Cardio Exam 1 (Kaur): HTN

Diuretics: Thiazide or Benzothiadiazine

• “Thiazide” or Benzothiadiazine Diuretics Exploration of biological and side effects of sulphonamides (such as _______, _______ diuretic activity) led to the discovery of diuretics.

• Originally _______ agents

• Structure + Concepts:

  • Sulphonamide → FG containing -_______- → _______ and pka range of _______

  • Acidic or basic FGs = _______!

  • Salt is _______ water-soluble compared to an acid or base

  • SAR:

    • Replacement or removal of the sulfonamide group at position __ = little or no diuretic activity

    • EWG is necessary at position __ → adding _______ are better (H’s are worse)

    • Saturation of the double bond to give a 3,4-dihydro derivative → _______ active!

    • Substitution with a lipophilic group at position __ → increases diuretic potency

      • Haloalkyl, aralkyl, or thioester substitution → increases _______ + longer _______

    • Alkyl substitution of the __ position → decreases polarity + increases the duration of action

hypoglycemia, high, antibacterial, SO2NH, acidic, 6-8, salt formation, more, 7, 6, halogens, more, 3, lipid solubility, duration of action, 2-N

Diuretics: Thiazide or Benzothiadiazine

• Metabolism

  • Not extensively metabolized + _______

• Adverse Effects: 

  • _______ irritation, _______, and _______

excreted unchanged in the urine, gastric, nausea, electrolyte imbalances

Which structure is this?

Benzothiazide

High-Ceiling or Loop: _______

• Structure: chlorine + sulfonamide

• _______ (pka = ___) is a stronger acid than the thiazide diuretic

• Metabolism: excreted primarily _______ and can take place on _______

• _______ effective, but may be used parentally when a more prompt diuretic effect is desired

• Short duration of action (_______)

• Adverse Effects: abnormalities of _______ + _______ balance; _______; hypersensitivity rxns

Furosemide, Furosemide, 3.9, unchanged, furan ring, orally, 6-8 hours, fluid, electrolyte, hypokalemia

High-Ceiling or Loop: Bumetadine

• Structure: phenoxy group (EWG/halogen) replaced chloro or trifluoromethyl substitutions

• Amine group at position 6 has been moved to position 5

• Minor variation led to increase in _______ → 50-fold _______ (KNOW!)

• Short duration of activity (_______)  (KNOW!)

• Adverse effects: similar to furosemide

diuretic potency, more potent, 4 hours

High-Ceiling or Loop: Structure/Concepts

• The smaller the pka → _______ the acid

  • COOH → _______

  • SO₂NH → _______

  • _______ is more acidic than _______

stronger, 3-5, 6-8, Carboxylic acid, sulfonamide

Potassium-Sparing: Structure/Concepts (_______ → (easier) to make into salt → increases solubility)

• _______

  • Weak organic base

  • Pteridine derivative

  • >70% absorbed on _______ administration

  • Rapid diuretic effect (_______)

  • t_1/2 = _______

• _______

  • Weak organic base → more _______ = more potent

  • Aminopyrazine derivative

  • 10-fold _______ than triamterene

  • t_1/2 = _______

Amines, Triamterene, oral, 30 mins, 4 hours, Amiloride, basic, more potent, 21 hours

Which structure is this?

Furosemide

Which structure is this?

Bumetanide

Which structure is this?

Triamterene

Which structure is this?

Amiloride

Potassium-Sparing: Metabolism

• Triamterene

  • Metabolized to __’-_______ + its _______ conjugate 

• Amiloride

  • Mostly _______ (_______)

• Adverse Effects

  • Traimterene

    • _______

  • Amiloride

    • Similar to triamterene

4, hydroxytriamterene, sulfate, excreted unchanged, renal, hyperkalemia

Aldosterone Antagonists (also called potassium-sparing diuretics)

• Aldosterone = steroid (_______ fused together) 

• A substance that _______ the effects of aldosterone could conceivably be a good diuretic drug

• Corticosteroids

  • Glucocorticoids (e.g. _______) → regulate _______, _______, and _______ metabolism

  • Mineralocorticoids (e.g. _______) → promote _______ and _______ ion _______

4 rings, antagonizes, hydrocortisone, carb, lipid, protein, aldosterone, salt and water retention, potassium and hydrogen, excretion

Aldosterone Antagonists (also called potassium-sparing diuretics)

• Eplerdone

  • Newer drug → _______ group it has lower affinity for _______ receptor than _______

  • _______ selective aldosterone antagonist with _______ or _______ effects on GR + PR → fewer _______

epoxy, MR, Spironolactone, more, limited, no inhibitory, sexual SEs

Aldosterone Antagonists (also called potassium-sparing diuretics)

• Spironolactone

  • _______ aldosterone binding to the _______ receptor → aldosterone antagonist.

Competitively inhibits, MR

What structure is this?

Spironolactone

What structure is this?

Eplerenone

Sympatholytics: Beta-Adrenergic Antagonists → Aryloxypropanolamines

• Aryl = _______

• Structure/Concepts

  • Zwitterion: A molecule that contains both positively (_______) + negatively (_______) charged FGs

  • More Lipophilic cleared by _______

  • More Hydrophilic = cleared by _______

  • Non-Selective: _______

    • Highly lipophilic → enters _______

    • t_1/2 = _______

    • (__) enantiomer = active form → cleared more _______

    • 4-hydroxyl propranolol = _______

Benzene ring, basic, acidic, liver, kidney, Propranolol, CNS better, 3-5 hours, -, slowly, active

Sympatholytics: Beta-Adrenergic Antagonists → Aryloxypropanolamines

• Beta-1 Selective: _______ + _______  (KNOW!)

  • _______ = selective antagonist

  • _-substituted aryloxypropranolamine

  • Esmolol t_1/2 = _______ 

  • Atenolol t_1/2 = _______

  • Esmolol: controls supraventricular tachycardia during surgery (short-acting beta-1 antagonist)

Atenolol, Esmolol, Esmolol, 4, 8 mins, 6-8 hours

Sympatholytics: Beta-Adrenergic Antagonists → Aryloxypropanolamines

• Metabolism

  • Non-Selective: Propranolol

    • Extensively metabolized by the _______

  • Beta-1 Selective: Atenolol and Esmolol

    • Methyl ester of a carboxylic acid → _______ by serum esterases

    • Acid metabolite is generated by _______ → _______ → excreted as a _______

• Adverse Effects

  • Non-Selective: Propranolol

    • _______ complicated due to _______ + _______

liver, hydrolysis, hydrolysis, inactive, Zwitterion, clearence, stereospecificity, liver disease

Sympatholytics: Selective Alpha-1-Adrenergic Antagonists: _______, _______, _______

• Structure/Concepts

  • _-amino-_,_-dimethoxyquinazoline attached to a _______ ring

  • The long half-lives and durations of action for terazosin, doxazosin, tamsulosin, and silodosin permit once-a-day dosing and generally lead to increased patient compliance.

  • Variations = different t_1/2

  • The Ones She Bolded in Presentation but didn’t talk about:

    • Terazosin = __ hrs

    • Doxazosin = __ hrs

    • Tamsulosin = __ hrs

    • Silodosin = __ hrs

• Metabolism

  • Reduction of the _______ ring for prazosin to the _______ ring of terazosin increases its duration of action by altering its rate of _______

Prazosin, Terazosin, Doxazosin, 4, 6, 7, piperazine, long, QD, different t1/2, 12, 22, 14-15, 13, furan, tetrahydrofuran, metabollism

Sympatholytics: Combined Alpha/Beta-Adrenergic Antagonists: Labetalol + Carvedilol

• Structure/Concepts

  • Labetalol

    • 2 chiral centers = 4 stereoisomers (2 active + 2 inactive isomers)

      • 4 molecules (R/S or S/R)

    • _______-blocking is approx. 1.5-fold more than _______-blocking activity  (KNOW!)

Beta, alpha-1

Sympatholytics: Combined Alpha/Beta-Adrenergic Antagonists: Labetalol + Carvedilol

• Structure/Concepts

  • Carvedilol

    • Beta Blocking activity 10-100-fold more than alpha-1 blocking

    • _______ portion of the molecule also has _______ properties that provide further protection to the _______ by scavenging _______ (KNOW!)

Carbazole, antioxidant, heart, free radicals

What structure is this?

Propranolol

What structure is this?

Atenolol

What structure is this?

Esmolol

What structure is this?

Prazosin

What structure is this?

Terazosin

What structure is this?

Doxazosin

What structure is this?

Labetalol

What structure is this?

Carvedilol

CCBs

• All CCBs, with the exception of _______, contain at least _______; all marketed as their racemic mixtures (except _______ which is administered as single enantiomer/stereoisomer). 

• Some enantiomers can be _______ potent than others.

nifedipine, 1 chiral center, Diltiazem, more

CCBs: Dihydropyridines (DHPs): Nifedipine, Amlodipine, Clevidipine

Structure/Concepts

• Ring currents

• 1,4-DHP (1,4 = where hydrogens are added)

  • Primarily unionized

  • _______ is essential for activity.  (KNOW!)

  • Substitution at the _______ position or the use of oxidized (pyridine) or reduced (piperidine) → decreases activity

  • With exception of amlodipine, all 1,4-DHPs have C2 + C6 methyl groups.

  • Ester groups at the _______ + _______ positions optimize activity. 

  • A substituted phenyl ring at the _______ position optimizes activity, and _______ substitution with a small nonplanar alkyl or cycloalkyl group decreases activity. 

  • Ortho or meta substitution of Phenyl ring gives optimal activity

  • All CCBs undergo extensive first-pass metabolism (EXCEPT clevidipine) in the liver and are substrates for CYP3A4. Additionally, several CCBs can inhibit CYP3A4

  • 1,4-DHPs do NOT have tertiary amine + much less basic (electrons are involved in resonance delocalization)

1,4-DHP ring, N1, C3, C5, C4, C4

CCBs: Dihydropyridines (DHPs): Nifedipine, Amlodipine, Clevidipine

Structure/Concepts

• Amlodipine Besylate

  • long t_1/2 + infrequent dosing + low cost + SE positive profile

• Clevidipine

  • _______ duration of action (_______)  (KNOW!)

ultra-short, 2-4 mins

CCBs: Dihydropyridines (DHPs): Nifedipine, Amlodipine, Clevidipine

• Metabolism

  • 1,4-DHPs

    • 1,4-DHPs (EXCEPT Clevidipine) are oxidatively metabolized to a variety of inactive compounds. In many cases, the dihydropyridine ring is initially oxidized to an inactive pyridine analog. These initial metabolites are then further transformed by hydrolysis, conjugation, and additional oxidation pathways. 

  • Clevidipine

    • _______ to _______ metabolites  (KNOW!)

• Adverse Effects of 1,4-DHPs

  • DDIs: _______ → increases systemic concentrations

rapid ester hydrolysis, inactive, grapefruit juice

CCBs: Non-DHPs: _______ + _______

Phenykalkylamine: _______

• Contain tertiary amines with pKa values of 8.9 and 7.7

• Primarily ionized

• Good lipid solubility

• Excellent oral absorption

Verapamil, Diltiazem, Verapamil

CCBs: Non-DHPs: _______ + _______

Benzothiazepine: _______

• Contain tertiary amines with pKa values of 8.9 and 7.7

• Primarily ionized

• Administered as single enantiomer/stereoisomer

Verapamil, Diltiazem, Diltiazem

CCBs: Non-DHPs: Verapamil + Diltiazem

• Metabolism

  • _______: Verapamil

    • Metabolized by CYP3A4 _______ to its principal metabolite, _______, which retains some activity of verapamil, and by _______ (CYP___) into _______ metabolites.

Phenykalkylamine, N-demethylation, norverapamil, O-demethylation, 2D6, inactive

CCBs: Non-DHPs: Verapamil + Diltiazem

• Metabolism

  • Benzothiazepine: Diltiazem

    • Enzyme hydrolysis

    • The oral bioavailability of diltiazem and verapamil can be increased with chronic use and increasing dose

    • Natural AA → _______ stereochemistry  (KNOW!)

    • D-AA → increases _______ (cannot be _______) + _______  (KNOW!)

L, stability, hydrolyzed, duration of action

What structure is this?

Nifedipine

What structure is this?

Amlodipine Besylate

What structure is this? What structure represents the inactive metabolite?

Clevidipine, right structure

What structure is this?

Verapamil

What structure is this?

Diltiazem

KNOW IMAGE

ACE-I: SAR of ACE-I

• N-ring must contain a carboxylic acid to mimic the C-terminal carboxylate of ACE substrates.

• Large hydrophobic heterocyclic rings (i.e., the N-ring) increase potency + alter pharmacokinetic parameters. 

• The _______ binding groups can be either a _______ (A), a _______ (B), or a _______ (C). (KNOW!)

• Esterification of the carboxylic acid or phosphinic acid produces an orally bioavailable prodrug. 

• X is usually methyl. 

• Optimum activity occurs when stereochemistry of the inhibitor is consistent with _______ stereochemistry present in normal substrates.  (KNOW!)

zinc, sulfhydryl, carboxylic acid, phosphinic acid, L-AA

ACE-I in General

• ACE is a stereoselective drug target. Because currently approved ACE inhibitors act as either di- or tripeptide substrate analogs, they must contain a stereochemistry that is consistent with the L-AA present in the natural substrates.

• The oral bioavailability of this class of drugs ranges from 13-95%

• Captopril + Fosinopril are acidic drugs, but all other ACE inhibitors are amphoteric (both acidic + basic groups).

• Several dicarboxylate-containing inhibitors have been approved.

• _______ has a more rapid onset of action (KNOW!); however, it also has a _______ duration (due to formation of disulfides or dimers) and requires a _______ dosing interval

• Sulfhydryl or thiol (SH = acidic) group easily gets oxidized to disulfide (S-S).

Captopril, shorter, more frequent

What structure is this?

Captopril

What structure is this?

Enalapril (prodrug)

What structure is this?

Fosinopril

What structure is this?

Losartan

ARBs: Losartan, Valsartan, Irbesartan, Telmisartan, Candesartan Cilexetil (prodrug)

• SAR  (KNOW!)

  • The “_______ group” is thought to mimic either the _______ phenol or the _______ carboxylate of _______. Groups capable of such a role include the 

    • carboxylic acid (A)

    • phenyl _______ or isostere (B)

    • phenyl _______ (C)

  • In the biphenyl series, the _______ + _______ groups must be in the _______ position for optimal activity (the _______ group is superior in terms of metabolic stability, lipophilicity, and oral bioavailability)

  • The _______ group (or an ethyl ether or an n-propyl group) provides hydrophobic binding and, most likely, mimics the side chain of _______ of _______ 

  • The _______ ring or an isosteric equivalent is required to mimic the _______ side chain of _______

  • Substitution can vary at the “_” position

acidic, Tyr4, Asp1, Ang II, tetrazole, carboxylate, tetrazole, carboxylate, ortho, tetrazole, n-butyl, Ile5, Ang II, imidazole, His6, Ang II, R

ARBs: Losartan, Valsartan, Irbesartan, Telmisartan, Candesartan Cilexetil (prodrug)

• With the exception of _______ + _______ (high), all of the compounds have low, but adequate, oral bioavailability. 

• Most of the compounds are _______, the most probable reasons for the low bioavailability = _______ + _______. 

• Highly _______, have elimination half-lives that allow _______- or _______-daily dosing.

Irbesartan, Temisartan, excreted unchanged, poor lipid solubulity, incomplete absorption, protein bound, once, twice

Name these structures from left to right.

Losartan, Valsartan, Irbesartan, Telmisartan, and Candesartan

Stereochemistry

• ________ + interaction with other ________ + environments (e.g. ________)

Rate of reaction, chiral compounds, receptor of enzymes

Class IA (Sodium CBs) 

• _______ → _______ = Na+ compound with _______ → brings _______ character

Quinidine, alkaloid, nitrogen, basic

Class IB (Sodium CBs) 

• Lidocaine → _______ (used _______)

• Mexiletine → _______ t_1/2 + _______ Metabolism Rate (contributes to good _______ activity)

15-30 mins, IV, 12-16 hours, Slow, oral

Class III Potassium Channel Blockers

• Amiodarone → _______

• Dronedarone → Noniodinated → iodine groups removed to reduce toxic effects on the _______ → _______

• Abutilide → _______ derivative

• Dofetilide → Bis-methanesulfonanilide

highly lipophilic, thyroid and other organs, methylsulfonamide, methanesulfonamide

Digoxin (Glycosidic Positive Ionotropic Drug)

• PK/Metabolism → Intestinal P-glycoprotein mediated efflux + _______dependent _______

• Digoxin-Quinidine Interaction → Quinidine (P-gp substrate) + _______ digoxin’s _______ concentration to TOXIC levels

• Digoxin-Verapamil Interaction → Verapamil inhibits intestinal P-gp efflux → _______ digoxin’s _______ levels to TOXIC levels

• Rifampin-Digoxin Interaction → rifampin induction of intestinal P-gp expression → _______ digoxin _______ levels to SUBTHERAPEUTIC concentrations

P-gp, renal elimination, increases, plasma, increases, blood, decreases, blood