PROFESSOR: DAVID KU AUTONOMIC PHARMACOLOGY Page1 of 7

PROFESSOR: DAVID KU AUTONOMIC PHARMACOLOGY Page1 of 7

CLASS: 11-12Scribe: CHRISTINE SIRNA

DATE: 12-1-10Proof: MEGAN GUTHMAN

PROFESSOR: DAVID KUAUTONOMIC PHARMACOLOGYPage1 of 7

  1. CHART [S32]
  2. First lecture is to give the basic fundamental principle of drug actions
  3. Pharmacologist have two arms of pharmacology
  4. Pharmacological Kinetics: absorption distribution, metabolism elimination (ATME) PK people
  5. Pharmacological dynamics: Mechanism of drug actions
  6. How the drug works
  7. He went over ATME already and he talked about signal transduction mechanism actions
  8. Pharmacology you need to know anatomy (cell structures) and physiology (normal cell function)
  9. Disease is when cell becomes out of whack
  10. Finally come to pharmacologists which bring abnormal cell function back to normal
  11. Need to study how cell functions and disease state, what happens to them and the function, and how to bring it back to normal
  12. Either use a mymeric because they are not working well and we try to stimulate them
  13. If overreactive we try to put in inhibitors antagonists to slow them down
  14. ALPHA 1 ADRENOCEPTOR AGONISTS [S33]
  15. Let’s talk about Alpha 1 agonist first: Phenylephrine
  16. One example it’s the prototype
  17. Methoxamine is also an alpha 1 agonist
  18. Don’t need to memorize this!
  19. Only need to remember Phenylephrine is the prototype
  20. Neo-synephrine: put in nose spray for nasal congestion,
  21. if congested it’s good nasal decongestant
  22. constricts the nasal alpha receptors
  23. Don’t need to know structures
  24. Other than if it’s not a catecholamine
  25. CHART [S34]
  26. Alpha 1 receptors have 3 subtypes
  27. Alpha 1A
  28. Alpha 1B
  29. Alpha 1D
  30. Don’t need to memorize this hence the X at the top of the page
  31. This is for what research is going on, they want to find a cloning receptor
  32. Trouble is there is no agonists for them other than the phenylephrine basically activates all alpha 1A,B,D
  33. Antagonist: we can only find some so don’t worry about this
  34. Only thing to remember is Alpha 1 receptors are mainly for constriction
  35. EXAMPLE OF THERAPEUTIC USE OF ALPHA 1 AGONISTS [S35]
  36. Treat nasal congestions
  37. Pseudoephedrine: very effective and long lasting 8-24 hours
  38. Phenylephrine is very short lived
  39. They are banning pseudoephedrine because people are using it to convert to methamphetamines
  40. Hard to get now so use combination antihistamine
  41. Sudafed put in phenlyephrine
  42. short half life so you need to keep taking it
  43. Also used to treat hypertension
  44. Hypotensive crisis: people go into shock and get alpha 1 agonists
  45. Treat paroxysmal atrial tachycardia
  46. Atria arrhythmia issues can cause mydriasis
  47. Cause local vasoconstriction to localize the local anesthetics: for dentistry always use lidocaine and some alpha agonist to constrict the blood vessel so the lidocaine does not diffuse into different areas.
  48. CHART [S36]
  49. Memorize alpha one and what they do and some uses
  50. ALPHA 2 ADRENOCEPTOR AGONISTS[S37]
  51. Clonidine is the prototype
  52. There are others such as methyldope and alpha methylnorepinephrine also activate alpha two
  53. All you have to remember is clonidine
  54. Clonidine is definitely not a catecholamine
  55. TERMINATION AND FEEDBACK MECHANISMS [S38]
  56. Most alpha 2 receptors are presynaptic at nerve terminals for negative feedback mechanisms
  57. Some are expressed on the post synaptic membrane
  58. Smooth muscle cells and some other cell types have alpha 2
  59. Predominantly alpha 2 on pre synaptic site
  60. Primary site of action for alpha 2 agonists is CNS
  61. for example highly selective alpha 2 agonist, Dexmedetomidine, is used as sedative during cardiovascular surgery
  62. Primary mechanism of action is mediated via a decreasein cAMP, K and Ca channels.
  63. Don’t worry about the additional mechanism action only know Alpha 2 mainly in CNS
  64. ALPHA 2 ADRENORECEPTOR AGONISTS [S39]
  65. Clonidine: usefulness is to treat hypertension
  66. Hypertension can be caused by many things so it’s not easy to treat, ediology is so complex
  67. Most patients are excitable type patients that have central actions because they release a lot of catecholamines from the brain and are highly active
  68. In those patients, Clonidine is effective in treating central mechanism of hypertension
  69. highly lipid soluble, crosses BBB readily, activatesa2 receptors in hypothalamus & medulla and resultsin a decrease in NE release, thus, decreases sympatheticoutflow to the heart
  70. that is the Primary mechanism action for clonidine for treating hypertension
  71. Does not interfere with baroreceptor function but it does sensitize the brain stem pressor response
  72. Does not produce postural hypotension
  73. Postural hypertension: When you have alpha blockers you block the alpha receptors in periphery, as soon as you stand up you will get postural hypotension
  74. Clonidine will not have this problem
  75. Not very severe side effects
  76. Caution there are partial alpha 1 agonist also
  77. Even though they are selective for alpha 2 they have a partial alpha agonist activites
  78. Will constrict blood vessel if too much clonidine and cause hypotension
  1. ALPHA 2 ADRENOCEPTOR SUBTYPES AND POSSIBLE FUNCTIONS [S40]
  2. Have alpha 2A,B,D
  3. Different subtypes involving different things
  4. Don’t worry about this
  5. CHART [S41]
  6. B receptors
  7. BETA 1 ADRENOCEPTOR AGONISTS [S42]
  8. Dobutamine:
  9. Structure is catechole
  10. Big substitution at amino terminal for B 1
  11. For B2: Substitution not as dramatic
  12. Selective for B2 for people who have asthma, the pump are alpha 2 agonist
  13. Q: Are B2 agonists catecholamines as well since they have 2 OH groups? No
  14. Catechole is distinct between C3 and C4
  15. Once you substitute this it will no longer be OH group (top picture)
  16. EXAMPLES OF THERAPEUTIC USE OF BETA 1 AGONISTS [S43]
  17. Dobutamines are for short term treatment of cardiac decompensation (heart failure)
  18. long term no good because receptor will down regulate
  19. The receptor is a dynamic process in the cell membrane
  20. An agonist holds onto it, if too many agonists autoexposure to receptor it will internalize
  21. Most drugs we use are antagonists very few agonists do we use because mimerics always make receptor down-regulate
  22. Not recommended for chronic use because of the down-regulation
  23. Undesirable side effects: tachycardia (heart goes too fast or stimulate B1), hypertension, and arrhythmias
  24. Characteristic for Dobutamine so that is why we only use them short term
  25. EXAMPLES OF THERAPEUTIC USE OF BEAT 2 AGONISTS [S44]
  26. B2 agonists: Dobutamine and Albuterol
  27. treat asthma, bronchospasm and emphysema
  28. Undesirable side effects: Nervousness, headache, tachycardia (heart is pumping), palpitations, sweating, muscle cramps.
  29. Spray for asthma will have problems because they are relative
  30. Only relatively selective for B2 over B1
  31. You will get tachycardia if you keep spraying by stimulating B1 even though bronchial smooth muscle is B2 primarily which is why we want to dilate them
  32. CHART [S45]
  33. Don’t worry about B3 because there are no FDA approved drugs
  34. BETA 3 RECEPTORS [S46]
  35. There are B4 receptors
  36. We don’t have good drugs for B3 or B4
  37. B4 talk about long term memory issues because cloning receptor people are finding out but don’t worry about this right now
  38. B3 gets attention because of metabolic syndromes
  39. People are obesity, diabetics
  40. Seem to have an issue with B3 receptors
  41. Localized in fat cells and mediate metabolic effects
  42. B3 may be involved in these populations
  43. Hopefully we will get drugs to treat obesity
  44. ADRENERGIC RECEPTOR ANTAGONISTS [S47]
  45. Antagonists: most drugs are this
  46. Antagonists are competitive
  47. Need to understand there are competitions between agonist and antagonist
  48. Receptors are governed by the Law of mass action
  49. depends on concentration and number of receptors
  50. More agonist more agonist activities
  51. More antagonist more antagonist activities
  52. Draw graph on board
  53. Y axis is response
  54. X axis is [D], drug concentration
  55. Normally you see sigmoidal curve
  56. More drug you put in more response you get until you reach a maximum
  57. When you put antagonist in it competes for same site, depends on how potent it is, and it will shift curve to the right
  58. Right graph is alpha antagonist
  59. By looking at the response curve you can say the drug is very potent
  60. If cure shifts farther right it is more potent
  61. Depends on number of receptors and how they compete
  62. Most receptors are hydrophobic, hydrogen bond are always reversible
  63. called reversible or competitive or equilibrium
  64. they reach the maximum, they are competing for same site
  65. If you increase agonist concentration you get same maximal response
  66. Exception is those with a covalent bond, any alkylating agents, any compound with Cl or Br or F substitution
  67. Most cancer drugs have Cl or F, form alkylating agents
  68. Binds and doesn’t come off, they are irreversible
  69. Irreversible is noncompetitive, take the receptors away
  70. When you put irreversible antagonists?
  71. Instead of 100% receptor you take the receptor away and now you only get 50% of max Y
  72. Put in irreversible noncompetitive antagonist so the maximum response has now dropped
  73. Takes receptor number away because they are no longer at equilibrium, they are now alkylating receptor so we call it irreversible no equilibrium
  74. By studying these graphs we can tell you the potency and what kind of competition
  75. PICTURE [S48]
  76. This is a picture illustrating receptors (top picture normal)
  77. An agonist for B receptor binds to a specific site on these receptorsbetween6 and 7 transmembrane domain
  78. all you need to know is there is specific site agonist will bind to
  79. then you will elicit some kind of conformational change
  80. There is a conformation change in receptor complex and this in turn activates G protein, signal transduction process
  81. Antagonist binds to the same site as agonist
  82. But does not elicit a conformational change
  83. Do not have activation of single transduction
  84. Inhibitors is anything that can inhibit the actions. Different from antagonist
  85. Antagonist is specific we are talking about they are competing for the receptor site
  86. Inhibitors we can find a drug that will break down this agonist and can inhibit anywhere downstream
  87. Agonist and antagonist are specific on the receptor site, they are competing for the same binding site
  88. Agonist elicits a response and antagonists do not elicit a response
  89. PICTURE [S49]
  90. Another concept I wanted to explain is, when you talk about agonist and you activate receptors and get conformation change and in turn active G protein and in turn activate adenyly cyclase which converts ATP to cAMP
  91. All of this process that is happening is called transducing the signals
  92. When some antagonists bind to this site, they’re not supposed to elicit a conformation change but some antagonists elicit partial agonist activities
  93. Once they bind to receptor they change some conformation and partially activate this
  94. We try to modulate them because we want a pure compound and sometimes we get side effects
  95. ALPHA 1 ADRENOCEPTOR ANTAGONISTS [S50]
  96. Alkylating agents like for example phenoxybenzamine has a Cl so it’s alkylating
  97. These are all alpha antagonists
  98. You have haloalkylamine, imidazoline, and quinazoline
  99. Phentolamine and tolazoline are non selective alpha blockers and are irreversible
  100. They are long lasting
  101. Use mostly phentolamine for non selective
  102. Quinazoline derivatives: Prazosin and Tamsulosin
  103. Prazosin and tamsulosin are selective for alpha 1
  104. PHENOXYBENZAMINE AND PHENTOLAMINE [S51]
  105. Irreversible v. reversible
  106. Want to decrease the number of receptor sites if non competitive and shift D-R curves if competitive
  107. Other actions they block other effects, they are not pure
  108. Most drugs it’s hard to find pure selective drugs
  109. Adverse Reactions: Postural hypotension (very characteristic of alpha blockers antagonists), tachycardia, miosis, nasal stuffiness, failure of ejaculation
  110. Therapeutic uses are for peripheral vascular disease especially people with excessive catecholamine release
  111. People with pheochromoctoma release a lot of epinephrine from adrenal glands, release a lot of catecholamines
  112. Those patients you give alpha blockers, so they will not have hypertension problems
  113. These are some key things to remember about alpha blockers
  114. THERAPEUTIC/ANTAGONISTIC EFFECTS OF THESE ANTAGONISTS DEPEND ON [S52]
  115. Depends on the cardiovascular status of the patient at the time of drug administration and the relative selectivity of the agents used
  116. Depends on thealpha receptors
  117. If you block something, you are lying down and the alpha receptor is not activated
  118. If you put agonist in, you don’t see much of an effect
  119. Because the receptor is not working, it is the minimal effect
  120. As soon as you stand up alpha is activated
  121. If you give alpha now while you are all sitting down, pressure will drop
  122. It depends on the status of the patient at the time of drug administration
  123. Sympathetic nervous system is down while we are sitting here and parasympathetic is very high
  124. If he gave us an alpha or beta blocker would not see much of an effect because sympathetic is very low
  125. If you are running and given B blocker you will see an effect, heart rate will drop
  126. Thing to remember: When you block something you have to remember what is going on in the basal levels
  127. PICTURE [S53]
  128. Why do we want selective alpha 1 and 2?
  129. When you give phentolaine (nonselective) you block off alpha 1 and 2
  130. So what happens when you block alpha 2? Alpha 2 is a negative feedback
  131. When you loose negative feedback it continues to release norepinephrine
  132. NE: Alpha one will not constrict the blood vessel but will activate the heart, heart rate will go up and you get get tachycardia
  133. Even though you won’t block the smoothmuscle because the NE is continually releasing you will activate alpha 1 and heart rate increases
  134. Because of all this you usually have a selective one

XVI. PICTURE [S54]

  1. If you give selective alpha 1 blockers here you will leave the alpha 2 blockers alone
  2. NE goes up and alpha 1 is shut down so NE is regulated and you will not see tachycardia issues
  3. That is example why we want selective one and not nonselective one
  1. CLINICAL PHARMACOLOGY/USES OF SELECTIVE ALPHA 1 ANTAGONISTS [S55]
  2. Another example of clinical usefulness is treating primary hypertension or people with BPH in prostate
  3. Will see Hytrin and Flomax agents are hyperactive in smooth muscle cell
  4. Don’t worry about bottom part
  5. Memorize selective alpha 1 antagonists are to treat hypertension and BPH
  6. CHART [S56]
  7. Alpha 2 antagonists
  8. CLINICAL PHARMACOLOGY OF SELECTIVE ALPHA 2 ANTAGONISTS [S57]
  9. Why do we want a selective alpha 2 antagonist?
  10. Alpha 2 is used for negative feedback
  11. Little clinical usefulness
  12. Theoretically, blockade of presynaptic 2 receptors could promote neurotransmitter release and improve autonomic function
  13. Yohimbine has been used to promote male sexual functions. That was before viagra came out
  14. Yohimbine is also a good antidote for clonidine toxicity
  15. Clonidine is alpha 2 agonist
  16. Best way to treat toxic dose of clonidine is to give alpha 2 blocker otherwise little usefulness for alpha 2
  1. STRUCTURES [S58]
  2. B blockers
  3. This is a catecholamine structure on top
  4. One thing characteristic of B blockers is they all share similar structure
  5. All have O methyl bridge
  6. Alpha blockers do not have similar structure
  7. Right side is selective for B1
  8. Left side are non selective, will block B1 and B2
  9. SALIENT FEATURES OF SOME B BLOCKERS[S59]
  10. There are a lot of B blockers
  11. B blockers were drug from the 70s
  12. Currently 13-14 B blockers
  13. To summarize these are the salient features of B blockers
  14. Propranolol: first B blocker approved in this country
  15. Prototype for all B blockers, non selective
  16. Timolo: first B blocker used for opththalmic
  17. used to treat glaucoma
  18. Metoprolol: first cardioselective approved B blocker
  19. second generation B blocker
  20. Need to know the different B blockers
  21. What are feature to know:
  22. Their metabolism
  23. propranolol, timolol, metoprolol all B blockers are metabolized through the liver by the enzyme
  24. they are lipophilic
  25. For patients with liver disease, you want to stay away from those B blockers
  26. Why? They could not metabolize those B blockers and you will have toxicity problems
  27. You need to give drugs that excrete through the kidney
  28. Atenolol is cardioselective but goes through the kidneys
  29. Nadolol B blocker metabolized through kidney
  30. Liver disease patient if you want cardioselective use atenolol
  31. If they have kidney problems stay away from atenolol and give propranolol
  32. Other things is plasma half life of B blocker is 3-6 hours
  33. Most B blockers you take twice a day
  34. Ideal drug wanted half life of 6-8 hours because you only take twice a day
  35. 3-4 hours will need to take 3 or 4 times a day
  36. Most patients will miss the middle dose
  37. Most doctors will not want to prescribe
  38. If once a month drug companies won’t make money
  39. Once a day is good but if you toxicity problem don’t want drug that lasts that long
  40. Ideal drug is twice a day
  41. There are once a day blockers and rapid onset (Esmolol) which is only about 9 minutes
  42. Why would you want B blocker that only lasts 9 minutes? Use in ER
  43. if you want to control patient because heart rate is too fast and want quick dose on and off
  44. do not want long lasting effect
  45. Research is not only worried about mechanism action but economics as well
  46. CHART [S60]
  47. Potency
  48. Everything is compared to propranolol
  49. For patient standpoint 1mg v. 6 mg doesn’t matter
  50. For scientists it is important
  51. Need to remember cardioselectivites
  52. B blockers are selective and non selective
  53. Partial agonist activity: some elicit but most do not
  54. Elicit conformation changes

vi. Membrane-stabalizing activity is important, be aware of that especially when we talk about cardiovascular drugs because of membrane stabilizing abilites

  1. PICTURE [S61]
  2. Recap of agonist and antagonist
  3. CLINICAL USES OF B BLOCKERS [S62]
  4. Anyone can use a B blocker to treat hypertension
  5. Short tern no change in BP
  6. Long term: decrease renin
  7. Better drugs now such as ACE
  8. Antiarrhythmic treat arrhythmia
  9. Supraventricular: decrease AV transmission
  10. Ventricular PVCs (Premature ventricular contraction): due to excessive catecholamines
  11. Antianginal: good for treating heart attack, redistribution of blood flow and decreasing heart muscle damage
  12. All CV related B blockers are very effective
  13. Hyperthyroidism
  14. Open angle-Glaucoma-Timolol
  15. Anxiety: people sometimes are overreactive, B blockers are good to calm the nerve, better than giving valium
  16. Migraine: block craniovascular B receptors and reduce vasodilation
  17. MAJOR ADVERSE SIDE EFFECTS OF B BLOCKERS [S63]
  18. Bradycardia (excessive decrease of B receptors): heart will go too slow
  19. Trigger congestive heart failure
  20. Bronchospasm: especially for non selective
  21. For patient with asthma stay away from non selective
  22. Repeated use of B blocker leads to:tiredness, dizziness, shortness of breath, diarrhea, flatulence & heartburn.
  23. CNS-related: hallucinations, depressions
  24. Chronic use of B blockers give us suicidal tendency depress the CNS
  25. Be very careful with those that can cross the blood brain barrier
  26. Potential hypoglycemia, especially in patients with insulin-dependent diabetes
  27. B receptor triggers glycogenolysis, conversion of glucose
  28. If you block that they will not release glucose, this will make it hard for them to recover
  29. PICTURE [S64]
  30. If you are a diabetic patient taking insulin you will decrease glucose levels and it will take a long time to recover from glucose
  31. CONTRAINDICATIONS FOR THE B BLOCKERS [S65]
  32. People use B blockers for all kinds of cardiovascular disease but they need to be careful because if you have those kind of problems you contraindicate
  33. Another problem is withdrawal problems
  34. PICTURE [S66]
  35. Overexposure to receptor agonists, receptor will down regulate
  36. If you give B blocker for long time the receptor becomes super sensitive, up regulate
  37. When patient is scheduled to do cardiovascular surgery the surgery says stop all medications
  38. If you stop overnight when patient comes to surgery the B receptor is super sensitive and they have problems with arrhythmias
  39. When you have to withdraw the B blocker you don’t stop it overnight do it over like 7 days
  40. Let receptor reestablish itself otherwise it will be supersensitive
  41. CHART [S67]
  42. Don’t worry about B3 no drug for this yet
  43. 1ST GENERATION OF B BLOCKERS [S68]
  44. This is to summarize B blocker generations over the years
  45. First generation: classic non selective
  46. Second generation: B selective
  47. If you had to develop a blocker antagonist would want to have selective alpha 1 or 2? Alpha 1
  48. B receptors do you want B 1 or 2? Beta 1
  49. So you don’t have lung problems
  50. During late 70s his charge was to develop a combined drug alpha1 blocker with B1 blocker
  51. Point is to really treat hypertension
  52. If you have selective B1 and alpha1 you can really do it
  53. 3rd generation: non selective B blocker and alpha blocker also have vasodilations
  54. Soon there will be fourth generation
  55. STRUCTURES [S69]
  56. Example of this
  57. Labetralol: alpha 1 and B1 and B2 antagonist
  58. Combined alpha and beta blocker
  59. Intent is to treat hypertension
  60. Carvedilol alpha 1 B1 and B2
  61. Structure is same O methyl bridge just like other B blockers, just with large substitution
  62. EFFECTS OF 3 SELECTIVE B BLOCKERS ON MORTALITY IN CHF [S70]
  63. Take home message
  64. When we developed drugs originally we just wanted to eliminate symptoms
  65. Now we want to improve survivalbecause we don’t want to die
  66. So prognosis always given with drugs
  67. Now it’s not about whether the drug works or not because we know the drug produces the effect
  68. No longer end point effects we want survival
  69. Now you will see drugs with survival index
  70. Far left is decrease mortality
  71. Middle in increased survival
  72. B blockers: metoprolol, bisoprolol and carvedilol are three drugs for treating for congestive heart failure
  73. Improve quality of life and Increase survival
  74. These are the third generation B blockers

[End 44:19 mins]

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