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med chem2-exam 1

Medicinal Chemistry & Pharmacology 2 - exam 1

general effect of sympathetic drugs on HR & BP -increase in HR -increase in BP
BP equation BP = CO * R *CO = Cardiac Output *R = arterial Resistance *CO is determined by stroke volume & HR
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
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+
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)
therapeutic uses of ACEIs -treatment of HTN, HF, left ventricular dysfunction (LVD) -reduction of the risk of MI, stroke, and death from cardiovascular causes
3 chemical classes of ACEIs -sulfhydryl-containing inhibitors -phosphonate-containing inhibitors -dicarboxylate-containing inhibitors
sulfhydryl-containing ACEIs captopril
phosphonate-containing ACEIs fosinopril
dicarboxylate-containing ACEIs benazepril, enalapril, lisinopril, perindopril, quinapril, ramipril, trandolapril, moexipril
main structural feature of all ACEIs Zn-binding pocket
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)
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
SE of captopril -skin rashes -taste disturbances (dysgeusia)
reason captopril is desired in patients with liver disease captopril does not require activation by liver enzymes
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
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
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
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
locations of ACE -tissue & plasma -affecting tissue ACE has better, more consistent effect on BP over time
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
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
fosinopril -prodrug -phosphate + proline derivative -phosphinic acid interacts with Zn -ionic, H, & hydrophobic bonds similar to enalapril -most lipophilic ACEI
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
N-ring of ACEIs -must have carboxylic acid group -large hydrophobic rings increases potency (ex. benazepril & ramipril) and alters PK parameters
duration of action of ACEIs -mostly 24 hours (QD/BID) -captopril = 6 - 12 hours (TID) -enalaprilat = 6 hours
metabolism of ACEIs -captopril: forms disulfide dimer or a captopril-cysteine disulfide -lisinopril & enalaprilat: no metabolism -rest are all prodrugs -further metabolic transformation: glucuronidation
receptor type that ARBs compete for AT2 receptor type 1
ARBs losartan, irbesartan, olmesartan, candesartan, valsartan, telmisartan, eprosartan, azilsartan kamedoxomil
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)
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
main structural difference of valsartan isosteric replacement of imidazole ring
ARB prodrugs -candesartan cilexitil -olmesartan medoxomil
ARB affinity for AT2 type I receptor (greatest to least) -azilsartan -candesartan/olmesartan -irbesartan/eprosartan -telmisartan/valsartan -losartan
ARBs whose clearance is not affected by hepatic insufficiency -candesartan -olmesartan -irbesartan -azilsartan
ARB protein binding highly protein bound (>90%) to albumin
metabolism of losartan -oxidized by CYP2C9 & 3A4 to produce EXP-3174 -EXP-3174 is 10 - 40x more potent than losartan
metabolism of other ARBs (besides losartan) irbe-, telmi-, & epro- sartan are all metabolized to inactive glucuronide conjugates
Created by: victorious623