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					Happy St. Patrick’s Day!
        HELPFUL STUDY HINTS:
-Dr Smith is not going to be tricky. He will ask you exactly what he taught you in class, so focus on that
and KNOWING THE STRUCTURES.
-Pay special attention to what Dr Vishnu drew in on your notes. This is where he tends to focus his
questions.


Alpha-1 agonists
        Q--what are the types of structures that can act as alpha-1 agonists?
              catecholamines, methoxamines, and imidazolines


*Catecholamines:
      Q--what are the structural requirements for this type of alpha-1 agonist?
            *catechol or 3’-OH (if you remove the 4’-OH, you decrease alpha affinity but you
            decrease beta affinity much more…what does that mean? MORE alpha
            SELECTIVE)
            *the beta-OH must have an R configuration
            *primary amine >> secondary amine when it comes to affinity/selectivity for α




        Q--how can you give these drugs? Preferably by injection
              --exceptions: phenylephrine, midodrine
        Q--WHY? They are polar; if you give them orally, they have increased first pass
        metabolism by MAO/COMT/etc.


*Methoxamines

        Methoxamine:
              -administration: IV/IM
              -metabolism: cytochrome (OOD)
              -specificity? almost completely α1, some beta blockade is possible
              -Uses? Hypotension, treat tachycardia (by increasing vagal reflex response)
                Q--is this a prodrug??
                         NO. Both the parent and the metabolite are active. “Prodrugs” have inactive
                         parent drugs.
                Q--what is the importance of the 3’OH on the metabolite?? Necessary for direct activity


        Midodrine:
               -administration: ORAL, IV
               -metabolism: amidases
               -half-life (compared to methoxamine): longer, but still only 3-4 hrs

                Q--is this a prodrug?? YES. It requires amide hydrolysis to be active.


*Imidazolines
      -notice the structural difference! The previous drugs still looked like the typical catecholamines,
      but these do not. They bind the same receptor, but at different sites.

        REVIEW: where do catecholamines bind on adrenergic receptors? What bonds do they form?
              TM III (ion-ion with the ionized amine)
              TM V (H bonding with the 3’OH)
              TM VI (Van der Waal’s with the aromatic ring)


Alpha-2 agonists
        Q--why an alpha-methyl group? To decrease alpha-1 activity
        Q--what does this do for alpha-2 selectivity? Increase or decrease? Increase
        Q--what other effects have we seen the alpha-methyl have?
               *decrease MAO metabolism (REVIEW: optimal target for MAO?)
               *increases indirect activity (see amphetamines)
               *increase enzyme inhibition (see inhibitors of biosynthesis)

        -notice that the requirements for alpha-2 binding are different than for alpha-1! Can you see the
        test question…? What are the requirements for alpha-2 binding?


α-methyl DOPA

        Q--what else does it do? Inhibit biosynthesis enzymes. Which ones?

        >primary mechanism: inhibit DOPA decarboxylase
        >metabolite (alpha-methyl-NE) is the centrally acting alpha-2 agonist (it decreases BP!)

        *it is AMPHOTERIC
                 -what does this mean for water solubility?
                 -does this increase/decrease/no effect (haha) its ability to cross membranes?
                 -NOW look at methyldopate. Is it amphoteric? What about its lipophilicity, etc.?
              >>Methyldopate: A PRODRUG
                    -why an ester? So you can make water soluble salts for IV administration
                    -does the body make methyldopate? No. It converts methydopate to its active
                    form.

       *minor point--what happens faster to alpha-methylDOPA: esterification or acid/base reactions?
              Acid/base reaction

       Q--why does it have low oral bioavailability? RAPID metabolism (ergo the prodrug formulation)
       Q—how is it metabolized? Decarboxylation, phenol conjugation (glucuronides, etc.)

       Q--how does it enter the CNS? Active or passive uptake? Active amino acid uptake

       Q--what must happen before alpha-Me-DOPA can act on its target alpha-2 receptors??
              1)esterase metabolism (methyldopate  alpha-Me-DOPA)
              2) get into CNS nerves (cross BBB)
              3) be converted to alpha-Me-NE

       ADRs: transient sedation, bradycardia (WHY??), decr libido, hyperprolactinemia (galactorrhea,
       gynecomastia
               >>>remember: alpha-methyl-NE is acting centrally, so these ADRs should make sense!


*Imidazolines
      -structure?




       *Tolazoline:
              -no ortho substituents on the aromatic ring
              -MAJOR site of action: alpha-2
              Q--what type of action does it have? Partial agonist
                      -so, compared to NE, is it an agonist or an antagonist? Antagonist
              Q--where else does it bind/act? Histamine, beta, ACh (N and M) receptors
                      -what might the results of this be??
        *Clonidine:
                Q--how is it different from tolazoline? It has 2 ortho Cl groups.
                Q--what does this addition do?
                       >increase agonist activity and selectivity (no longer a partial agonist, more
                       alpha-2 selective)

                         >forced stereochemistry: the two rings are going to be perpendicular to each
                         other to accommodate the bulk of those Chlorines

                         >reduce the pKa compared to tolazoline (now it is ~7.5-8.5). Remember
                         clonidine is a BASE, so it will be LESS ionized at physiologic pH.

                         >increased lipophilicity. What does this mean for BBB crossing? (increased)
                         What about length of action? (decreased—it enters CNS more quickly but also
                         leaves more quickly)

                -TAUTOMERIZATION: which form is favored in the human body?

                -ACTION: acts on alpha-2 in the CNS in the hypothalamus and medulla oblongata;
                decreases NE release, which decreases efferent sympathetic output…decreases BP and
                CO…treat HTN!

                -rapid, complete absorption (WHY?? Lipophilic….Cl groups)
                -MINIMAL first pass
                -metabolism: aromatic hydroxylation (CYP) + glucuronidation  inactive
                                **some enterohepatic recycling! (glucuronidation-only is reversible)

                Q--is the onset slower or faster than alpha-Me-DOPA? FASTER (any ideas why??)


OKAY…here is where we talk about the complexity of alpha-2 receptors…

Alpha-2a: presynaptic, decreases sympathetic output; the predominant alpha-2 receptor, especially in
the brain

Alpha-2b: postsynaptic; actually causes vasoconstriction, like alpha-1; found in the periphery

**initially when you give clonidine, before it has a chance to distribute to the CNS, it may cause
vasoconstriction b/c of these alpha-2b receptors. But long term, the effect is decreased BP because of
the alpha-2a.

>>don’t over-complicate this! The overall effect of clonidine (and other alpha-2 agonists) is STILL to
decrease NE release and therefore decrease BP, etc.


        Q—other uses of clonidine? (there are 4)
*Guanidines

        >compare the structures here to the indirect-acting guanidines (don’t get them confused!!) and
        to clonidine. Notice any similarities/differences?

        Q—what makes these guanidines alpha-2 agonists and the previous ones indirect acting drugs?
             *guanidine is linked to an electron-deficient ring (chlorines on an aromatic ring)

-rapid and complete absorption (they are lipophilic and have low first pass)
-metabolism: aromatic hydroxylation + conjugation of the phenol  renal elimination

        Q—which conjugate occurs most? Glucuronide. WHY? It is less easily saturated (more cofactors
        available to use).
        Q—which has a longer half-life? WHY?

-pKa: for guanabenz (8.1) and for guanfacine (7.1)----WHY is there a difference?? (clue: resonance)

-ADRs: bradycardia, xerostomia, nausea, dizzy, sexual dysfunction, Na/H2O retention
       **b/c of Na/H2O retention, you may want to combine these drugs with a diuretic or
       vasodilators (minoxidil, hydralazine). This will decrease BP quickly and stop any reflex HTN.

				
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posted:11/7/2012
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