Medicinal Chemistry & Pharmacology 2 - exam 1
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| general effect of sympathetic drugs on HR & BP | -increase in HR
-increase in BP
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| BP equation | BP = CO * R
*CO = Cardiac Output
*R = arterial Resistance
*CO is determined by stroke volume & HR
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| Renin-Angiotensin-Aldosterone System (RAAS) pathway and how it increases BP | angiotensinogen -(renin)-> angiotensin 1 -(ACE)-> angiotensin 2 -> AT2 receptors ->
*vasoconstriction (inc. R)
*or aldosterone -> inc. NaCl abs. = inc. water retention = inc. CO
*AT2 is the active compound
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| ACE inhibitors and ARBs | -ACE inhibitors are structurally similar to AT1 and compete for the enzyme ACE
-ARBs are structurally similar to AT2 and compete for AT2 receptors
-leads to dec. BP by dec. Na+ & water retention
-SE is inc. in K+
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| effects of ACEIs & ARBs on: 1) Na+ 2) K+ 3) BP 4) Cl- | 1) decreases
2) increases
3) decreases, could lead to hypotension
4) (does not increase)
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| therapeutic uses of ACEIs | -treatment of HTN, HF, left ventricular dysfunction (LVD)
-reduction of the risk of MI, stroke, and death from cardiovascular causes
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| 3 chemical classes of ACEIs | -sulfhydryl-containing inhibitors
-phosphonate-containing inhibitors
-dicarboxylate-containing inhibitors
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| sulfhydryl-containing ACEIs | captopril
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| phosphonate-containing ACEIs | fosinopril
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| dicarboxylate-containing ACEIs | benazepril, enalapril, lisinopril, perindopril, quinapril, ramipril, trandolapril, moexipril
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| main structural feature of all ACEIs | Zn-binding pocket
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| binding interactions of ACEIs | -ionic bond with Zn on ACE
-double bonded O of amide group can form H-bonds with ACE
-side chains contribute to overall binding affinity (hydrophobic/Van der Waals interactions)
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| captopril (not including SE) | -first ACEI
-sulfhydryl/mercapto group + proline (AA - active transport)
*substituting proline for another AA -> less potency
-mercapto group -> excellent inhib. activity, faster metabolism (shorter t_1/2)
-TID
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| SE of captopril | -skin rashes
-taste disturbances (dysgeusia)
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| reason captopril is desired in patients with liver disease | captopril does not require activation by liver enzymes
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| enalaprilat | - -SH group of captopril replaced with -COOH
-proline is still the AA for good activity
- ~10x more potent than captopril
-excellent IV activity but very poor oral bioavailability
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| enalapril | -ester prodrug of enalaprilat (2 carboxylate groups & secondary amine are responsible for low lipophilicity/oral bioavailability)
-once abosorbed, bioactivation by hepatic esterases leads to enalaprilat formation
-drawback in pts. w/hepatic problems
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| lisinopril (not including bioavailability) | -also has lysine to further inc. affinity to ACE
-not a prodrug, so does not require hepatic enzymes for activation (advantage)
-good tissue penetration
-eliminated by kidneys
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| lisinopril bioavailability | -most hydrophilic ACEI
-presence of NH2 & COOH groups make it a double zwitterion -> neutralization -> absorbs readily in gut
-active transport across intestinal epithelium
-good oral bioavailability, long t_1/2
-QD
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| locations of ACE | -tissue & plasma
-affecting tissue ACE has better, more consistent effect on BP over time
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| other ACEIs that are ester prodrugs & associated advantages and disadvantages | -benazepril & ramipril
-higher potency than lisinopril
*these two have rings that are bio-isosteric replacements of proline
-advantage: better bioavailability
-disadvantage: requires hepatic activation = bad in hepatic disease
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| Gupta's tricky use of the words "equivalent" and "similar" | -apparently, according to his superior intellect, "similar" means = number of mg's while "equivalent" means doses that produce similar therapeutic effect
-ex: at similar doses, ramipril has inc. potency compared to lisinopril
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| fosinopril | -prodrug
-phosphate + proline derivative
-phosphinic acid interacts with Zn
-ionic, H, & hydrophobic bonds similar to enalapril
-most lipophilic ACEI
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| advantage of fosinopril | -doesn't depend on kidneys for elimination
-if kidney function is compromised, more can be removed by liver
**do not need to adjust dose when kidney function is compromised
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| N-ring of ACEIs | -must have carboxylic acid group
-large hydrophobic rings increases potency (ex. benazepril & ramipril) and alters PK parameters
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| duration of action of ACEIs | -mostly 24 hours (QD/BID)
-captopril = 6 - 12 hours (TID)
-enalaprilat = 6 hours
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| metabolism of ACEIs | -captopril: forms disulfide dimer or a captopril-cysteine disulfide
-lisinopril & enalaprilat: no metabolism
-rest are all prodrugs
-further metabolic transformation: glucuronidation
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| receptor type that ARBs compete for | AT2 receptor type 1
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| ARBs | losartan, irbesartan, olmesartan, candesartan, valsartan, telmisartan, eprosartan, azilsartan kamedoxomil
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| groups important for activity & binding efficiency of ARBs | -imidazole ring forms H-bonds
-aromatic group/n-butyl chain forms hydrophobic interactioins
-ionizable (R1) group binds with receptor via dipole interactions
-R2 group is acidic group (absorbs well in stomach)
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| structural similarities between ARBs & AT2 | -ionizable (R1) group -> C-terminal carboxylate
-imidazole ring -> imidazole side chain of the His_6 residue
- n-butyl -> hydrocarbon side chain of the Ile_5 residue
-tetrazole ring (R2) must be in ortho position for optimal activity
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| main structural difference of valsartan | isosteric replacement of imidazole ring
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| ARB prodrugs | -candesartan cilexitil
-olmesartan medoxomil
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| ARB affinity for AT2 type I receptor (greatest to least) | -azilsartan
-candesartan/olmesartan
-irbesartan/eprosartan
-telmisartan/valsartan
-losartan
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| ARBs whose clearance is not affected by hepatic insufficiency | -candesartan
-olmesartan
-irbesartan
-azilsartan
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| ARB protein binding | highly protein bound (>90%) to albumin
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| metabolism of losartan | -oxidized by CYP2C9 & 3A4 to produce EXP-3174
-EXP-3174 is 10 - 40x more potent than losartan
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| metabolism of other ARBs (besides losartan) | irbe-, telmi-, & epro- sartan are all metabolized to inactive glucuronide conjugates
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