tyrosine -> DOPA (dihydroxyphenylalanine)-> dopamine -> norepinephrine -> epinephrine

• catecholamines are derivatives of catechol (o-dihyrdoxybenzene)

• dopamine is an intermediate for NE and Epi

1. has an aryloxypropanolamine group (exception is sotalol -> arylethanolamine)
2. no para-substitution (exception is sotalol and metipranolol)
3. having a tert-butyl or isopropyl group attached to the amine, this eliminates any alpha binding

1. para-substitution is important; reduces metabolism
2. there must be a beta-directing group on the nitrogen in order to eliminate any alpha activity

• Sugar alcohols
• Low molecular weight
• Nonreabsorbable solutes - once in the renal tubule, osmotics have limited reabsorption due to their high water solubility
• Not extensively metabolized
• Not currently used, but in the prophylaxis of acute renal failure -> inhibit water reabsorption and maintain urine flow

• produces sweet solutions used mainly in the formulation of pharmaceutical formulations for cough syrups

• creates an osmotic gradient within the proximal tubules, distal tubules, and collecting ducts of the kidney
• used to treat increased intracranial pressure

• carbonic acid formation decreases -> sodium cannot be exchanged with a proton at the Na/H antiport -> sodium and large amounts of water are excreted

CO₂ + H₂O <-> H₂CO₃ <-> HCO₃^- + H⁺

• an enzyme that assists in the rapid inter-conversion of CO2 and H2O into carbonic acid, protons, and bicarbonate ions
• enzyme is in the renal tubule and RBCs
• the protons are exchanged for Na ions in the kidney, while bicarbonate is decomposed through a shift of the equilibrium to the left
• in the enzyme, three histidines hold the Zn2+, CO2, and H2O molecule

• A sulfonamide CAI
• thiadiazole derivative
• not an ideal drug, as it promotes K+ excretion and causes very high urine pH

• A sulfonamide, CAI
• Has a methyl group on N that decreases polarity and has a greater penetration into the ocular fluid

• derivatives of benzothiadiazine
• they differ from one another in the nature of the substituent on C-3
• site of action is the distal tubule
• compete for the Cl- binding site of the Na/Cl symporter
• inhibit the reabsorption of Na and Cl ions

• the acidic protons on the 2N and C-7 sulfonamide allow for salt formation
• electron withdrawing group at C-6 is necessary for activity -> trifluoro-methyl groups at C-6 are better than their chlorinated counterparts in terms of solubility and duration of action
• sulfonamide at C-7 is necessary for activity
• saturation of the double bond at C-3 makes it more active
• Lipophilic substituent at C-3 enhances activity
• Alkyl subsitution on N-2 decreases polarity, thus increasing duration of action

• loops diuretics inhibit the Na/2Cl/K co-transporter in the thick ascending limb of the loop of henle
• the transporter reabsorbs about 25% of the Na load
• inhibition of this pump can lead to a significant increase in the distal tubular concentrations of Na, and less water reabsorption in the collecting duct -> this altered handling of Na and water leads to both diuresis and natriuresis

• Furosemide is a loop diuretic
• a derivative of anthranillic acid
• it has a free acid thus stronger than thiazides
• some metabolism on furan ring (aromatic hydroxylation)
• mainly excreted unchanged

• bumetanide is a loop diuretic
• compared to furosemide, it has a phenoxy ring instead of a Cl and the amino-substituent has been moved to position 5 -> this makes it more potent than furosemide
• replacement of phenoxy with Ar-NH or Ar-S also results in a potent compound

• potassium-sparing diuretic
• competitive antagonist to mineralocorticoids (aldosterone)
• inhibits aldosterone binding to the receptor
• since aldosterone cannot bind to receptor, Na reabsorption is prevented
• spironolactone is metabolized to canrenone , which is an active metabolite

• potassium-sparing diuretic
• a pteridine
• not much flexibility in terms of SAR
• lower alkylamine group instead of the amine reduces the activity by half
• para-hydroxylation or a para-methyl group are detrimental to activity
• possesses basic nitrogens (the nitrogens are weak bases)
• metabolism: mostly aromatic hydroxylation, followed by sulfation

• potassium-sparing diuretic
• an aminopyrazine derivative, similar to triamterene but open chain
• extensively metabolized, 50% excreted unchanged
• blocks reabsorption of Na ions and secretion of K
• No effect on aldosterone