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
Q--what are the types of structures that can act as alpha-1 agonists?
catecholamines, methoxamines, and imidazolines
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
*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.
-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
Q--what is the importance of the 3’OH on the metabolite?? Necessary for direct activity
-administration: ORAL, IV
-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.
-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)
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?
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
*minor point--what happens faster to alpha-methylDOPA: esterification or acid/base reactions?
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,
>>>remember: alpha-methyl-NE is acting centrally, so these ADRs should make sense!
-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??
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
>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
-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
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
>>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)
>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.