Pharmacology: Your Learning is Never Over

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Pharmacology Your Learning is Never Over

• Joseph Awad, MD
• February 23, 2005

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Some Examples

• Things are more complicated than we can imagine
• Cilostazol (Pletal)
• Do we really know what we need to teach ?
• Alpha adrenergic agents
• Finally a clinical partial agonist !
• Aripiprazol (Abilify)
• Moving targets
• Lipid lowering therapy
• Estrogen replacement

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Test 1 Question

• Cilostazol (Pletal) is approved by FDA (2000)
  for long-term treatment of claudication. It is a
  PDE3 inhibitor. Given what you know about other
  drugs with this mechanism of action, patients
  with which one of the following conditions should
  not get this drug.
• Cerebrovascular disease
• Congestive heart failure
• Diabetes
• Erectile dysfunction
• Hypertension

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Phosphodiesterase 3 Inhibitors

• Inamrinone (formerly amrinone) and Milrinone are
  PDE3 inhibitors with inotropic effect and some
  vasodilation.
• Long-term use of such drugs increases mortality
  in heart failure.
• CHF patients excluded from cilostazol clinical
  trials
• How about the real world?
• NO!!
• Is there a danger?
• Is cilostazol different?

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Cilastazol is Different

• Cilastazol is a less potent PDE3A inhibitor than
  milrinone
• Cilastazol also blocks uptake of adenosine into
  cardiac and other cells.
• Makes cilastazol like an adenosine agonist
• Additional Effects
• Reduces inotropic influence on heart
• More vasodilation
• Anti-platelet activity
• Other effects dec. TG and inc. HDL

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Things are more Complicated

• This drug has another MOA
• We often dont know everything about a drug
  actions, even many years later.
• Many drugs have more than one MOA and may not be
  like other members of the class
• Vasodilatory effects marketed in this country
• Anti-platelet effects underplayed
• We still dont have hard data on long-term safety
  in CHF patients ! ! !
• Keep an Open Mind

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What to Teach ?

• A decade ago
• Alpha 1 blockers dead as antihypertensives
• Tachyphylaxis, trigger baroreflex sympathetic
  output
• Alpha 2 agonists dead as antihypertensives
• Too sedating, too many side effects, clonidine
  rebound
• Phentolamine and Phenoxybenzamine
• How many pheos am I ever going to see ?
• 15 minutes, max !
• Ephedra and phenylpropanolamine banned ! !

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Relevant Again

• Alpha-1 blockers
• 4 drugs marketed for prostatic outflow problems
• Afluzosin (Uroxatral) new in US last year
• Is alpha-1A blockade important for tolerance ?
• Alpha-2 Agonists
• Tizanidine (Zanaflex) for muscular spasm
• Rebound can occur
• Dexmedetomidine (Precedex) post-surgical
  sedation and analgesia
• Are these drugs different from clonidine?

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Dexmedetomidine (Precedex)

• Primarily alpha-2 agonist (some alpha-1 at high
  doses)
• ? Alpha-2A specificity
• Post-surgical sedation and anesthesia,
• Supresses sympathetic stimulation
• Sedating without suppressing respiratory drive
• Some analgesia
• Pharmacokinetics
• Terminal T1/2 is 2h
• Glucuronidation
• Rebound ?

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Finally, a Partial Agonist

• Aripirazole (Abilify)
• FDA approved 2002
• Pharmacodynamics
• Partial agonist D2 and 5-HT1A receptors
• Antagonist at 5-HT2A receptors
• Clinically Effective
• Less EPS (extrapyramidal side effects)
• Monthly cost 300-600

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Key Brain Dopamine Sites
Mesocortical Nigrostriatal
(EPS) Tubero- Infundibular (Prolactin)
Mesolimbic (Psych Sx)
AN
VTA
SN
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Sites of Anti-Psychotic Action
Dopamine Mesolimbic Neuron
X
DA
D2
X
5-HT2A
Atypical Antipsychotics
5-HT
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D2 Receptor Interactions
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Real Receptor Interactions
Dopamine
100
Max. DA response
50
0
10-10 10-9 10-8
10-7 10-6 10-5
Drug
Chinese hamster ovary D2L cells exposed to 10 mM
EEDQ
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Moving Targets

• Lipid Lowering How much is enough?
• Optimal LDL
• How hard to push depends on RF
• With DM or CAD use statin even with optimal LDL
• Estrogen Replacment Is it too risky?
• Prempro (conj. Estrogen/progestin)
• More breast Ca
• More cardiovascular events
• Better ways to protect heart and bones in
  post-menopausal woman
• But what to do about hot flashes ?

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Summary

• You cant quit learning
• We cant teach you everything
• Sometimes we dont even know what to teach
• Be humble about how much you know
• We dont know everything
• Always ask questions
• Everyone should be from Missouri
• Make us proud