action is slow, but the effect of single dose of drug may last 3 to 4 days.

    —- Principal peripheral effects following its administration are an increase in systemic
    blood flow, increase in skin temperature, and a lowering of blood pressure.

    —- It has no effect on parasympathetic system and little effect on the gastrointestinal tract.

    —- Most common side effects are miosis, tachycardia, nasal stuffiness and postural
    Phenoxybenzamine (BN)
  88. Selective α1-blockers
    • Prazosin (BN)
    • Terazosin (BN)
    • Doxasozin (BN)
  89. - They are quinazoline α1-blockers.

    -These drugs dilate both arterioles and veins and are used in the treatment of

    -They produce peripheral vasodilation without an increase in heart rate or cardiac output
    selective a1 blockers
  90. selective a1 blockers are consist of three components:
    • quinazoline ring
    • piperazine ring
    • acyl moiety.
  91. Yohimbine is an indole alkylamine alkaloid and is found in the bark of the tree ___________ and in _____ root.
    • Pausinystalia yohimbe
    • Rauwolfia
  92. Yohimbine is a selective __ -blockers;
    Corynanthine is a selective __ -blocker.
    • α2
    • a1
  93. increases heart rate and blood pressure as a result of its blockade of α2-receptors in the CNS. It has been used experimentally to treat male erectile impotence.
  94. ◦  Used as antidepressant.

    ◦  It is a potent blocker of 5-HT2 and 5-HT3, serotonin receptors and at histamine H1-receptors.
    Mirtazapine (BN)
  95. • First ß-Blockers

    • Was reported in 1958 by Powell and Slater

    •  Unfortunately, not a pure antagonist but a partial agonist.
  96. It had much less intrinsic sympathomimetic activity (ISA) than DCI, it was withdrawn from clinical testing because of reports that it caused thymic tumors in mice.
  97. - One of the most thoroughly studied and widely used drugs in the therapeutic armamentarium.

    —- It is the standard against which all other ß-blockers are compared.

    —- belongs to the group of ß-blockers known as aryloxypropanolamines
  98. - prototypical

    —- nonselective ß-blocker.

    —- It blocks the  ß1 and ß2 receptors with
    equal affinity, lacks ISA, and does not block α –receptors

    - is approved for use in the United States for hypertension, cardiac arrhythmias,
    angina pectoris, postmyocardial infarction, hypertrophic cardiomyopathy,
    pheochromocytoma, migraine prophylaxis, and essential tremor.
  99. is also used in the long-term management of angina pectoris.
  100. use in the prophylaxis of migraine headaches and in the therapy following
    myocardial infarction.
  101. used as an antiarrhythmic in treating ventricular arrhythmias and atrial fibrillation
  102. are used topically to treat open-angle glaucoma
    Carteolol, Timolol, Levobunolol, and Metipranolol
  103. possesses modest membrane-stabilizing activity and significant intrinsic  ß-agonistic activity.
  104. have half-life values in the same range as Propranolol.
    Timolol, pindolol, penbutolol, and carteolol
  105. undergoes very little hepatic metabolism and most of this drug is excreted unchanged in
    the urine.
  106. Cardioselective  ß-blockers should provide two important therapeutic advantages.
    • The first advantage should be the lack of a blocking effect on the ß2-receptors in
    • the bronchi.

    • The second advantage should be the absence of blockade of the vascular
    • ß2-receptors, which mediate vasodilation.
  107. are also approved for use in treating angina
    pectoris and in therapy following myocardial infarction.
    Atenolol and Metoprolol
  108. is the only  ß1-selective blocker indicated
    for the treatment of glaucoma.
  109. was designed specifically to possess a very short DOA; it has an elimination
    half-life of 9 minutes. Its effects disappear within 20 to 30 minutes after the
    infusion is discontinued.
  110. are also indicated for treating certain cardiac arrhythmias.
    Esmolol and Acebutolol
  111. with a half-life ranging between 14 and 22 hours,has the longest DOA of the
    ß1-selective blockers
  112. is absorbed well from the gastrointestinal tract, but it undergoes extensive
    first-pass metabolic conversion to diacetolol by hydrolytic conversion of the amide.
  113. - Phenylethanolamine derivative, is representative of a class of drugs that act as competitive blockers at α1-, ß1-,and ß2-receptors.

    - more potent  ß-blocker than α-blocker.

    — - clinically useful antihypertensive agent.

    —- The rationale for its use in the management of hypertension is that its α-receptor–blocking effects produce vasodilation and its α-receptor–blocking effects prevent the reflex tachycardia usually associated with vasodilation
    Labetalol (2 BN)
  114. —- ß-blocker that possesses α-blocking activity.

    —- Its ß-blocking activity is 10- to 100-fold of its α-blocking activity.

    - Possesses antioxidant activity and an anti-proliferative effect on vascular smooth muscle cells.

    - It has a neuroprotective effect and the ability to provide major cardiovascular
    organ protection.

    —- Used in treating hypertension and congestive heart failure.
    Carvedilol (BN)