VIEWS: 2 PAGES: 5 POSTED ON: 11/7/2012
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.
Pages to are hidden for
"Alpha"Please download to view full document